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

Phase 3

Recruiting

• Conditions: Community-acquired Pneumonia, Influenza, COVID-19
• Interventions: Other: No systemic corticosteroid; Other: No antiviral agent for COVID-19; Other: No immune modulation for COVID-19; Drug: Standard course macrolide; Other: No antiviral agent for influenza; Drug: Local standard venous thromboprophylaxis; Other: No immunoglobulin; Other: No simvastatin; Other: No cysteamine; Other: No Immune Modulator for Influenza; Other: No vitamin C; Other: No antiplatelet; Procedure: Clinician-preferred mechanical ventilation strategy; Other: No renin-angiotensin system inhibitor; Other: No endothelial modulator; Drug: Ceftriaxone; Drug: Eritoran; Drug: Moxifloxacin or Levofloxacin; Drug: Fixed-duration Hydrocortisone; Drug: Extended course macrolide; Drug: Five-days oseltamivir; Drug: Lopinavir / Ritonavir; Biological: Convalescent plasma; Drug: Angiotensin converting enzyme inhibitor; Drug: Nirmatrelvir/ritonavir; Drug: Therapeutic dose anticoagulation; Procedure: Protocolised mechanical ventilation strategy; Drug: Interferon beta-1a; Drug: Vitamin C; Drug: Simvastatin; Drug: Aspirin; Drug: Cysteamine; Drug: Imatinib; Drug: Angiotensin Receptor Blockers; Drug: Shock-dependent hydrocortisone; Drug: Ten-days oseltamivir; Drug: P2Y12 inhibitor; Drug: Conventional low dose thromboprophylaxis; Biological: Delayed administration of convalescent plasma; Drug: Piperacillin-tazobactam; Drug: Hydroxychloroquine; Drug: Anakinra; Drug: Apremilast; Drug: Baricitinib; Drug: Remdesivir; Drug: Hydroxychloroquine + lopinavir/ritonavir; Drug: Nirmatrelvir/ritonavir + remdesivir; Drug: Fixed-duration higher dose Hydrocortisone; Drug: Intermediate dose thromboprophylaxis; Drug: ARB + DMX-200; Drug: Ceftaroline; Drug: Baloxavir Marboxil; Drug: Tocilizumab; Drug: Fixed-duration dexamethasone; Drug: Amoxicillin-clavulanate; Drug: Five-days oseltamivir + baloxavir marboxil; Drug: Continuation of therapeutic dose anticoagulation; Drug: Ivermectin; Drug: Sarilumab; Drug: Ten-days oseltamivir + baloxavir marboxil

• Registration Number: NCT02735707
• Lead Sponsor: UMC Utrecht

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 Timeline

• Study First Submitted: 2015-12-11
• Study First Submitted QC: 2016-04-06
• Study Start: 2016-04-11
• Study First Posted: 2016-04-13
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-10
• Last Update Posted: 2024-07-12
• Primary Completion: 2026-02
• Study Completion: 2028-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20000

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
COVID-19 Immune Modulation (2) Domain	Eritoran	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.
ACE2 RAS Domain	Angiotensin Receptor Blockers	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.
Antibiotic Domain	Moxifloxacin or Levofloxacin	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.
COVID-19 Antiviral Domain	Hydroxychloroquine + lopinavir/ritonavir	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.
Corticosteroid Domain	Fixed-duration dexamethasone	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
COVID-19 Antiviral (II) Domain	Nirmatrelvir/ritonavir + remdesivir	Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to one of up to four interventions.
Corticosteroid Domain	Fixed-duration Hydrocortisone	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
Antibiotic Domain	Amoxicillin-clavulanate	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.
Macrolide Duration Domain	Extended course macrolide	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
Corticosteroid Domain	No systemic corticosteroid	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
COVID-19 Antiviral Domain	No antiviral agent for COVID-19	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.
COVID-19 Immune Modulation Domain	No immune modulation for COVID-19	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.
Macrolide Duration Domain	Standard course macrolide	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
Corticosteroid Domain	Fixed-duration higher dose Hydrocortisone	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
Influenza Antiviral Domain	No antiviral agent for influenza	Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
Corticosteroid Domain	Shock-dependent hydrocortisone	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
Influenza Antiviral Domain	Five-days oseltamivir	Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
COVID-19 Antiviral Domain	Lopinavir / Ritonavir	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.
Influenza Antiviral Domain	Ten-days oseltamivir	Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
Immunoglobulin Domain	Convalescent plasma	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.
Influenza Antiviral Domain	Ten-days oseltamivir + baloxavir marboxil	Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
COVID-19 Immune Modulation (2) Domain	No immune modulation for COVID-19	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.
ACE2 RAS Domain	Angiotensin converting enzyme inhibitor	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.
Influenza Antiviral Domain	Five-days oseltamivir + baloxavir marboxil	Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
Anticoagulation Domain	Intermediate dose thromboprophylaxis	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.
Antiplatelet Domain	P2Y12 inhibitor	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.
COVID-19 Antiviral (II) Domain	Nirmatrelvir/ritonavir	Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to one of up to four interventions.
Anticoagulation Domain	Local standard venous thromboprophylaxis	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.
Anticoagulation Domain	Therapeutic dose anticoagulation	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.
Anticoagulation Domain	Conventional low dose thromboprophylaxis	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.
Immunoglobulin Domain	No immunoglobulin	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.
Anticoagulation Domain	Continuation of therapeutic dose anticoagulation	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.
Simvastatin Domain	No simvastatin	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.
Cysteamine Domain	No cysteamine	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.
Influenza Immune Modulation	No Immune Modulator for Influenza	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.
Immunoglobulin Domain	Delayed administration of convalescent plasma	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.
Vitamin C Domain	No vitamin C	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.
Antiplatelet Domain	No antiplatelet	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.
Mechanical Ventilation Domain	Clinician-preferred mechanical ventilation strategy	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
Mechanical Ventilation Domain	Protocolised mechanical ventilation strategy	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
ACE2 RAS Domain	No renin-angiotensin system inhibitor	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.
ACE2 RAS Domain	ARB + DMX-200	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.
Endothelial Domain	No endothelial modulator	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.
COVID-19 Antiviral (II) Domain	No antiviral agent for COVID-19	Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to one of up to four interventions.
Antibiotic Domain	Ceftriaxone	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.
Antibiotic Domain	Piperacillin-tazobactam	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.
Antibiotic Domain	Ceftaroline	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.
Influenza Antiviral Domain	Baloxavir Marboxil	Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.
COVID-19 Antiviral Domain	Hydroxychloroquine	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.
COVID-19 Antiviral Domain	Ivermectin	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.
COVID-19 Immune Modulation Domain	Interferon beta-1a	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.
COVID-19 Immune Modulation Domain	Anakinra	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.
COVID-19 Immune Modulation Domain	Tocilizumab	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.
COVID-19 Immune Modulation Domain	Sarilumab	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.
Vitamin C Domain	Vitamin C	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.
Simvastatin Domain	Simvastatin	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.
Antiplatelet Domain	Aspirin	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.
COVID-19 Immune Modulation (2) Domain	Apremilast	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.
Cysteamine Domain	Cysteamine	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.
Influenza Immune Modulation	Tocilizumab	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.
Endothelial Domain	Imatinib	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.
Influenza Immune Modulation	Baricitinib	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.
COVID-19 Antiviral (II) Domain	Remdesivir	Patients admitted to participating hospitals with microbiological testing confirmed COVID-19 will be randomised to one of up to four interventions.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (408)

University of Florida; 🇺🇸 Jacksonville, Florida, United States

Augusta University; 🇺🇸 Augusta, Georgia, United States

University of Illinois Health; 🇺🇸 Chicago, Illinois, United States

Tulane Medical Center; 🇺🇸 New Orleans, Louisiana, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Wake Forest Baptist Health; 🇺🇸 Winston-Salem, North Carolina, United States

The Ohio State University Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

University of Pittsburgh Medical Centre; 🇺🇸 Pittsburgh, Pennsylvania, United States

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