Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (REMAP-CAP)

• ClinicalTrials.gov Identifier: NCT02735707
• Recruitment Status: Recruiting
• First Posted: April 13, 2016
• Last Update Posted: December 21, 2021
• Sponsor: UMC Utrecht
• Collaborators: Australian and New Zealand Intensive Care Research Centre; Medical Research Institute of New Zealand; Unity Health; Berry Consultants; Global Coalition for Adaptive Research; University of Pittsburgh Medical Center; Intensive Care National Audit & Research Centre; St. Marianna University School of Medicine; National Intensive Care Surveillance MORU
• Information provided by (Responsible Party): Lennie Derde, UMC Utrecht

Tracking Information

• First Submitted Date: December 11, 2015
• First Posted Date: April 13, 2016
• Last Update Posted Date: December 21, 2021
• Actual Study Start Date: April 11, 2016
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 17, 2020)

• All-cause mortality [ Time Frame: Day 90 ]
• Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ]
  Primary end-point for patients with suspected or proven COVID-19 pandemic infection

Original Primary Outcome Measures (submitted: April 6, 2016)

Mortality (%) measured at day 60 after randomization of the patients included in this trial. [ Time Frame: 60 days ]

Mortality (%) measured at day 60 after randomization of the patients included in this trial for all different interventions.

Current Secondary Outcome Measures (submitted: April 15, 2020)

• ICU Mortality [ Time Frame: Day 90 ]
• ICU length of stay [ Time Frame: Day 90 ]
• Hospital length of stay [ Time Frame: Day 90 ]
• Ventilator free days [ Time Frame: Day 28 ]
• Organ failure free days [ Time Frame: Day 28 ]
• All-cause mortality [ Time Frame: 6 months ]
• Health-related Quality of life assessment [ Time Frame: 6 months ]
  EQ5D-5L and WHODAS 2.0 (not completed in all regions)
• Proportion of intubated patients who receive a tracheostomy [ Time Frame: Day 28 ]
• Destination at time of hospital discharge [ Time Frame: Free text Day 90 ]
  Characterised as home, rehabilitation hospital, nursing home or long-term care facility, or another acute hospital
• Readmission to the index ICU during the index hospitalization [ Time Frame: Day 90 ]
• World Health Organisation 8-point ordinal scale outcome [ Time Frame: Hospital discharge ]

Original Secondary Outcome Measures (submitted: April 6, 2016)

• ICU length of stay of the patients included in this trial. [ Time Frame: Through study completion, average of 6 days ]
  ICU length of stay of the patients included in this trial, measured in number of days for all interventions
• Hospital length of stay of the patients included in this trial. [ Time Frame: Through study completion, average of 10 days ]
  Hospital length of stay of the patients included in this trial, measured in number of days for all interventions.
• Ventilator free days. [ Time Frame: Day 30 ]
  Measure the number of ventilator free days of the patients included in this trial at day 30.
• Ventilator free days. [ Time Frame: Day 60 ]
  Measure the number of ventilator free days of the patients included in this trial at day 60.
• Organ failure free days. [ Time Frame: Day 30 ]
  Measure the number of organ failure free days of the patients included in this trial at day 30.
• Organ failure free days. [ Time Frame: Day 60 ]
  Measure the number of organ failure free days of the patients included in this trial at day 60.

Current Other Pre-specified Outcome Measures (submitted: December 3, 2021)

• Occurrence of multi-resistant organism colonisation/infection [ Time Frame: Day 90, censored at hospital discharge ]
  Antibiotic Domain specific outcome
• Occurrence clostridium difficile [ Time Frame: Day 90, censored at hospital discharge ]
  Antibiotic Domain specific outcome
• Occurrence of serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected death [ Time Frame: Day 90, censored at hospital discharge ]
  Macrolide Duration Domain specific outcome.
• Change from baseline influenza virus levels in upper and lower respiratory tract specimens [ Time Frame: Day 3, up to Day 7 ]
  Antiviral Domain specific outcome. Only required at selected sites.
• Confirmed deep vein thrombosis [ Time Frame: Between randomisation and hospital discharge ]
  Domain-specific outcome for Anticoagulation, Immunoglobulin, and Antiplatelet Domains.
• Confirmed pulmonary embolism [ Time Frame: Between randomisation and hospital discharge ]
  Domain-specific outcome for Anticoagulation, Immunoglobulin, and Antiplatelet Domains.
• Confirmed ischaemic cerebrovascular event [ Time Frame: Between randomisation and hospital discharge ]
  Domain-specific outcome for Anticoagulation, Immunoglobulin, and Antiplatelet Domains.
• Total red blood cell units transfused [ Time Frame: Between randomisation and end of study day 15 ]
  Domain-specific outcome for Anticoagulation and Antiplatelet Domains.
• Confirmed acute myocardial infarction [ Time Frame: Between randomisation and hospital discharge ]
  Domain-specific outcome for Anticoagulation, Immunoglobulin, and Antiplatelet Domains.
• Peak troponin [ Time Frame: Between randomisation and end of study day 15 ]
  Domain-specific outcome for Anticoagulation and Antiplatelet Domains.
• Major bleeding event [ Time Frame: Between randomisation and end of study day 15 ]
  Domain-specific outcome for Anticoagulation and Antiplatelet Domains.
• Other confirmed thrombotic event, including mesenteric ischaemia and limb ischaemia [ Time Frame: Between randomisation and hospital discharge ]
  Domain-specific outcome for Anticoagulation, Immunoglobulin, and Antiplatelet Domains.
• Acute kidney injury (KDIGO stage >= 2 acute kidney injury) [ Time Frame: Between randomisation and 7 days ]
  Domain-specific outcome for ACE2 RAS Domain
• Change from baseline to peak creatinine [ Time Frame: Between randomisation and 14 days ]
  Domain-specific outcome for ACE2 RAS Domain
• Angioedema [ Time Frame: Between randomisation and end of study day 12 ]
  Domain-specific outcome for ACE2 RAS Domain
• Change from baseline AST, ALT and bilirubin [ Time Frame: Between randomisation and 14 days ]
  Domain-specific outcome for ACE2 RAS Domain

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia
• Official Title: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia

Brief Summary

REMAP-CAP is a randomised, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia.

The purpose of this study is to evaluate the effect of a range of interventions to improve outcome of patients admitted to intensive care with community-acquired pneumonia.

In addition, REMAP-CAP provides and adaptive research platform for evaluation of multiple treatment modalities in the event of a respiratory pandemic such as COVID-19.

REMAP-COVID is a sub-platform of REMAP-CAP that evaluates treatments specific to COVID-19 in the United States of America.

Detailed Description

Community-acquired pneumonia (CAP) that is of sufficient severity to require admission to an intensive care unit (ICU) is associated with substantial mortality.

Patients with pneumonia who are being treated in an ICU will receive therapy that consists of many different treatments, as many as 20 or 30. These treatments act together to treat both the infection and its effects on the body. When treating a patient, doctors choose from many different treatments, most of which are known or believed to be safe and effective. However, doctors don't always know which treatment option is the better one, as individuals or groups of individuals may respond differently. This study aims to help doctors understand which treatments work best.

This clinical study has been designed in a way that allows the information from patients already in the study to help new patients joining the study. Most studies aren't able to do that. REMAP-CAP has been designed to:

• Evaluate multiple treatment strategies, at the same time, in the same patient.
• Reach platform conclusions when sufficient data is accrued, rather than when a pre-specified sample size is reached
• Utilise data that is already accrued to increase the likelihood that patients within the trial are randomised to treatments that are more likely to be beneficial
• New questions can be substituted into the trial as initial questions are answered, meaning that the trial can be perpetual or open-ended
• Interactions between interventions in different domains can be evaluated

It is reasonable to presume that any pandemic respiratory infection of major significance to public health will manifest as life-threatening respiratory infection including Severe Acute Respiratory illness and severe Community Acquired Pneumonia (CAP) with concomitant admission to hospital, and for some patients, admission to an Intensive Care Unit (ICU). Previous pandemics and more localized outbreaks of respiratory emerging infections have resulted in severe CAP and ICU admission.

Previous pandemics and outbreaks of emerging infectious diseases have outlined the urgent need for evidence, preferably from Randomized Controlled Trials (RCTs), to guide best treatment. However, there are substantial challenges associated with being able to organize such trials when the time of onset of a pandemic and its exact nature are unpredictable. As an adaptive platform trial that enrolls patients during the interpandemic period, REMAP-CAP is ideally positioned to adapt, in the event of a respiratory pandemic, to evaluate existing treatments as well as novel approaches.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

Adaptive Bayesian Platform Trial evaluating multiple interventions in multiple domains

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Community-acquired Pneumonia, Influenza, COVID-19

Intervention

• Drug: Ceftriaxone
  The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
• Drug: Moxifloxacin or Levofloxacin
  The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
• Drug: Piperacillin-tazobactam
  The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
• Drug: Ceftaroline
  The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
• Drug: Amoxicillin-clavulanate
  The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
• Drug: Standard course macrolide

  Standard course of macrolide therapy, discontinued between study day 3 and the end of study day 5.

  The dosing of and route of administration is not protocolised, the following guidance is provided:

  • Initial IV administration of a macrolide is strongly preferred
  • The preferred IV macrolide is azithromycin, but IV clarithromycin may be substituted.
  • The preferred enteral macrolide is azithromycin, but enteral clarithromycin or roxithromycin may be substituted.
• Drug: Extended course macrolide

  Extended course of macrolide therapy discontinued at the end of study day 14 or hospital discharge (whichever occurs first).

  The dosing of and route of administration is not protocolised, the following guidance is provided:

  • Initial IV administration of a macrolide is strongly preferred
  • The preferred IV macrolide is azithromycin, but IV clarithromycin may be substituted.
  • The preferred enteral macrolide is azithromycin, but enteral clarithromycin or roxithromycin may be substituted.
• Other: No systemic corticosteroid
  Patients are not to receive any systemic corticosteroids, including hydrocortisone, to study day 28 or hospital discharge (whichever occurs first).
• Drug: Fixed-duration Hydrocortisone
  50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.
• Drug: Shock-dependent hydrocortisone
  50mg IV hydrocortisone every 6 hours while the patient is in septic shock
• Drug: Fixed-duration higher dose Hydrocortisone

  100mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.

  Note: this intervention was only available to patients with suspected or proven COVID-19 and is now closed.

• Other: No antiviral agent for influenza
  No antiviral agent intended to be active against influenza infection is to be administered
• Drug: Five-days oseltamivir
  Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first)
• Drug: Ten-days oseltamivir
  Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first)
• Other: No antiviral agent for COVID-19
  No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered
• Drug: Lopinavir / Ritonavir

  Lopinavir/ritonavir 400/100mg administered enterally, or 5ml 80/20mg per mL solution suspension via gastric tube, every 12 hours. Administered for a minimum of 5 days, including if discharged from ICU prior to end of study day 5. For patients discharged from ICU between study day 6 and study day 14, lopinavir/ritonavir is ceased at ICU discharge. Lopinavir/ritonavir is ceased at the end of study day 14 if the patient remains in ICU.

  Note: this intervention is now closed.

• Drug: Hydroxychloroquine

  Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge (whichever occurs first).

  Note: this intervention is now closed.

• Drug: Hydroxychloroquine + lopinavir/ritonavir

  Lopinavir/ritonavir 400/100mg administered enterally, or 5ml 80/20mg per mL solution suspension via gastric tube, every 12 hours. Administered for a minimum of 5 days, including if discharged from ICU prior to end of study day 5. For patients discharged from ICU between study day 6 and study day 14, lopinavir/ritonavir is ceased at ICU discharge. Lopinavir/ritonavir is ceased at the end of study day 14 if the patient remains in ICU.

  Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge (whichever occurs first).

  Note: this intervention is now closed.

• Drug: Ivermectin
  Ivermectin administered enterally at a dose of 0.2 mg/kg once daily with a maximum daily dose of 24mg/day.
• Other: No immune modulation for COVID-19

  No immune modulating agent intended to be active against COVID-19 is to be administered.

  Note: this intervention is now closed.

• Drug: Interferon beta-1a

  IFN-β1a 10 μg will be administered as an intravenous bolus injection via a central or peripheral line. IFN-β1a will be administered once daily for 6 days or until ICU discharge, whichever occurs first.

  Note: this intervention is now closed.

  Other Name: IFN-β1a
• Drug: Anakinra

  A loading dose of 300mg anakinra will be administered as a bolus via central or peripheral line. This is followed by maintenance doses of 100mg of anakinra administered every 6 hours.

  In patients with renal impairment, anakinra will be administered on alternate days.

  Note: this intervention is now closed.

• Drug: Tocilizumab

  Tocilizumab will be administered as a single dose of 8mg/kg estimated or measured body weight, with a maximum total dose of 800mg.

  Note: this intervention is now closed.

  Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period.

• Drug: Sarilumab

  Sarilumab will be administered as a single dose of 400mg, via IV infusion through peripheral or central line over a one-hour period.

  Note: this intervention is now closed.

• Drug: Local standard venous thromboprophylaxis

  Standard venous thromboprophylaxis that complies with local guidelines or usual practice will be administered for 14 days following randomisation or until hospital discharge, whichever occurs first.

  Note: this intervention is now closed.

• Drug: Therapeutic anticoagulation

  Patients will be administered either low molecular weight heparin (LMWH) or unfractionated heparin (UFH) to achieve systemic anticoagulation. Either agent may be used and the same patient may be switched between UFH and LMWH at the discretion of the treating clinician.

  Note: this intervention is now closed.

• Drug: Conventional low dose thromboprophylaxis
  Low dose thromboprophylaxis will be administered for 14 days following randomisation or until hospital discharge, whichever occurs first. Dosing is outlined in the relevant protocol documents for this domain.
• Drug: Intermediate dose thromboprophylaxis
  Intermediate dose thromboprophylaxis will be administered for 14 days following randomisation or until hospital discharge, whichever occurs first. Dosing is outlined in the relevant protocol documents for this domain.
• Drug: Continuation of therapeutic dose anticoagulation
  Patients already receiving therapeutic dose anticoagulation at the time of randomisation to this intervention will be administered either unfractionated heparin by IV infusion or low-molecular weight heparin to achieve systemic anticoagulation according to local practice for acute VTE treatment for 14 days following randomisation or until hospital discharge, whichever occurs first.
• Other: No immunoglobulin

  No immunoglobulin intended to be active against SARS-CoV-2 infection is to be administered.

  Note: this intervention is now closed.

• Biological: Convalescent plasma

  Patients will receive at least one and no more than two units of ABO compatible convalescent plasma within 48 hours of randomisation.

  Note: this intervention is now closed.

• Biological: Delayed administration of convalescent plasma
  Note: this intervention is now closed.
• Other: No vitamin C
  No high dose intravenous vitamin C is to be administered
• Drug: Vitamin C
  Intravenous Vitamin C 50mg/kg administered every 6 hours for 16 doses
• Other: No antiplatelet

  No antiplatelet agent or NSAID to be administered.

  Note: this intervention is now closed.

• Drug: Aspirin

  Aspirin administered at either 75mg or 100mg once per day for 14 days or until hospital discharge, whichever occurs first.

  Note: this intervention is now closed.

  Other Name: acetylsalicylic acid
• Drug: P2Y12 inhibitor

  Site-selected P2Y12 inhibitor:

  • Clopidogrel: administered 75 mg once per day for 14 days or until hospital discharge, whichever occurs first.
  • Prasugrel: If patient is aged less than 75 years and measured or estimated weight if 60kg or more, and initial loading dose of prasugrel 60 mg will be administered, followed by maintenance dose of 10 mg per day.
  • Ticagrelor: administered enterally at 60mg twice daily for 14 days or until hospital discharge, whichever occurs first.

  Note: this intervention is now closed.

  Other Names:

  • Clopidogrel
  • Prasugrel
  • Ticagrelor
• Other: No simvastatin
  No simvastatin intended to be active against COVID-19 is to be administered
• Drug: Simvastatin
  Simvastatin 80mg administered once daily via enteral route, while the patient remains in hospital up to 28 days after randomisation
• Other: Placebo
• Drug: Eritoran
  Eritoran initiated with a 26.24 mg loading dose (6.56 mg/h IV for 4 hours), followed by a second 13.12 mg loading dose (6.56 mg/h IV for 2 hours) at 12 hours after initiation. Patients will then receive twenty-six 6.56 mg maintenance doses (3.28 mg/h IV for 2 hours) every 12 hours thereafter (total of 14 days). Dosing will be stopped if the patient is discharged from hospital
• Drug: Apremilast

  Apremilast administered 30mg twice daily for 14 days or until hospital discharge, whichever occurs first.

  Note: this intervention is now closed.

• Procedure: Clinician-preferred mechanical ventilation strategy
  Clinician-preferred ventilation strategy, including mode of ventilation and all ventilatory parameters
• Procedure: Protocolised mechanical ventilation strategy
  Invasive mechanical ventilation strategy delivered as outlined in relevant protocol documents for this domain.
• Other: No renin-angiotensin system inhibitor
  No RAS inhibitor (i.e. no ACEi or ARB) is to be administered up to the end of study day 10.
• Drug: Angiotensin converting enzyme inhibitor
  Site-preferred ACEi agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.
  Other Names:

  • Ramipril
  • Lisinopril
  • Perindopril
  • Enalapril
  • Trandolapril
  • Captopril
• Drug: Angiotensin Receptor Blockers
  Site-preferred ARB agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.
  Other Names:

  • Losartan
  • Valsartan
  • Candesartan
  • Irbesartan
  • Telmisartan
  • Olmesartan
• Drug: ARB + DMX-200

  Site-preferred ARB agent administered in combination with DMX-200 for 10 days or until hospital discharge, whichever occurs first.

  ARB administered as directed by the treating clinician. DMX-200 administered enterally at a dose of 120mg twice daily.

• Other: No cysteamine
  No cysteamine to be administered until the end of study day 10 or hospital discharge, whichever occurs first.
• Drug: Cysteamine
  Cysteamine administered every 8 hours at a dose of 5 mg/kg estimated or measured body weight (maximum dose of 500mg), for ten days or until ICU discharge, whichever occurs first.

Study Arms

• Antibiotic Domain
  Patients with community-acquired pneumonia admitted to participating intensive care units and requiring empiric antibiotic therapy will be randomised one of five antibiotic interventions
  Interventions:

  • Drug: Ceftriaxone
  • Drug: Moxifloxacin or Levofloxacin
  • Drug: Piperacillin-tazobactam
  • Drug: Ceftaroline
  • Drug: Amoxicillin-clavulanate
• Macrolide Duration Domain
  Patients with community-acquired pneumonia admitted to participating intensive care units who have been allocated to a beta-lactam antibiotic intervention in the Antibiotic Domain will be randomised to either a standard course or extended course of macrolide therapy
  Interventions:

  • Drug: Standard course macrolide
  • Drug: Extended course macrolide
• Corticosteroid Domain

  Patients with community acquired pneumonia admitted to participating intensive care units will be randomised to a steroid use strategy

  Note: this domain is now closed to patients with suspected or proven COVID-19

  Interventions:

  • Other: No systemic corticosteroid
  • Drug: Fixed-duration Hydrocortisone
  • Drug: Shock-dependent hydrocortisone
  • Drug: Fixed-duration higher dose Hydrocortisone
• Influenza Antiviral Domain
  Patients with community-acquired pneumonia admitted to participating intensive care units with suspected or microbiological testing confirmed influenza infection will be randomised to one of three interventions
  Interventions:

  • Other: No antiviral agent for influenza
  • Drug: Five-days oseltamivir
  • Drug: Ten-days oseltamivir
• COVID-19 Antiviral Domain

  Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to no ivermectin or ivermectin.

  Note: lopinavir-ritonavir, hydroxychloroquine, and combination lopinavir-ritonavir and hydroxychloroquine interventions are now closed.

  Interventions:

  • Other: No antiviral agent for COVID-19
  • Drug: Lopinavir / Ritonavir
  • Drug: Hydroxychloroquine
  • Drug: Hydroxychloroquine + lopinavir/ritonavir
  • Drug: Ivermectin
• COVID-19 Immune Modulation Domain

  Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to one of up to five interventions.

  Note: this domain is now closed

  Interventions:

  • Other: No immune modulation for COVID-19
  • Drug: Interferon beta-1a
  • Drug: Anakinra
  • Drug: Tocilizumab
  • Drug: Sarilumab
• Anticoagulation Domain

  Patients admitted to participating intensive care units with suspected or microbiological testing confirmed COVID-19 will be randomised to an anticoagulation strategy.

  Note: the local standard venous thromboprophylaxis and therapeutic anticoagulation interventions are now closed.

  Interventions:

  • Drug: Local standard venous thromboprophylaxis
  • Drug: Therapeutic anticoagulation
  • Drug: Conventional low dose thromboprophylaxis
  • Drug: Intermediate dose thromboprophylaxis
  • Drug: Continuation of therapeutic dose anticoagulation
• Immunoglobulin Domain

  Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to receive no immunoglobulin for COVID-19, or to receive convalescent plasma.

  Note: this domain is now closed

  Interventions:

  • Other: No immunoglobulin
  • Biological: Convalescent plasma
  • Biological: Delayed administration of convalescent plasma
• Vitamin C Domain
  Patients admitted to participating hospitals with community-acquired pneumonia will be randomised to receive no vitamin C, or vitamin C
  Interventions:

  • Other: No vitamin C
  • Drug: Vitamin C
• Simvastatin Domain
  Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to receive no simvastatin, or simvastatin.
  Interventions:

  • Other: No simvastatin
  • Drug: Simvastatin
• Antiplatelet Domain

  Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to receive no antiplatelet, aspirin, or site-preferred P2Y12 inhibitor.

  Note: this domain is now closed

  Interventions:

  • Other: No antiplatelet
  • Drug: Aspirin
  • Drug: P2Y12 inhibitor
• Mechanical Ventilation Domain
  Patients with community-acquired pneumonia admitted to participating intensive care units who are intubated and receiving invasive mechanical ventilation will be randomised to protocolised mechanical ventilation strategy, or clinician-preferred mechanical ventilation strategy
  Interventions:

  • Procedure: Clinician-preferred mechanical ventilation strategy
  • Procedure: Protocolised mechanical ventilation strategy
• COVID-19 Immune Modulation (2) Domain
  Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to receive one of three interventions
  Interventions:

  • Other: Placebo
  • Drug: Eritoran
  • Drug: Apremilast
• ACE2 RAS Domain
  Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to one of up to three renin-angiotensin system blockade strategies.
  Interventions:

  • Other: No renin-angiotensin system inhibitor
  • Drug: Angiotensin converting enzyme inhibitor
  • Drug: Angiotensin Receptor Blockers
  • Drug: ARB + DMX-200
• Cysteamine Domain
  Patients admitted to participating hospitals with severe community-acquired pneumonia, including patients with suspected or proven influenza or COVID-19, will be randomised to receive no cysteamine, or cysteamine
  Interventions:

  • Other: No cysteamine
  • Drug: Cysteamine

Publications *

• REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury CA, Lawler PR, Stanworth SJ, McVerry BJ, McQuilten Z, Higgins AM, Mouncey PR, Al-Beidh F, Rowan KM, Berry LR, Lorenzi E, Zarychanski R, Arabi YM, Annane D, Beane A, van Bentum-Puijk W, Bhimani Z, Bihari S, Bonten MJM, Brunkhorst FM, Buzgau A, Buxton M, Carrier M, Cheng AC, Cove M, Detry MA, Estcourt LJ, Fitzgerald M, Girard TD, Goligher EC, Goossens H, Haniffa R, Hills T, Huang DT, Horvat CM, Hunt BJ, Ichihara N, Lamontagne F, Leavis HL, Linstrum KM, Litton E, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Morpeth SC, Murthy S, Neal MD, Nichol AD, Parke RL, Parker JC, Reyes LF, Saito H, Santos MS, Saunders CT, Serpa-Neto A, Seymour CW, Shankar-Hari M, Singh V, Tolppa T, Turgeon AF, Turner AM, van de Veerdonk FL, Green C, Lewis RJ, Angus DC, McArthur CJ, Berry S, Derde LPG, Webb SA, Gordon AC. Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2022 Apr 5;327(13):1247-1259. doi: 10.1001/jama.2022.2910.
• Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, van Bentum-Puijk W, Berry LR, Bhimani Z, Birchall JE, Bonten MJM, Bradbury CA, Brunkhorst FM, Buxton M, Callum JL, Chassé M, Cheng AC, Cove ME, Daly J, Derde L, Detry MA, De Jong M, Evans A, Fergusson DA, Fish M, Fitzgerald M, Foley C, Goossens H, Gordon AC, Gosbell IB, Green C, Haniffa R, Harvala H, Higgins AM, Hills TE, Hoad VC, Horvat C, Huang DT, Hudson CL, Ichihara N, Laing E, Lamikanra AA, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, MacLennan S, Marshall J, McAuley DF, McDyer JF, McGlothlin A, McGuinness S, Miflin G, Montgomery S, Mouncey PR, Murthy S, Nichol A, Parke R, Parker JC, Priddee N, Purcell DFJ, Reyes LF, Richardson P, Robitaille N, Rowan KM, Rynne J, Saito H, Santos M, Saunders CT, Serpa Neto A, Seymour CW, Silversides JA, Tinmouth AA, Triulzi DJ, Turner AM, van de Veerdonk F, Walsh TS, Wood EM, Berry S, Lewis RJ, Menon DK, McArthur C, Zarychanski R, Angus DC, Webb SA, Roberts DJ, Shankar-Hari M. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2021 Nov 2;326(17):1690-1702. doi: 10.1001/jama.2021.18178.
• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9:CD013825. doi: 10.1002/14651858.CD013825.pub2. Review.
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• UPMC REMAP-COVID Group, on behalf of the REMAP-CAP Investigators. Implementation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 (REMAP-COVID) trial in a US health system-lessons learned and recommendations. Trials. 2021 Jan 28;22(1):100. doi: 10.1186/s13063-020-04997-6. Erratum in: Trials. 2021 Feb 16;22(1):145.
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• Angus DC, Berry S, Lewis RJ, Al-Beidh F, Arabi Y, van Bentum-Puijk W, Bhimani Z, Bonten M, Broglio K, Brunkhorst F, Cheng AC, Chiche JD, De Jong M, Detry M, Goossens H, Gordon A, Green C, Higgins AM, Hullegie SJ, Kruger P, Lamontagne F, Litton E, Marshall J, McGlothlin A, McGuinness S, Mouncey P, Murthy S, Nichol A, O'Neill GK, Parke R, Parker J, Rohde G, Rowan K, Turner A, Young P, Derde L, McArthur C, Webb SA. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design. Ann Am Thorac Soc. 2020 Jul;17(7):879-891. doi: 10.1513/AnnalsATS.202003-192SD.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 3, 2021): 10000
• Original Estimated Enrollment (submitted: April 6, 2016): 4000
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

REMAP-CAP PLATFORM INCLUSION CRITERIA:

1. Adult patient admitted to an ICU for severe CAP within 48 hours of hospital admission with:

   1. symptoms or signs or both that are consistent with lower respiratory tract infection AND
   2. Radiological evidence of new onset consolidation (in patients with pre-existing radiological changes, evidence of new infiltrate)

2. Up to 48 hours after ICU admission, receiving organ support with one or more of:

   1. Non-invasive or Invasive ventilatory support;
   2. Receiving infusion of vasopressor or inotropes or both

PLATFORM EXCLUSION CRITERIA:

1. Healthcare-associated pneumonia:

   1. Prior to this illness, is known to have been an inpatient in any healthcare facility within the last 30 days
   2. Resident of a nursing home or long term care facility
2. 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
3. Previous participation in this REMAP within the last 90 days

REMAP-COVID PLATFORM INCLUSION CRITERIA

1. Adult patients (≥ 18 years) admitted to hospital with acute illness due to suspected or proven pandemic infection.

REMAP-COVID PLATFORM 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

DOMAIN-SPECIFIC ELIGIBLE CRITERIA:

Each domain may have additional eligibility criteria. Refer to the study website for more information (www.remapcap.org).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cameron Green, MSc; info@remapcap.org

Contact: Wilma Van Bentum-Puijk, MSc; +31 (0) 88 755 5555; EU.remapcap@umcutrecht.nl

• Listed Location Countries: Australia, Belgium, Canada, Colombia, Croatia, Germany, Hungary, India, Ireland, Japan, Nepal, Netherlands, New Zealand, Pakistan, Portugal, Romania, Saudi Arabia, Spain, United Kingdom, United States
• Removed Location Countries: France

Administrative Information

• NCT Number: NCT02735707
• Other Study ID Numbers: U1111-1189-1653; 2015-002340-14 ( EudraCT Number ); 602525 ( Other Grant/Funding Number: European Union, FP7-HEALTH-2013-INNOVATION-1, PREPARE ); 16/631 ( Other Grant/Funding Number: Health Research Council of New Zealand ); APP1101719 ( Other Grant/Funding Number: National Health and Medical Research Council, Australia ); 158584 ( Other Grant/Funding Number: Canadian Institute of Health Research )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Responsible Party: Lennie Derde, UMC Utrecht
• Study Sponsor: UMC Utrecht

Collaborators

• Australian and New Zealand Intensive Care Research Centre
• Medical Research Institute of New Zealand
• Unity Health
• Berry Consultants
• Global Coalition for Adaptive Research
• University of Pittsburgh Medical Center
• Intensive Care National Audit & Research Centre
• St. Marianna University School of Medicine
• National Intensive Care Surveillance MORU

Investigators

• Study Chair: Steve Webb, Prof; Monash University, Study Chair REMAP-CAP Australia
• Study Chair: Colin McArthur, Dr; Medical Research Institute of New Zealand, Study Chair REMAP-CAP New Zealand
• Study Chair: Marc Bonten, Prof; UMC Utrecht, Study Chair REMAP-CAP Europe
• Study Chair: Lennie Derde, MD; UMC Utrecht, Coordinating Investigator REMAP-CAP Europe
• Study Chair: John Marshall, Prof; Unity Health Toronto, Study Chair REMAP-CAP Canada
• Study Chair: Derek Angus, Prof; University of Pittsburgh Medical Center, Study Chair REMAP-CAP USA

• PRS Account: UMC Utrecht
• Verification Date: December 2021