Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia

Purpose

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.

Condition

  • Community-acquired Pneumonia, Influenza, COVID-19

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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).

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Factorial Assignment
Intervention Model Description
Adaptive Bayesian Platform Trial evaluating multiple interventions in multiple domains
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Other
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. Note: the ceftaroline + macrolide intervention has been closed to recruitment.
  • 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. Note: this intervention is now closed.
  • Drug: Amoxicillin-clavulanate
    The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
Other
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
  • 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
Corticosteroid Domain 		Patients with community acquired pneumonia (CAP) admitted to participating hospitals will be randomised to a steroid use strategy. Note: this domain is now closed to patients with suspected or proven COVID-19. It remains open to patients with CAP without COVID-19. Note: the fixed-course hydrocortisone has been closed to recruitment
  • 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. Note: this intervention is now closed.
  • 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.
  • Drug: Fixed-duration dexamethasone
    6 mg of IV or enteral dexamethasone will be administered daily for up to 10 days while in hospital.
Other
Influenza Antiviral Domain 		Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
  • 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)
  • Drug: Baloxavir Marboxil
    Baloxavir marboxil administered on days 1 and 4 post-randomisation.
  • Drug: Five-days oseltamivir + baloxavir marboxil
    Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first), in addition to baloxavir marboxil administered on days 1 and 4 post-randomisation.
  • Drug: Ten-days oseltamivir + baloxavir marboxil
    Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first), in addition to baloxavir marboxil administered on days 1 and 4 post-randomisation.
Other
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: an earlier version of this domain evaluated lopinavir-ritonavir, hydroxychloroquine, and combination lopinavir-ritonavir and hydroxychloroquine against a 'no antiviral' control. This domain is now closed.
  • 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. Note: this intervention is now closed.
Other
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.
  • 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 names:
    • 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. Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period. Note: this intervention is now closed.
  • 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.
Other
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: A previous version of this domain evaluated local standard venous thromboprophylaxis against therapeutic dose anticoagulation. This domain 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 dose 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. Note: this intervention is now closed.
Other
Immunoglobulin Domain 		Immunosuppressed patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to receive no immunoglobulin for COVID-19, or to receive high-titre convalescent plasma. Note: an earlier version of this domain was not restricted to immunosuppressed patients.
  • Other: No immunoglobulin
    No immunoglobulin intended to be active against SARS-CoV-2 infection is to be administered.
  • 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.
  • Biological: Delayed administration of convalescent plasma
    Note: this intervention is now closed.
Other
Vitamin C Domain 		Patients admitted to participating hospitals with community-acquired pneumonia will be randomised to receive no vitamin C, or vitamin C. Note: this domain is now closed.
  • Other: No vitamin C
    No high dose intravenous vitamin C is to be administered Note: this intervention is now closed.
  • Drug: Vitamin C
    Intravenous Vitamin C 50mg/kg administered every 6 hours for 16 doses Note: this intervention is now closed.
Other
Simvastatin Domain 		Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to receive no simvastatin, or simvastatin. Note: this domain is now closed.
  • Other: No simvastatin
    No simvastatin intended to be active against COVID-19 is to be administered Note: this intervention is now closed.
  • Drug: Simvastatin
    Simvastatin 80mg administered once daily via enteral route, while the patient remains in hospital up to 28 days after randomisation Note: this intervention is now closed.
Other
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.
  • 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 names:
    • 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
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
  • 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
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. Note: this domain is now closed.
  • 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: 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 Note: this intervention is now closed.
  • Drug: Apremilast
    Apremilast administered 30mg twice daily for 14 days or until hospital discharge, whichever occurs first. Note: this intervention is now closed.
Other
ACE2 RAS Domain 		Patients admitted to participating hospitals with suspected or microbiological testing confirmed COVID-19 will be randomised to one of up to five renin-angiotensin system blockade strategies. Note: this domain is now closed.
  • 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. Note: this intervention is now closed.
  • 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. Note: this intervention is now closed.
    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. Note: this intervention is now closed.
    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. Note: this intervention is now closed.
Other
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. Note: this domain is now closed.
  • Other: No cysteamine
    No cysteamine to be administered until the end of study day 10 or hospital discharge, whichever occurs first. Note: this intervention is now closed.
  • 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. Note: this intervention is now closed.
Other
Endothelial 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 endothelial modulator or enteral imatinib.
  • Other: No endothelial modulator
    No endothelial modulator (imatinib or another tyrosine kinase inhibitor targeting the same pathway as imatinib) is to be administered.
  • Drug: Imatinib
    Enteral imatinib will be administered as a single 800mg loading dose (study day 1) followed by 400mg daily until study day 14 or discharge.
Other
Influenza Immune Modulation 		Patients with community-acquired pneumonia admitted to participating intensive care units with microbiological testing confirmed influenza infection will be randomised to one of three interventions.
  • Other: No Immune Modulator for Influenza
    No immune modulating agent intended to be active against influenza is to be administered.
  • 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. In children weighing less than 30kg, tocilizumab dose will be 12mg/kg. Tocilizumab will be administered as an IV infusion via central or peripheral line over a one-hour period.
  • Drug: Baricitinib
    Baricitinib will be administered at a dose that is determined by age and renal function, for up to 10 days or hospital discharge (whichever occurs first).
Other
COVID-19 Antiviral (II) Domain 		Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to one of up to four interventions.
  • Other: No antiviral agent for COVID-19
    No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered
  • Drug: Nirmatrelvir/ritonavir
    Nirmatrelvir-ritonavir will be administered at a dose that is dependent on renal function, for five days.
    Other names:
    • Paxlovid
  • Drug: Remdesivir
    Remdesivir is administered at 200 mg on day one followed by 100 mg daily for a further four doses (i.e., for five doses in total) or until hospital discharge, whichever occurs first.
  • Drug: Nirmatrelvir/ritonavir + remdesivir
    Nirmatrelvir-ritonavir will be administered at a dose that is dependent on renal function, for five days. Remdesivir is administered at 200 mg on day one followed by 100 mg daily for a further four doses (i.e., for five doses in total) or until hospital discharge, whichever occurs first.

Recruiting Locations

University of Florida
Jacksonville, Florida 32209
Contact:
Hadi Hatoum, MD

University of Illinois Health
Chicago, Illinois 60612
Contact:
Jeffrey Jacobson, MD

University of Michigan
Ann Arbor, Michigan 48109
Contact:
Robert Hyzy, MD

Memorial Sloan Kettering Cancer Center
New York, New York 10065
Contact:
Stephen Pastores, MD

The Ohio State University Wexner Medical Center
Columbus, Ohio 43210
Contact:
Matthew Exline, MD

Oregon Health and Science University
Portland, Oregon 97239-3098
Contact:
Akram Khankhana, MD

University of Pittsburgh Medical Centre
Pittsburgh, Pennsylvania
Contact:
Stephanie Mongomery

More Details

NCT ID
NCT02735707
Status
Recruiting
Sponsor
UMC Utrecht

Study Contact

Cameron Green, MSc
info@remapcap.org

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.