Site Initiation Visit Version 2.7_20221031 - PowerPoint Presentation

1. Site Initiation VisitVersion 2.7_20221031

2. Agenda BackgroundEpidemics & Pandemics Design: adaptive platform trialsREMAP-CAPSponsor & study managementModular protocol structurePopulationEndpointsEligibility criteriaInformed Consent ProcessSafetyMedicationeCRFPracticalInvestigator Site FileDuring recruitmentStay up to dateClose-Out2

3. Background: Epidemics & Pandemics -Study Design

4. commencedsubmittedapproval4Epidemics & Pandemics

5. How to improve?Pre-plannedPre-approvedPracticedRespiratory infection: (REMAP-)CAP!5

6. OutcomesInt A1Int A2Int A3…5Trial AOutcomesInt B1Int B2Trial BTraditional RCTs – serial testing of single hypothesesSet randomization ratioREMAP – parallel testing of multiple hypothesesResponse Adaptive Randomization (RAR) a self-learning systemInt C1Int C2Trial COutcomes6Design: adaptive platform trial

7. Response Adaptive Randomization7

8. Sponsor introduction

9. Sponsor & study managementChief Investigator EU: Marc BontenScientific EU Lead: Lennie DerdeScientific EU Co-lead: Helen Leavis, Marjolein HensgensUK Chief Investigator and UK Medical Monitor: Professor Anthony GordonProject Management Team – Imperial College LondonClinical Trials Unit - ICNARC9

10. Modular protocol structure10Non-pandemic situation

11. Modular protocol structure11Pandemic situation

12. Modular protocol structure – Domains Non Pandemic only CCorticosteroidC.1 - No Hydrocortisone or other systemic corticosteroidC.2 - IV Hydrocortisone 50 mg every 6 hours for 7 daysC.3 - IV Hydrocortisone 50 mg every 6 hours while in septic shockC.4 - Fixed duration dexamethasone for 10 daysIAntiviralI.1 - No Oseltamivir or other antiviral agent active against influenzaI.2 - 5 days of OseltamivirI.3 - 10 days of OseltamivirI.4 - Baloxavir on days 1 and 4I.5 - 5 days oseltamivir + baloxavir on days 1 and 4I.6 - 10 days oseltamivir + baloxavir on days 1 and 4 DomainInterventions

13. Modular protocol structure – Domains  COVID-19 and Non Pandemic AAntibiotic    A.1 - Ceftriaxone + MacrolideA.2 - Moxifloxacin or levofloxacinA.3 - Piperacillin-tazobactam + MacrolideA.4 - Ceftaroline + MacrolideA.5 - Amoxicillin-clavulanate + MacrolideMMacrolide duration  M.1 - Standard course (3 to 5 days) M.2 - Extended course (14 days or hospital discharge, whichever occurs first)DCysteamine Domain(Severe only)D.1- No Cysteamine (no placebo)D.2- Cysteamine DomainInterventions

14. Modular protocol structure – Domains  DomainInterventions COVID-19 only SCOVID-19 Statin Therapy(Severe and moderate)S.1 - No simvastatin (no placebo)S.2 - SimvastatinHCOVID-19 Anticoagulation 3(Severe only)H.3- Conventional low dose thromboprophylaxis with prior TACH.4 - Intermediate dose thromboprophylaxis with prior TACH.5 - Continuation of therapeutic dose anticoagulation with prior TACH.6- Conventional low dose thromboprophylaxis no prior TACH.7 - Intermediate dose thromboprophylaxis no prior TAC RCOVID-19 ACE2 RAS(Closed for Severe and on hold for moderate)R.1 - No RAS inhibitor (no placebo)R.2 - Angiotensin converting enzyme inhibitor (ACEi)R.3 - Angiotensin II receptor blocker (ARB)R.4 - ARB in combination with DMX-200, a chemokine receptor-2 [CCR2] inhibitor (ARB + DMX-200)PCOVID-19 Immunoglobulin Therapy (Severe and moderate)P1 – No immunoglobulin against COVID-19P4 – High titre convalescent plasma

15. Patient Population Adult patients, divided into 3 strata & 2 states:PISOP PINSNP (Pandemic infection is (Pandemic infection is neither suspected or proven) suspected nor proven) Pandemic: PISOP (COVID-19)Severe State Moderate State(receiving organ Not being admitted to an ICU, or admitted failure support in an ICU) to an ICU & not receiving organ support Non-Pandemic: PINSNP (severe CAP) Adult patient admitted to an ICU for acute severe CAP within 48 hours of hospital admission Up to 48 hours after ICU admission, receiving organ support Non-Pandemic: PINSNP (influenza)Adults and children admitted to hospital acutely unwell with confirmed influenza 15

16. Trial end pointsPrimary end point(s)Pandemic patients: Day 21 mortality and organ support free daysNon-pandemic patients: Day 90 mortalitySecondary end pointPandemic patients: Day 90 mortality and Day 180 mortality/QoL (optional for subject)Non-pandemic patients: Day 180 mortality/QoL (optional for subject)NB: end points require timely entry in the eCRF > Response Adaptive Randomization!16

17. Modular protocol structure -randomization17

18. Eligibility Criteria – Core ProtocolREMAP Inclusion Criteria 1. Adult or pediatric patient (28 days or older) hospitalized with an acute illness due to a lower respiratory tract infection18

19. Eligibility Criteria – Core ProtocolREMAP Exclusion Criteria If receiving organ failure support in an ICU, more than 48 hours has elapsed since admission to ICU More than 14 days has elapsed since admission to hospital Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker or attending physician are not committed to full active treatment.Previous participation in this REMAP within the last 90 daysExpected to be discharged from this hospital admission within the next 24 hours 19

20. Eligibility Criteria - PAtCInclusion criteria: 1. Adult patient admitted to hospital with acute illness due to suspected or proven pandemic infection Exclusion criteria: 1. Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker or attending physician are not committed to full active treatment 2. Patient is expected to be discharged from hospital today or tomorrow 3. More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection 4. Previous participation in this REMAP within the last 90 days 20

21. Eligibility Criteria - DomainsRefer to domain presentations on Domain Specific Appendices for:Domain specific Eligibility criteriaDomain rationaleConcomitant CarePotential domain-specific adverse eventsOther domain specific informationDocument review of DSA (and/or DSA training slides) Reach out to the Project Team with any questions21

22. Informed Consent ProcessPatient Information Leaflet & Informed Consent form (PIL/ICF)General principlesDeferred consent: Patient not capable to provide consent  PerLR - Personal Legal Representative (NOK/relative/friend) or ProLR - Professional Legal RepresentativeDelayed consent: ProLR/PerLR not available prior to randomization  consent must be obtained as soon as possible (preferably within 24 hrs.) after initiation of the study interventionsVerbal consent: Pandemic situation: verbal consent possible in UK.Taking consent – must be taken by a site member listed on the delegation log as permitted to take consentProLR – must be an independent doctor NOT listed on the delegation logOnce patient regains capacity always obtain patient informed consentDOCUMENT the Informed consent process!22

23. SafetyProtocol deviation/violationComplete form in eCRF Update form in Investigator Site File (ISF)E.g. Antiviral domain (randomized to 5 days treatment, but given for 7 days)Serious Adverse Event (SAE)Report SAE if (suspected to be) related to study treatment / study participation Or if it is a defined domain-specific serious adverse event that requires reportingUse an SAE form in the eCRF Send a SAE form via email ONLY if eCRF is not accessible (ukremap-cap@icnarc.ac.uk)Within 24 hours of becoming aware of eventDocument in patient file We don’t expect many SAEs E.g. if a patient dies as a deterioration of CAP  not considered SAE23

24. ICH-GCP – Investigator ResponsibilitiesThe investigator has overall responsibility for all aspects of the trial conducted at site.The investigator must ensure the trial is conducted in accordance with ICH-GCP requirements and local law and regulations.The investigator must ensure that the documentation is complete, accurate, legible and recorded in a timely manner. Avoid premature destruction or loss of essential documents by:immediately filing all documents in the correct binderkeeping documents in a fireproof cabinet/lockable cupboard or room24

25. Investigational Medicinal Product (IMP)Drug accountability:ICH/GCPDrug accountability records should include dates, quantities, batch/serial numbers, expiration dates, and the unique code numbers assigned to the investigational product(s) and trial subjects. EU GMP Annex 13 - relabeling of IMPs:If required: central distribution re-labelled IMPs from the Netherlandsor re-labelling of local stock at site.IMP temperature logs should be filed in the ISFPreparation, storage and administration of IMPs:Refer to DSA VX.X, Pharmacy Guide VX.X and Administration guide VX.X25

26. eCRF - Spiral26

27. eCRF - SPIRALhttps://remapcap.spinnakersoftware.com Login screenOption 1: Login as individual (PI, RC)Option 2: Generic site login (randomization only)eCRF test accountUsername: RohanInfirmary Password: COVID-1927

28. eCRF – SPIRAL – General informationRecommended browsers- Mozilla Firefox- Google Chrome- SafariSPIRAL database form needed to set up site in SPIRAL according to domain/intervention selectionto create personal user accountsuser invitation will expire after 5 days. If the invitation has expired, ask the project manager to re-send the invitation.usernames must be an email addressdetailed info available in the SPIRAL Database user guide and eCRF completion guidelines28

29. eCRF dashboard1.2.3.4.5.29Total and site enrolments List of patients randomized at site (test-site in this example)Subjects for which additional information is required If applicable: patients that are being transferred from one REMAP-CAP hospital to another Open queries which require action

30. eCRF: RandomizationRandomization dashboardInfo box: also in completion guidelines30

31. eCRF: Randomization - general31No need to check all domain criteria upfront; All eligibility criteria are reviewed with the questions asked in the eCRF randomization process.All questions on each page must be answered before clicking “Next” to load the next page.The database reviews eligibility after every page (when you click “Next”) to avoid unnecessary data entry.The database will inform the user if the patient is no longer eligible.If you are using the generic site account, you will be prompted to enter your name and designation. If you are using an individual account this section will not appear as it is automatically filled with your details.Eligibility defined at multiple levels: Platform criteria, Domain criteria, Intervention criteriaData entry for randomization takes approx. 10 minutesDo not enter privacy sensitive data in the eCRF (e.g. name of the patient)

32. eCRF: Randomization32

33. eCRF: RandomizationSystem can calculate time-window and decide whether patient (CAP/COVID-19) is eligible CAP (ICU only): max. 48 hours between hospital admission and ICU admissionCOVID-19 (ICU & ward): randomization within 2 weeks of hospital admissionDomain specific criteria (ICU): randomization within specified amount of hours after ICU admission33

34. eCRF: RandomizationIf yes: ineligible for randomisation  screening list34

35. eCRF: Randomization35

36. eCRF: RandomizationDomain-specific exclusion questions:N.B. Patient might be ineligible for a certain domain, but other domains might still be an option!36

37. eCRF: RandomizationN.B. Known contraindication for a certain drug leads to exclusion for that intervention, but not necessarily the domain to which the intervention belongs. As long as there are at least 2 interventions remaining, randomization in that domain can continue!37

38. eCRF: Randomization38or

39. eCRF: RandomizationN.B. final manual step before randomization to decide whether or not to randomize a patient in that domain!”EMERGENCY BRAKE”39

40. eCRF: Randomization result1.2.3.4.Patient credentialsRandomization result per domainNext stepsInformation to be updated in the eCRF (later moment in time)40

41. eCRF navigation tab: patient - patient listE-mail notificationsClick on individual pt to see details & complete eCRF41

42. eCRF: patient summary1.2.3.4.5.421. eCRF Navigation tab: Clicking the eCRF name or icon (tick or cross) will open the corresponding CRF page2. Patient Details: a summary of the patient’s details and the link to transfer the patient to another site. You can also add a note for other people reviewing the patient’s eCRF3. Randomization allocation4. Event reporting: links to adverse event, serious adverse event, and protocol deviation eCRFs .5. Change log

43. eCRF navigation Tab: patient - eligibility list (screenings)43

44. eCRF navigation - Investigator sign off441. Navigate to the patient summary page, and click on the "investigator sign off" button.

45. eCRF navigation - Investigator sign off452. The investigator will then be asked to confirm 

46. eCRF navigation - Investigator sign off463. If confirmed, the CRF will be locked. This will appear on the patient summary and change log.

47. eCRF: overview47

48. eCRF resources tabAlso check www.remapcap.orgFor:Protocol documentsAdministration guidesCRF completion guidelines48

49. Practical49

50. Practical: Investigator Site FileA (digital) Investigator Site File (ISF) will be sent to you prior to activationUpdated documents will be shared by Sponsor/Project Management teamSite’s responsibility to keep the ISF up-to-date File ISF updates and correspondenceAdd documents of new team members (CV, GCP, FDF, training log, authorization form)Add updates of laboratory certificatesKeep logs up-to-date Some documents will always need to be collected in paper, e.g.PIS/ICFsDocuments signed by PI (e.g. protocol signature pages, retention of records statement, domain choice pages)N.B. Make use of document referral notes to ensure transparancy (for auditors/monitors) on where to find specific documents50

51. Practical: during recruitmentOn-site monitor visit by CRA - each recruiting site will be visited by a monitor during the study. Audits/Inspections – please notify the Sponsor immediately when announcedAmendments to the protocol, such as addition/removal domains: Notification before change is implemented.Platform Conclusion relevant to public health will be:Presentation and/or publication Site staff is acknowledged by their names being listed as collaboratorsSite investigators may not publish or present interim or definite results51

52. Practical: Source Data and MonitoringRequirements for the source data (essential documents)Requirement for source data (ICH- GCP 4.9.0): The investigator/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit trail)It must be clear from documentation that study-related tasks are carried out by delegated personnelChecking and evaluation of laboratory values ​​and medical findings for clinical significance needs to be documented in the source data (incl. date and signature of investigator)52

53. Practical: Source Data and MonitoringRequirements for the source data (essential documents)Requirement for electronic patient records:Access rights regulatedSecurity systems in placeLaboratory values etc. can be evaluated electronically (checked for clinical significance)Audit trail Monitor account can be set up with access limited to study participants If read only access to study subjects (or audit trail) is not possible, certified copies of source data must be printed.53

54. Practical: Close-OutIn theory, REMAP-CAP will run indefinitely Limiting factorsFundingPoor site performanceSite’s request to stop recruitmentAll scientific questions have been answeredClose-Out visit by Project Management Team/SponsorNotification Ethics Committee/Competent Authority & local hospitalStudy records should be retained for 25 Years54

55. CONTACT USGeneral e-mail adress (always in cc):Ukremap-cap@icnarc.ac.ukSee also https://www.icnarc.org/Our-Research/Studies/Remap-Cap/ 55

56. Thank you!56