Browse site A to Z

Search results

Go To Advanced Search

STHW841-V1-Biomerieux-Blood-culture-guidance

Description: BLOOD CULTURE A key investigation for diagnosis of bloodstream infections OUR SPECIAL THANKS GO TO Dr Susan M. Novak-Weekley Ph.D. D(ABMM), S(M)ASCP Vice-President, Medical Affairs, Qvella, Carlsbad, CA, USA Wm. Michael Dunne, Jr. Ph.D. D(ABMM), F(AAM, CCM, IDSA, PIDJ) Senior Fellow, Clinical Microbiology, Data Analytics Group, bioMérieux, Inc., Durham, NC, USA Adjunct Professor of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA Adjunct Professor of Pediatrics, Duke University School of Medicine, Durham, NC, USA for their helpful advice and comprehensive review of this booklet. INTRODUCTION “…the laboratory detection of bacteremia and fungemia remains one of the most important functions of clinical microbiology laboratories... A positive blood culture establishes or confirms that there is an infectious etiology of the patient’s illness. Moreover, it provides the etiologic agent and allows antibiotic susceptibility testing for optimization of therapy.”1 The laboratory detection of bacteremia and fungemia using blood cultures is one of the most simple and commonly used investigations to establish the etiology of bloodstream infections. Rapid, accurate identification of the bacteria or fungi causing bloodstream infections provides vital clinical information required to diagnose and treat sepsis. Sepsis is a complex inflammatory process that is largely underrecognized as a major cause of morbidity and mortality worldwide. There are an estimated 19 million cases worldwide each year,2 meaning that sepsis causes 1 death every 3-4 seconds.3 Early diagnosis and appropriate treatment make a critical difference when it comes to improving sepsis patient outcomes. Chances of survival go down drastically the longer initiation of treatment is delayed. If a patient receives antimicrobial therapy within the first hour of diagnosis, chances of survival are close to 80%; this is reduced by 7.6% for every hour after. Yet, if a patient initially receives inappropriate antimicrobial treatment, they are five times less likely to survive.4 This booklet aims to: a nswer key questions commonly asked in relation to blood culture p rovide practical recommendations for routine blood culture procedures o ffer an illustrated step-by-step guide to best blood culture collection practices. This booklet is intended to be a useful reference tool for physicians, nurses, phlebotomists, laboratory personnel and all other healthcare professionals involved in the blood culture process. DEFINITIONS Bacteremia: the presence of bacteria in the blood. It may be transient, intermittent or continuous. Blood culture: blood specimen submitted for culture of microorganisms. It enables the recovery of potential pathogens from patients suspected of having bacteremia or fungemia. Blood culture series: a group of temporally related blood cultures that are collected to determine whether a patient has bacteremia or fungemia. Blood culture set: the combination of blood culture bottles (one aerobic and one anaerobic) into which a single blood collection is inoculated. Bloodstream Infection (BSI): an infection associated with bacteremia or fungemia. Contaminant: a microorganism isolated from a blood culture that was introduced during specimen collection or processing and is not considered responsible for BSI (i.e., the isolates were not present in the patient’s blood when the blood was sampled for culture). Contamination: presence of microorganisms in the bottle that entered during sampling but were not actually circulating in the patient’s bloodstream. Fungemia: the presence of fungi in the blood. Sepsis: life-threatening organ dysfunction caused by a dysregulated host response to infection.5 Septicemia: clinical syndrome characterized by fever, chills, malaise, tachycardia, etc. when circulating bacteria multiply at a rate that exceeds removal by phagocytosis.6 Septic episode: an episode of sepsis or septic shock for which a blood culture or blood culture series is drawn. Septic shock: a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality.5 Source: Wayne, P.A. Principles and procedures for Blood Cultures; Approved Guideline, CLSI document M47-A. Clinical and Laboratory Standards Institute (CLSI); 2007 unless otherwise specified. 2 TABLE OF CONTENTS 1 BLOOD CULTURE ESSENTIALS p. 2 1 What is a blood culture? p. 4 2 Why are blood cultures important? p. 4 3 When should a blood culture be performed? p. 5 4 What volume of blood should be collected? p. 6 5 How many blood culture sets should be collected? p. 8 6 Which media to use? p. 10 7 Timing of blood cultures p. 11 8 How to collect blood cultures p. 12 9 How many days of incubation are recommended? p. 14 10 Is it a contaminant or a true pathogen? p. 15 2 SPECIAL TOPIC : INFECTIVE ENDOCARDITIS p. 18 3 PROCESSING POSITIVE BLOOD CULTURES p. 20 4 INTERPRETATION OF RESULTS p. 22 5 BLOOD CULTURE/ SEPSIS GUIDELINES p. 24 REFERENCES p. 26 RECOMMENDATIONS FOR BLOOD CULTURE COLLECTION p. 30 3 1 BLOOD CULTURE ESSENTIALS 1 What is a blood culture? A blood culture is a laboratory test in which blood, taken from the patient, is inoculated into bottles containing culture media to determine whether infection-causing microorganisms (bacteria or fungi) are present in the patient’s bloodstream. v B lood cultures are intended to: Confirm the presence of microorganisms in the bloodstream Identify the microbial etiology of the bloodstream infection 3 MAIN AIMS OF BLOOD CULTURE*: Help determine the source of • Confirm infectious etiology infection (e.g., endocarditis) • Identify the etiological agent P rovide an organism for • Guide antimicrobial susceptibility testing and optimization therapy of antimicrobial therapy * Adapted from ESCMID (European Society of Clinical Microbiology and Infectious Diseases) guidelines, 2012.7 2 Why are blood cultures important? Blood culture is the most widely used diagnostic tool for the detection of bacteremia and fungemia. It is the most important way to diagnose the etiology of bloodstream infections and sepsis and has major implications for the treatment of those patients. A positive blood culture either establishes or confirms that there is an infectious etiology for the patient’s illness.3 A positive blood culture also provides the etiologic agent for antimicrobial susceptibility testing, enabling optimization of antibiotic therapy.3 Sepsis is one of the most significant challenges in critical care, and early diagnosis is one of the most decisive factors in determining patient outcome. Early identification of pathogens in the blood can be a crucial step in assuring appropriate therapy, and beginning 4 BLOOD CULTURE ESSENTIALS effective antibiotic therapy as early as possible can have a significant impact on the outcome of the disease.8, 9 v P roviding adequate antibiotic therapy within the first 24-48 hours leads to:10-14 Decreased infection-related mortality (20-30%) Earlier recovery and shorter length of hospital stay Less risk of adverse effects Reduced risk of antimicrobial resistance Cost reduction (length of stay, therapy, diagnostic testing) Figure 1: Fast effective antimicrobial therapy increases survival chances Adapted from Kumar A, et al. Crit Care Med. 2006;34(6):1589-96.15 Total patients (%) Patient survival rate (%) 100 Patients with e ective antibiotic therapy 80 60 40 20 0 0 hours 1 2 3 4 5 6 9 12 24 36 Time to antibiotics 3 When should a blood culture be performed? Blood cultures should always be requested when a bloodstream infection or sepsis is suspected. v C linical symptoms in a patient which may lead to a suspicion of a bloodstream infection are: undetermined fever (≥38°C) or hypothermia (≤36°C) shock, chills, rigors s evere local infections (meningitis, endocarditis, pneumonia, pyelonephritis, intra-abdominal suppuration…). abnormally raised heart rate low or raised blood pressure raised respiratory rate 5 BLOOD CULTURE ESSENTIALS v B lood cultures should be collected: as soon as possible after the onset of clinical symptoms; ideally, prior to the administration of antimicrobial therapy.16 If the patient is already on antimicrobial therapy, recovery of microorganisms may be increased by collecting the blood sample immediately before administering the next dose and by inoculating the blood into bottles containing specialized antimicrobial neutralization media. 4 W hat volume of blood should be collected? The optimal recovery of bacteria and fungi from blood depends on culturing an adequate volume of blood. The collection of a sufficient quantity of blood improves the detection of pathogenic bacteria or fungi present in low quantities. This is essential when an endovascular infection (such as endocarditis) is suspected. The volume of blood that is obtained for each blood culture set is the most significant variable in recovering microorganisms from patients with bloodstream infections.17, 18 Blood culture bottles are designed to accommodate the recommended bloodto-broth ratio (1:5 to 1:10) with optimal blood volume. Commercial continuously monitoring blood culture systems may use a smaller blood-to-broth ratio ( 200 4 2 6 12.8-36.3 28-80 > 800 10 10 20 > 36.3 > 80 > 2,200 20-30 20-30 40-60 % of patient’s total blood volume 4 4 3 2.5 1.8-2.7 7 BLOOD CULTURE ESSENTIALS 5 H ow many blood culture sets should be collected? Since bacteria and fungi may not be constantly present in the bloodstream, the sensitivity of a single blood culture set is limited. Using continuous-monitoring blood culture systems, a study investigated the cumulative sensitivity of blood cultures obtained sequentially over a 24-hour time period. It was observed that the cumulative yield of pathogens from three blood culture sets (2 bottles per set), with a blood volume of 20 ml in each set (10 ml per bottle), was 73.1% with the first set, 89.7% with the first two sets and 98.3% with the first three sets. However, to achieve a detection rate of > 99% of bloodstream infections, as many as four blood culture sets may be needed.22 Figure 2: Cumulative sensitivity of blood culture sets22 Adapted from Lee A, Mirrett S, Reller LB, Weinstein MP. Detection of Bloodstream Infections in Adults: How Many Blood Cultures Are Needed? J Clin Microbiol 2007;45:3546-3548. Detection sensitivity 100% 90% 89.7% 98.3% 80% 73.1% 70% 20 ml 40 ml 60 ml A single blood culture bottle or set should never be drawn from adult patients, since this practice will result in an inadequate volume of blood cultured and a substantial number of bacteremias may be missed.3, 22 8 BLOOD CULTURE ESSENTIALS A contaminant will usually be present in only one bottle of a set of blood culture bottles, in contrast to a true bloodstream infection, in which multiple blood culture bottles/sets will be positive. Therefore, guidelines recommend to collect 2, or preferably 3, blood culture sets for each septic episode.3, 7, 16 If 2 to 3 sets are taken and cultures are still negative after 24-48 hours incubation, and the patient is still potentially septic, 2 to 3 additional cultures may be collected, as indicated in the following diagram.16 Figure 3: Recommended number of blood culture sets Adapted from Baron EJ, Cumitech 1C, Blood Cultures IV. Coordinating ed., E.J. Baron. ASM Press, Washington, D.C. 2005 Collect 2 to 3 sets of bottles (aerobic + anaerobic) for each septic episode If culture is negative after 24-48 h incubation and patient is still potentially septic without an identified source Collect 2 to 3 additional sets of bottles (aerobic + anaerobic) If culture is negative after 24 h incubation Repeat protocol Prolong if necessary incubation Investigate non-microbial etiology 9 BLOOD CULTURE ESSENTIALS 6 W hich media to use? Microorganisms causing bloodstream infections are highly varied (aerobes, anaerobes, fungi, fastidious microorganisms…) and, in addition to nutrient elements, may require specific growth factors and/or a special atmosphere. In cases where the patient is receiving antimicrobial therapy, specialized media with antibiotic neutralization capabilities should be used. Antibiotic neutralization media have been shown to increase recovery and provide faster time to detection versus standard media.23-26 It is recommended that each adult routine blood culture set include paired aerobic and anaerobic blood culture bottles. The blood drawn should be divided equally between the aerobic and anaerobic bottles. If an anaerobic bottle is not used, it should always be replaced by an additional aerobic bottle to ensure that a sufficient volume of blood is cultured.27 v A blood culture medium must be: sensitive enough to recover: - a broad range of clinically relevant microorganisms, even the most fastidious (Neisseria, Haemophilus…) - microorganisms releasing small amounts of CO2 (Brucella, Acinetobacter…) versatile: able to provide a result for all types of sample collection (adults, infants, patients receiving antibiotic therapy, sterile body fluids…) v Which bottle should be inoculated first? If using a winged blood collection set, then the aerobic bottle should be filled first to prevent transfer of air in the device into the anaerobic bottle. If using a needle and syringe, inoculate the anaerobic bottle first to avoid entry of air. If the amount of blood drawn is less than the recommended volume*, then approximately 10 ml of blood should be inoculated into the aerobic bottle first, since most cases of bacteremia are caused by aerobic and facultative bacteria. In addition, pathogenic yeasts and strict aerobes (e.g., Pseudomonas) are recovered almost exclusively from aerobic bottles. Any remaining blood should then be inoculated into the anaerobic bottle.8 * For recommended volumes, see page 6 “What volume of blood should be collected? 10 BLOOD CULTURE ESSENTIALS 7 T iming of blood cultures Studies have shown that the time interval between collecting two blood culture samples is not considered to be a critical factor as the diagnostic yield remains the same.7 Guidelines recommend that the first two/three sets (2 bottles/set) of blood culture be obtained either at one time or over a brief time period (e.g., within 1 hour) from multiple venipuncture sites.1,16 Drawing blood at spaced intervals, such as 1 to 2 hours apart, is only recommended to monitor continuous bacteremia/fungemia in patients with suspected infective endocarditis or other endovascular (i.e., catheterrelated) infections.16 Two to three additional blood culture sets can be performed if the first 2-3 blood cultures are negative after 24-48 hours incubation in cases of severe infection or in order to increase detection sensitivity (in cases of pyelonephritis for example). This also depends on the microorganisms involved: while sensitivity is relatively good for organisms like Escherichia coli or Staphylococcus aureus, it is lower for Pseudomonas aeruginosa, streptococci or fungi.28 8 H ow to collect blood cultures Sample collection is a crucial step in the blood culture process. Standard precautions must be taken, and strict aseptic conditions observed throughout the procedure. Compliance with blood culture collection recommendations can significantly improve the quality and clinical value of blood culture investigations and reduce the incidence of sample contamination and “false-positive” readings. A properly collected sample, that is free of contaminants, is key to providing accurate and reliable blood culture results. It is recommended that blood cultures should be collected only by members of staff (medical, nursing, phlebotomist or technician) who have been fully trained and whose competence in blood culture collection has been assessed.29 11 BLOOD CULTURE ESSENTIALS 10 Key Steps to Good Sample Collection: For an illustrated step-by-step, see page 30. 1 Prior to use, examine the bottles for evidence of damage, deterioration or contamination. Do not use a bottle containing media which exhibits turbidity or excess gas pressure, as these are signs of possible contamination. 2 Check the expiry date printed on each bottle. Discard bottles that have expired. 3 S trictly follow the collection protocol in use in the healthcare setting, including standard precautions for handling blood at the bedside. 4 Blood culture bottles should be clearly and correctly labelled, including patient identification, date and collection time, puncture site (venipuncture or intravascular device). 5 E ach blood culture set should include an aerobic and an anaerobic bottle. 6 Blood for culture should be drawn from veins, not arteries.30 7 It is recommended to avoid drawing blood from a venous or arterial catheter, since these devices are often associated with higher contamination rates.31 12 BLOOD CULTURE ESSENTIALS 8 Carefully disinfect the skin prior to collection of the sample using an appropriate disinfectant, such as chlorhexidine in 70% isopropyl alcohol or tincture of iodine in swab or applicator form.1 9 Transport the inoculated bottles and the completed blood culture request to the clinical microbiology laboratory as quickly as possible, preferably within 2 hours per CLSI.1 Any delay in testing the inoculated bottles may potentially lead to an increased risk of false negative results. If delays are expected, it is important to refer to the manufacturer’s Instructions for Use (IFU) for guidance. As an example for guidance regarding delays, the ESCMID guidelines recommend that blood culture bottles for testing in continuous monitoring systems should be stored temporarily at room temperature, whereas bottles for manual testing should be incubated as soon as possible.32Again, refer to the manufacturer’s IFU for guidance. The use of vacuum tube transport systems can facilitate the rapid transmission of bottles to the microbiology laboratory. However these systems should be used with caution if using glass bottles.33 10 All blood cultures should be documented in the patient’s notes, including date, time, collection site and indications. 13 BLOOD CULTURE ESSENTIALS 9 H ow many days of incubation are recommended? The current recommendation, and standard incubation period, for routine blood cultures performed by continuous-monitoring blood systems is five days.34 However, published data suggest that three days may be adequate to recover over 97% of clinically significant microorganisms. A study by Bourbeau, et al. (JCM, 2005) showed the number of significant microorganisms isolated per day for 35,500 consecutive blood cultures collected over 30 months, of which 2,609 were clinically significant isolates and 1,097 were contaminants.35 Figure 4: Clinically significant isolates per day35 Adapted from Bourbeau PP, Foltzer M. Routine incubation of BACT/ALERT* FA and FN blood culture bottles for mo10re0t%han 3 days may not be necessary. J Clin Microbiol. 2005;43:2506-2509. 80% 74.1% 60% 40% 19.7% 20% 3.6% 1.7% 0.9% 0% Day 1 Day 2 Day 3 Day 4 Day 5 These results demonstrate that 97.4% of clinically significant isolates were recovered within the first 3 days of incubation and 93.8% within 2 days of incubation. v Incubation of Fastidious Microorganisms Another study by Cockerill, et al. (CID, 2004) demonstrated that, when using a continuous-monitoring blood culture system, 99.5% of non-endocarditis bloodstream infections and 100% of endocarditis episodes were detected within 5 days of incubation.19 This data suggests that extended incubation periods previously recommended for detection of the fastidious microorganisms* that sometimes cause endocarditis, are no longer necessary when using continuous-monitoring blood culture systems.16 * including Brucella, Capnocytophaga and Campylobacter spp., and the HACEK group (Haemophilus (except H. influenzae) species, Aggregatibacter (previously Actinobacillus) species, Cardiobacterium hominis, Eikenella corrodens and Kingella species)36 14 BLOOD CULTURE ESSENTIALS 10 I s it a contaminant or a true pathogen? Contamination of blood cultures during the collection process can produce a significant level of false-positive results, which can have a negative impact on patient outcome. A false positive is defined as growth of bacteria in the blood culture bottle that were not present in the patient’s bloodstream, and were most likely introduced during sample collection. Contamination can come from a number of sources: the patient’s skin, the equipment used to take the sample, the hands of the person taking the blood sample, or the environment. Collecting a contaminant-free blood sample is critical to providing a blood culture result that has clinical value. Certain microorganisms such as coagulase-negative staphylococci, viridansgroup streptococci, Bacillus spp, Propionibacterium spp., diphtheroids, Micrococcus spp. rarely cause severe bacterial infections or bloodstream infections. These are common skin contaminants, and a though they are capable of causing serious infection in the appropriate setting, their detection in a single blood culture set can reasonably be identified as a possible contaminant without clinical significance. However, it is important to consider that coagulase-negative staphylococci are the primary cause of both catheterand prosthetic device-associated infections and may be clinically significant in up to 20% of cases.37 The most difficult interpretation problem for the physician is whether the organism recovered from a blood culture is a true pathogen causing bloodstream infection, or a contaminant. If it is a contaminant, the patient may be treated unnecessarily with antibiotics, leading to additional patient risks. Interpretation of true pathogen versus contaminant should be based on whether the blood has been collected with a venipuncture or an intra-vascular device, and multiplicity of isolation of the same species. This illustrates the crucial nature of having collection site information included with the blood culture request sent to the laboratory. 15 BLOOD CULTURE ESSENTIALS In contrast to patients with infective endocarditis or other true positive bloodstream infections, patients whose blood cultures grow contaminants usually have only a single blood culture that is positive. This information is of great practical value for physicians, and underlines the importance of taking two to three blood culture sets from different anatomical sites.16 Contamination rates can be most effectively reduced by strict compliance with hand hygiene rules and best practices for blood collection, particularly during the stages of skin antisepsis, venipuncture and sample transfer to blood culture bottles. However, even when the best blood collection protocols are used, it may not be possible to reduce the contamination rate below 2%.38 The American Society for Microbiology and CLSI recommend targeting contamination rates not exceeding 3% of the total of collected sets.1, 16 v Impact of contamination rates A contaminated blood culture can result in unnecessary antibiotic therapy, increased length of hospitalization and higher costs. It has been found that each false positive result can lead to: Increased length of stay - on average 1 day.39 39% increase in intravenous antibiotic charges.39 $5,000 to $8,720 additional charges.40, 41 20% increase in laboratory charges.39 3 days longer on antibiotics.39 16 BLOOD CULTURE ESSENTIALS Figure 5: E xample of a laboratory-based algorithm to determine blood culture contamination42 Adapted from Richter SS, Beekman SE, Croco JL, Diekema DJ, et al. Minimizing the workup of blood culture contaminants: implementation and evaluation of a laboratory-based algorithm. J Clin Microbiol. 2002;40:2437-2444. Potential contaminant* isolated from blood culture Additional draws +/48 hours? NO YES Positive with same organism? NO YES Evaluation by qualified personnel Probable contaminant; AST** not performed unless requested Viridans group streptococci? NO YES Evaluation by qualified personnel Pathogen; set up AST† * Microorganisms such as coagulase-negative staphylococci, Streptococcus viridans, Bacillus spp, Propionibacterium spp., diphtheroids, Micrococcus spp. † AST: Antimicrobial Susceptibility Testing 17 2 SPECIAL TOPIC: INFECTIVE ENDOCARDITIS Blood culture is essential in the diagnosis of infective endocarditis (infection of the heart valves). In this elusive disease, blood cultures may need to be taken repeatedly during febrile episodes, when bacteria are shed from the heart valves into the bloodstream. For patients with infective endocarditis, positive blood cultures will be obtained in greater than 90% of cases, if optimal culture conditions are respected.43 v Acute Infective Endocarditis This is a fulminant illness progressing rapidly over days to weeks, which may be caused by highly virulent pathogens, such as Staphylococcus aureus. When suspected, the severity of this disease requires blood cultures to be drawn immediately to avoid unnecessary delays in treatment. Multiple blood culture sets should be drawn during a 30-minute period prior to administration of empiric antimicrobial therapy.44 v Subacute Infective Endocarditis If sub-acute infection is suspected, there is usually not an urgent need to initiate empiric therapy. It is more important to attempt to establish the microbiological diagnosis. Multiple blood culture sets should be obtained prior to initiation of antimicrobial therapy, with sets spaced 30 minutes to one hour apart. This may help document a continuous bacteremia, and could be of additional clinical value.3 v Fungal Infective Endocarditis Once a rare occurrence, the incidence of fungal endocarditis is increasing considerably.45 Candida species are the most common fungal pathogens involved in infective endocarditis.46 If optimum collection conditions are observed, the yield for positive blood cultures in fungal endocarditis for Candida spp. is 83 to 95%.47 18 SPECIAL TOPIC: INFECTIVE ENDOCARDITIS v How many cultures? In order to distinguish between contamination and true bacteremia, a total of three to five blood culture sets should be sufficient. Initially, two to three blood culture sets should be obtained from patients with suspected infective endocarditis. If the first 2-3 sets are negative after 24-48 hours, collect two to three more sets of cultures.3 Often patients with suspected infective endocarditis have been put on antibiotics prior to blood collection. This is the most common reason for “culture-negative” infective endocarditis. It is therefore important to use a blood culture medium that has antimicrobial neutralization capacity in order to sustain microbial growth in the presence of antibiotics (see page 10 “Which media to use?”).48,49 However, “culture-negative” endocarditis may also be due to fastidious microorganisms, such as Aspergillus spp., Brucella spp., Coxiella burnetii, Chlamydia spp. and HACEK* microorganisms. S ince current continuous-monitoring blood culture systems can recover all HACEK and other fastidious organisms within a 5-day period, extending incubation beyond this period is no longer considered to be necessary. However, if all blood culture bottles are negative after 5 days, and infectious endocarditis is still suspected, all bottles should be subcultured to chocolate agar.50 19 3 PROCESSING POSITIVE BLOOD CULTURES Today, continuously-monitored blood culture systems provide the optimum solution for blood sample processing. Generally accepted incubation periods can vary from 5-7 days, with 5 days being most popular.27 The study discussed in Figure 4 shows that 98% of all positive specimens were detected within the first 3 days (see page 14).35 Patients who progress to septic shock have a 7.6% increase in mortality every hour while not on appropriate therapy.15 Following an instrument-flagged positive event, the bottle is removed from the system and a Gram stain and subculture is performed. If the sample is Gram stain positive, the morphology of the organism should be reported immediately to the physician. Subcultures or rapid techniques (e.g., molecular diagnostics) should be initiated immediately in order to provide further organism identification and antibiotic susceptibility testing should be performed as soon as possible. If a sample is Gram stain negative, no report is made to the clinician unless there is growth on subculture. A positive blood culture is a critical result and must be reported as soon as available, due to the immediate impact on patient care decisions. When reports are delivered rapidly, studies have shown broadly improved outcomes and efficiencies in patient management.51, 52 A study by Barenfanger, et al. (Am J Clin Pathol. 2008) validated that Gram stains of positive blood cultures are a very important factor influencing appropriate therapy and patient outcomes. The study documented a statistically significant increase in the mortality rate for patients who had blood cultures processed after a delay (i.e., Gram stain performed ≥1 hour after being detected as positive; P= 0.0389). The timely removal and reporting of Gram stain results have a positive impact on patient care and this study supports the need for 24/7 coverage of blood culture instruments.53 20 PROCESSING POSITIVE BLOOD CULTURES Recent technological advances such as MALDI-TOF (Matrix-Assisted Laser Desorption Ionization Time of Flight) provide the ability to rapidly deliver definitive organism identification. Molecular diagnostics can identify the most common pathogens in positive blood cultures as well as specific antibiotic resistance genes associated with bloodstream infections. Rapid identification allows physicians to prescribe more targeted and effective antimicrobial therapy earlier to positively influence outcomes.54-56 Additionally, antibiotic susceptibility testing techniques should be performed on positive blood cultures to provide the clinician with a complete result. Appropriate use of antibiotics is crucial in cases of bloodstream infections and sepsis. Accurately determining the antimicrobial resistance profile of the causative pathogen in order to select the most effective antibiotic therapy can have a significant impact on patient outcomes. When processed correctly, blood cultures provide clinically relevant information that can help improve patient outcomes, decrease length of hospital stay and reduce use of antibiotics. 21 4 INTERPRETATION OF RESULTS The microbiology laboratory can provide useful information to clinicians to help them determine whether a blood culture sample is a true positive or a false positive (contaminant). For example, the identity of the micro- organism isolated can help determine if the culture is contaminated, and the number of Figure 6: Example of interpretation algorithm for blood culture results 1 More than one positive bottle monomicrobial culture + clinical symptoms (e.g., endocarditis, meningitis, pneumonia…) polymicrobial culture (from the appropriate clinical setting (e.g., transplants, intraabdominal infection, immunocompromized patient…) bloodstream infection probable bloodstream infection 3 Negative blood cultures but clinical symptoms 22 INTERPRETATION OF RESULTS cultures positive with the same organism can help predict true infections.57 Time to positivity is also a factor used to determine potential contamination as contaminants usually have a delayed (longer) time-to-detection due to a lower overall bio-load. Laboratories should consult with their medical director to create an algorithm which helps determine whether or not an isolated organism is a contaminant vs. an infective agent. Models, such as the algorithm below, can give guidance only on the interpretation of blood culture results.42, 57, 58 These guidelines should be used in conjunction with clinical guidelines e.g., patient’s full blood count, presence of catheters, radiological findings, etc. 2 Only one positive bottle if pathogenic organism: Listeria, S. aureus, Brucella, Haemophilus, Enterobacteriaceae, … if normal skin flora: Propionibacterium, corynebacterium, Bacillus, coagulase-negative staphylococci if viridans streptococci or coagulase-negative staphylococci and consistent with clinical setting (e.g., indwelling catheter, prosthetic heart valve, immunocompromized patient) probable bloodstream infection probable contamination probable bloodstream infection Repeat blood samples Consider non-infectious etiology Investigate viral etiology or non-culturable microorganism 23 5 BLOOD CULTURE/SEPSIS GUIDELINES v International Guidelines WHO guidelines on drawing blood: best practices in Phlebotomy. World Health Organization 2010. http://whqlibdoc.who.int/publications/2010/9789241599221_eng.pdf Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Dellinger RP., et al. Crit Care Med. 2013;41:580-637. http://www.survivingsepsis.org/guidelines/Pages/default.aspx The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Singer M., et al. JAMA. 2016;315(8):801-810. http://jama.jamanetwork.com/article.aspx?articleid=2492881 v National Guidelines COUNTRY/ REGION GUIDELINES Australia Clinical Excellence Commission. SEPSIS KILLS Adult Blood Culture Guideline Updated September 2016. SHPN (CEC) 160406. http://www.cec.health.nsw.gov.au/__data/assets/pdf_ file/0005/259412/adult-blood-culture-guideline-updated-sept2016.pdf Brazil Elmor de Araujo MR, Hemocultura: recomendações de coleta, processamento e interpretação dos resultados, J Infect Control 2012; 1: 08-19 http://www.iqg.com.br/pbsp/img_up/01355393320.pdf Europe European Society for Clinical Microbiology and Infectious Diseases, European Manual for Clinical Microbiology, 1st Edition, 2012. https://www.escmid.org/escmid_publications/manual_of_microbiology/ 24 BLOOD CULTURE/SEPSIS GUIDELINES COUNTRY/ REGION France GUIDELINES REMIC 2015. Automatisation des cultures microbiennes : quel cahier des charges ? Chapitre 11 http://www.sfm-microbiologie.org/ Germany Reinhart K, Brunkhorst FM, Bone HG, Bardutzky J, et al., Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (DIVI). German Medical Science, 2010, Vol. 8: 1-86 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899863/pdf/ GMS-08-14.pdf South Africa Guideline for the optimal use of blood cultures. SAMJ 2010; Vol. 100, No. 12: 839-843 SAMJ https://www.fidssa.co.za/Content/Documents/Guideline_for_the_optimal_use_of_blood_cultures.pdf UK UK Standards for Microbiology Investigations. Investigation of Blood Cultures (for Organisms other than Mycobacte- rium species). Bacteriology | B 37 | Issue no: 8 | Issue date: 04.11.14 | Page: 1 of 51. Issued by the Standards Unit, Health Protection Agency, PHE. https://assets.publishing.service.gov.uk/government/uploads/sys- tem/uploads/attachment_data/file/372070/B_37i8.pdf Taking blood cultures - a summary of best practice: Saving lives reducing infection, delivering clean and safe care. London: Department of Health; 2007. http://webarchive.nationalarchives.gov.uk/20120118171812/http://hcai. dh.gov.uk/files/2011/03/Document_Blood_culture_FINAL_100826.pdf USA American Society for Microbiology: Cumitech 1C, 2005 (EJ Baron et al.) ASM Press Clinical and Laboratory Standards Institute (CLSI®), document M47-A, Vol 27, 2007 (ML Wilson et al.) E mergency Nurses Association (ENA). Clinical Practice Guideline: Prevention of Blood Culture Contamination https://www.ena.org/docs/default-source/resource-library/practice-resources/cpg/bcccpg2c37f1815b664d2fa8d7e9fd0f475a41.pdf E .Septimus.CDCClinicianGuideforCollectingCultures.2015 https://www.cdc.gov/antibiotic-use/healthcare/implementation/clinicianguide.html 25 REFERENCES 1. P rinciples and procedures for Blood Cultures; Approved Guideline, CLSI document M47-A. Clinical and Laboratory Standards Institute (CLSI); Wayne, P.A. 2007 2. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet 2010;376(9749):1339–1346. 3. WSD fact sheet 2013. www.world-sepsis-day.org 4. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136(5):1237-1248. 5. Singer M, Deutschmann CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. 6. Koneman EW. Color Atlas and Textbook of Diagnostic Microbiology. Third Edition. 7. European Society for Clinical Microbiology and Infectious Diseases, European Manual for Clinical Microbiology, 1st Edition, 2012 8. Garey KW, Rege M, Pai MP, Mingo DE, et al. Time to Initiation of Fluconazole Therapy Impacts Mortality in Patients with Candidemia: A Multi-Institutional Study. Clin Infect Dis. 2006;43(1):25-31. 9. Khatib R, Saeed S, Sharma M, Riederer K, Fakih MG, Johnson LB. Impact of initial antibiotic choice and delayed appropriate treatment on the outcome of Staphylococcus aureus bacteremia. Eur J Clin Microbial Infect Dis. 2006; 25(3):181185. 10. K ollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462-474. 11. H arbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115(7):529-535. 12. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of Delayed Antibiotic Treatment for Hospital-Acquired Staphylococcus aureus Bacteremia. CID 2003;36:1419-1423. 13. Kang CL, Kim SH, Kim HB, et al. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin Infect Dis. 2003; 37(6): 745-51 14. Forrest GN, Mankes K, Jabra-Rizk MA, et al. Peptide Nucleic Acid Fluorescence In Situ Hybridization Based Identification of Candida albicans and Its Impact on Mortality and Antifungal Therapy Costs. J Clin Microbiol. 2006;44(9):3381-3383. 26 15. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. 16. B aron EJ, Weinstein MP, Dunne Jr. WM, Yagupsky P, Welch DF, Wilson DM. Cumitech 1C, Blood Cultures IV. Coordinating ed., E.J. Baron. ASM Press, Washington D.C. 2005. 17. M ermel LA, Maki DG. Detection of bacteremia in adults: consequences of culturing an inadequate volume of blood. Ann Intern Med. 1993;119:270-272. 18. Bouza E, Sousa D, Rodriguez-Creixems M, Lechuz JG, Munoz P. Is the volume of blood cultured still a significant factor in the diagnosis of bloodstream infections? J Clin Microbiol. 2007 45:2765-2769. 19. Cockerill FR 3rd, Wilson JW, Vetter EA, et al. Optimal testing parameters for blood cultures. Clin Infect Dis. 2004;38:1724-1730. 20. K ellog JA, Manzella JP, Bankert DA. Frequency of low-level bacteremia in children from birth to fifteen years of age. J Clin Microbiol. 2000;38:2181-2185. 21. Freedman SB, Roosevelt GE. Utility of anaerobic blood cultures in a pediatric emergency department. Pediatr Emerg Care. 2004;20(7):433-436. 22. Lee A, Mirrett S, Reller LB, Weinstein MP. Detection of Bloodstream Infections in Adults: How Many Blood Cultures Are Needed? J Clin Microbiol. 2007;45:3546-3548. 23. Lee DH, Kim SC, Bae IG, Koh EH, Kim S. Clinical Evaluation of BACT/ALERT FA Plus and FN Plus Bottles Compared with Standard Bottles. J Clin Microbiol. 2013;51(12):4150-4155. 24. Amarsy-Guerle R, Mougari F, Jacquier H, et al. High medical impact of implementing the new polymeric bead-based BACT/ALERT FA Plus and FN Plus blood culture bottles in standard care. Eur J Clin Microbiol Dis. 2015:34(5):1031-1037. 25. Kirn TJ, Mirrett S, Reller LB, Weinstein MP. Controlled Clinical Comparison of BACT/ ALERT FA Plus and FN Plus Blood Culture Media with BACT/ALERT FA and FN Blood Culture Media. J Clin Microbiol. 2014;52(3):839-843. 26. Doern CD, Mirrett S, Halstead D, Abid J, Okada P, Reller LB. Controlled Clinical Comparison of New Pediatric Medium with Adsorbent Polymeric Beads (PF Plus) versus Charcoal-Containing PF Medium in the BACT/ALERT Blood Culture System. J Clin Microbiol. 2014;52(6):1898-1900. 27. R iley JA, Heiter BJ, Bourbeau PP. Comparison of recovery of blood culture isolates from two BACT/ALERT FAN aerobic blood culture bottles with recovery from one FAN aerobic bottle and one FAN anaerobic bottle. J Clin Microbiol. 2003;41:213-217. 27 REFERENCES 28. W einstein MP,Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s; a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24:584-602. 29. U K Department of Health: Taking Blood Cultures – A summary of best practice. 2007 30. W einstein MP. Current blood culture methods and systems: clinical concepts, technology, and interpretation of results. Clin Infect Dis. 1996;23:40-46. 31. E verts RJ, Vinson EN, Aholla PO, Reller LB. Contamination of catheter-drawn blood cultures. J Clin Microbiol. 2001;39:3393-3394. 32. Cornaglia G, Courcol R, Hermann JL, Kahlmeter G. European Manual of Microbiology. ESCMID-SFM 2012. 33. K irm TJ, Weinstein MP. Update on blood cultures: how to obtain, process, report, and interpret. Clin Microbiol Infect. 2013;19(6):513-520. 34. W ilson ML, Mirrett S, Reller LB, Weinstein MP, Reimer LG. Recovery of clinically important microorganisms from the BACT/ALERT blood culture system does not require testing for 7 days. Diagn Microbiol Infect Dis. 1993;16:31-34. 35. Bourbeau PP, Foltzer M. Routine Incubation of BACT/ALERT FA and FN blood culture for more than 3 days may not be necessary. J Clin Microbiol. 2005;43:2506-2509. 36. S chlossberg D, ed. Clinical Infectious Disease. Cambridge University Press, 2015. 37. Hall KK, Lyman JA. Updated Review of Blood Culture Contamination. Clin Microbiol Rev. 2006,19(4):788. 38. D unne Jr. WM, Nolte FS, Wilson ML. Cumitech 1B, Blood Cultures III. coordinating ed. Hindler JA. ASM Press. Washington, D.C. 1997. 39. Hall KK, Lyman JA. Updated review of blood culture contamination. Clinical Microbiology Reviews. 2006;19:788-802. 40. Bamber AI, Cunniffe JG, Nayar D, Ganguly R, Falconer E. The effectiveness of introducing blood culture collection packs to reduce contamination. Br J Biomed Sci. 2009;66(1):1-9. 41. Gander RM, Byrd L, DeCrescenzo, Hirany S, Bowen M, Baughman J. Impact of Blood Cultures Drawn by Phlebotomy on Contamination Rates and Health Care Costs in a Hospital Emergency Department. J Clin Microbiol. 2009;47:1021-1024. 42. Richter SS, Beekman SE, Croco DJ, et al. Minimizing the workup of blood culture contaminants: implementation and evaluation of a laboratory-based algorithm. J Clin Microbiol. 2002;40:2437-2444. 43.T owns ML, Reller LB. Diagnostic methods: current best practices and guidelines for isolation of bacteria and fungi in infective endocarditis. Infect Dis Clin N Am. 2002;16:363-376. 44. Osborn TM, Nguyen HB, Rivers EP. Emergency medicine and the surviving sepsis campaign: an international approach to managing severe sepsis and septic shock. Ann Emerg Med. 2005;46:228-231. 45. R ubenstein E, Lang R. Fungal endocarditis. Eur Heart J. 1995:16(Suppl B):84-89. 46. E llis ME,Al-Abdely H, Sandridge A, Greer W,Ventura W. Fungal endocarditis: evidence in the world literature, 1965-1995. Clin Infect Dis. 2001; 32:50-62. 28 REFERENCES 47. M cLeod R., Remington JS. Fungal endocarditis. In: Rahimtoola SH et al., eds. Infective Endocarditis. New York, NY: Gune & Stratton.1978:211-290 48. Z iegler R, Johnscher I, Martus P, Lenhardt D, Just HM. Controlled Clinical Laboratory Comparison of Two Supplemented Aerobic and Anaerobic Media Used in Automated Blood Culture Systems to Detect Bloodstream Infections. J Clin Microbiol. 1998;36:657-661. 49. Pohlman JK, Kirkley BA, Easley KA, Basille BA, Washington JA. Controlled Clinical Evaluation of BACTEC Plus Aerobic/F and BACT/ALERT Aerobic FAN Bottles for Detection of Bloodstream Infections. J Clin Microbiol. 1995;33:2856-2858. 50. B aron EJ, Scott JD,Tompkins LS. Prolonged incubation and extensive subculturing do not increase recovery of clinically significant microorganisms from standard automated blood cultures. Clin Infect Dis. 2005;41:1677-1680. 51. Beekmann SE, Diekema DJ, Chapin KC, Doern GV. Effects of rapid detection of bloodstream infections on length of hospitalization and hospital charges. J Clin Microbiol. 2003;41:3119-3125. 52. Munson EL, Diekema DJ, Beekmann SE, Chapin KC, Doern GV. Detection and treatment of bloodstream infection: laboratory reporting and antimicrobial management. J Clin Microbiol. 2003;41:495-497. 53. B arenfanger J, Graham DR, Kolluri L, et al. Decreased Mortality Associated With Prompt Gram Staining of Blood Cultures. Am J Clin Pathol. 2008;130:870-876. 54. Timbrook T, Boger MS, Steed LL, Hurst JM. Unanticipated Multiplex PCR Identification of Polymicrobial Blood Culture Resulting in Earlier Isolation, Susceptibilities, and Optimization of Clinical Care. J Clin Microbiol. 2015;53(7):2371-2373. 55. Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An Antimicrobial Stewardship Program’s Impact with Rapid Polymerase Chain Reaction Methicillin-Resistant Staphylococcus aureus/S. aureus Blood Culture Test in Patients with S. aureus Bacteremia. Clin Infect Dis. 2010;51(9):1074-1080. 56. Dierkes C, Ehrenstein B, Siebig S, Linde HJ, Reischl U, Salzberger B. Clinical impact of a commercially available multiplex PCR system for rapid detection of pathogens in patients with presumed sepsis. BMC Infect Dis. 2009; 9(1):126 57. Weinstein MP. Blood Culture Contamination: Persisting Problems and Partial Progress. J Clin Microbiol. 2003;41:2275-2278. 58. Weinstein MP, Towns ML Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24:584-602. 59. Ernst DJ. Applied Phlebotomy. Dennis J. Ernst (MT(ASCP)). Lippincott Williams & Wilkins, 2005. 60. Lieseke CL, Zeibig EA. Essentials of Medical Laboratory Practice. F.A. Davis, 2012. 61. Q amruddin A, Khanna N, Orr D. Peripheral blood culture contamination in adults and venipuncture technique: prospective cohort study. J Clin Pathol. 2008;61:509513. 29 RECOMMENDATIONS FOR BLOOD CULTURE COLLECTION A) USING WINGED BLOOD COLLECTION SET (preferred method of collection)59-61 1 PREPARE BLOOD COLLECTION KIT Confirm the patient’s identity and gather all required materials before beginning the collection process. Do not use blood culture bottles beyond their expiration date, or bottles which show signs of damage, deterioration or contamination. It is recommended to identify the Fill-to Mark or mark the target fill level on the blood culture bottle label about 10 ml above the media level. 2 PREPARE BOTTLES FOR INOCULATION Wash hands with soap and water then dry, or apply an alcohol hand rub or another recognized effective hand rub solution. Remove the plastic “flip-cap” from the blood culture bottles and disinfect the septum using an appropriate and recognized effective disinfectant, such as chlorhexidine in 70% isopropyl alcohol, 70% isopropyl alcohol, or tincture of iodine in swab or applicator form. Use a fresh swab/applicator for each bottle. Allow bottle tops to dry in order to fully disinfect. 30 3 PREPARE VENIPUNCTURE SITE If skin is visibly soiled, clean with soap and water. Apply a disposable tourniquet and palpate for a vein. Apply clean examination gloves (sterile gloves are not necessary). Cleanse the skin using an appropriate disinfectant, such as chlorhexidine in 70% isopropyl alcohol or tincture of iodine in swab or applicator form. The venipuncture site is not fully clean until the disinfectant has fully evaporated. 6 OTHER BLOOD TESTS If blood is being collected for other tests, an insert placed into the adapter cap may be required. The insert is used to guide blood collection tubes onto the needle. If other blood tests are requested, always collect the blood culture first. 4 VENIPUNCTURE Attach a winged blood collection set to a collection adapter cap.* To prevent contaminating the puncture site, do not re-palpate the prepared vein before inserting the needle. Insert the needle into the prepared vein. 5 CULTURE BOTTLE INOCULATION Place the adapter cap over the aerobic bottle and press straight down to pierce the septum. Hold the bottle upright, below the level of the draw site, and add up to 10 ml of blood per adult bottle and up to 4 ml per pediatric bottle.† Ensure the bottle is correctly filled to the Fill-to Mark or target fill level. Once the aerobic bottle has been inoculated, repeat the procedure for the anaerobic bottle. 7 FINISH THE PROCEDURE Discard the winged collection set into a sharps container and cover the puncture site with an appropriate dressing. Remove gloves and wash hands before recording the procedure, including indication for culture, date, time, site of venipuncture, and any complications. Ensure additional labels are placed in the space provided on the bottle label and do not cover the bottle barcodes, and that the tear-off barcode labels are not removed. If additional labels contain a barcode, they should be positioned in the same manner as the bottle barcode. Inoculated bottl
Url: /Media/SUHTExtranet/DepartmentOfInfection/STHW841-V1-Biomerieux-Blood-culture-guidance.pdf

cancer-genetics-referral-guidelines

Description: Wessex Clinical Genetics Service, G Level, Mailpoint 627, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA Tel: 023 8120 6170 https://www.uhs.nhs.uk/departments/genetics E-mail: GeneticsTeam@uhs.nhs.uk Cancer Genetics Referral Guidelines In general the person being referred should be affected or have an affected first degree relative (Except in families with breast/ovarian cancer where the affected relative is through a male). All affected relatives should be on the same side of the family. Fulfilling the referral criteria does not mean a person will definitely be seen in the genetics clinic. In most cases, genetic testing needs to start in an affected family member. If an affected family member is available, we would recommend that they be referred to their local genetics service in the first instance. For all cancer referrals please provide: * Clinical information (including histology reports) for your patient if they have had cancer * A completed Family History Enquiry form (insert link) completed by your patient * Clinical information about relatives if appropriate (for example genetic test reports). Known cancer susceptibility gene * If a cancer susceptibility gene has been identified in the family Breast cancer Families with: * four or more breast cancers* * three breast cancers* diagnosed at average age under 60 years * two breast cancers* diagnosed at average age under 50 years * both breast and ovarian cancer. This includes a single individual who develops both cancers * male breast cancer at any age * Ashkenazi Jewish ancestry and at least 1 breast or ovarian cancer * a recognised BRCA1 or BRCA2 gene mutation in family Female diagnosed with invasive breast cancer who: * was diagnosed under 40 years * has triple negative breast cancer** diagnosed under 60 years (Please include pathology report with referral) * was diagnosed under 50 years and has an affected relative* diagnosed under 50 years * was also diagnosed with ovarian cancer * meets the family history described above (counting her own breast cancer as one of the cases) * Someone with bilateral breast cancer counts as two affected individuals. ** Triple negative breast cancer relates to a breast cancer that is negative for oestrogen receptors, progesterone receptors and HER-2 expression. If your patient does not fulfil our guidelines, you may wish to refer them to the local secondary breast care service, to assess whether or not they may be eligible for additional screening. Colon cancer An individual with: * colorectal cancer diagnosed at any age that has loss of mismatch repair proteins (MMR) on immunohistochemistry (IHC)* * colorectal cancer diagnosed under 40 years (irrespective of MMR IHC status) * * a parent, sibling or child diagnosed with colorectal cancer under 50 years * two close relatives with colorectal cancer diagnosed under 60 years * three close relatives with colorectal cancer diagnosed under 70 years * a close relative with colorectal cancer diagnosed under 50 years AND a family history of endometrial, ovarian, urothelial, gastric or hepatobiliary cancer * a diagnosis of or family history of a high-risk susceptibility condition, for example: Familial Adenomatous Polyposis (FAP), MutYH Associated Polyposis (MAP), Juvenile Polyposis, Peutz Jegher syndrome, Lynch syndrome (also known as hereditary non-polyposis colorectal cancer (HNPCC) * 10 or more colorectal adenomas *Please include histopathology and immunohistochemistry reports with referral. Please refer to guidelines for colorectal screening for moderate and high risk groups: https://www.bsg.org.uk/wp-content/uploads/2019/12/Guidelines-for-the-management-of-hereditary-colorectal-cancer.full_.pdf Gynaecological cancer * Individual diagnosed with high-grade serous ovarian cancer (not borderline or low grade) * Any family with two or more cases of ovarian cancer * Any family with endometrial cancer AND colorectal cancer or ovarian cancer with at least one case under the age of 50 years * Any family with ovarian cancer at any age with two or more cases of breast cancer under the age of 60 years * Individual diagnosed with endometrial cancer under the age of 50 years Endocrine cancer An individual/family with: * Medullary thyroid carcinoma * MEN (Multiple Endocrine Neoplasia) * Phaeochromocytomas / paragangliomas * Parathyroid carcinoma or familial hyperparathyroidism Kidney cancer An individual/family with: * Confirmed diagnosis of a genetic kidney cancer syndrome (eg Von Hippel-Lindau (VHL), Birt-Hogg-Dubé, hereditary leiomyomatosis and renal cell cancer, 3p translocation, tuberous sclerosis) * Kidney cancer under the age of 30 * Multiple kidney cancers in the same individual * 2 first or second degree relatives with kidney cancer * Kidney lesion and clinical features suggestive of an underlying genetic cause eg. skin lesions or other primary tumour(s) * Multiple renal angiomyolipomas (2 or more of >3cm, or more than 3 of any size) Other unusual cancers / childhood cancer An individual/family with: * Bilateral Wilms tumour * Choroid plexus carcinoma or childhood adrenal cortical carcinoma * Atypical rhabdoid teratoid tumour * Multiple cancer or sarcoma at a young age (<45 years) on the same side of the family In any families with unusual patterns of cancer where there is a suspicion of an inherited predisposition, please contact us to discuss on an individual basis. Secondary care services The following are examples of secondary care services available in the Wessex region: Dorset (excluding Poole and Bournemouth) All family history of breast cancer referrals will be initially assessed by radiographers at the Dorset breast screening unit at Poole Hospital who will arrange screening, with annual recall, for those deemed to be at moderate additional risk. Those thought to be at high additional risk will be referred onto the genetics service. Please make referrals to: Gemma Marsden Breast Cancer Research Nurse Dorset Breast Screening Unit Poole Hospital Longfleet Road Poole BH15 2JB The referral letter must be accompanied by a completed family history questionnaire|. Referrals regarding other types of cancer should be made direct to the genetics service if they meet the above criteria. Bournemouth and Poole All referrals for a family history of cancer should be sent to: Community Oncology Nurse Specialist Team Cancer Genetics Family History Risk Assessment Clinic Dorset Healthcare University NHS Foundation Trust Acorn Building 241 Ringwood Road St Leonards BH24 2RR Tel: 01202 714965 The team will assess each referral and triage appropriately. High additional risk families will be sent on to the cancer genetic service. Referrals can be sent without a family history questionnaire|, but if possible but your patient may still wish to complete one as this may speed up the risk assessment process. Winchester and Basingstoke A family history of breast cancer is usually initially assessed by the breast family history clinic. Referrals should be made to: Dr Karen Anderson North and Mid Hants Breast Screening Unit Florence Portal House Royal Hampshire County Hospital Romsey Road Winchester Hampshire SO22 5DG The team will assess each referral and triage appropriately. High additional risk families will be sent on to the cancer genetic service. Southampton A family history of breast cancer is usually initially assessed by the breast family history clinic. Referrals should be made to: Mr Ramsey Cutress Consultant Surgeon Southampton Breast Imaging Unit Mailpoint 105 Princess Anne Hospital Coxford Road Southampton SO16 5YA A family history of colorectal cancer is usually initially assessed by the bowel family history clinic. Referrals should be made to: Sue Park Colorectal Nurse Practitioner Colorectal Surgery Southampton General Hospital Tremona Road Southampton SO16 5YA The team will assess each referral and triage appropriately. High additional risk families will be sent on to the cancer genetic service. Bailiwick of Guernsey Family histories of breast cancer are usually initially assessed by the breast family history clinic. Referrals should be made to: Sharon Treacey Breast Care Nurse Breast Unit Princess Elizabeth Hospital Rue Mignot St Andrews Guernsey GY6 8TW The team will assess each referral and triage appropriately. High additional risk families will be sent on to the cancer genetic service. Portsmouth Family histories of breast cancer are usually initially assessed by the breast family history clinic. Referrals should be made to: Rosemary Buck Breast Services Queen Alexandra Hospital Southwick Hill Road Cosham Portsmouth PO6 3LY Isle of Wight Family histories of breast cancer are usually initially assessed by the breast family history clinic. Referrals should be made to: Heather Nelson Clinical Nurse Specialist Applegate Breast Care Nurses St Mary’s Hospital Newport Isle of Wight PO30 5TG The team will assess each referral and triage appropriately. High additional risk families will be sent on to the cancer genetic service. Salisbury Family histories of breast cancer are usually initially assessed by the breast family history clinic. Referrals should be made to: Sonnya Dabill Specialist Breast care Nurse Salisbury District Hospital Salisbury Wiltshire SP2 8BJOther unusual cancers / childhood cancer An individual/family with: * Bilateral Wilms tumour * Choroid plexus carcinoma or childhood adrenal cortical carcinoma * Atypical rhabdoid teratoid tumour * Multiple cancer or sarcoma at a young age (<45 years) on the same side of the family In any families with unusual patterns of cancer where there is a suspicion of an inherited predisposition, please contact us to discuss on an individual basis. Version 5. 18.09.2023 Review date: March 2024
Url: /Media/UHS-website-2019/Docs/Services/Genetics/Cancer-genetics/cancer-genetics-referral-guidelines2.docx

Prof Tom Wilkinson, research lead for airways diseases

Description: NIHR Southampton Biomedical Research Centre Auto Generated Title Prof Tom Wilkinson is a clinician and researcher interested in asthma and chronic obstructive pu
Url: /ClinicalResearchinSouthampton/Our-people/Respiratory-research-people/Prof-Tom-Wilkinson-research-lead-for-airways-diseases.aspx

Health and safety policy

Description: Health and Safety Policy Date Issued: 21/11/18 Review Date: 21/11/21 Document Type: Policy Version: 10.0 Contents Paragraph 1 2 3 4 5 6 7 8 9 Appendices Appendix A Appendix B Appendix C Appendix D Appendix E Appendix F Appendix G Appendix H Appendix J Executive Summary / Policy Statement / Flowchart Scope and Purpose Definitions Details of Procedure to be followed Roles and Responsibilities Related Trust Policies Communication Plan Process for Monitoring Compliance/Effectiveness of this Policy Arrangements for Review of this Policy References Trade Unions and Professional Organisations Health and Safety Risk Assessment Form Risk Grading Matrix Fees for Intervention Health and Safety Self Auditing Non Patient Slips Trips and Falls First Aid Provision Display Screen Equipment Noise at Work Page 2 6 7 8 10 21 22 22 22 22 Page 24 25 27 30 34 38 41 43 44 Document Status This is a controlled document. Whilst this document may be printed, the electronic version posted on the intranet is the controlled copy. Any printed copies of this document are not controlled. As a controlled document, this document should not be saved onto local or network drives but should always be accessed from the intranet. Page 1 of 48 Executive Summary The Health and Safety at Work etc. Act 1974 (HASAWA) places the duty on an employer to ensure, so far as is reasonably practicable, the health, safety and welfare of all employees and others who may be affected by its acts or omissions. This includes the provision and maintenance of safe plant, machinery, equipment and safe systems of work. Although the ultimate responsibility for compliance with the Act rests with employers, every employee also has a responsibility to ensure that no one is harmed or put at risk as a result of their acts or omissions during the course of their work. It shall be the duty of every employer to conduct his undertaking in such a way as to ensure, so far as reasonably practicable, that persons not his employment who may be affected thereby are not thereby exposed to risks to their health or safety (Section 3 HASAWA) Compliance with the Health and Safety at Work Act is a legal requirement. As such, an offence, committed under the Act would constitute a criminal offence and could lead to prosecution, resulting in a fine and/or a term of imprisonment. If the Trust commits an offence which is a material breach in the opinion of the Health & Safety Executive (HSE) inspector, or if there is or has been a contravention of health and safety law then a notice may be issued to the Trust. If a notice is issued or the inspector sees a material breach of the law, the trust will have to pay a fee. Reference Appendix D In addition to the Health and Safety at Work Act 1974, other Regulations, Approved Codes of Practice, Guidance Notes and Directives will apply. The Trust uses the Health & Safety Executive (HSE) model HSG 65 (see page 3) as a method of ensuring that the work of the Trust is conducted in a safe manner as far as is reasonably practicable. Page 2 of 48 HSG65: Managing for Health and Safety (Third Edition) Page 3 of 48 Health and Safety Policy - Flow Chart Page 4 of 48 UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST Health & Safety Policy Statement of Intent The University Hospital Southampton (UHS) NHS Foundation Trust Board of Directors and I are totally committed to ensuring the health, safety & wellbeing of all staff, patients, contractors and members of the public who are in any way affected by the undertaking of UHS’s activities. We will ensure the provision of appropriate resources, including staff, finance and equipment in a timely manner so as to conduct our activities in accordance with all statutory and regulatory requirements, seeking to exceed such requirements wherever reasonably practicable. We will develop and implement a range of policies and procedures in support of this statement and will ensure their effective communication to all staff and contractors. We will seek to embrace best practice from the wider healthcare community and will proactively seek out innovative and dynamic initiatives that will assist UHS in achieving the highest levels of safety performance and delivering the highest standards of clinical care, reviewing and amending our policies and procedures on a continuous basis. It will not be acceptable for any hazard, risk or safety incident to be ignored by any member of staff, or contractor, and we will ensure that systems and processes exist to identify and mitigate risk as well as for reporting, investigating and learning from incidents when they do occur. In delivering these aims, the Board expects and requires all staff and contractors to conduct themselves in a safe manner at all times and to engage with the Board in any and all safety initiatives that it identifies and implements in order to deliver continual safety improvement Paula Head Chief Executive University Hospital Southampton NHS Foundation Trust Page 5 of 48 1 Scope and Purpose This policy sets out the principles and arrangements by which University Hospital Southampton (UHS) Foundation Trust base both their commitment to Health and Safety and their compliance with legislation. The policy forms part of the UHS’s overall approach to staff and patient safety as set out in the Health and Safety and Patient Safety Strategies. This policy applies to all staff employed by the Trust, either directly or indirectly, and to any other person or organisation which uses Trust services or premises for any purpose. It will also apply to bank, temporary staff, volunteers, young workers, staff working from home and contractors working on Trust business. The principles of this policy shall apply to all Trust work activities, regardless of who has or is supplying or providing them. The aims of this policy are to: o Outline the requirements of Health & Safety Regulations, Health & Safety Guidance and Approved Codes of Practise that apply to the Trust. o To inform managers and staff as to their roles and responsibilities with respect to these. o To demonstrate the Trust’s commitment to reducing accidents and incidents causing ill-health as well as other environmental hazards and risks in the workplace o To set out the organisation’s arrangements for Health and Safety in accordance with HSG 65 o To set out the organisation’s training requirements for Health & Safety The objectives of this policy are to: o To ensure that the Trust has a proactive management system in place to enable it to comply with all relevant statutory health and safety legislation. o To reduce the numbers of accidents and incidents which cause harm o To prevent foreseeable accidents or incidents so far as is reasonably practicable by undertaking suitable and sufficient risk assessments o To demonstrate how UHS complies with its Statutory Health and Safety compliance against Legislation, Regulations, Approved Code of Practice (ACOPs), best practice, etc o To prevent reoccurrence of adverse events as far as is reasonably practicable o To ensure compliance with relevant NHS Litigation Authority standards, Care Quality Commission (CQC) Essential Standards of Quality and Safety and other Department of Health (DoH) requirements such as Health Technical Memorandum (HTM) or Health Building Note (HBN) where practicable. o To ensure that contractors recognise their duty of care to the Trust and their employees and will be bound by their terms of contract to comply with The Health and Safety at Work Act, subordinate regulations and the Trust Consultant’s and Contractor’s Handbook’ Page 6 of 48 2 Definitions o Reasonably Practicable: means that you have to take action to control the health and safety risks in your workplace except where the cost (in terms of time and effort as well as money) of doing so is "grossly disproportionate" to the reduction in the risk. o Competency: knowledge, skills, qualifications, training, experience or ability to undertake a particular job, the term ‘competent person’ also refers to the roles and responsibilities of those managing health & safety matters o Employee: means any member of staff who holds a contract of employment directly with the Trust o Contractors: persons or agencies engaged by the Trust to provide a specific service. This includes bank staff, agency staff, staff employed by other Trusts, organisations and agencies occupying Trust premises o Hazard: a hazard is anything with the potential to cause harm e.g. chemicals, electricity, working at height, noise etc. o Risk: the likelihood that the hazard will actually cause harm, injury or damage; it also considers the consequences, extent and outcome of a hazardous event occurring o Suitable and Sufficient: that all significant hazards have been identified, the risks have been properly evaluated considering likelihood and severity of harm, measures necessary to achieve acceptable levels of risk have been identified, actions have been prioritised to reduce risks, the assessment will be valid for some time, actual conditions and events likely to occur have been considered during the assessment, everyone who may be harmed has been considered o Young person: is anyone under eighteen years of age (young people). The law on working time defines a young worker as being below 18 years of age and above the Minimum School Leaving Age. o Approved Code of Practice (ACOPs): Approved Codes of Practice give practical guidance on compliance. o Volunteer: A person carrying out work activities within the Trust, for the benefit of staff, patients and/or visitors without reward in cash or kind, and on behalf of one of the Trust’s recognised volunteer groups. Reasonable expenses received from the recognised volunteer group will not affect a volunteer’s status. Page 7 of 48 3 Details of Procedure to be followed 3.1 Risk Assessment The law places an ‘absolute duty’ on employers to carry out risk assessments, which should be a record of:  identified hazards arising from or in connection with the work;  who will be affected by the hazards;  the control measures in place or proposed control measures;  evaluation of the risk  review date Health & Safety Risk assessments are required to be undertaken for tasks/ environments/ situations identified as presenting a significant risk of injury either to Trust staff, visitors or patients. Risk assessments should be completed using the Trust’s Generic Health & Safety Risk Assessment Form Appendix B, and scored according to the guidance in Appendix C, and these should be monitored and reviewed in the following circumstances:  whenever there is a significant change e.g. staff, environment or equipment;  after an accident or ‘near miss’;  after non compliance identified through audits and inspection programmes  at least annually Risks that cannot be managed and actioned locally should be escalated to the risk register following guidance contained in the Risk Management Policy and Procedures Health & Safety Risks relating to the following hazards, should be identified and recorded using the specialised risk assessment forms contained in the related Trust policies, listed under section 5 of this policy:  Ionising or Non-Ionising radiation including lasers and other intense light sources  Magnetic Resonance (MR) fields  COSHH,  Visual Display Unit use,  Moving and Handling of patients or equipment  Stress 3.2 Health and Safety Training Details of training course dates and registration information, Statutory and Mandatory Training, Corporate Induction and refresher training are advertised on the Virtual Learning Environment (VLE) and details of training requirements are outlined in the Training Needs Analysis. Specific training including local induction related to the particular work activity must be provided by managers. Where the use of specialist equipment or work practices is required, suitable training will be arranged by the relevant manager. A range of Health and Safety training courses is provided for managers and staff by the Health & Safety Manager/Advisor/Moving & Handling Adviser. These include:  H&S Lead coordinators  H&S Risk Assessments  Control of substance hazardous to health (COSHH)  Moving and Handling clinical handling leads  Moving and Handling load handling leads Page 8 of 48 3.3 Auditing Departments will carry out a health and safety self-audit annually, following the process outlined in Appendix E. Once self audits are submitted to the Health and Safety team, the team will summarise results and report to the Corporate Health and Safety Committee and QGSG. Self audit returns will be followed up in Health and Safety Tours in departments, and in incident investigations and inspections. 3.4 Non Patient Slips Trips and Falls Non Patient Slips Trips and Falls will be controlled as outlined in Appendix F. 3.5 Provision for Emergencies Planning for fire emergencies is the responsibility of the Fire Safety Advisor and controlled as outlined in the Fire Safety Management Policy. Spillages of hazardous substances are managed according to the COSHH policy Planning and provision of first aid is managed as outlined in Appendix G to this policy 3.6 Incident Reporting. All staff are expected to report accidents and incidents using the “Safeguard” incident reporting system, from where appropriate managers will investigate and take appropriate remedial actions. Incidents reportable to the Health and Safety Executive under the RIDDOR Regulations must be brought to the attention of the Health and Safety Team, who will investigate and report appropriately. Guidance on which incidents are reportable under RIDDOR is available on StaffNet at http://staffnet/Workinghere/Staffessentials/Staffhealthandsafety/RIDDOR.aspx Page 9 of 48 4 Roles and Responsibilities 4.1 Chief Executive The Chief Executive (CEO) has overall responsibility to provide a safe environment throughout the Trust, ensuring compliance with the requirements of The Health and Safety at Work etc, Act 1974, all subordinate Health and Safety Regulations, ACOPs & Guidance, the requirements of this policy and any subsequent amendments to these. The CEO has overall accountability for the safety of any member of staff, patient, visitor, contractor, and others, whilst they are on those Trust premises under their control. The CEO is also responsible for the health and safety of other stakeholders and neighbours who may be affected by the work and undertakings of the Trust. The CEO has overall responsibility to make arrangements to ensure:  That the requirements of the Trust’s Health and Safety Policy are organised, planned and implemented  That the Trust Board is informed of relevant health and safety matters affecting the Trust, its employees, contractors, patients, neighbours, other stakeholders and the wider public  That suitable and sufficient resources and support are provided for the training and development of Trust staff in all relevant health and safety matters  That monitoring, measuring, reviewing and auditing of the Trust’s health and safety performance is undertaken  That the Trust's Health and Safety plans and performance are discussed at Board level 4.2 Director of Nursing and Organisational Development The Director of Nursing and Organisational Development, in liaison with the Medical Director, has delegated executive responsibility for health and safety in particular for:  Informing the Board on all relevant health & safety management issues, including alerting the Board to the requirements of this policy and any actual or potential breaches of Health and Safety Legislation  Ensuring, through the Quality Governance Committee structure, that relevant persons are consulted with and informed of any changes that may substantially affect their health and safety e.g. in procedures, equipment or ways of working  Ensuring clear lines of accountability throughout the organisation for the management of health and safety and that all staff groups are represented in the Quality Governance Committee structure  Ensuring that staff are provided with information on the likely risks and dangers arising from Trust work and activity, introduce measures to reduce or get rid of those risks and inform staff as to what they need to do if they have to deal with a risk or danger  Putting arrangements in place to get competent people to help them satisfy health and safety legislative requirements  Ensuring co-ordination and co-operation on health and safety matters between the Trust, its neighbours, contractors and any other relevant stakeholder  Ensuring that suitable plans are in place to manage health and safety Page 10 of 48  Ensuring that adverse health and safety consequences of introducing new technology, equipment or procedures and ways of working are mitigated so far as is reasonably practicable 4.3 Executive and non-Executive Directors All Executive and Non Executive Directors have corporate responsibility to provide a safe working environment and shall ensure adequate arrangements and resources are provided to implement the requirements of this policy, all relevant Safety Regulations and any associated procedures and safe systems of work; and apply this within their respective areas of responsibility. They ensure that health and safety arrangements are adequately resourced and that they obtain competent advice and that they review reports, performance and action plans to ensure compliance. They recognise that it is a criminal offence for a company to fail in any of the duties imposed by the Act, and an accident may give rise to civil liability as well. Directors can be prosecuted for the criminal offence as well as the organisation. 4.4 Director of Quality  Is the operational lead for health and safety, reporting to the Director of Nursing and Organisational Development  Deputise and carry out the duties of the Director of Nursing and Organisational Development in their absence 4.5 Divisional Clinical Directors / Divisional Directors of Operations / Divisional Heads of Nursing / Heads of Departments / Senior Managers/ Managers / Supervisors The following is not an exhaustive list but in general terms, managers at all levels must ensure:  That they have or undertake to obtain such information, instruction and training to enable them to lead on matters of health and safety commensurate with their respective role or position  That all risk assessments are carried out and documented by persons competent to undertake such assessments following Trust policy  That risk assessments are systematically reviewed and where necessary ensure that suitable protocols, plans and procedures are further updated or developed to provide adequate controls and safety precautions  That they support local managers and work with lead risk assessors, staff and staff representatives to provide suitable and sufficient equipment which is serviced and maintained and put systems and procedures in place to control and safely manage any identified risks  That they and local managers discuss and disseminate Trust safety policies and implement the requirements of those respective policies to ensure cooperation and communication by all  That they make adequate funding available to provide any necessary equipment, procedures and ongoing training and supervision to meet the requirements of the Health and Safety Policy and/or where a risk assessment has identified such control measures as being necessary Page 11 of 48  That health and safety performance standards and objectives are set for their managers and those under their supervision  That they manage the timely reporting of accidents and incidents in accordance with the Incident Reporting, Analysis, Investigation and Management Policy  That investigations are undertaken, the Incident Reporting Procedure is followed and that the Significant Incident Requiring Investigation (SIRI) and Reporting of Injuries, Diseases and Dangerous Occurrences Regulations (RIDDOR) procedures are followed, where necessary  That they intervene to prevent poor Health and Safety practice or procedures, as needs be  That they ensure any member of staff who ignores or deliberately fails to discharge their responsibilities for health and safety has been reprimanded or disciplined as per the Trust Disciplinary procedure and HR Policies  That they provide safe access and egress to Trust buildings, wards, departments and areas they are responsible for and provide safe means of transport and methods of movement of patients and staff; particularly when evacuation is required.  That they ensure the managers, supervisors and staff under their control or responsibility attend the appropriate training and health surveillance, including induction training, local induction and familiarisation, mandatory and statutory training; health surveillance for dermatitis, latex allergy, upper limb disorder, stress or occupational asthma, and any other training or health surveillance that is deemed necessary  That they maintain a system of regular inspections and audits to determine the degree of compliance with both Trust and local policies & procedures and take appropriate remedial action to address any areas of non-compliance  That they ensure that all staff under their control or supervision are afforded the same level of protection  That health and safety matters are discussed and incorporated as necessary into staff’s job descriptions, appraisals, team meetings and escalated through the local Governance Committee structure. 4.6 Director of Estates & Capital Development The Director of Estates and Capital Development is responsible for ensuring that the H&S Policy is implemented throughout the Estates and Capital Development (E&CD) department, together with its monitoring and updating. The Director of E&CD will be assisted in this by the members of the Estates Management Team, namely: the Deputy Director of E&CD, Head of Estates Maintenance; the Head of Estate Projects; the Head of Compliance; the Infrastructure Services Manager, the Estates Health & Safety Manager, the Head of Clinical Engineering, and Building Maintenance Managers. The Director of E&CD is also responsible for ensuring that the H&S Policy is applied to all work undertaken by design consultants, cost advisers, contractors and subcontractors and suppliers, as is appropriate. 4.7 Health & Safety Manager  Ensures that the Trust has a robust Health & Safety Policy outlining the commitment of the CEO and the Trust Board, to ensuring the Health & Safety of Page 12 of 48 all persons who either work for, or come into contact with, the Trust’s estates and activities.  To liaise effectively with the Health & Safety Executive (HSE), and other safety related external agencies, on behalf of the Trust  To regularly monitor and review all existing Trust wide policies relating to H&S and ensure that all H&S policies are readily available to all staff, that changes are effectively communicated and that they are robustly implemented.  Develop H&S training and ensure implementation strategies facilitate compliance and contribute to the Trust broader Education Strategy.  Analyse H&S related Trust wide adverse H&S events, ensuring appropriate investigation, production of detailed reports, and reporting as appropriate. To analyse health & safety data contained on the system, producing reports as necessary for relevant groups, identifying trends and recommending consequential change/s as required.  Produce an Annual Health & Safety Report for the Board setting out the achievements and shortcomings of the previous 12 months and making recommendations to bring about future improvements  To manage and provide leadership for the Trust Manual Handling Advisor and the Health and Safety Advisor.  Chair the Corporate Health & Safety Committee  Provide Health and Safety Reports to the Trust Board as required  Act as the nominated ‘competent person’ for the Trust as required by law, including providing input to planning of refurbishments, equipment sourcing and implementation, and other work likely to affect the health, safety and welfare of staff, visitors and patients. 4.8 Health & Safety Advisor  Will assist in the development, production and delivery of strategies that procures Trust wide compliance regarding health & safety, with statutory national and local regulations, Department of Health Directives and Trust Policies.  Will prepare and deliver as required senior management reports to various forums where health & safety is discussed.  Take part in investigations of accidents, near misses and other incidents and provide Health and Safety perspective to recommendations for remedial and preventive actions.  Working with the colleagues from the health & safety team to put in place an effective system in order to audit divisional compliance with the Trust Health & Safety strategies, producing reports for that identify both compliant and noncompliant areas.  Will coordinate visits, inspections by the Health & Safety Executive and the provision of such documents that may be requested by an inspector regarding the Trusts statutory duty.  Will provide expert advice and guidance on health and safety policy, guidance and assessment. Page 13 of 48  Work with colleagues in identification of appropriate health & safety training, strategies and contribute to the Trust health & safety education strategy..  Will chair the Health & Safety Leads meetings. 4.9 Trust Moving & Handling Advisor  Acts as the principle advisor for all Trust moving and handling activities by providing moving and handling information, expertise and advice within the Trust on the suitability of moving and handling aids and appropriate training for both staff and patients in order to ensure Trust wide compliance with statutory national and local moving and handling regulations  Undertakes moving and handling audits across the Trust alongside the Trust Health and Safety Team in order to put in place an effective system to audit compliance with the Trust moving and handling strategies. To provide a detailed report of any findings to Senior Managers informing of appropriate actions  Supports Nominated Moving and Handling Leads in providing moving and handling information, expertise and advice to their areas by chairing bi-monthly meetings in order to promote and adapt safer moving and handling practice in areas where moving and handling is challenging. 4.10 Radiation Protection Advisor The Radiation Protection Adviser is a suitably qualified and competent person appointed under the Ionising Radiations Regulations 1999, and is responsible for:  Providing advice and guidance in the safe management and use of radionuclide and radiation generating equipment and the safe storage and disposal of any contaminated waste  Advising the Trust regarding arrangements to undertake and document risk assessments, procedures and systems of work relating to radiation generating equipment and the use of radioactive materials  Providing reports for committees and advising on the updating of relevant Trust Policies  Advising on the investigation of incidents involving ionising radiation and on planning for major incidents involving radioactive material 4.11 Laser Protection Advisor The Laser Protection Adviser must be a suitably qualified, competent person appointed according to the Guidance on the Safe Use of Lasers, Intense Light Source Systems and Light Emitting Diodes (LED’s) in Medical, Surgical, Dental and Aesthetic Practices (MHRA 2015) and is responsible for:  Providing advice and guidance in the safe management and use of lasers and associated equipment  Advising the Trust regarding arrangements to undertake and document risk assessments relating to lasers  Providing reports for committees and updating relevant Trust Policies 4.12 Magnetic Resonance Safety Expert The MHRA Safety Guidelines for Magnetic Resonance Imaging Equipment in Clinical Use 2015 (v4.2) state that the MR Safety Expert is a designated professional with Page 14 of 48 adequate training, knowledge and experience of MRI equipment, its uses and associated requirements. They should:  Develop safe operating procedures and policies and risk management solutions to ensure MR safety for patients, staff and visitors.  Develop an appropriate framework for managing safety in relation to MR, including effective review processes and reporting mechanisms within the Trust.  Prepare and periodically review the MRI local rules for the MRI units across the Trust.  Provide reports regarding MR safety developments to Trust committees and contribute to/update relevant Trust policies (including the Policy for the Safe Use of MRI).  Advise on the implementation of national and international MR guidelines and legislation within the Trust.  Carry out MR safety audits and risk assessments to assess and ensure compliance with national guidelines and good safe practice and to monitor the effectiveness of safety procedures.  Advise on the planning and the configuration of MR facilities in order to promote safety, working with, and recognising the experience of, the system vendor installation team.  Provide patient (and staff/visitor) specific advice with regard to MRI safety, such as that concerning implants (for example).  Assist with the investigation of incidents relating to MR equipment. 4.13 Fire Safety Advisor The Fire Safety Advisor (FSA) is responsible for ensuring the development and implementation of the Fire Safety Management Policy ensuring that safe systems and processes are in place for the continuous effective management of fire safety risks as required by statutory, national, local regulations, department of health directives and related trust policies. The FSA will work with the Fire Manager to put in place an effective system in order to audit divisional compliance with the Trust Fire Management Policy and to analyse fire related Trust wide adverse events producing reports as necessary for relevant groups, identifying trends and implementing change as required. 4.14 Occupational Health The Occupational Health Service are responsible for the assessment and enhancement of fitness for work, for advising about control of health risks in the workplace, and for leading staff health and wellbeing, specifically by providing:  co-ordination and provision of staff health and wellbeing support/services  pre-placement screening  immunisations against infectious diseases  management of sharps and contamination incidents  health surveillance  staff support and counselling  advice about adjustments to work on health grounds Page 15 of 48  rehabilitation back to work after illness  special advice to managers on generic risk assessments  advice to managers on individual risk assessments (taking account of individual susceptibility due to pregnancy or health problems)  health promotion and wellbeing advice  regular feedback to Trust Board on work-related ill health The Occupational Health service is impartial and confidential, aiming to give objective advice to both employees and managers. Employees’ OH records are held securely and are not accessible to anyone outside the OH service. Information about individuals will not be passed to anyone without that individual’s consent. 4.15 HR Department The Director of Human Resources has delegated responsibility for ensuring a robust strategic approach is adopted addressing issues of employee’s health, safety and wellbeing. This includes:  The development and implementation of a series of Human Resource policies which are compliant with health and safety legislation and which reflect the support mechanisms in place to assist and support employees health, safety and well-being.  The commissioning and development of appropriate staff support services. HR Teams are responsible for providing awareness sessions for staff and coaching for managers on the implementation of policies and HR best practice. 4.16 Security Manager The Security Manager for the Trust is the appointed Local Security Management Specialist (LSMS) and will undertake the duties of an LSMS in accordance with Secretary of State Directions to health bodies on measures to tackle violence and general security management measures, and any subsequent advice or guidance issued by the NHS SMS. This includes:  To ensure that all NHS security management work is carried out within a professional and ethical framework developed and provided by the NHS Security Management Specialist (SMS).  To ensure that an inclusive approach to security management work is taken, involving both internal and external NHS stakeholders where appropriate and necessary  To report to the health body’s Chief Operations Officer on security management work locally  To lead on day-to-day work in their health body to tackle violence against staff and professionals in accordance with the NHS SMS national framework and guidance.  Ensure appropriate steps are taken to create a pro-security culture within the health body and amongst contractors so that staff and patients accept responsibility for this issue and ensure that any security incidents or breaches that occur are detected and reported  Attend the health body’s risk management, health and safety and audit committee meetings and ensure appropriate links are made with the health body’s risk assessment process, including the health body’s health and safety Page 16 of 48 representatives, so that security-related issues are an integral part of that process  Participate in the health body’s induction programme for new staff and develop and deliver security awareness sessions for stakeholders  Ensure lessons learnt from security incidents and breaches are fed into risk analysis, both locally and nationally, so that appropriate preventative measures can be developed  Ensure security incidents are reported using the NHS SMS reporting system, ensuring that investigations take place where appropriate, risks are assessed and preventative measures are developed (this will include participation in local and national risk identification projects)  Ensure security incidents and breaches are investigated in a fair, objective and professional manner so that the appropriate sanctions are applied and measures put in place to prevent recurrence  Ensure consideration is given to cases not progressed by the police or CPS and, where appropriate, work is undertaken with the NHS SMS Legal Protection Unit and the health body, and redress is sought where appropriate. 4.17 Infection Prevention Team The Infection Prevention Team are responsible for providing the Trust with advice and guidance on infection prevention and control matters, for supporting staff in the implementation of infection prevention policies, and assisting with risk assessment where complex decisions are required. The Infection Prevention Team are also responsible for escalating concerns to the Quality Governance Steering Group and the Corporate Health & Safety Committee (CHSC). 4.18 Litigation and Insurance Services Department The Litigation and Insurance Services Department is responsible for:  Managing all clinical negligence and personal injury (extending to contract challenges where required) claims ethically and cost effectively on behalf of the Trust. This should be in accordance with Trust policy and procedures, based on NHSLA and NHS Executive (NHSE) guidelines. Ensuring the Trust complies with its statutory legal responsibilities in relation to the management of all claims.  In accordance with the Pre-Action Protocol and Civil Procedure Rules undertake all pre-action investigations; communicate with clinical and non-clinical staff to obtain evidence in the form of statements, internal expert medical and nonmedical opinion and documentation in the context of allegations of negligence or breach of statutory duty, consider the complexities of each case and perform a preliminary analysis of each individual claim to form a reasoned opinion on liability and quantum on the basis of evidence obtained.  In respect of the National Health Service Litigation Authority (NHSLA), Clinical Negligence Scheme for Trusts (CNST), Liabilities to Third Parties Scheme (LTPS) and Properties Expenses Scheme (PES), liaise and negotiate with insurers and external solicitors (both claimant and Trust) on claims covered under the various NHSLA compensation schemes.  Provide regular reports via the Health & Safety Report reporting on a quarterly an annual basis identifying newly reported claims and reporting on lessons learned, themes and actions taken Page 17 of 48  Attend Trust committees as required and to provide ad hoc general healthcare related advice.  Ensure that the Trust’s insurance provision is both adequate and maintained on annual basis. 4.19 National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility (WTCRF) is responsible for:  Ensuring that all research studies, including clinical and non-clinical interventions conducted within its facilities/ in the community by staff/visiting researchers are following Trust policies. The facilities include clinical, non-clinical and research laboratory areas.  Reporting health & safety concerns rising from the management of research that are serious and impact on business to the Research & Development (R&D).  Directly reporting to the Trust’s relevant governance meeting/s as required by those meetings (currently quarterly audits).  Keeping and maintaining the WTCRF risk register and reporting directly to the Trust. Biomedical Research Unit (BRU) is responsible for:  Ensuring that all research studies, including clinical and non-clinical interventions conducted within its facilities/ in the community by staff/visiting researchers are following Trust policies. The facilities include clinical, non-clinical and research laboratory areas.  Reporting health & safety concerns rising from the management of research that are serious and impact on business to the R&D Department.  Directly reporting to the Trust’s relevant governance meeting/s as required by those meetings (currently quarterly audits).  Keeping and maintaining the BRU risk register and reporting directly to the Trust. 4.20 Employees All employees have a responsibility to:  Take reasonable care of their own health and safety and that of others who may be affected by what they do or do not do  Co-operate with the Trust on Health and Safety issues  Not interfere with or misuse anything provided for their or other’s health, safety or welfare  Use any equipment, Personnel Protection Equipment (PPE), and procedures provided by the Trust, take reasonable care of it and to report any accidents, defects, damage, unsafe acts or conditions, near misses, or loss as soon as reasonably possible.  Be aware that willfully or intentionally interfering with or misusing equipment, procedures or safe systems of work will be subject to disciplinary action (See Trust Policy on Disciplinary procedures)  Read and understand the requirements of the Trust’s health and safety policies, other relevant safety procedures, risk assessments, local rules etc, and carry out work in accordance with these requirements Page 18 of 48  Ensure they report immediately any ill health, stress or other medical condition which may be work related or affect their ability to work safely  Ensure they attend any Health and Safety induction or training courses provided for them. 4.21 Trade Union and Staff-side Representatives Trade Union and Staff-side Health and Safety Representatives have the following responsibilities:  To represent Trust employees in consultation and co-operation with managers with a view to developing measures to ensure the health and safety at work of employees  To highlight potential hazards, risks and dangerous occurrences in the workplace (whether or not they are drawn to their attention by employees they represent) and to be proactive by assisting in preventing accidents and adverse incidents in the workplace  To investigate complaints by any employee whom they represent relating to that employee’s health, safety or welfare at work  To make representations to Trust management on any matter affecting the health and safety of employees in the workplace  To assist in Health and Safety audits when requested  To attend and contribute towards Health and Safety Committee meetings Recognised Trade Unions and Staff Organisations for the Trust are listed in Appendix A. It is the responsibility of each of the accredited Trades Unions and the Joint Staff Committee to inform the Corporate Health & Safety Committee, in writing, of their current health and safety representatives and any subsequent changes 4.22 Estates and Capital Developments The Estates Team are responsible for the management of the Estate which covers both new construction works and maintenance of existing assets. Activities related to working at height, roof work, use of cranes, internal flooring, external grounds & gardens and routine inspections, fall within the scope of areas highlighted in this policy. Estates and Capital Developments oversee construction work activity which is defined in detail in Regulation 2(1) of the Construction (Design and Management) Regulations 2015. 4.23 Serco (Cleaning and catering contractors) Serco, our cleaning and catering contractor, has a Health and Safety Policy which their employees must all adhere to. This policy includes the statement below: ‘ “Our work is never so urgent or important that we cannot take time to do it safely and with respect for the environment. Wherever we work, we are committed to the promotion of wellbeing and the prevention of injury, ill health and pollution including seeking to reduce the amount of carbon produced and the sustainable use of global resources, while reducing our waste through good waste management and recycling.” Page 19 of 48 4.24 All Contractors employed by the Trust All contractors and sub-contractors under the control of or employed directly or indirectly by the Trust must undertake their work in a safe manner. This work must be undertaken in accordance with statutory safety requirements and the Trust’s policies and procedures. Contractors and sub-contractors must fully co-operate with the guidance set out in the document Consultant’s and Contractor’s Handbook’ part of the contract documents issued prior to the commencement of any works. They must ensure that:  They and other self-employed persons (engaged on Trust business) assess and document the risks of their work and undertakings and make provision to protect themselves and others in respect of their own work activities.  That they are competent and authorised to carry out the required work and they have the supporting documentation to evidence this through risk assessments, safety plans and/or method statements, permits to work, etc  That all their employees (& sub-contractors) are appropriately informed, instructed and trained in health, safety and welfare related matters pertaining to their own and Trust work activities  That reasonable steps are taken to ensure co-operation and communication between all contractors and Trust staff and other relevant persons  That they report significant accidents and incidents to the Trust when undertaking their work and incidents that fall within Reporting of Injuries, Diseases and Dangerous Occurrences Regulations (RIDDOR)1995 which occur as a result of the contractor’s undertakings  That they provide safe access to and from their workplace for their own staff and all others affected by their undertakings and put in place provisions to deal with a fire and do nothing to compromise the fire systems and procedures already in place within the Trust 4.25 Volunteers and Charitable organisations Even though charity and voluntary workers generously give their time, work and expertise to the Trust, these people are regarded as honorary employees in the eyes of the law and as such are bound and protected by the same health and safety conditions as all other Trust staff. Charity or voluntary workers or any Trust manager or representative responsible for them must ensure that risk assessments of their activities are undertaken and the identified risks are managed 4.26 Health & Safety Management Framework  Quality Governance Steering Group (QGSG) The delegated committee for overseeing the compliance with this Policy and the operation of the Corporate Health and Safety Committee is the Quality Governance Steering Group which is accountable to the Trust Executive Committee and the Trust Board.  Corporate Health and Safety Committee In accordance with the Health and Safety at Work Act 1974, the Safety Representatives and Safety Committees Regulations 1977 and at the request of staff representatives, the Trust has a Corporate Health and Safety Committee which acts in accordance with the Approved Code of Practice as per the requirements of these Regulations. Page 20 of 48  The Corporate Health and Safety Committee sits within the Trust’s Quality Governance & Risk Committee structure and is a key part of the arrangements for managing health and safety issues in the Trust. The details of the functions and Terms of Reference of the Committee and the means of making contact with its members can be found on the Staffnet http://staffnet/WorkingHere/Staffhealthandsafety/Healthandsafetycommittees/Cor porateHealthandSafetyCommittee/CorporateHealthandSafetyCommittee.aspx 5 Related Trust Policies  Patient Safety Strategy  Risk Management Policy and Procedures  Incident Reporting, Analysis, Investigation and Management Policy  Fire Safety Management Policy  Moving and Handling of Loads Policy  Control of Substances Hazardous to Health (COSHH) Policy  Security Policy  Sharps Safety Policy  Lone Worker Policy  Patient Falls Policy – The Management and Prevention of falls  Waste Management Policy  Non-Ionising Radiations, Policy for the Safe Use of  Safe Use of Ionising Radiations Policy  Magnetic Resonance Imaging, Policy for the Safe Use of  All Occupational Health policies relating to Health and Safety  All other Estates policies and procedures relating to Health and Safety  Whistle Blowing Policy Page 21 of 48 6 Communication Plan 6.1 The Trust Health and Safety Policy will be displayed on the Staffnet. 6.2 The Trust Health and Safety Manager/Adviser will provide updated information to nominated care group leads at bi-monthly meetings. . 6.3 The nominated care group leads will disseminate health and safety information through departmental co-ordinators as appropriate and ensure that this information is passed onto all staff. 6.4 Health and Safety is included in the Trust Corporate induction programme held monthly for all new staff. 7 Process for Monitoring Compliance/Effectiveness Key aspects of the procedural document that will be monitored: Element of Policy to be monitored Completion by wards and departments of the H&S self audit tool Monitoring the requirement to undertake appropriate risk assessments Lead Tool/Method Frequency Who will Where results undertake will be reported The completed audit tools and action plans /completed Health & Safety Tour reports Risk assessments Weekly via Health & Safety Tours and on receipt of completed Health & Safety audit tools each March. During inspections, incident investigations and tours All Health and Safety audited areas annually During inspections, incident investigations and tours Corporate Health and Safety Team Health & Safety Team The Corporate Health and Safety Committee The Corporate Health and Safety Committee Where monitoring identifies deficiencies actions plans will be developed to address them. 8 Arrangements for Review of the Policy This policy will be reviewed and validated before the end of September 2019 or sooner if new evidence demonstrates need for a change to current practice. 9 References  The Health and Safety at Work etc Act 1974  Management of Health and Safety at Work Regulations 1999 (2002)  The Health and Safety Executive (HSE) http://www.hse.gov.uk/  Corporate Health and Safety Committee Terms of Reference Page 22 of 48  Safety Representatives and Safety Committees Regulations 1977 (as amended) and Health and Safety (Consultation with Employees) Regulations 1996 (as amended)  HSE-Slips trips and falls in the health service http://www.hse.gov.uk/pubns/hsis2.pdf  HSE-Preventing slips and trips at work http://www.hse.gov.uk/pubns/indg225.pdf  HSE-What causes slips and trips http://www.hse.gov.uk/slips/causes.htm  HSE-‘Falls from Height http://www.hse.gov.uk/falls/  HSE-‘Watch Your Step Campaign http://www.hse.gov.uk/watchyourstep/  HSE- ‘Slips Assessment Tool’ http://www.hse.gov.uk/slips/sat/index.htm Page 23 of 48 Trust Health and Safety Policy Appendix A – Trade Unions and Professional Organisations Appendix A The Trade Unions and Professional Organisations listed below are formally recognised by the Trust as being able to represent their members on individual issues, and for collective bargaining purposes: Association of Clinical Biochemists British Association of Occupational Therapists British Dental Association British Dietetic Association British Medical Association British Orthoptic Society Chartered Society of Physiotherapy Federation of Clinical Scientists General and Municipal Boilermakers Union Royal College of Midwives Royal College of Nursing Society of Chiropodists and Podiatrists Society of Radiographers Union of Construction, Allied Trades and Technicians UNISON UNITE THE UNION ACB BAOT BDA B Diet A BMA BOS CSP FCS GMB RCM RCN SOCP SoR UCATT UNISON UNITE Page 24 of 48 Trust Health and Safety Policy Appendix B – Generic Risk Assessment Form Appendix B - Generic Health & Saf
Url: /Media/UHS-website-2019/Docs/Policies/Health-and-safety-policy.pdf

ACCORD-2 master protocol

Description: CONFIDENTIAL ACCORD-2-001 – Master Protocol TITLE PAGE Protocol Title: ACCORD-2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients Master Protocol Number: ACCORD-2-001 Product: Multiple candidate agents Study Phase: 2 Sponsor Name: University Hospital Southampton NHS Foundation Trust Legal Registered Address: Southampton General Hospital Level E, Laboratory & Pathology Block, SCBR - MP138 Tremona Road Southampton SO16 6YD, UK Regulatory Agency Identifying Number(s): IRAS Number: RHM Number: EudraCT 2020-001736-95 282769 Date of Protocol: 22 April 2020 Version: Final Final, 22 April 2020 1 CONFIDENTIAL Chief Investigator Signatory: ACCORD-2-001 – Master Protocol I have read this protocol in its entirety and agree to conduct the study accordingly: Professor Tom Wilkinson MA Cantab MBBS PhD FRCP Professor of Respiratory Medicine and Honorary NHS Consultant Physician 22/04/2020 Date Final, 22 April 2020 2 CONFIDENTIAL ACCORD-2-001 – Master Protocol TABLE OF CONTENTS TABLE OF TABLES...............................................................................................................6 TABLE OF FIGURES.............................................................................................................7 1.0 PROTOCOL SUMMARY ..........................................................................................8 1.1 Synopsis.............................................................................................................8 1.2 Schema ............................................................................................................13 1.3 Example Schedule of Activities.....................................................................14 2.0 INTRODUCTION......................................................................................................18 2.1 Study Rationale ..............................................................................................18 2.2 Background ....................................................................................................18 2.3 Benefit/Risk Assessment ................................................................................19 3.0 OBJECTIVES AND ENDPOINTS ..........................................................................20 4.0 STUDY DESIGN........................................................................................................22 4.1 Overall Design ................................................................................................22 4.2 Scientific Rationale for Study Design...........................................................24 4.3 Justification for Dose .....................................................................................24 4.4 End of Study Definition .................................................................................24 5.0 STUDY POPULATION ............................................................................................25 5.1 Inclusion Criteria ...........................................................................................25 5.2 Exclusion Criteria ..........................................................................................25 5.3 Lifestyle Considerations ................................................................................26 5.4 Screen Failures ...............................................................................................26 6.0 STUDY TREATMENT .............................................................................................27 6.1 Study Treatment(s) Administered................................................................27 6.2 Preparation/Handling/Storage/Accountability ...........................................27 6.3 Measures to Minimise Bias: Randomisation and Blinding ........................28 6.4 Study Treatment Compliance.......................................................................28 6.5 Concomitant Therapy....................................................................................28 6.5.1 Rescue Medicine ...............................................................................29 6.6 Dose Modification ..........................................................................................29 6.7 Treatment after the End of the Study ..........................................................29 7.0 DISCONTINUATION OF STUDY TREATMENT AND PATIENT DISCONTINUATION/WITHDRAWAL ................................................................30 7.1 Discontinuation of Study Treatment ............................................................30 Final, 22 April 2020 3 CONFIDENTIAL ACCORD-2-001 – Master Protocol 7.2 Patient Discontinuation/Withdrawal from the Study.................................30 7.3 Lost to Follow-up ...........................................................................................30 8.0 STUDY ASSESSMENTS AND PROCEDURES ....................................................32 8.1 Efficacy Assessments .....................................................................................33 8.1.1 Improvement on the 9-Point Scale ....................................................33 8.1.2 Other Efficacy Assessments ..............................................................34 8.2 Safety Assessments.........................................................................................34 8.2.1 Physical Examinations.......................................................................34 8.2.2 Vital Signs and Blood Gases .............................................................34 8.2.3 Clinical Safety Laboratory Assessments ...........................................35 8.3 Virologic Load ................................................................................................35 8.4 Adverse Events ...............................................................................................35 8.4.1 Time Period and Frequency for Collecting AE and SAE Information ........................................................................................35 8.4.2 Method of Detecting AEs and SAEs .................................................36 8.4.3 Follow-up of AEs and SAEs .............................................................36 8.4.4 Regulatory Reporting Requirements for SAEs .................................36 8.4.5 Pregnancy ..........................................................................................37 8.4.6 Adverse Events of Special Interest ....................................................37 8.4.7 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as Adverse Events or Serious Adverse Events.........37 8.5 Treatment of Overdose..................................................................................37 8.6 Pharmacokinetics ...........................................................................................37 8.7 Pharmacodynamics........................................................................................38 8.8 Immunology....................................................................................................38 8.9 Genomics.........................................................................................................38 8.10 Serology Research (Host Response) .............................................................39 9.0 STATISTICAL CONSIDERATIONS .....................................................................39 9.1 Design Overview.............................................................................................39 9.2 Statistical Hypotheses ....................................................................................39 9.3 Sample Size Determination ...........................................................................40 9.4 Populations for Analyses ...............................................................................42 9.5 Statistical Analyses.........................................................................................42 9.5.1 Efficacy Analyses ..............................................................................43 9.5.2 Safety Analyses .................................................................................43 9.5.3 Other Analyses ..................................................................................44 9.5.4 Missing Data......................................................................................44 9.6 Interim Analyses ............................................................................................45 9.7 Review Committees........................................................................................45 9.7.1 Steering Committee (Scientific Review Committee) ........................45 9.7.2 Independent Data and Safety Monitoring Committee.......................45 Final, 22 April 2020 4 CONFIDENTIAL ACCORD-2-001 – Master Protocol 10.0 REFERENCES...........................................................................................................47 11.0 APPENDICES ............................................................................................................48 Appendix 1 Abbreviations ...................................................................................49 Appendix 2 Regulatory, Ethical, and Study Oversight Considerations..........51 Protocol Compliance........................................................................................51 Regulatory and Ethical Considerations............................................................51 Financial Disclosure.........................................................................................52 Indemnity .........................................................................................................52 Informed Consent Process ...............................................................................52 Data Protection.................................................................................................53 Administrative Structure ..................................................................................54 Dissemination of Clinical Study Data..............................................................54 Data Quality Assurance ...................................................................................54 Source Documents ...........................................................................................55 Study and Study Centre Closure ......................................................................55 Publication Policy ............................................................................................56 Appendix 3 Clinical Laboratory Tests ...............................................................57 Appendix 4 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting .....................................59 Appendix 5 Collection of Pregnancy Information ............................................63 Appendix 6 Genetics ............................................................................................65 Appendix 7 Signature of Investigator ................................................................66 Final, 22 April 2020 5 CONFIDENTIAL ACCORD-2-001 – Master Protocol Table 1 Table 2 Table 3 Table 4 Table 5 TABLE OF TABLES Study Objectives and Endpoints ......................................................................20 Sample Size for 80% and 90% Power for Time to Improvement, Discharge from Hospital, or Fit for Discharge Using Log-rank Test for a Hazard Ratio of 1.6 in Treatment Arm to Standard of Care ...................41 Analysis Sets ....................................................................................................42 Efficacy Analyses ............................................................................................43 Protocol-required Safety Laboratory Assessments..........................................58 Final, 22 April 2020 6 CONFIDENTIAL ACCORD-2-001 – Master Protocol Figure 1 TABLE OF FIGURES Study Schema...................................................................................................13 Final, 22 April 2020 7 CONFIDENTIAL ACCORD-2-001 – Master Protocol 1.0 PROTOCOL SUMMARY 1.1 Synopsis Protocol Title: ACCORD-2: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients Rationale: There are currently no approved therapeutic agents available to treat coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. Objectives and Endpoints Objectives Primary • Stage 1: To evaluate the efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. • Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID-19 in an expansion stage. Endpoints • Time to clinical improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). 9-point category ordinal scale: 0. Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalised – mild disease, no oxygen therapy 4. Hospitalised – mild disease, oxygen by mask or nasal prongs 5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death Final, 22 April 2020 8 CONFIDENTIAL ACCORD-2-001 – Master Protocol Secondary • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points • The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, 22, and 29. • To evaluate the number of oxygen-free days. • Duration (days) of oxygen use and oxygen-free days. • To evaluate ventilator-free days and incidence and • Duration (days) of ventilation and ventilation-free duration of any form of new ventilation use. days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. • To evaluate SARS-CoV-2 viral load. • Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 • To evaluate response rate (see primary endpoint for definition of responder). • Response rate (number and %) by treatment arm at Days 2, 8, 15, 22, and 29. • To evaluate time to discharge. • Time to live discharge from the hospital. • To evaluate overall mortality. • Mortality at Days 15, 29, and 60. • Time from treatment start date to death. • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2), • SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death • To evaluate the safety of candidate agents as • Physical examination. add-on therapy to SoC in patients with COVID-19. • Clinical laboratory examinations. • Vital signs (blood pressure/heart rate/temperature/respiratory rate). • Adverse events. • To evaluate intensive care unit (ICU) and hospitalisation length. • Duration (days) of ICU and hospitalisation. • To evaluate National Early Warning Score 2 (NEWS2). • NEWS2 assessed daily while hospitalised and on Days 15 and 29. • Time to a NEWS2 of ≤2, maintained for at least 24 hours. Final, 22 April 2020 9 CONFIDENTIAL ACCORD-2-001 – Master Protocol Exploratory • To evaluate SARS-CoV-2 viral load. • Qualitative and quantitative PCR determination of SARS-CoV-2 in blood and saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 (may be become a secondary endpoint once the assays are available). • To collect samples for translational research on • Analysis of samples collected at baseline prior to host and viral genomics, serum antibody treatment and at specific time points. production, COVID-19 diagnostics, and validation of laboratory testing methods. Overall Design: ACCORD-2 is a seamless, Phase 2, adaptive, randomisation platform study, designed to rapidly test candidate agents in the treatment of COVID-19 disease. The study will include hospitalised adult patients (≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised – mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, noninvasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale. This study will aim to identify efficacious candidate agents for treatment of COVID-19 disease. These candidate agents may include, but will not be limited to, anti-virals, human plasma-derived agents, or immunomodulatory agents. Experimental (first-in-human) agents will not be considered as candidate agents for ACCORD-2, but will instead be considered for inclusion in the separate, but linked, ACCORD-1 Phase 1/2 platform study, which will first determine the dose and assess early activity and safety signals for later consideration for inclusion into ACCORD-2. The ACCORD-2 candidate agents evaluated will include those intended as a treatment for SARS-CoV-2 infection; the study design and/or inclusion and exclusion criteria may subsequently be revised (using a protocol amendment) or a separate protocol may be initiated to include agents intended to prevent COVID-19 disease. This Master Protocol outlines the overall structure of the study, including the population, inclusion and exclusion criteria, randomisation scheme, primary, secondary, and exploratory outcomes, study design, statistical methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is structured such that multiple candidate agents from different pharmaceutical companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, and to remove therapies once they have completed their evaluation, with the control group for a candidate agent including only patients randomised during the period in which the candidate agent group was randomised, with patients being randomised equally (ie, 1:1:1…) to the sub-protocols with inclusion/exclusion criteria that they meet. Sub-protocols will outline the scientific rationale, eligibility, treatment schema, and other specifics for each candidate agent. The sub-protocols may define adverse events of special interest (AESIs), and can include pharmacokinetic and/or pharmacodynamic assessments that are appropriate for the specific candidate agent (pharmacodynamic assessments may require equivalent blood samples from controls). The study consists of 2 stages: • Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add-on to the standard of care (SoC) to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29. The time to response will be analysed on Day 29 and used to evaluate if an agent should proceed to Stage 2 of the Final, 22 April 2020 10 CONFIDENTIAL ACCORD-2-001 – Master Protocol study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. • Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe adverse events (AEs), overall AEs, disease-related co-infection complications (eg, pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2. Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2. Patients will be randomised to receive one of the candidate agents that is being evaluated at the time of randomisation and whose inclusion/exclusion criteria they meet (as an add-on to SoC) or to a control arm where only SoC is administered. Enrolment of patients will be continuous throughout the study for each candidate agent until the total randomisation number of planned patients for Stage 1 and Stage 2 is achieved. Enrolment under a sub-protocol for a specific candidate agent may also be stopped in the event of success or failure of the candidate agent. The Master Protocol will continue enrolling patients as long as there are candidate agents that are enrolling. Number of Investigators and Study Centres: Study centres will be located in the United Kingdom. Overall, it is estimated that approximately 18 centres and investigators will initially take part in the study. Number of Patients: The expected number of patients for each treatment arm is presented as part of the sample size determination below. It is estimated that up to 1800 patients will participate in the overall study. Treatment Groups and Duration: In each stage of the study, patients will be screened on Day -1 or Day 1, and will remain in the clinic from Day 1 until fit for discharge. Dosing with the candidate agent (as an add-on to SoC) will commence on Day 1. The last day of assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with an end-of-study visit conducted on Day 90 (±6 days). Statistical methods: Sample size determination: Stage 1: Based on the chosen endpoint, a preliminary analysis will be carried out when an estimated 81 events have been observed across each agent treatment and SoC or 28 days after the last patient has been randomised, whichever occurs sooner, as determined by the Independent Data and Safety Monitoring Committee (IDMC). In order to achieve this number of events, it is expected that 54 patients are needed per arm, which will provide 80% power to detect a hazard ratio of 1.6 for the occurrence of the event, when comparing each candidate agent with SoC. To allow for uncertainty in the recruitment rates, it is expected that up to 60 patients will be randomised to each arm in order to achieve the required number of events for the preliminary analysis. Stage 2: The number of patients will be determined more precisely at the end of Stage 1, but approximately 126 patients will be randomised to each arm. Analysis sets: • Intention to Treat (ITT): All patients who are randomised and match the inclusion/exclusion criteria of the Master Protocol and relevant sub-protocol will be included in the ITT. • Safety Set: All patients who are randomised and take at least 1 dose of study medication will be included in the safety set. Final, 22 April 2020 11 CONFIDENTIAL ACCORD-2-001 – Master Protocol • Pharmacokinetic Analysis Set (PKS): All patients who are randomised and take at least 1 dose of the candidate agent and have quantifiable candidate agent concentrations postdose without protocol deviations or events affecting the pharmacokinetic results will be included in the PKS. • Pharmacodynamic Analysis Set (PDS): All patients who are randomised and take at least 1 dose of study medication (candidate agent or SoC) and have evaluable results for at least 1 pharmacodynamic endpoint postdose. All analyses of the PDS will be based on each patient’s randomised assigned treatment (not actual treatment received). Efficacy, safety, pharmacokinetic, and pharmacodynamic results will be listed and summarised by stage, dose, and scheduled time for the respective analysis sets, where appropriate. Candidate agent concentration versus response variables may be graphically displayed for selected endpoints. Exposure-response data obtained from this study may be combined with data from other studies and used for modelling and simulations. Data Monitoring Committee: A Steering Committee will evaluate interim analysis data to make decisions on further progression of the candidate agents within the study, and will provide guidance, advice, and recommendations to the ACCORD program on relevant clinical issues related to the strategy, implementation, and conduct of the study. An IDMC will objectively monitor safety data throughout the study to make recommendations to the Steering Committee regarding study conduct. Final, 22 April 2020 12 CONFIDENTIAL 1.2 Schema Figure 1 Study Schema ACCORD-2-001 – Master Protocol IA=interim analysis; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SoC=standard of care. Note: This figure shows a hypothetical situation, where in Stage 1 of the study there are 4 candidate agents being compared with the SoC, of which 2 candidate agents progress to Stage 2. Final, 22 April 2020 13 CONFIDENTIAL ACCORD-2-001 – Master Protocol 1.3 Example Schedule of Activities Screening Baseline Day (± Window) ELIGIBILITY Informed consent Demographics Relevant medical historyb Review of SARS-CoV-2 diagnostic tests Inclusion and exclusion criteria 12-lead Electrocardiogram STUDY INTERVENTION Randomisation Administration of candidate agent Treatment with SoC STUDY PROCEDURES Clinical frailty score Diagnostic imaging (X-ray and/or computed tomography) Physical examination (including presenting symptoms, height, weight) Targeted physical examination (focused on lung auscultation) Vital signs, including oral temperature, pulse rate, blood pressure, respiratory rate, SpO2 Day -1 or Day 1 X X X X X X X X X Day 1 X X Xc Daily Until Hospital Discharge Day 15a (±2 days) Defined in subprotocol X X X X Day 29a (±3 days) X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Final, 22 April 2020 14 CONFIDENTIAL ACCORD-2-001 – Master Protocol Screening Baseline Day (± Window) Clinical assessmentsd Targeted medication review (including use of vasopressors) Adverse event evaluation Disease-related co-infection evaluation (including microbiologic/infectious agent assessment/results; bacteria, viral, fungi) Survival status Blood gases and FiO2 at worst PO2e SAFETY LABORATORY Haematology, chemistry, liver function tests, coagulationf Day -1 or Day 1 X Xg Day 1 Xc Xc X X X X Xc,h Pregnancy test for females of childbearing potential Xg RESEARCH LABORATORY Blood (SST) for exploratory inflammatory cytokine analysis X (others to be defined in sub-protocols) Blood (sodium heparin tube) for PBMC phenotypingi X Blood (EDTA) for SARS-CoV-2 PCR (qualitative and quantitative) X Daily Until Hospital Discharge X X X X X X Days 3, 5, 8, 11 (all ±1 day) while hospitalised Day 8 Day 8 Days 3, 5, 8, 11 (all ±1 day) while hospitalised Day 15a (±2 days) X X X X X X X X Day 29a (±3 days) X X X Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) X X X X X X X X Final, 22 April 2020 15 CONFIDENTIAL ACCORD-2-001 – Master Protocol Screening Baseline Day (± Window) Day -1 or Day 1 Day 1 Daily Until Hospital Discharge Day 15a (±2 days) Day 29a (±3 days) Day 60a Day 90a (±4 days) (±6 days) (Follow-up) (End of Study) Oropharyngeal/nasal swab for SARS-CoV-2 PCR (qualitative and quantitative) Days 3, 5, 8, 11 (all X ±1 day) while X X hospitalised Saliva for SARS-CoV-2 PCR (qualitative and quantitative) Days 3, 5, 8, 11 (all X ±1 day) while X X hospitalised Blood (SST) for SARS-CoV-2 serology research (host response) X Day 8 X X X Blood (PAXGENE) for transcriptome analysis (host genome)j X Day 8 X Blood (EDTA) host genome (host DNA)j X Mid-turbinate nasal swab viral genomej X EDTA=ethylenediaminetetraacetic acid; FiO2=fraction of inspired oxygen; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; PO2=partial pressure of oxygen; RT PCR=reverse transcription polymerase chain reaction; SARS-CoV-2= severe acute respiratory syndrome coronavirus 2; SoC=standard of care; SpO2=oxygen saturation; SST=serum separator tube. Note: Additional assessments, if required, will be defined in the sub-protocol. a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, in-person visits are preferred, but recognising that quarantine and other factors may limit the patient’s ability to return to the clinic, these visits may be conducted by telephone or with a home visit by study staff. For visits conducted by telephone, it will not be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will also be performed, where possible, for patients who discontinue the study prematurely. b Medical history includes estimated date and time of first symptoms and number of co-morbidities (eg, respiratory, cardiovascular, metabolic, malignancy, endocrine, gastrointestinal, immunologic, renal). c Baseline assessments should be performed prior to study drug administration. d Includes ordinal score, National Early Warning Score 2 (NEWS2), oxygen requirement, noninvasive or invasive ventilator requirement, including start and stop of low- or high-flow oxygen supply or of any form of ventilation etc. e If done as part of SoC, blood gases results to be fully recorded with date and time. f For parameters, see Table 5. Final, 22 April 2020 16 CONFIDENTIAL ACCORD-2-001 – Master Protocol g Laboratory tests performed in the 48 hours prior to enrolment will be accepted for determination of eligibility. h Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. i Samples collected for immediate laboratory processing and frozen storage. j Samples collected dependent on capacity of study centre, need for reduced study burden on staff, and potentially limited access to patients. Final, 22 April 2020 17 CONFIDENTIAL ACCORD-2-001 – Master Protocol 2.0 INTRODUCTION 2.1 Study Rationale There are currently no approved therapeutic agents available to treat coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. 2.2 Background Coronaviruses are single-stranded RNA viruses, capable of causing life-threatening disease in humans and animals. The novel coronavirus SARS-CoV-2 was initially identified during an outbreak of viral pneumonia cases of unknown cause in China. Most of the initial infections outside of China were travel associated (ie, from people who had travelled from the infected regions of China to other countries), although person-to-person transmission in other countries was quickly established. The disease caused by the SARS-CoV-2 virus has been designated COVID-19. SARS-CoV-2 binds via the angiotensin-converting enzyme (ACE) receptor located on alveolar cells and intestinal epithelia.1 The virus is mutating, indicating that virulence and transmission will shift over time, and showing diversity in critical surface protein. New evidence suggests there are 2 groups of SARS-CoV-2; L-type and S-type.2 S-type is the less aggressive (30%); the L-type is now the most prevalent version (70%) and is more aggressive. Additionally, individuals appear to be affected to different degree with varying symptoms and outcomes. These findings strongly support an urgent need for immediate comprehensive studies and robust validation of testing methods that combine genomic data, chart records and clinical symptoms, to help better understand the disease, enable risk assessment, triage and support public health resource planning. Due to the rapid global widespread of SARS-CoV-2, there is an urgent need to develop efficacious treatments for the disease. Current clinical studies involve the use of already approved medications for other indications (repurposing) where it is thought that they might also be effective in the treatment of COVID-19 disease, as well as development of antibody-based therapies against the virus. Final, 22 April 2020 18 CONFIDENTIAL ACCORD-2-001 – Master Protocol This platform study will test multiple candidate agents, with the aim of identifying potentially efficacious treatments in the shortest timeframe possible. In addition, it will support secondary research objectives that are critical for understanding the disease, spread of infection and robust tests to track it. 2.3 Benefit/Risk Assessment There are currently no approved therapeutic agents available to treat coronaviruses such as SARS-CoV-2, and so while there may not be benefits for an individual patient participating in this study, there may be benefits to society if a safe and efficacious therapeutic agent can be identified during the global COVID-19 outbreak. Detailed information about the known and expected risks and reasonably expected adverse events (AEs) of each candidate agent may be found in the corresponding sub-protocol for that agent. Final, 22 April 2020 19 CONFIDENTIAL ACCORD-2-001 – Master Protocol 3.0 OBJECTIVES AND ENDPOINTS Table 1 Study Objectives and Endpoints Objectives Primary • Stage 1: To evaluate the efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. • Stage 2: To confirm the efficacy of identified efficacious candidate agents in patients hospitalised with COVID-19 in an expansion stage. Secondary • To evaluate the ability to prevent deterioration according to the ordinal scale by 1, 2, or 3 points • To evaluate the number of oxygen-free days. • To evaluate ventilator-free days and incidence and duration of any form of new ventilation use. • To evaluate SARS-CoV-2 viral load. Endpoints • Time to clinical improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). 9-point category ordinal scale: 0. Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalised – mild disease, no oxygen therapy 4. Hospitalised – mild disease, oxygen by mask or nasal prongs 5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 8. Death • The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, 22, and 29. • Duration (days) of oxygen use and oxygen-free days. • Duration (days) of ventilation and ventilation-free days. • Incidence of any form of new ventilation use and duration (days) of new ventilation use. • Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 Final, 22 April 2020 20 CONFIDENTIAL ACCORD-2-001 – Master Protocol • To evaluate response rate (see primary endpoint for definition of responder). • Response rate (number and %) by treatment arm at Days 2, 8, 15, and 29. • To evaluate time to discharge. • Time to live discharge from the hospital. • To evaluate overall mortality. • Mortality at Days 15, 29, and 60. • Time from treatment start date to death. • Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2), • SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death • To evaluate the safety of candidate agents as • Physical examination. add-on therapy to SoC in patients with COVID-19. • Clinical laboratory examinations. • Vital signs (blood pressure/heart rate/temperature/respiratory rate). • Adverse events. • To evaluate intensive care unit (ICU) and hospitalisation length. • Duration (days) of ICU and hospitalisation. • To evaluate National Early Warning Score 2 (NEWS2). • NEWS2 assessed daily while hospitalised and on Days 15 and 29. • Time to a NEWS2 of ≤2, maintained for at least 24 hours. Exploratory • To evaluate SARS-CoV-2 viral load. • Qualitative and quantitative PCR determination of SARS-CoV-2 in blood and saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 15, and (optional) Day 29 (may be become a secondary endpoint once the assays are available). • To collect samples for translational research on • Analysis of samples collected at baseline prior to host and viral genomics, serum antibody treatment and at specific time points. production, COVID-19 diagnostics, and validation of laboratory testing methods. Final, 22 April 2020 21 CONFIDENTIAL ACCORD-2-001 – Master Protocol 4.0 STUDY DESIGN 4.1 Overall Design ACCORD-2 is a seamless, Phase 2, adaptive, randomisation platform study, designed to rapidly test candidate agents in the treatment of COVID-19 disease. The study will include hospitalised adult patients (≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or validated point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised - mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, noninvasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale, which was detailed in the World Health Organization R&D Blueprint “Novel Coronavirus - COVID-19 Therapeutic Trial Synopsis” (February 2020). Medical history will record the estimated date and time of first symptoms. This study will aim to identify efficacious candidate agents for treatment of COVID-19 disease. These candidate agents may include, but will not be limited to, anti-virals, human plasma-derived agents, or immunomodulatory agents. Experimental (first-in-human) agents will not be considered as candidate agents for ACCORD-2, but will instead be considered for inclusion in the separate, but linked, ACCORD-1 Phase 1/2 platform study, which will first determine the dose and assess early activity and safety signals for later consideration for inclusion into ACCORD-2. The ACCORD-2 candidate agents evaluated will include those intended as a treatment for SARS-CoV-2 infection; the study design and/or inclusion and exclusion criteria may subsequently be revised (using a protocol amendment) or a separate protocol may be initiated to include agents intended to prevent COVID-19 disease. A Steering Committee will evaluate candidate agents for progression in the study (see Section 9.7.1). This Master Protocol outlines the overall structure of the study, including the population, inclusion and exclusion criteria, randomisation scheme, primary, secondary, and exploratory outcomes, study design, statistical methodology, and planned analyses that are common for all candidate agents to be tested. The Master Protocol is structured such that multiple candidate agents from different pharmaceutical companies can be evaluated simultaneously. The plan is to add candidate agents as they are identified, and to remove therapies once they have completed their evaluation, with the control group for a candidate agent including only patients randomised during the period in which the candidate agent group was randomised, with patients being randomised equally (ie, 1:1:1…) to the sub protocols with inclusion/exclusion criteria that they meet. Sub-protocols will outline the scientific rationale, eligibility, treatment schema, and other specifics for each candidate agent. The sub-protocols may define adverse events of special interest (AESIs), and can include pharmacokinetic and/or pharmacodynamic assessments that are appropriate for the specific candidate agent (pharmacodynamic assessments may require Final, 22 April 2020 22 CONFIDENTIAL ACCORD-2-001 – Master Protocol equivalent blood samples from controls). Additional patients will be recruited into the study each time a new sub-protocol (candidate agent) is added. The study consists of 2 stages: • Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add-on to the standard of care (SoC) to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9-point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29. The time to response will be analysed on Day 29 and used to evaluate if an agent should proceed to Stage 2 of the study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. • Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe AEs, overall AEs, disease-related co-infection complications (eg, pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2. Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2. Patients will be randomised to receive one of the candidate agents that is being evaluated at the time of randomisation and whose inclusion/exclusion criteria they meet (as an add-on to SoC) or to a control arm where only SoC is administered. In each stage of the study, patients will be screened on Day -1 or Day 1, and will remain in the clinic from Day 1 until fit for discharge. Dosing with the candidate agent (as an add-on to SoC) will commence on Day 1. The last day of assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with an end-of-study visit conducted on Day 90 (±6 days). Enrolment of patients will be continuous throughout the study for each candidate agent until the total randomisation number of planned patients for Stage 1 and Stage 2 is achieved. Enrolment under a sub-protocol for a specific candidate agent may also be stopped in the event of success or failure of the candidate agent. The Master Protocol will continue enrolling patients as long as there are candidate agents that are enrolling. It is estimated that up to 1800 patients will participate in the overall study. Study centres will be located in the United Kingdom. Overall, it is estimated that approximately 18 centres and investigators will initially take part in the study. Final, 22 April 2020 23 CONFIDENTIAL ACCORD-2-001 – Master Protocol 4.2 Scientific Rationale for Study Design There are currently no approved therapeutic agents available to treat coronaviruses such SARS-CoV-2, the causative agent of as COVID-19 disease, and there is an urgent public health need for rapid development of such interventions. This adaptive platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19. Candidate drugs that are initially assessed as being efficacious will be moved from an evaluation (pilot) stage to a confirmatory stage, with candidate agents being added to and removed from the study on an ongoing basis, depending on the results of their evaluation. Patients to be included in the study will be hospitalised and may require either supplemental oxygen, noninvasive ventilation or high-flow oxygen devices. This study utilises an adaptive design that maximises efficiency in identifying a safe and efficacious therapeutic agent for COVID-19. Some candidate agents may be in limited supply and this study design enables continuation of the study even if an agent becomes unavailable. In addition, the adaptive design allows for the evaluation of new candidate agents as they are identified. 4.3 Justification for Dose Justification for the dose of each candidate agent will be included in the corresponding sub-protocol. 4.4 End of Study Definition For each sub-protocol, the end of the study for that candidate agent will be defined as the date on which the last patient completes the last visit for that sub-protocol. For the overall study, the end of the study will be defined as the date on which the last patient completes the last visit for the final sub-protocol to be concluded. Once a patient has completed this study, there are no restrictions on them entering another study, subject to the eligibility criteria of that subsequent study. Final, 22 April 2020 24 CONFIDENTIAL ACCORD-2-001 – Master Protocol 5.0 STUDY POPULATION Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as protocol waivers or exemptions, is not permitted. The inclusion and exclusion criteria listed below may be supplemented by additional criteria stipulated in the sub-protocols that are specific to the target candidate being tested (eg, criteria related to prohibited medications). In order to enrol, a patient or legally authorised representative must sign an informed consent form (ICF) and meet all entry criteria for both the Master Protocol and at least 1 respective sub-protocol. 5.1 Inclusion Criteria Patients are eligible to be included in the study only if all of the following criteria apply (as well as all criteria from the appropriate sub-protocol): 1. Adults (≥18 years) with SARS-CoV-2 infection confirmed by laboratory tests and/or point of care tests. 2. A score of Grade 3 to 5 on the 9-point ordinal scale. 3. Is a woman who is not of childbearing potential (as defined in Appendix 5) or The patient, and their partner(s), agree to use medically-accepted double-barrier methods of contraception (eg, barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study and for at least 6 weeks after termination of study therapy. 4. Ability to provide informed consent signed by the study patient or legally authorised representative. 5.2 Exclusion Criteria Patients are excluded from the study if any of the following criteria apply (or any of the criteria from the appropriate sub-protocol): 1. Patients who have previously had a score of 6 or 7 on the 9-point ordinal scale. 2. Any patient whose interests are not best served by study participation, as determined by a senior attending clinician. 3. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 5 × the upper limit of normal (ULN). 4. Known active infection with HIV or hepatitis B or C. 5. Stage 4 severe chronic kidney disease or requiring dialysis (ie, estimated glomerular filtration rate 500 ms. 8. Anticipated transfer to another hospital that is not a study centre within 72 hours. 9. Allergy to any study medication. 10. Experimental off-label usage of medicinal products as treatments for COVID-19. 11. Patients participating in another clinical study of an investigational medicinal product. 5.3 Lifestyle Considerations Any lifestyle considerations that are specific to the candidate agent will be defined in the corresponding sub-protocol. Female patients are advised to avoid becoming pregnant during the study. 5.4 Screen Failures Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently randomly assigned to study treatment. A minimal set of screen failure information is required to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). Individuals who do not meet the criteria for participation in this study (screen failure) due to hypokalaemia, hypomagnese
Url: /Media/Southampton-Clinical-Research/COVID-19/ACCORD/ACCORD-2-master-protocol.pdf

Annual-report-24-25-final

Description: 2024/25 Incorporating the quality account University Hospital Southampton NHS Foundation Trust Annual Report and Accounts 2024/25 Presented to Parliament
Url: /Media/UHS-website-2019/Docs/About-the-Trust/Annual-reports-and-quality-accounts/Annual-report-24-25-final.pdf

UHS AR 23-24 Final

Description: 2023/24 Incorporating the quality account University Hospital Southampton NHS Foundation Trust Annual Report and Accounts 2023/24 Presented to Parliament
Url: /Media/UHS-website-2019/Docs/About-the-Trust/Annual-reports-and-quality-accounts/UHS-AR-23-24-Final.pdf

UHS AR 22-23-6

Description: 2022/23 Incorporating the quality account University Hospital Southampton NHS Foundation Trust Annual Report and Accounts 2022/23 Presented to Parliament
Url: /Media/UHS-website-2019/Docs/About-the-Trust/Annual-reports-and-quality-accounts/UHS-AR-22-23-6.pdf

Annual report 2021-2022

Description: 2021/22 Incorporating the quality report University Hospital Southampton NHS Foundation Trust Annual Report and Accounts 2021/22 Presented to Parliament
Url: /Media/UHS-website-2019/Docs/About-the-Trust/Annual-reports-and-quality-accounts/Annual-report-2021-2022.pdf

1 to 9 of 9

Browse site A to Z

Search results

STHW841-V1-Biomerieux-Blood-culture-guidance

cancer-genetics-referral-guidelines

Prof Tom Wilkinson, research lead for airways diseases

Health and safety policy

ACCORD-2 master protocol

Annual-report-24-25-final

UHS AR 23-24 Final

UHS AR 22-23-6

Annual report 2021-2022

Site policies

Contact details

Useful links