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Papers Trust Board - 30 January 2020

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Date Time Location Chair Apologies Agenda Trust Board – Open Session 30/01/2020 9:00 - 11:45 Conference Room, Heartbeat Education
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/Media/UHS-website-2019/Docs/About-the-Trust/Trust-governance-and-corporate-docs/2020/Papers-Trust-Board-30-January-2020.pdf

BEACON protocol v8.0 07Mar2023 signed

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A randomised phase IIb trial of BE AC v izumab added to Temozolomide O ± Irin tecan for children with N refractory/relapsed euroblastoma Version 8.0 dated 07-Mar-2023 Dinutuximab beta amendment Coordinating Sponsor: Sponsor Protocol Number: CAS Code: EudraCT Number: ISRCTN Reference Number: ITCC Number: Roche Study Reference Number: Email: University of Birmingham RG_ 11-087 BN2008 2012-000072-42 40708286 032 MO28245 beacon@trials.bham.ac.uk This application is supported by the facilities funded through Birmingham Science City: Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) funded project which forms part of the Science City University of Warwick and University of Birmingham Research Alliance. BEACON-Neuroblastoma Protocol_vn 8.0_vd 07Mar2023 Page1 of 157 BEACON-Neuroblastoma Trial Protocol AMENDMENTS The following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved version Amendment Date of number amendment Protocol version number Type of amendment SA 1 29-Jan-2013 2.0 Substantial Amendment N/A 23-Apr-2013 2.0a Non-Substantial Amendment N/A 01-Jul-2013 2.0b Non-Substantial Amendment Summary of amendment Introduction of the recommendation of weekly monitoring of blood counts for all patients receiving irinotecan. Addition of planned vaccination with live vaccination to exclusion criteria and prohibited medications section. ITCC Number has been corrected. Roche Study Reference Number and ISRCTN Reference Number have been added. Contact details for Plasma & Tumour Angiogenesis-Related Biomarkers have been amended. Table numbers have been corrected. Addition of guidance for research bone marrow sampling in Schedule of Activities table and sections 7.4.2.2 and 7.5.2. Addition of paragraph to sections 7.2, 7.6.1 – 7.6.4 detailing arrangements for handling dose modifications for Irinotecan + Temozolomide for patients receiving Bevacizumab. Discontinuation rules for osteonecrosis of the jaw and eye disorders added to table 13 in section 7.6.4. Correction to table number references in section 7.6.3. Clarification made in section 13.4.1 concerning Planned Interim Analysis. SA 3 06-Oct-2014 4.0 Substantial Amendment Changes to the Trial Personnel section of the protocol to include the addition of contact details for Denmark and Ireland Lead Investigators. Amendments to reflect the changes in study sampling requirements to Trial Synopsis, Schedule of Activities table and sections 1.2.6, 2.1, 2.2, 5.1, 5.2, 7.3, 7.4.2 and 7.5. Amendment to exclusion criteria in Trial Synopsis and section 4.2. Changes to the Schedule of Activities table to include the addition of an echocardiogram to be performed at screening and Tanner staging at screening and yearly in follow up. Changes to the time line for measuring renal function prior to commencing treatment in the Trial Synopsis, Schedule of Activities and section 4.1. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 3 of 157 BEACON-Neuroblastoma Trial SA 4 06-Oct-2014 4.0 SA 5 30-Jul-2015 5.0 Substantial Amendment Substantial Amendment Protocol Option to fax emergency randomisation removed. Telephone only in section 6.2 Changes to guidelines in section 7.2 for dose calculation in patients whose weight exceeds the 98th centile for age. Removal of enhanced data collection for Adverse Events of Special Interest (AESI) in section 7.6 and 9.1.2. Addition of option to extend treatment delay with agreement from Sponsor in Section 7.6.1 Addition of necrotising fasciitis as an adverse event requiring bevacizumab discontinuation in section 7.6.4. Changes to section 7.10 concerning the documenting of concomitant medications in patient medical notes and administration of bisphosphonates. Changes to section 9.1 regarding reporting of laboratory adverse events. Clarification on the arrangements for Follow Up Form completion for patients who do not require further follow up visits in section 11. Changes to bevacizumab and irinotecan preparation and dispensing guidelines in sections 8.2.4 and 8.3.3. Clarification on fasting arrangements prior to temozolomide administration added to section 8.4.3. Changes to events that should be reported on an Expected SAR Form in section 9.1.3.1. Clarification on SAEs that should be reported to F.Hoffman-La Roche Ltd in section 9.2.6 Addition of Trial Management Group meeting frequency in section 14.4. Changes to the wording of irinotecan randomisation in section 13.4.2. Addition of guidelines for dose reduction and discontinuation of temozolomide for liver toxicity in tables 8, 9, 10 & 11. Reference to the National Coordinating Centres has been changed to National CoSponsor throughout. Reference to Sponsor has been changed to Coordinating Sponsor. Change of Chief Investigator to Professor Pamela Kearns. Change of Principal Investigator at Royal Marsden Hospital to Dr Sucheta Vaidya. No changes made to the Protocol version. Chief Investigator and UK Lead Investigator changed to Dr Lucas Moreno Switzerland details added Schedule of events table amended for End Of Treatment clarity BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 4 of 157 BEACON-Neuroblastoma Trial N/A 23-Sep-2015 5.0a SA 6 16-Jan-2019 6.0a Protocol Topotecan added to the study as a new trial question and 2 new randomisation arms. The following sections are amended accordingly: Synopsis (Primary Objectives, sample size, Trial Duration, Trial therapy) Section 1 Background and rationale (Trial rationale) Section 3 Trial design (Randomisation) Section7.1 and 7.2 Treatment details Section7.6.1 Dose modifications Table 6 amended, Tables 11 and 12 added Section 8.4 Pharmaceutical Information Section 13 Statistical considerations The following changes were made to the Eligibility: Inclusion criteria – further details regarding birth control Exclusion criteria – Defined wash out period following prior IMP according to IMP half-life or 14 days. Lifestyle guidelines - further details regarding birth control Section 7.6 Dose modifications Figure 1 – reference to “chemo” changed to Temozolomide/Irinotecan/Topotecan” for clarity Section 8.2.4 Reference to “chemo” removed for clarity Section 7.6.4 AEs requiring Bevacizumab discontinuation – additional AEs added following Bevacizumab IB v22 Addendum Additional mRNA and exploratory sampling. Non-Substantial Amendment Substantial amendment The requirement for confirmatory scans was removed from the Schedule of Activities and Response assessment section 7.4.3. Lead Investigator for France amended to Dr Marion Gambart Minor wording corrections and clarifications Schedule of events table corrected Introduction of two new treatment arms (dinutuximab beta) for additional 64 patients Addition of eligibility criteria, schedule of events, treatment details, duration, cross over and dose modification details for new dinutuximab beta arms Adaptation of objectives, trial design, supporting treatment, pharmaceutical information and statistical consideration sections with new, relevant information. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 5 of 157 BEACON-Neuroblastoma Trial N/A 11-Apr-2019 6.0b SA 7 07-Feb-2020 7.0 SA 22 07-Mar-2023 8.0 Protocol Non-Substantial Amendment Substantial Amendment Substantial Amendment Minor wording corrections and clarifications Version amended from 6.0 to 6.0a to add. Additional rationale to update typographical errors.) Trial Synopsis: Clarification of recruitment targets Clarification of Section 10 title: “Dinutuximab beta and topotecan randomisations” Clarification that not all biological studies will be open at any one time (Section 10.2 and 15.5) Minor wording corrections and clarifications Urgent Safety Measure – implemented on 28th January 2020 Closure of Temozolomide (T) and Dinutuximab beta and Temozolomide (dBT) arms with immediate effect. Section 1.1 Background Section 1.2.3 Benefit Risk assessment Section 3.1 Randomisation Section 10 Headings changed Section 10.3 Trial therapy Update of contact details Change of definition of End of Trial (Section 21). Protocol previously defined two stages of end of trial (6 months after last patient completes treatment and 12 months after last data capture after 5 years follow up). This has been combined into one End of Trial definition: 6 months after last patient last visit (i.e. after 5 years follow up) Also addition of option to email SAE form (Section 18.2.1.2) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 6 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL PERSONNEL Chief Investigator: Co-Investigators: Exploratory Biomarkers Dr Lucas Moreno Dr. Lucas Moreno, MD, PhD Director Paediatric Oncology & Haematology Division Vall d’Hebron Barcelona Hospital Campus Passeig de la Vall d’Hebron, 119-129, 08035, Barcelona, Spain  +34 93 489 3000  +34 93 489 4060  lucas.moreno@vhebron.net Professor Keith Wheatley Professor of Clinical Trials Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 415 9119  k.wheatley@bham.ac.uk Dr Juliet Gray Associate Professor and Consultant in Paediatric Oncology Southampton Children’s Hospital Tremona Road Southampton SO16 6YD  +44 (0) 790 1507929  juliet.gray@uhs.nhs.uk Dr Gudrun Schleiermacher Senior Scientist Institute Curie 26 rue d'Ulm 75248 Paris cedex 05 France  +33 (0)1 56 24 45 50  +33 (0)1 56 24 66 30  gudrun.schleiermacher@curie.net Professor Louis Chesler Paediatric Tumour Biology Team Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0) 208 722 4035 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 7 of 157 BEACON-Neuroblastoma Trial Protocol  louis.chesler@icr.ac.uk Functional Imaging Study: Professor Andrew Peet Institute of Child Health University of Birmingham Whittall Street Birmingham, UK B4 6NH  +44 (0) 121 333 8234  +44 (0) 121 333 8241  a.peet@bham.ac.uk Dr Dow-Mu Koh Consultant Radiologist in Functional Imaging Royal Marsden Hospital Downs Road, Sutton, Surrey, UK SM2 5PT  +44 (0) 208 6613857  dow-mu.koh@icr.ac.uk Professor Martin Leach Co-Director, Cancer Research UK and EPSRC Centre for Cancer Imaging, Director, NIHR Clinical Research Facility Deputy Head, Division of Radiotherapy and Imaging Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0 208 661 3338  Martin.Leach@icr.ac.uk Molecular Monitoring mRNA Study: Professor Sue Burchill Leeds Institute of Cancer & Pathology St. James University Hospital Beckett Street Leeds, UK LS9 7TF  +44 (0) 113 206 5873  +44 (0) 113 242 9886  S.A.Burchill@leeds.ac.uk Professor Walter Gregory Clinical Trials Research Unit (CTRU) University of Leeds Clinical Trials Research House 71-75 Clarendon Road Leeds LS2 9PH  +44 (0) 113 343 1489  +44 (0) 113 343 1471 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 8 of 157 BEACON-Neuroblastoma Trial Protocol Trial Statistician: Trial Coordinator & Trial Office: Randomisation Service: SAE Reporting:  W.M.Gregory@leeds.ac.uk Miss Grace Holt Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 8328  +44 (0)121 414 3700  G.C.Holt@bham.ac.uk Miss Punam Mistry Children’s Cancer Trials Team Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  beacon@trials.bham.ac.uk Provided by the CRCTU at the University of Birmingham Randomisation should be performed by sites online at: https://www.cancertrials.bham.ac.uk/BEACONLive In case of any problems with online randomisation, randomisation can be performed over the phone by the CRCTU on: 0800 371 969 or +44 (0)121 414 3366 SAEs should be faxed to the BEACON-Neuroblastoma Trial Office, CRCTU, University of Birmingham, UK  + 44 (0)121 414 9520 or +44 (0)121 414 3700 National Coordinating Investigators: Austria – Lead Investigator: Prof Dr Ruth Ladenstein St. Anna Children’s Hospital and CCRI /Studies and Statistics Department for Integrated Research and Projects (S²IRP) Kinderspitalgasse 6, Zimmermannplatz 10 A-1090 Vienna Austria +43-1-40470-4750  +43-1- 40470- 7430  ruth.ladenstein@ccri.at BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 9 of 157 BEACON-Neuroblastoma Trial Belgium Lead Investigator: Prof Genevieve Laureys Ghent University Hospital 9000 Ghent De Pinterlaan 185 Belgium  +32 93 32 34 48  genevieve.laureys@uzgent.be Denmark – Lead Investigator: Dr Karsten Nysom Dept. of Paediatrics & Adolescent Medicine Rigshospitalet Blegdamsvej 9 DK2100 Copenhagen Denmark  +45 35 45 08 09  +45 35 45 50 55  Karsten.nysom@regionh.dk France – Lead Investigator: Dr Marion Gambart Unité d'Hémato-Oncologie Hôpital des Enfants 330, avenue de Grande Bretagne TSA 70034 31059 Toulouse Cedex France  +33 (0)5 34 55 86 11  +33 (0)5 34 55 86 12  gambart.m@chu-toulouse.fr Germany - Lead Investigator: Dr. Simone Hettmer Zentrum für Kinder- und Jugendmedizin UNIVERSITÄTSKLINIKUM FREIBURG Mathildenstr. 1, 79106 Freiburg Germany  +49 761 270-43000  +49 761 270-45180  simone.hettmer@uniklinik-freiburg.de Ireland – Lead Investigator: Dr Cormac Owens Our Lady’s Children’s Hospital Crumlin Road, Crumlin Dublin 12 Ireland  +35314096659  +35313453041  Cormac.owens@olchc.ie Protocol BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 10 of 157 BEACON-Neuroblastoma Trial Protocol Italy – Lead Investigator: Dr. Aurora Castellano U.O.Oncoematologia Ospedale Pediatrico Bambino Gesù Pzza S. Onofrio 4 00165 Roma Italy +39 06 68592957-2678  +39 06 68592826  aurora.castellano@opbg.net Netherlands – Lead Investigator: Dr. C Michel Zwaan Erasmus Medical Center Sophia’s Children's Hospital Dr. Molewaterplein 60 3015 GJ Rotterdam +31 (0) 10 703 6691  +31(0) 10 703 6681  c.m.zwaan@erasmusmc.nl Spain – Lead Investigator: Dr. Victoria Castel Instituto de Investigación Sanitaria Unidad de Oncología Pediátrica Hospital Universitario La Fe Bulevar Sur, S/N 46026 Valencia Spain +34 963862758 Ext 50040  +34 963494416  castel_vic@gva.es Switzerland – Lead Investigator: Dr. Nicolas Gerber University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland +41 44 266 31 17  +41 44 266 34 61  Nicolas.gerber@kispi.uzh.ch UK – Lead Investigator: Dr Lucas Moreno Honorary Research Fellow University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  lucas.moreno@vhebron.net, lmorenom@ext.cnio.es BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 11 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL SYNOPSIS Title A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma – BEACON-Neuroblastoma Trial Trial Design A phase II, randomised, open label, international multicentre 3x2 factorial trial. The dinutuximab beta amendment did utilise a 2x2 factorial design it will now be a simple two-way randomisation. Objectives Primary: - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan + temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma - To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma - To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma (“topotecan randomisation”) - To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma (“dinutuximab beta randomisation”) Secondary: - To evaluate the safety of the regimens Tertiary: - To undertake preliminary evaluation of the changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis - To undertake preliminary evaluation of the role of circulating mRNA levels for tyrosine hydroxylase (TH), paired-like homeobox 2b (PHOX2B) and doublecortin (DCX) as prognostic/predictive biomarkers in this refractory/relapsed setting - To undertake a preliminary evaluation of the role of tumour molecular profiles in blood and archival tumour tissue profiles as prognostic and predictive biomarkers - To undertake a preliminary evaluation of biomarkers of response to anti-GD2 therapy (Fc/KIR polymorphisms, Antibody Dependant Cell-Mediated Cytotoxicity (ADCC) and Anti-Drug Antibodies (ADAs) and of dinutuximab beta pharmacokinetics (PK) Outcome Measures Primary Endpoint: - Best response (Complete Response [CR] or Partial Response [PR]) [1] at any time during the first 6 cycles of trial treatment - For the bevacizumab part 2 only: Progression-free survival (PFS) Secondary Endpoints: - Safety of the regimens: Incidence and severity of Adverse Events (AE)s - PFS - Overall survival (OS) - Event-free survival (EFS) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 12 of 157 BEACON-Neuroblastoma Trial Protocol Exploratory/Tertiary Endpoints: - Changes in (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2* - Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples - Pilot descriptive study of angiogenesis and neuroblastoma markers that may include O6methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling - A preliminary correlation of the different biomarkers [Fc/KIR polymorphisms, Antibody – Dependent Cellular Toxicity (ADCC), and Anti-Drug Antibodies (ADAs)] will be made with parameters of anti-tumour activity (response rate, PFS and OS). PK parameters (dinutuximab beta trough levels) for this chemo-immunotherapy regimen will be described. Patient Population Children and young adults aged 1 to 21 years of age with relapsed/refractory neuroblastoma. Sample Size Approximately 224 patients, including 160 for the bevacizumab randomisation and 64 for the dinutuximab beta amendment. Trial Duration 8 years of patient recruitment, 5 years of patient follow up BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 13 of 157 BEACON-Neuroblastoma Trial Protocol Abbreviations ADA ANTI-DRUG ANTIBODIES ADCC ANTIBODY – DEPENDENT CELL-MEDIATED CYTOTOXICITY AE ADVERSE EVENT AESI ADVERSE EVENT OF SPECIAL INTEREST AFSAPPS COMPETENT AUTHORITY FOR FRANCE ALT ALANINE AMINOTRANSFERASE ANC ABSOLUTE NEUTROPHIL COUNT APPT ACTIVATED PARTIAL THROMBOPLASTIN TIME ASCT AUTOLOGOUS STEM CELL TRANSPLANTATION AST ASPARTATE AMINOTRANSFERASE AUC AREA UNDER THE CURVE AR ADVERSE REACTION BIT BEVACIZUMAB + IRINOTECAN + TEMOZOLOMIDE ARM BM BONE MARROW BP BLOOD PRESSURE BSA BODY SURFACE AREA BT BEVACIZUMAB + TEMOZOLOMIDE ARM BTTo BEVACIZUMAB + TEMOZOLOMIDE + TOPOTECAN ARM CI CHIEF INVESTIGATOR CIs CONFIDENCE INTERVALS COG CHILDREN’S ONCOLOGY GROUP CNS CENTRAL NERVOUS SYSTEM CR COMPLETE RESPONSE CRF CASE REPORT FORM CR UK CANCER RESEARCH UK CRCTU CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) CRN CLINICAL RESEARCH NETWORK CSR CLINICAL STUDY REPORT CT COMPUTERISED TOMOGRAPHY CTC COMMON TERMINOLOGY CRITERIA CTCAE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS CXR CHEST X-RAY dBT DINUTUXIMAB BETA + TEMOZOLOMIDE ARM dBTTo DINUTUXIMAB BETA + TEMOZOLOMIDE + TOPOTECAN ARM DCX DOUBLECORTIN DLT DOSE LIMITING TOXICITY DMC DATA MONITORING COMMITTEE DNA DEOXYRIBONUCLEIC ACID ECHO ECHOCARDIOGRAM ECOG EASTERN COOPERATIVE ONCOLOGY GROUP EFS EVENT FREE SURVIVAL EMA EUROPEAN MEDICINES AGENCY ERDC ELECTRONIC REMOTE DATA CAPTURE EOT END OF TREATMENT FFPE FORMALIN-FIXED PARAFFIN EMBEDDED GCP GOOD CLINICAL PRACTICE G-CSF GRANULOCYTE COLONY STIMULATING FACTOR BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 14 of 157 BEACON-Neuroblastoma Trial Protocol GFR GM-CSF GGT GP GPOH HR IB ICF ICH IMP INR INRC INRG INSS IRF ISF IT ITCC IV MGMT MIBG MHRA MRD MRI MSKCC MTD MYCN NANT NCI NCS NR OS OTC PCP PD PFS PHOX2B PI PIS PK PMA PRES PO PPTP PR REC RECIST RNA GLOMERULAR FILTRATION RATE GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR GAMMA-GLUTAMYL TRANSPEPTIDASE GENERAL PRACTITIONER GERMAN SOCIETY FOR PAEDIATRIC ONCOLOGY & HAEMATOLOGY HEART RATE INVESTIGATOR BROCHURE INFORMED CONSENT FORM INTERNATIONAL CONFERENCE ON HARMONISATION INVESTIGATIONAL MEDICINAL PRODUCT INTERNATIONAL NORMALISED RATIO INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA INTERNATIONAL NEUROBLASTOMA RISK GROUP INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM INSTITUTIONAL REVIEW BOARD INVESTIGATOR SITE FILE IRINOTECAN + TEMOZOLOMIDE ARM INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER INTRAVENOUS O6-METHYGUANINE METHYLTRANSFERASE META-IODO-BENZYL-GUANIDINE MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY MINIMAL RESIDUAL DISEASE MAGNETIC RESONANCE IMAGING MEMORIAL SLOAN KETTERING CANCER CENTRE MAXIMUM TOLERATED DOSE MYELOCYTOMATOSIS VIRAL RELATED ONCOGENE NEW AGENTS FOR NEUROBLASTOMA THERAPY NATIONAL COORDINATING INVESTIGATOR NATIONAL CO-SPONSOR NO RESPONSE OVERALL SURVIVAL OVER THE COUNTER PNEUMOCYSTIS CARNI PNEUMONITIS PROGRESSSIVE DISEASE PROGRESSION FREE SURVIVAL PAIRED-LIKE HOMEOBOX2B PRINCIPAL INVESTIGATOR PATIENT INFORMATION SHEET PHARMACOKINETICS POPULATION-MODELLING ANALYSIS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME ORALLY PAEDIATRIC PRECLINICAL TESTING PROGRAM PARTIAL RESPONSE RESEARCH ETHICS COMMITTEE RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS RIBONUCLEIC ACID BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 15 of 157 BEACON-Neuroblastoma Trial Protocol RTKI RT-qPCR SAE SAR SCT SD SFOP SIOPEN SNP SPC SUSAR SWFI T TH TMA TMG TSC TTo TVD UAR UKCCSG ULN VTE VEGF VGPR WMA RECEPTOR TYROSINE KINASE INHIBITORS REVERSE TRANSCRIPTASE QUANTITATIVE POLYMERASE CHAIN REACTION SERIOUS ADVERSE EVENT SERIOUS ADVERSE REACTION STEM CELL TRANSPLANT STABLE DISEASE FRENCH SOCIETY OF PAEDIATRIC ONCOLOGY INTERNATIONAL SOCIETY PAEDIATRIC ONCOLOGY EUROPEAN NEUROBLASTOMA GROUP SINGLE NUCLEOTIDE POLYMORPHISM SUMMARY OF PRODUCT CHARACTERISTICS SUSPECTED UNEXPECTED SEVERE ADVERSE REACTION STERILE WATER FOR INJECTION TEMOZOLOMIDE ARM TYROSINE HYDROXYLASE TISSUE MICROARRAY TRIAL MANAGEMENT GROUP TRIAL STEERING COMMITTEE TEMOZOLOMIDE + TOPOTECAN ARM TOPOTECAN, VINCRISTINE & DOXORUBICIN UNEXPECTED ADVERSE REACTION UNITED KINGDOM CHILDREN’S CANCER STUDY GROUP UPPER LIMIT OF NORMAL VENOUS THROMBO-EMBOLISM VASCULAR ENDOTHELIAL GROWTH FACTOR VERY GOOD PARTIAL RESPONSE WORLD MEDICAL ASSOCIATION FORMULAE Mosteller formula: BSA (m²) = BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 16 of 157 BEACON-Neuroblastoma Trial Protocol Table of Contents Trial Synopsis ...................................................................................................................................... 12 Title .................................................................................................................................................... 12 Trial Design ........................................................................................................................................ 12 Objectives .......................................................................................................................................... 12 Outcome Measures............................................................................................................................ 12 Patient Population .............................................................................................................................. 13 Sample Size ....................................................................................................................................... 13 Trial Duration...................................................................................................................................... 13 Abbreviations ..................................................................................................................................... 14 1. Background and Rationale ............................................................................................................. 22 1.1 Background............................................................................................................................ 22 1.1.1 Background for the dinutuximab beta amendment............................................................ 28 1.2 Trial Rational.......................................................................................................................... 29 1.2.1 Justification for design ....................................................................................................... 29 1.2.2 Rationale for patient population ......................................................................................... 30 1.2.3 Benefit-risk assessment .................................................................................................... 31 1.2.4 Rationale for the selected backbone schedules: Temozolomide, irinotecan + temozolomide and temozolomide + topotecan .............................................................................. 31 1.2.5 Rationale for dosing schedule of bevacizumab................................................................. 32 1.2.6 Rationale for evaluating chemo-immunotherapy in the BEACON-Neuroblastoma Trial... 32 1.2.7 Rationale for dosing schedule of dinutuximab beta........................................................... 33 1.2.8 Rationale for the use of biomarker studies ........................................................................ 34 1.3 Relevance and future importance ......................................................................................... 35 2. Objectives and Outcome Measures ............................................................................................. 36 2.1 Objectives .............................................................................................................................. 36 2.2 Outcome Measures ............................................................................................................... 37 3. Trial Design ..................................................................................................................................... 37 3.1 Randomisation....................................................................................................................... 37 3.2 Duration of treatment............................................................................................................. 38 3.3 Frequency and duration of follow-up ..................................................................................... 38 4. Eligibility.......................................................................................................................................... 39 4.1 Lifestyle guidelines ................................................................................................................ 39 5. Schedule of activities..................................................................................................................... 39 6. Screening and Consent ................................................................................................................. 40 6.1 Informed Consent .................................................................................................................. 40 6.2 Screening............................................................................................................................... 41 7. Trial Entry........................................................................................................................................ 42 7.1 Procedure for online patient randomisation........................................................................... 42 7.2 Emergency Randomisation ................................................................................................... 42 8. Treatment Details ........................................................................................................................... 43 8.1 Definition of Investigational Medicinal Products (IMPs) ........................................................ 43 9. Bevacizumab randomisation......................................................................................................... 43 9.1 Eligibility criteria for the bevacizumab randomisation............................................................ 43 9.1.1 Inclusion criteria for the bevacizumab randomisation ....................................................... 43 9.1.2 Exclusion criteria for the bevacizumab randomisation ...................................................... 44 9.2 Schedule of activities for the bevacizumab randomisation ................................................... 45 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 17 of 157 BEACON-Neuroblastoma Trial Protocol 9.3 Trial Therapy (bevacizumab randomisation) ......................................................................... 49 9.3.1 Bevacizumab randomisation trial treatment ...................................................................... 49 9.4 Treatment Schedule..................................................................................................................... 51 9.4.1 Day 1 of Cycle 1 ................................................................................................................ 51 9.4.2 Day 1 of subsequent cycles............................................................................................... 51 9.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12) ........................................................ 52 9.4.4 End of Treatment ............................................................................................................... 52 9.4.5 Treatment Duration............................................................................................................ 52 9.5 Dose Modifications for the bevacizumab randomisation ....................................................... 53 9.5.1 Dose Modifications for AEs due to chemotherapy - for the bevacizumab randomisation. 56 9.5.2 Bevacizumab – Infusion-related Reaction/Infusional Site Extravasation Management Guidelines ...................................................................................................................................... 62 9.5.3 Bevacizumab - Treatment Delays ..................................................................................... 63 9.5.4 Bevacizumab - Discontinuation ........................................................................................ 64 9.5.5 Bevacizumab - Toxicity Management guidelines .............................................................. 65 9.6 Central Venous Access Device (CVAD)................................................................................ 67 10 Dinutuximab beta and topotecan randomisations...................................................................... 68 10.1 Eligibility for the dinutuximab beta randomisation ................................................................. 68 10.1.1 Inclusion criteria for the dinutuximab beta randomisation ............................................. 68 10.1.2 Exclusion criteria for the dinutuximab beta randomisation ............................................ 69 10.2 Schedule of events for the dinutuximab beta and topotecan randomisations....................... 70 10.3 Trial therapy (dinutuximab beta and topotecan randomisations) .......................................... 74 10.3.1 Dinutuximab beta and topotecan trial treatment................................................................ 75 10.4 Treatment Schedule .............................................................................................................. 76 10.4.1 Day 1 of Cycle 1 ............................................................................................................ 76 10.4.2 Day 1 of subsequent cycles........................................................................................... 76 10.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12 on chemotherapy only) ............... 77 10.4.4 End of Treatment ........................................................................................................... 77 10.4.5 Treatment Duration............................................................................................................ 78 10.4.6 Cross-over ......................................................................................................................... 78 10.5 Dose Modifications – dinutuximab beta and topotecan randomisations ............................... 79 10.5.1 Dose modifications for dinutuximab beta specific toxicities .......................................... 79 10.5.2 Dose modifications for haematological toxicity.............................................................. 81 10.5.3 Dose modifications for hepatic toxicity .......................................................................... 82 11 Treatment Compliance................................................................................................................... 84 12 Supportive Treatment .................................................................................................................... 84 12.1 Nausea and Vomiting ............................................................................................................ 84 12.2 Growth Factors ...................................................................................................................... 84 12.3 Fever and neutropenia .......................................................................................................... 84 12.4 Blood products....................................................................................................................... 84 12.5 Pneumocystis jirovecii pneumonia (PJP) prophylaxis ........................................................... 84 12.6 Management of side effects caused by non-selective NSAIDs as cyclooxygenase (COX) type I and II inhibitors ......................................................................................................................... 84 12.7 Supportive care during Dinutuximab beta infusion................................................................ 85 12.7.1 Pain Management.......................................................................................................... 85 12.7.2 Prevention of dinutuximab beta related infusion reactions............................................ 86 13 Concomitant Medication................................................................................................................ 87 14 Assessments .................................................................................................................................. 87 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 18 of 157 BEACON-Neuroblastoma Trial Protocol 14.1 Response assessment .......................................................................................................... 88 15 Biomarkers...................................................................................................................................... 88 15.1 Blood sampling safety ........................................................................................................... 88 15.2 MRI-derived functional imaging biomarkers of angiogenesis................................................ 90 15.3 Molecular monitoring mRNA.................................................................................................. 90 15.4 Neuroblastoma exploratory biomarker analyses ................................................................... 90 15.5 Sample Collection.................................................................................................................. 92 15.5.1 Peripheral blood samples .............................................................................................. 92 15.5.2 Bone Marrow Samples .................................................................................................. 92 15.5.3 Archival tumour samples ............................................................................................... 92 16 Patient Follow Up ........................................................................................................................... 93 16.1 Patient Withdrawal................................................................................................................. 93 17 Pharmaceutical Information .......................................................................................................... 94 17.1 Definition of Investigational Medicinal Product ...................................................................... 94 17.2 Bevacizumab ......................................................................................................................... 94 17.2.1 Bevacizumab - Drug Supply .......................................................................................... 94 17.2.2 Bevacizumab - Ordering ............................................................................................... 94 17.2.3 Bevacizumab - Formulation, Packaging and Labelling ................................................. 94 17.2.4 Bevacizumab - Preparation and Dispensing ................................................................. 95 17.2.5 Compatibility information ............................................................................................... 95 17.2.6 Bevacizumab - Administration ....................................................................................... 95 17.2.7 Bevacizumab – Accountability....................................................................................... 96 17.2.8 Bevacizumab - Destruction............................................................................................ 96 17.3 Cyclophosphamide ................................................................................................................ 96 17.4 Dinutuximab beta................................................................................................................... 96 17.5 Irinotecan ............................................................................................................................... 96 17.5.1 Irinotecan - Drug Supply ............................................................................................... 96 17.5.2 Irinotecan - Formulation, Packaging and Labelling ....................................................... 96 17.5.3 Irinotecan - Preparation and Dispensing ....................................................................... 97 17.5.4 Compatibility information ............................................................................................... 97 17.5.5 Irinotecan - Administration ............................................................................................. 97 17.6 Temozolomide ....................................................................................................................... 97 17.6.1 Temozolomide – Drug Supply ....................................................................................... 97 17.6.2 Temozolomide - Formulation, Packaging and Labelling ............................................... 97 17.6.3 Temozolomide - Administration ..................................................................................... 97 17.7 Topotecan.............................................................................................................................. 98 17.7.1 Topotecan - Drug Supply.............................................................................................. 98 17.7.2 Topotecan - Formulation, Packaging and Labelling ..................................................... 98 17.7.3 Topotecan - Preparation and Dispensing ..................................................................... 98 17.7.4 Topotecan - Compatibility information ........................................................................... 98 17.7.5 Topotecan - Administration........................................................................................... 99 18 Adverse Event Reporting .............................................................................................................. 99 18.1 Reporting Requirements........................................................................................................ 99 18.1.1 Adverse Events (AE) ..................................................................................................... 99 18.1.2 AESIs of Bevacizumab .................................................................................................. 99 18.1.3 Serious Adverse Advents (SAE).................................................................................... 99 18.1.4 Reporting period .......................................................................................................... 100 18.2 Reporting Procedure ........................................................................................................... 100 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 19 of 157 BEACON-Neuroblastoma Trial Protocol 18.2.1 Site............................................................................................................................... 100 18.2.2 Trial Office ................................................................................................................... 102 18.2.3 Reporting to the Competent Authority and main Research Ethics Committee ........... 102 18.2.4 Investigators ................................................................................................................ 102 18.2.5 Data Monitoring Committee ......................................................................................... 102 18.2.6 Manufacturer of Investigational Medicinal Product...................................................... 102 19 Data Handling and Record Keeping ........................................................................................... 103 19.1 Data Collection .................................................................................................................... 103 19.2 Archiving .............................................................................................................................. 103 20 Quality Management .................................................................................................................... 103 20.1 Site Set-up and Initiation ..................................................................................................... 103 20.2 On-site Monitoring ............................................................................................................... 104 20.3 Central Monitoring ............................................................................................................... 104 20.4 Audit and Inspection ............................................................................................................ 104 20.5 Notification of Serious Breaches ......................................................................................... 104 21 End of Trial Definition .................................................................................................................. 105 22 Statistical Considerations ........................................................................................................... 105 22.1 Trial Design.......................................................................................................................... 105 22.2 Definition of Outcome Measures ......................................................................................... 106 22.2.1 Primary ........................................................................................................................ 106 22.2.2 Secondary.................................................................................................................... 106 22.2.3 Exploratory/Tertiary ..................................................................................................... 106 22.3 Sample Size......................................................................................................................... 106 22.4 Interim and Main Analyses of Outcome Measures.............................................................. 108 22.4.1 Planned Interim Analyses ............................................................................................ 108 22.4.2 Main Analysis............................................................................................................... 108 22.5 Stopping Guidelines ............................................................................................................ 110 23 Trial Organisational Structure..................................................................................................... 110 23.1 Coordinating Sponsor .......................................................................................................... 110 23.2 Co-Sponsor Centres ........................................................................................................... 110 23.3 Relationship of trial committees........................................................................................... 112 23.4 Trial Management Group..................................................................................................... 112 23.5 Trial Steering Committee ..................................................................................................... 112 23.6 Data Monitoring Committee................................................................................................. 112 23.7 Finance ................................................................................................................................ 113 23.8 NIHR CRN Portfolio ............................................................................................................. 113 24 Ethical Considerations ................................................................................................................ 113 25 Confidentiality and Data Protection ........................................................................................... 114 26 Insurance and Indemnity ............................................................................................................. 115 27 Publication Policy ........................................................................................................................ 116 28 Reference List............................................................................................................................... 117 Appendix 1 – WMA Declaration of Helsinki .................................................................................... 124 Appendix 2 - Definition of Adverse Events ..................................................................................... 127 Appendix 3 - Common Toxicity Criteria Grading ........................................................................... 129 Appendix 4 – RECIST Criteria 1.1 .................................................................................................... 130 Appendix 5 – Tumor Response at Metastatic Soft Tissue and Bone Sites (Park et al. 2017) ... 133 Appendix 6 - CURIE & SIOPEN scoring methods for neuroblastoma ......................................... 134 Appendix 7 – Temozolomide Dosing............................................................................................... 136 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 20 of 157 BEACON-Neuroblastoma Trial Protocol Appendix 8 – Blood Pressure Levels by Age and Height Percentile for Children and Adolescents ....................................................................................................................................... 139 Appendix 9 – Height for Age Chart - Girls ...................................................................................... 144 Appendix 10 – Height for Age Chart - Boys.................................................................................... 149 Appendix 11 – Lansky and Karnofsky/ECOG Scales .................................................................... 154 Appendix 12 – Tanner Staging ......................................................................................................... 156 Appendix 13 – Clinical studies of anti-GD2 therapies in combination with chemotherapy ...... 157 LIST OF TABLES Table 1 - Second line chemotherapy regimens tested in phase II in relapsed or refractory neuroblastoma since 2000 ..........
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ACCORD-2 master protocol

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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
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