Composition of the coordinating centre and trial steering committee {5d}
The day-to-day management of the trial will be co-ordinated through the Imperial Clinical Trials Unit and the Chief Investigator. A Trial Management Group (TMG) will also be convened including the Chief Investigator, co-investigators and key collaborators, trial statistician and trial manager. The TMG will be responsible for operational issues including recruitment and other practical aspects of the trial.
A Trial Steering Committee (TSC) will be convened including as a minimum an independent Chair, 2 independent clinicians, a lay representative (also independent), the Chief Investigator and Trial Manager. The role of the TSC is to provide overall supervision of trial conduct and progress. A TSC Charter will be devised to list the roles and responsibilities of the TSC members. Frequency of meetings will be defined in the Charter. The first TSC meeting to take place following the start of recruitment will be after the first 10 patients have been randomised to the study and thereafter frequency of meetings will be determined by the DMEC and TSC based on this initial data.
Composition of the data monitoring committee, its role and reporting structure {21a}
An independent Data Monitoring and Ethical Committee (DMEC) will be set up to monitor progress, patient safety and any ethical issues involved in this trial. They will review trial progress, recruitment rates, event rates and safety data. A separate charter will be drawn up defining their exact remit and criteria for reporting to the trial steering committee. Frequency of meetings will be defined in the Charter. The first DMEC meeting to take place following the start of recruitment will be after the first 10 patients have been randomised to the study and thereafter frequency of meetings will be determined by the DMEC and TSC based on this initial data.
Adverse event reporting and harms {22}
The Imperial Clinical Trials Unit (ICTU) has been delegated by the Sponsor to undertake all sponsor duties relating to pharmacovigilance. All non-serious AR/AEs, whether expected or not, should be recorded in the adverse event section of the relevant case report form. All new SAEs regardless of causality, occurring after the patient has signed informed consent and until the last patient visit must be reported to ICTU within 24 h of learning of its occurrence and must also be recorded on adverse event case report form (AE CRF) within the InForm database. Recurrent episodes, complications, or progression of the initial SAE must be reported as a follow-up to the original episode, regardless of when the event occurs. This report must be submitted according to the study-specific reporting procedures. An SAE that is considered completely unrelated to a previously reported one should be reported separately as a new event.
At each contact with the subject during the treatment period, the Investigator must seek information on adverse events by specific questioning and, as appropriate, by examination. Information elicited should be recorded immediately in the source document, and the AE CRF. All clearly related signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source document using the event terms and grading given in the relevant eCRF pages. The clinical course of each event should be followed until resolution or stabilisation.
Many clinical events are likely to occur which would ordinarily need recording as adverse events. However, events that are recognised and expected complications of the condition (listed in Appendix 1 of study protocol) are exempt from the normal recording procedures, unless they become ‘serious’ by definition.
A pre-existing condition should not be reported as an AE unless the condition worsens during the trial. The condition, however, must be reported in the Medical History Form.
All serious adverse events and reactions must be reported immediately by the Principal Investigator or delegate to ICTU. In turn, ICTU will inform the Sponsor (within 24 h of becoming aware of the event) and the Funder (as soon as becoming aware and not more than 15 calendar days). Summary of product characteristics (SmPC) should be used as the Reference Safety Information. Serious adverse events expected to occur with Canakinumab should be recorded on an SAE/SUSAR Report Form on InForm and the ICTU/Sponsor informed within 24 h. A submitted SAE form on InForm will automatically send alert emails to the Chief Investigator, the Project Manager, and the Sponsor. Adverse Events considered to be expected for Reporting purposes are detailed in Appendix 2 of the study protocol. These reports should be followed by further detailed SAE/SUSAR Report Forms until resolution of the event. The SAE/SUSAR Report Form should be completed as though the patients were taking active form of IMP, even though all parties are blinded.
ICTU will report SUSARs to the regulatory authorities (MHRA and the relevant ethics committees) as follows:
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SUSARs which are fatal or life-threatening will be reported within 7 calendar days of the CTU first becoming aware of the reaction. Any additional relevant information must be reported within a further 8 days (i.e. by day 15).
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SUSARs that are not fatal or life-threatening will be reported within 15 days of the CTU first becoming aware of the reaction.
Annual Safety reports will be submitted to the Sponsor, the Ethics Committee and Regulatory Authority in accordance with regulatory requirements. Novartis Pharmaceuticals UK Limited will be responsible for submission of the Development Safety Update Report (DSUR). The Sponsor (via ICTU) will provide information required by Novartis to include the study in the Novartis DSUR in an integrated manner. Novartis will provide a copy of the submitted DSUR to ICTU for filing in the study TMF.
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later than 3 days from the date the measures are taken, give written notice to the relevant REC of the measures taken and the circumstances giving rise to those measures.
Infections
Episodes of infection are of special interest in this study given the mode of action of the intervention and the patient population. Infections will therefore be prospectively recorded in the eCRF. Serious infections will additionally be recorded by SAE reporting. SAE reports will be further subdivided by MedDRA categorisation that will document the site of infection. Infections will be tabulated and presented using both methods of reporting.
Frequency and plans for auditing trial conduct {23}
Initiation visits will be completed at all trial sites prior to the recruitment of participants and will consist of a review of protocol and trial documents, training with respect to trial procedures (informed consent, SAE reporting, inclusion, and exclusion criteria), review of recruitment strategy, review of site facilities and equipment, essential document receipt, collection and filing, and archiving and inspection.
The study will be monitored periodically by a trial monitor to assess the progress of the study, verify adherence to the protocol, ICH GCP E6 guidelines and other national/international requirements and to review the completeness, accuracy, and consistency of the data. A monitoring plan will be devised based on risk analysis and described in detail in the monitoring manual. A Trial Monitor will visit all sites and facilities where the trial will take place to ensure compliance with the protocol, GCP and local regulatory compliance.
The investigators will allow the monitors to:
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Inspect the site, the facilities, IMP management and materials used for the trial
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Meet all members of the team involved in the trial, and ensure all staff working on the trial are experienced and appropriately trained, and have access to review all of the documents relevant to the trial
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Have access to the electronic case record forms and source data
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Discuss with the investigator and site staff trial progress and any issues on a regular basis
The monitor will ensure that:
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All participant records will be inspected for confirmation of existence, eligibility and informed consent
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There is adherence to the protocol, including consistency with inclusion/exclusion criteria
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There is GCP and regulatory compliance
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Trial Documentation is complete and up to date (e.g. correct versions of documents being used, source data captured) and relevant documents are collected for the Trial Master File (TMF)
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The eCRFs have been completed correctly and accurately, and all entries correspond to data captured in source documents
At the end of the trial, close out visits will be performed by the monitor after the final participant visit has been completed.
Each investigator will also be notified that an audit or inspection may be carried out—by the sponsor, sponsor’s representatives or the host institution, or regulatory authorities—at any time, before, during or after the end of the trial. The investigator must allow the representatives of the audit or inspection team:
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To inspect the site, facilities and material used for the trial
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To meet all members of his/her team involved in the trial
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To have direct access to trial data and source documents
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To consult all of the documents relevant to the trial
If an Investigator is informed of an impending audit or inspection, the trial coordination centre should be notified immediately.
Quality Control will be performed according to Imperial Clinical Trials Unit internal procedures. The study may be audited by a Quality Assurance representative of the Sponsor and/or ICTU. All necessary data and documents will be made available for inspection.
The study may also be subject to inspection and audit by Imperial College London under their remit as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to GCP.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Approved protocol modifications will be communicated to sites by the Trial Manager and relevant site documentation will be updated.
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later than 3 days from the date the measures are taken, give written notice to the relevant REC of the measures taken and the circumstances giving rise to those measures.
If, in the opinion of the Chief Investigator, clinical events indicate that it is not justifiable to continue the trial, the Trial Steering Committee may terminate the trial following consultation with the Sponsor.
Dissemination plans {31a}
Verbal or written discussion of results prior to study completion and full reporting should only be undertaken with written consent from the Sponsor. All information obtained as a result of the study will be regarded as confidential, at least until appropriate analysis and review by the investigator(s) are completed.
The results may be published or presented by the investigator(s), but the Sponsor will be given the opportunity to review and comment on any such results before any presentations or publications are produced. All publications and presentations relating to the study will be authorised by the Trial Management Group. Authorship will be determined according to the internationally agreed criteria for authorship (www.icmje.org). Authorship of parallel studies initiated outside of the Trial Management Group will be according to the individuals involved in the project but must acknowledge the contribution of the Trial Management Group and the Study Coordination Centre.
Novartis, as study funder, will be informed of study publications as per the contract between Novartis and Imperial College.
Internet and social media will be used to disseminate trial results to wider stakeholders such as healthcare professionals, patients and the public.