Wards Essential Training - PowerPoint Presentation

1. Wards Essential TrainingVersion 1.0_20221128

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 LeavisUK Chief Investigator: 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.5 - 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 4Immune modulation(coming in 2023)XX – No immune modulatorXX – TocilizumabXX – Barictinib 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)Day 90 mortality and organ support free daysSecondary end point – vary by domainInfluenza patients: organ support free days, duration of hospital stay and health related QoL (optional for subject).NB: end points require timely entry in the eCRF > Response Adaptive Randomization!16

17. Eligibility Criteria – InfluenzaREMAP Inclusion Criteria - InfluenzaAdult or paediatric patient (28 days or older) hospitalised (in the general ward or an ICU) with an acute illness due to influenza REMAP Exclusion Criteria - InfluenzaMore than 14 days has elapsed since admission to hospitalIf receiving organ failure support in an ICU, more than 48 hours has elapsed since admission to ICU 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. Expected to be discharged from this hospital admission within the next 24 hoursPrevious participation in REMAP-CAP within the last 90 days 17

18. Eligibility Criteria – Influenza Domain specificPatient must meet criteria on previous slide AND:-Anti-viral domainExclusion criteria:More than 96 hours has elapsed since hospital or ICU admissionAlready received ≥2 doses of doses of oseltamivir or ≥1 dose of Baloxavir for this illnessCorticosteroid domainInclusion criteriaReceiving supplemental oxygenExclusion criteriaReceiving or planned to receive, corticosteroids for alternate indicationIf in ICU, >24 hours since ICU admission18

19. Immune modulation domain (starting early 2023)Inclusion criteria:Receiving respiratory support more than simple supplemental oxygen (i.e. high-flow nasal cannula therapy / non-invasive ventilation (including CPAP) / invasive mechanical ventilation)Exclusion criteria (based on those successfully used in COVID-19):More than 48 hours of respiratory support in ICUKnown immunosuppressionAlready received any IL-6 or IL-1 receptor antagonists or JAK inhibitorConfirmed mycobacterial, strongyloides, or fungal infectionsLiver enzymes (ALT/AST) more than five times the upper limit of normal will result in exclusion from receiving tocilizumabBaseline platelet count < 50 x 109 / L will result in exclusion from receiving tocilizumabA baseline eGFR/CrCl <15 mL/min and/or receipt of renal replacement therapy will result in exclusion from receiving baricitinib19

20. Informed Consent ProcessPatient Information Sheet & Informed Consent form (PIS/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 possibleTaking 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!20

21. 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 SAE21

22. 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 room22

23. 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.X23