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Joint Partnership Policy and Guidance on Pre-clinical and Clinical Research Publications

Description: Joint Partnership Policy and Guidance on Pre-clinical and Clinical Research Publications ? ? ? ? Background Scope: who this policy and guidance applie
Url: /Media/Southampton-Clinical-Research/Downloads/Joint-Partnership-Policy-and-Guidance-on-Pre-clinical-and-Clinical-Research-Publications.pdf

BRC Research-imaging-proposal-form_v2 2025 FINAL

Description: BRC Research Imaging Proposal form The BRC Research Imaging Proposal form should be completed by the chief/principal investigator of any new rese
Url: /Media/Southampton-Clinical-Research/Downloads/BRC-Research-imaging-proposal-form-v2-2025-FINAL.docx

BRC Research-imaging-proposal-form_v1 FINAL 10.12.2024

Description: BRC Research Imaging Proposal form The BRC Research Imaging Proposal form should be completed by the chief/principal investigator of any new rese
Url: /Media/Southampton-Clinical-Research/Grants/Download/BRC-Research-imaging-proposal-form-v1-FINAL-10.12.2024.docx

BRC Research-imaging-proposal-form_v1 FINAL 10.12.2024

Description: BRC Research Imaging Proposal form The BRC Research Imaging Proposal form should be completed by the chief/principal investigator of any new research study requiring access to imaging resources at University Hospital Southampton. The BRC Imaging Research Panel (BRC IRP) will use this information to determine the availability of resource and provide advice on costings for imaging research. Ideally, this form should be completed before a submission for this pilot scheme is made, to enable accurate costings for the MR imaging to be estimated. For the BRC MRI pump-priming research project award, this form will provide imaging specific background information, to help assess the feasibility of the project, alongside the full award application form. Please complete both Part 1 and Part 2 (detailed application). If detailed information is not known then please complete as much as possible (especially for Part 2), submit the form and we will be in contact to assist with this. Part 1 – Expression of interest Study title: Short title: Research question / summary of imaging requirements: Investigator: Email: Are you acting in your capacity as a UHS or UoS principal investigator? Select one only. UHS (Trust) UoS (University) Principal grant admin (n/a for BRC pump priming scheme) UHS (Trust) UoS (University) Other Part 2 – Detailed application Proposed start date: Proposed end date: Number of subjects: Statistical advice sought? Please circle Yes / No Type of study: Part of a multi-centre trial? Please circle Yes / No Approvals required? Please state Imaging required Imaging protocol (state if new or existing and who this has been discussed with) Frequency/timing/routine? Hardware/software/data storage/archiving and image processing and image analysis requirements? 1. 2. 3. 4. New imaging protocols (including MRI sequences) should be discussed with the MRI Research Radiographer, MRI Physics and relevant Consultant Radiologist (if required). Existing imaging protocols should be confirmed with the MRI Research Radiographer and relevant MRI Superintendent Radiographer (including protocol name and version date). Please indicate if each imaging event is routine (i.e. part of clinical care), additional as part of this proposal, and whether this will continue once the trial has ended. Hardware/software/data storage and post-processing requirements, including image archiving, should be discussed with radiology/medical physics/UoS. Please sign electronically to indicate that you have read and agree with the attached Joint UHS and UoS Policy for imaging research in Southampton and BRC award terms and conditions Name: Signature: Date: Please submit to the RIMG (on behalf of the BRC) by emailing: Angela.Darekar@uhs.nhs.uk Joint UHS and UoS policy for imaging research in Southampton – BRC/MRI specific Version 2, December 2019, Research Imaging Management Group This Joint Policy applies to any academic activity, hereby referred to as “Project”, which involves imaging or imaging results at UHS, whether it is research, case report, case series, audit, service evaluation or other description not specifically mentioned here. Planning and costing research 1. For research only: please inform RIMG (by emailing Angela.Darekar@uhs.nhs.uk) of the research at least one month prior to grant/award application form submission by completing the attached form 2. Please discuss protocols with the appropriate radiographer/radiologist/medical physicist assigned to the project by the Radiology Research Coordinator. This will ensure that accurate costings (or equivalent hours of scanning time) can be provided. 3. When costing grant applications, the Radiology Research team will advise on costing attribution across institutions. Ethical approval 1. The appropriate Health Research Authority and institutional (UHS or UoS) approvals need to be in place before the Project starts. Bookings 1. Please provide as much notice as possible for research bookings (at least 48 hours), and appreciate that they cannot always be accommodated at short notice. If particular procedures/personnel are required for bookings, these should be discussed with the Radiology Research team before RIMG approval is granted. 2. Liaise with the research radiographers for bookings, copying in RadiologyResearch@uhs.nhs.uk and provide: Name, DoB, Address, GP details, hospital ID (if available) and patient’s study ID. 3. Please use either the radiology research referral form or electronic requesting. Please clearly indicate the project title in the request and indicate that this is a research scan. Overlap between research and clinical imaging 1. If requesting clinical imaging that will later be used for research purposes, please clarify this to the reporting radiologist on the request form. Appropriate funding and ethical approvals must be in place. Publication 1. If manuscripts arise from Projects which make use of imaging data reported by UHS radiologists or involving UHS medical physicists, co-authorship or acknowledgement of these individuals should be discussed with them at the point of manuscript preparation. 2. Please include both UHS and UoS as affiliations, unless none of the authors have a honorary or substantive connection with UoS, and no use was made of any UoS facility. Please abide by the “Joint Partnership Policy and Guidance on Pre-clinical and Clinical Research Publications” v2.6, jointly approved by UHS and UoS. 3. Acknowledge resources (staff, space or equipment) of a particular imaging unit or department if these have been used. 4. Please remember to acknowledge any sponsorship you have received. 5. Please acknowledge BRC support using wording in section 4.5 below 6. For grants, please include the grant number and source. 7. Please inform RIMG of publications arising from imaging performed at UHS. Incidental findings 1. It is the recommendation of the RIMG that the Research Ethics Committee approved protocol defines precise instructions on how to consent for and manage incidental findings. These should specify a named clinician who will be responsible for managing incidental findings (reported by the radiologist(s) associated with the study) including informing the subject, arranging follow up tests and liaising with the GP as necessary. In the absence of clarity in the study protocol of any aspect relating to incidental findings, the Royal College of Radiologists’ guidance (https://www.rcr.ac.uk/publication/management-incidental-findings-detected-during-research-imaging), will need to be adhered to. Data management 1. Please ensure that data uploads/transfers and archiving processes have been discussed with the relevant people within PACS/Radiology Research/Medical Physics (as appropriate) and have been funded accordingly (to be confirmed for the BRC MRI pump-priming scheme). 2. Please ensure that all data management is in compliance with the General Data Protection Regulation or its UK equivalent. The award will only be made available if you meet the following conditions: BRC award terms and conditions 1. The award is subject to the terms and conditions of the BRC4 Research Contract signed by the Department for Health and Social Care and University Hospital Southampton NHS Foundation Trust on 8th November 2022. Specific applicable BRC terms are set out in Schedule 1 attached to this award letter. 2. The BRC funding is subject to the terms and conditions detailed in the BRC Collaboration Agreement signed by University Hospital Southampton NHS Foundation Trust and the University of Southampton, dated 15th September 2023. 3. Any additional grant funding secured by the postholder as a result of the BRC funding will be considered as grant income to the BRC. As the successful applicant awarded funding you will be required to: * Provide the BRC Manager with progress reports as requested by them, including a report at least 1 month prior to award end, plus information required to meet reporting requirements for NIHR, such as dates of submission of external applications * Contribute to the relevant School/Faculty conference and seminar programmes and BRC and NIHR-related training and development events in accordance with NIHR guidance. * Include an acknowledgement of NIHR Southampton BRC support on all publications, posters and other outputs resulting from this award. Schedule 1 – Specific Applicable NIHR Southampton Biomedical Research Centre Terms 1 Definitions: 1.1 "Award” means the funding applied for in this application. 1.2 BRC Manager means the member of staff at UHS employed to have overall management responsibility for the BRC. 1.3 “BRC Research Contract” means the Biomedical Research Centre grant contract signed by University Hospital Southampton NHS Foundation Trust and the Department for Health and Social Care and which is incorporate by reference, to the Award Letter. 1.4 “Background IP” means any Intellectual Property in existence at the commencement of the Reseacrh or created, devised or generated other than in the performance of the Research and which is actually used in the performance of the Research. 1.5 “Confidential Information” means all information of a commercially sensitive nature including (but not limited to) specifications, drawings, circuit diagrams, tapes, discs and other computable readable media, documents, techniques and know-how which are disclosed by one Party to the other for use in or in connection with the BRC or any Research. 1.6 “Foreground IP” means any Intellectual Property (and/or property right in Samples) that is created, generated or developed (whether in whole or in part) during the course of and for the purpose of any part of the Research. 1.7 “Parties” means Awardee and University Hospital Southampton NHS Foundation Trust. 1.8 “Research” means the project undertaken supported by the Award. 1.9 “Research Data” means information or data that is collected, collated or generated in the performance of the Research and includes (but is not limited to) information or data that is presented or stored in searchable form. For the avoidance of doubt, Research Data: a) does not include, without limitation, information or data that has been analysed as part of the Research; b) does include, but is not limited to, images. 1.10 “Samples” means material (including but not limited to biological material, organisms and chemical compounds), specimens or extracts collected, obtained or generated (whether in whole or in part) during the course of and for the purpose of any part of the Research. 1.11 “UHS” means University Hospital Southampton NHS Foundation Trust. 2 Intellectual Property 2.1 Awardee shall promptly report all Foreground IP to UHS. 2.2 Each Party shall own the Research Data and Foreground IP generated by it under the BRC or Project and the terms of clauses 11, 16 and 17 of BRC Research Contract shall apply to the use, management and exploitation of Research Data and Foreground IP. 2.3 Nothing contained in the Award Letter related to this funding shall affect the absolute and unfettered rights of each Party in all inventions, discoveries and intellectual property contained in its Background IP. 2.4 Subject to the BRC Research Contract, each Awardee shall undertake and continue at its expense the timely prosecution and maintenance of all Foreground IP which is solely owned by Awardee. In the event that the Awardee is unable or unwilling to comply with its obligation under this Clause 2.4, UHS and Funder shall consider how best to deal with such Foreground IP and shall have the option to require an assignment of such Foreground IP to the other Party to enable prosecution and maintenance of such Foreground IP by that other Party at its own cost. In the event that any Party wishes to exploit commercially any Foreground IP assigned pursuant to this Clause 2.4 that Party shall pay to the assigning Party a royalty and/or other appropriate form of remuneration which is fair and reasonable taking into consideration the factors set out under Clause 3.3. 2.5 In the event that any of the Parties are jointly responsible for generating Research Data and/or Foreground IP such Research Data and/or Foreground IP shall be jointly owned by the Parties. Ownership in Foreground IP shall be in accordance with the inventive contribution made by each Party to the generation of such Foreground IP and ownership in Research Data shall be in accordance with the relative contributions of each Party to the generation of the Research Data. 2.6 Joint owners of Foreground IP shall agree between them on who shall be responsible for the timely prosecution and maintenance of all such Foreground IP and the Party that is nominated to be so responsible shall be entitled to charge the other joint owners with a percentage of the costs of so doing as agreed between the joint owners. In the absence of any agreement to the contrary between joint owners the costs shall be equally shared. 3 Exploitation of Intellectual Property 3.1 Each Party grants to the other Party a non-exclusive, royalty-free licence (without the right to sublicence) to: 3.1.1 use its Research Data and Foreground IP for their own non-commercial research and development purposes but not for the purposes of commercial exploitation; and 3.1.2 in the case of UHS to use University of Southampton Research Data and Foreground IP in clinical activities within UHS; 3.1.3 subject to any existing third party obligations, use its Background IP for the purpose of undertaking the BRC and to enable the use of the Foreground IP pursuant to Clause 3.1.1 and 3.1.2 but not for the purposes of commercial exploitation. 3.2 The Parties will review and consider the optimum use of all Research Data and Foreground IP and agree which is the most suitable to effectively exploit or disseminate any Research Data and Foreground IP, subject to approval of the Funder. 3.3 In the event that any Party wishes to exploit commercially Foreground IP owned by the other Party, the owner of the Foreground IP shall grant to such Party a non-exclusive licence to use such Foreground IP for that purpose, subject to the agreement of appropriate terms in relation thereto, including a royalty and/or other appropriate form of remuneration which is fair and reasonable taking into consideration the respective financial and technical contributions of the Parties concerned to the development of the Foreground IP, the expenses incurred in securing intellectual property protection thereof and the costs of its commercial exploitation and any use of Background IP. 3.4 Should any of the Parties wish to exploit its own Foreground IP with a third party during the duration of the BRC, that Party must notify the other Party before approaching said third party, always provided that the disclosure of information required for such exploitation is subject to the obligations of confidentiality at least equivalent to those under Clause 11. Further any necessary notification to NIHR shall be made and their respective approval should be obtained or commercialisation agreement in place, if required, prior to exploitation. 3.5 In recognition of the Parties joint involvement with the BRC and the contribution to development of the Foreground IP a Party exploiting its own Foreground IP will provide a fair revenue share to the other Party. In the event any revenues are due to the Funder revenues shall first be distributed to the Funder prior to sharing between the Parties. 3.6 Subject to Clause 3.4 each Party agrees (where it is free and reasonably able to do so) to license on fair and reasonable terms its Foreground IP and Background IP that may be required to enable any other Party to exploit its own Foreground IP or Background IP, always subject to the obligations of confidentiality under Clause 5. 3.7 With regard to joint inventions, the Parties owning such inventions agree to co-operate fully in the protection of such joint inventions and each Party shall be entitled to make use of such joint inventions subject only to negotiating a licence in good faith from the other Party for its interest in such joint inventions on similar terms to those set out in clause 3.3. 3.8 The University shall grant to the Funder a non-exclusive, irrevocable, royalty-free, worldwide licence together with the right to grant sub-licences to health service bodies or others directly engaged in providing health care, permitting the Funder to use and publish 3.9 any information relating to the Research which is not Confidential Information of the University 3.9.1 any Foreground IP; 3.9.2 Research Data; 3.9.3 Reports; 3.9.4 arising know how; and, 3.9.5 conclusions arising from the Research 3.10 and in each case, the University acknowledges the Funder intends to exercise this right only where the Funder’s reasonable opinion the University is not appropriately managing, disseminating or using such items and in each case Funder is permitted to use or make available such items as it sees fit in support of: (i) the development, promotion or provision of health care that is not a commercial use; and/or (ii) for any other purpose that is not a commercial use. 4 Publication 4.1 Subject to the provisions of Clauses 2, 3 and 5 neither Party shall disclose or publish information or Foreground IP for the duration of the BRC and for 3 (three) years thereafter without the consent of the other Party , such consent, not to be unreasonably withheld or delayed. Further the Parties must seek to obtain all necessary consents from NIHR and any Collaborating Parties prior to publication. The obligation to seek consent of NIHR or continues after the end of the Research. 4.2 Subject to 4.1, the Parties shall be permitted to publish the Research Data of the BRC which they have undertaken in accordance with normal academic practice, subject always to the provisions of Clauses 8 and 5, and providing such disclosure does not jeopardise any application for Foreground IP protection by any Party. Request for such consent must be submitted together with the material proposed for publication to the BRC Manager. If any Party can reasonably demonstrate that such a disclosure contains material that would prejudice the value of any Background IP and/or Foreground IP, that Party shall inform the BRC Manager in writing within 28 days of that Party receiving a copy of the proposed publication and in that event the disclosure shall be amended so as to meet the objections of that Party or delayed to address their concerns. 4.3 Subject to the provisions of Clause 3 where in the opinion of UHS a proposed publication contains patentable or commercially sensitive subject matter which needs protection then the Party proposing to publish may be requested to refrain from doing so for a maximum of six 6 months in order to allow for application for patent protection in the name and at the cost of the relevant owner of the Foreground IP. The provisions of Clause 2 and 3 shall apply in respect of any licence to such Foreground IP. 4.4 Nothing contained in the Award Letter related to this funding shall prevent the submission of a thesis to examiners in accordance with the normal regulations of the Parties subject where appropriate to such examiners being bound by conditions of confidentiality in no less terms than those outlined in Clause 5 nor to the placing of such thesis in the library of the appropriate Research Party provided that access to such thesis shall only be available on conditions of confidentiality no less onerous than those contained in Clause 5 hereof. 4.5 The University shall ensure that all project investigators acknowledge in all theses, papers and other publications (including from non-BRC projects) that they receive support from the NIHR Southampton BRC, in accordance with BRC Research Contract. The form of words is: “[investigator initials] is supported by the National Institute for Health and Care Research through the NIHR Southampton Biomedical Research Centre”. 4.6 The Parties acknowledge that NIHR is entitled to publish the whole or any part of the Report. If the Parties wishes NIHR to delay such publication, it must submit a request in writing to the NIHR giving reasons for the requested delay which shall be considered in accordance with the NIHR’s Information for Authors’ Dual Publication Guidance and Embargo Policy as defined in the NIHR Contract and amended from time-to-time. 4.7 Neither Party shall use the other's name, crest, logo or registered image for any purpose without the express permission of the other Party. The Parties will agree treatment for referencing each others involvement in the BRC and joint branding for their activities subject to compliance with Clause 4.8 and the BRC Research Contract. 4.8 Neither Party shall issue any press release, public statement, or other media announcement related to the BRC or any Research Data or Foreground IP without the prior consent of the other Party and Funder, as applicable. 4.9 The Parties (in the case of the University via UHS must notify the Funder of any intention to issue a press release at least three (3) business days prior to any press release issued by it or on its behalf, directly related to the Research or Foreground IP, arising now how or Research Data or of matters arising from such Research. Awardee shall send one draft copy of the proposed press release to UHS at least five (5) business days before the date intended for release. For the avoidance of doubt this obligation shall continue in full force and effect following expiry of the Award letter 4.10 The Parties shall comply with guidance and advice from Funder on branding and publicity which may be issued from time to time including, but not limited to Funder’s guidance on the format for websites, press releases and use of social media, permitted use of the NIHR, BRC, NHS and Department of Health and Social Care brands, names and logos and ensuring all branding references to the BRC are prefixed with the term “NIHR”. 5 Confidentiality 5.1 The Parties hereto agree to use all reasonable endeavours to ensure that any Confidential Information disclosed or submitted in writing or any other tangible form to one Party (“Receiving Party”) by the other (“Disclosing Party”) shall be treated with the same care and discretion to avoid disclosure as the Receiving Party uses with its own similar information which it does not wish to disclose. Any information disclosed orally that is identified by the Disclosing Party as Confidential Information shall be treated the same as if it had been reduced to writing at the time of disclosure to the Receiving Party. 5.2 The Receiving Party shall not, during a period of seven (7) years after the termination of this Award Letter, use any such Confidential Information for any purpose other than the carrying out of its obligations under this Award funding or other than in accordance with the terms of this Award funding. 5.3 The undertaking in Clause 5.1 above shall not apply to Confidential Information: 5.3.1 which, at the time of disclosure, has already been published or is otherwise in the public domain other than through breach of the terms of this Award funding; 5.3.2 which, after disclosure to the Parties, is subsequently published or comes into the public domain by means other than an action or omission on the part of any of the Parties; 5.3.3 which a Party can demonstrate was known to him or subsequently independently developed by them; 5.3.4 lawfully acquired from third parties who had a right to disclose it with no obligations of confidentiality to any of the Parties; or 5.3.5 is required to be disclosed by applicable law or court order or by any Party's regulatory body, which is empowered by Statute or Statutory Instrument, but only to the extent of such disclosure and the Receiving Party shall notify the Disclosing Party promptly of any such request. 5.4 Staff and students and any agents, consultants or sub-contractors engaged to work on the BRC will be subject to the principles of confidentiality outlined in this Clause 5. 6 Term and Termination 6.1 The terms of this award shall come into force on the date when the Acceptance Statement is signed by the Awardee and remain in full force and effect until 31st March 2028 unless terminated earlier in accordance with the provisions of this Clause 6. 6.2 In the event that any Party shall commit any breach of or default in any terms or conditions of this Award funding, the other Party may serve written notice of such breach or default on the defaulting Party and in the event that such Party fails to remedy such default or breach within sixty (60) days after receipt of such written notice the other Party may, at their option and in addition to any other remedies which they may have at law or equity, terminate this Award funding by sending notice of termination in writing to the other Party. 6.3 If any Party (a) materially breaches any provisions of this Award funding ; or (b) passes a resolution for its winding-up; or if (c) a court of competent jurisdiction makes an order for that Party’s winding-up or dissolution; or makes an administration order in relation to that Party; or if any Party (e) appoints a receiver over, or an encumbrancer takes possession of or sells an asset of, that Party; or (f) makes an arrangement or composition with its creditors generally; or (g) makes an application to a court of competent jurisdiction for protection from its creditors generally; the other Party may terminate their involvement in the BRC. 6.4 In the event the BRC Research Contract terminates UHS may terminate this Award funding with immediate effect. 7 General 7.1 Each Party shall indemnify each of the other Parties, within the limits set out in this Clause 6, in respect of liability resulting from acts or omissions of itself, its employees or its students provided always that such indemnity shall not extend to claims for indirect or consequential loss or damages such as, but not limited to, loss of profit, revenue, contracts or the like. 7.2 Any amendments to this Award funding shall be valid only if made in writing and signed by authorised signatories of the Parties. 7.3 If any part or any provision of this Award funding shall to any extent prove invalid or unenforceable in law the remainder of such provision and all other provisions of this Award funding shall remain valid and enforceable to the fullest extent permissible by law, and such provision shall be deemed to be omitted from this Award funding to the extent of such invalidity or unenforceability. The remainder of this Award funding shall continue in full force and effect and the Parties shall negotiate in good faith to replace the invalid or unenforceable provision with a valid, legal and enforceable provision which has an effect as close as possible to the provision or terms being replaced. 7.4 No failure to exercise or delay in the exercise of any right or remedy which any Party may have under this Award funding or in connection with this Award funding shall operate as a waiver thereof, and nor shall any single or partial exercise of any such right or remedy prevent any further or other exercise thereof or of any other such right or remedy. 7.5 This Award funding including its Schedule supersedes all other agreements and understandings, whether written or oral, between the Parties about the BRC constitutes the entire agreement between the Parties regarding the BRC. 7.6 Except as otherwise expressly provided for herein, the Parties confirm that nothing in this Award funding shall confer or purport to confer on any third party any benefit or any right to enforce any term of this Award funding for the purposes of Contracts (Rights of Third Parties) Act 1999. 7.7 This Award funding shall be governed by and construed in accordance with English Law and each Party agrees to submit to the exclusive jurisdiction of the English Courts as regards any claim or matter arising under this Award funding. 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Url: /Media/Southampton-Clinical-Research/Downloads/BRC-Research-imaging-proposal-form-v1-FINAL-10.12.2024.docx

BEACON protocol v8.0 07Mar2023 signed

Description: 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 ..........
Url: /Media/UHS-website-2019/Docs/PaediatricOncology/beacon-protocol-v8.0-07mar2023-signed.pdf

CHINA Protocol v2 4.1.11

Description: REC reference 10/H0501/67 1 The CHildren's INterval Appendicectomy (CHINA) Study A Prospective Randomised Evaluation of Interval Appendicectomy versus Conservative Follow-Up Following Successful Non-Operative Treatment of Appendix Mass in Children STUDY PROTOCOL Version 2, 4th January 2011 Principal investigator: Co-investigators: Mr Nigel Hall Mr David Burge Mr Michael Stanton Professor Agostino Pierro Dr Simon Eaton Southampton General Hospital, London, UK Lead institution: Collaborating institutions: Great Ormond Street Hospital, London, UK Royal London Hospital, London, UK Chelsea and Westminster Hospital, London, UK Hull Royal Infirmary, Kingston-upon-Hull, UK Norfolk and Norwich University Hospital, Norwich, UK Birmingham Children's Hospital, UK Alder Hey Childrens Hospital, Liverpool, UK King's College Hospital, London, UK Leicester Royal Infirmary, UK Royal Hospital for Sick Children, Edinburgh, UK Royal Victoria Infirmary, Newcastle, UK Leeds General Infirmary, UK John Radcliffe Hospital, Oxford, UK Evelina Children's Hospital, London, UK Karolinska Institute, Stockholm, Sweden Royal Alexandra Children's Hospital, Brighton, UK Royal Belfast Hospital for Sick Children, Belfast, UK Queens Medical Centre, Nottingham, UK Addenbrookes Hospital, Cambridge, UK ISRCTN number: 93815412 MREC approval number: 10/H05014/67 CHINA study Protocol Version 2, 4th January 2011 REC reference 10/H0501/67 1. Introduction 2 Up to 22% of children with acute appendicitis present with a walled-off mass surrounding the inflamed appendix known as an appendix mass (AM). Patients presenting with AM are usually treated non-operatively with broad spectrum intravenous antibiotics as the risk of complications from operative intervention in the presence of an inflammatory mass is high.1 Traditional surgical teaching states that interval appendicectomy (IA) should be performed following successful non-operative treatment in order to avoid future recurrence of acute appendicitis. However this approach has recently been questioned in both the paediatric2 and adult literature.3 Proponents of IA argue that the risk of recurrent appendicitis is high and that interval appendicectomy is safe, carries minimal complications and has a low morbidity. Those who argue that IA is unnecessary cite the opposite: a low incidence of recurrent appendicitis and avoidable morbidity, hospital stay and cost associated with IA. Additionally there may be a small risk of missing an underlying diagnosis in patients who do not have an IA. Whilst the risk of recurrent appendicitis is difficult to directly compare with the complications and morbidity of interval appendicectomy, accurate reliable data relating to these two methods of management would allow clinicians, patients and parents to make an evidence-based decision. Such data are not currently available. 2. Aim of the study The principle research question that we aim to address is whether interval appendicectomy is justified following successful non-operative treatment of appendix mass in children. The main factors that contribute to answering this question are: 1. the true incidence of recurrence of acute appendicitis following successful conservative treatment of appendix mass 2. the morbidity and risks associated with interval appendicectomy 3. the risk of missing an alternative diagnosis by not performing an interval appendicectomy 4. the cost effectiveness of each method of treatment We hypothesise that the risk of recurrent acute appendicitis is low and that therefore routine interval appendicectomy is unnecessary. This research aims to generate reliable, accurate data relating to these factors from a prospective randomised study. Only once such data exist can clinicians, patients, parents and policy makers truly assess whether interval appendicectomy is necessary and cost effective. 3. Scientific background Risk of recurrent appendicitis The actual risk of recurrent acute appendicitis in children is largely unknown due to a lack of quality data. No prospective studies comparing IA with continued conservative management ? a watch-and-wait approach - exist. In the largest cohort study of paediatric patients available. Puapong et al4 described a recurrence rate of 8% in 61 children. The time to recurrence was 72hrs post-operatively). Conversion of a laparoscopic to open interval appendicectomy for a technically difficult procedure in the absence of other complications shall not be regarded as a significant complication. Additional data to be collected includes: Interval appendicectomy group duration of hospital admission for interval appendicectomy cost of treatment (full economic analysis) days off school / normal daily activities following interval appendicectomy histopathological assessment of resected appendix Watchful waiting group duration of hospital admission for recurrence outcome of recurrence including all complications days off school / normal daily activities relating to recurrence cost of treatment of recurrence (full economic analysis) episodes of otherwise unexplained abdominal pain during the first year following discharge and time off school / normal daily activities relating to these (assessed at clinic appointment) 1. 2. 3. 4. 1. 2. 3. 4. 5. Parents/Patients who do not consent for the study Parents/Patients who do not consent for the study will be asked for permission to collect data on their child for the purposes of establishing a dataset of children who are eligible but not enrolled. Such data will be anonymised and handled in an identical way to the data relating to patients in the study. An identical dataset to that being collected from individuals in the study will be collected but the course of treatment for these children will be determined by their treating clinician rather than by randomisation. Written consent will be obtained from the parents of such children. If parents do not consent to such data collection then a minimal dataset will be recorded consisting solely of demographic data. It is important to collect such data to validate the applicability of any findings of the study. 5. Sample size calculation We have based this calculation on an assumption of a 20% risk of recurrent acute appendicitis within the first year in the wait-and-see group and a zero incidence of recurrence on the interval appendicectomy group. In order to detect a statistically significant difference in the incidence of recurrent acute appendicitis in the wait-andsee group compared with the interval appendicectomy group will require 40 patients CHINA study Protocol Version 2, 4th January 2011 REC reference 10/H0501/67 per group at 90% power (a=0.05). However, in order to provide as strong evidence as possible on the natural history of this condition we will aim to recruit 50 patients per group. 6. Data collection and statistical analysis 6 A designated administrator at every collaborating centre will obtain data that will be forwarded to the study coordinators. Data will be entered into a specifically designed database and analysed on an intention-to-treat basis. Primary outcome measures will be reported quantitatively as it is not clinically appropriate to compare a recurrence rate with complications of a procedure. Moreover the reporting of these data will allow for an evidence based decision to be taken in the management of these patients in the future. Other outcome variables will be analysed with multivariate binary regression analysis, ordinal regression analysis, Mann-Whitney U test, and ? tests, as appropriate. All statistical analyses will be calculated with adjustment for all minimisation criteria. Skewed continuous data will be transformed to resemble a normal distribution before analysis. Statistical analysis will be performed by one of the research team who has experience in statistical analysis of prospective randomised studies of this nature. Stopping rules In order to ensure that equipoise is maintained throughout the duration of the study, an interim analysis will be performed after data are available for the first half of the recruited patients. Stopping rules will be established prior to study initiation based on the incidence of recurrent appendicitis in the watchful waiting group. The interim analysis will be performed by a statistician with experience in the statistical analysis of randomised studies and not involved in the clinical management of subjects in the study. 7. Organisation and monitoring The study will be co-ordinated by a Research Fellow based at Southampton University Hospitals NHS Trust. In order to maximise the compliance of participating centres in the study, a link surgeon will be identified at each centre who will liaise with the trial co-ordinating centre. Confidentiality of data will be ensured. To ensure that the study progress is in accordance with Medical Research Council (U.K.) guidelines for good clinical practice in multicentre studies, a Study Steering Committee will be established. This will include a limited number of members including: a) independent Chairman (not involved in Study); b) independent members (Paediatric Surgeon and Paediatrician); c) study co-ordinator; d) principal investigator or nominated deputy The role of the steering Committee is to provide overall supervision of the study and ensure that the study is conducted to rigorous scientific, clinical and ethical standards. It will particularly concentrate on progress of the study, adherence to the CHINA study Protocol Version 2, 4th January 2011 REC reference 10/H0501/67 7 protocol, data collection and maximise the chances of completion within the agreed timetable. This committee will meet 6 monthly or more frequently if required. 8. Feasibility and timetable One hundred children are required to fulfil the sample size requirements for this study. On average each Paediatric Surgical Unit in the UK will see 5-10 cases of appendix mass each year. The involvement of 10 centres in this study would therefore see recruitment to the study completed in 2 years with a further year for follow-up to be completed. This project will be co-ordinated by a co-ordinator at the lead centre. A nominated investigator will be identified at each collaborating centre who will be responsible for the implementation of the study locally. The co-ordinator will liaise with the nominated investigator at each centre to ensure compliance with the research protocol, provide assistance where possible and ensure all data are collected. The research team has been selected for its clinical and research experience, particularly in the design and running of randomised controlled studies in the field of Paediatric Surgery. 9. Relevance and Publication Policy It is anticipated that the proposed project will provide quality evidence on which clinicians, parents and patients can base the decision of whether IA is justified following successful non-operative treatment of an appendix mass. Data from this study will we submitted for presentation at local, national and international meetings and submitted for publication in international peer reviewed journals. Authorship of any such presentations and publications will be in accordance with the requirements of the International Committee of Medical Journal Editors (ICMJE) and as follows: Authorship of any presentation or publication will be limited to the principle investigator and those named as co-investigators at the top of this document. The nominated investigator at each collaborating centre will be acknowledged in the manuscript under the heading `Acknowledgements' as having contributed to the study. The National Library of Medicine now lists and indexes both the study group and the individuals acknowledged such that the nominated investigator at each collaborating centre will be identified as having contributed to this study. The nominated investigators contribution to the study will thus be recognisable. Results of the study will be made available to those participants or their parents who specifically request it. 10. Financial implications Unfortunately it will not be possible to offer any financial incentive for institutions who agree to collaborate in this study. However, it is anticipated that the recruitment of patients into this study should not result in any significant costs to institutions involved. Whilst it is likely that the additional out-patient reviews in the `watchful waiting' group will result in a small additional costs to each institution, there may be cost savings in the `interval appendicectomy' group as a fewer number of children will undergo interval appendicectomy than is current practice in many centres. We CHINA study Protocol Version 2, 4th January 2011 REC reference 10/H0501/67 8 therefore anticipate that, at worst, the involvement of any centre in this study will be `cost neutral'. Reference List (1) Erdogan D, Karaman I, Narci A, Karaman A, Cavusoglu YH, Aslan MK, et al. Comparison of two methods for the management of appendicular mass in children. Pediatr Surg Int 21:81-3, 2005 (2) Freitas MS, Glick PL. Interval appendectomy for acute appendicitis. J Pediatr Surg 44:1056-8, 2009 (3) Meshikhes AW. Management of appendiceal mass: controversial issues revisited. J Gastrointest Surg 12:767-75, 2008 (4) Puapong D, Lee SL, Haigh PI, Kaminski A, Liu IL, Applebaum H. Routine interval appendectomy in children is not indicated. J Pediatr Surg 42:1500-3, 2007 (5) Karaca I, Altintoprak Z, Karkiner A, Temir G, Mir E. The management of appendiceal mass in children: is interval appendectomy necessary? Surg Today 31:675-7, 2001 (6) Ein SH, Shandling B. Is interval appendectomy necessary after rupture of an appendiceal mass? J Pediatr Surg 31:849-50, 1996 (7) Gierup J, Karpe B. Aspects on appendiceal abscess in children with special reference to delayed appendectomy. Acta Chir Scand 141:801-3, 1975 (8) Wison-Storey D, Scobie WG. Appendix mass. Pediatr Surg Int 4:168-70, 1989 (9) Gahukamble DB, Khamage AS, Gahukamble LD. Management of appendicular mass in children. Ann Trop Paediatr 13:365-7, 1993 (10) Surana R, Puri P. Appendiceal mass in children. Pediatr Surg Int 10:79-81, 1995 (11) Gahukamble DB, Gahukamble LD. Surgical and pathological basis for interval appendicectomy after resolution of appendicular mass in children. J Pediatr Surg 35:424-7, 2000 (12) Andersson RE, Petzold MG. Nonsurgical treatment of appendiceal abscess or phlegmon: a systematic review and meta-analysis. Ann Surg 246:741-8, 2007 (13) Kumar S, Jain S. Treatment of appendiceal mass: prospective, randomized clinical trial. Indian J Gastroenterol 23:165-7, 2004 (14) Karp MP, Caldarola VA, Cooney DR, Allen JE, Jewett TC, Jr. The avoidable excesses in the management of perforated appendicitis in children. J Pediatr Surg 21:506-10, 1986 (15) Truty MJ, Stulak JM, Utter PA, Solberg JJ, Degnim AC. Appendicitis after appendectomy. Arch Surg 143:413-5, 2008 CHINA study Protocol Version 2, 4th January 2011 REC reference 10/H0501/67 (16) Rees CM, Eaton S, Kiely EM, Wade AM, McHugh K, Pierro A. Peritoneal drainage or laparotomy for neonatal bowel perforation? A randomized controlled trial. Ann Surg 248:44-51, 2008 9 (17) Hall NJ, Pacilli M, Eaton S, Reblock K, Gaines BA, Pastor A, et al. Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a doubleblind multicentre randomised controlled trial. Lancet 373:390-8, 2009 CHINA study Protocol Version 2, 4th January 2011
Url: /Media/Southampton-Clinical-Research/Research-protocol/CHINA-Protocol-v2-4.1.11.pdf

ACCORD-2 master protocol

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