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

UMC Utrecht

Status and phase: Enrolling; Phase 3

Conditions: Community-acquired Pneumonia, Influenza, COVID-19

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

Study type: Interventional

Funder types: Other

Identifiers

NCT02735707

APP1101719 (Other Grant/Funding Number)

U1111-1189-1653

965313 (Other Grant/Funding Number)

16/631 (Other Grant/Funding Number)

2023-507889-89-00 (EU Trial (CTIS) Number)

2015-002340-14 (EudraCT Number)

602525 (Other Grant/Funding Number)

158584 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 20,000 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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20,000 participants in 18 patient groups

Antibiotic Domain

Other group

Description:

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.

Treatment:

Drug: Ceftaroline

Drug: Ceftriaxone

Drug: Moxifloxacin or Levofloxacin

Drug: Amoxicillin-clavulanate

Drug: Piperacillin-tazobactam

Macrolide Duration Domain

Other group

Description:

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

Treatment:

Drug: Standard course macrolide

Drug: Extended course macrolide

Corticosteroid Domain

Other group

Description:

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

Treatment:

Drug: Fixed-duration dexamethasone

Drug: Fixed-duration higher dose Hydrocortisone

Other: No systemic corticosteroid

Drug: Fixed-duration Hydrocortisone

Drug: Shock-dependent hydrocortisone

Influenza Antiviral Domain

Other group

Description:

Patients with community-acquired pneumonia admitted to participating hospitals with microbiological testing confirmed influenza infection will be randomised to one of six interventions.

Treatment:

Drug: Five-days oseltamivir

Other: No antiviral agent for influenza

Drug: Baloxavir Marboxil

Drug: Five-days oseltamivir + baloxavir marboxil

Drug: Ten-days oseltamivir + baloxavir marboxil

Drug: Ten-days oseltamivir

COVID-19 Antiviral Domain

Other group

Description:

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.

Treatment:

Drug: Hydroxychloroquine

Other: No antiviral agent for COVID-19

Drug: Lopinavir / Ritonavir

Drug: Ivermectin

Drug: Hydroxychloroquine + lopinavir/ritonavir

Other: No antiviral agent for COVID-19

COVID-19 Immune Modulation Domain

Other group

Description:

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.

Treatment:

Other: No immune modulation for COVID-19

Drug: Tocilizumab

Drug: Interferon beta-1a

Drug: Anakinra

Drug: Tocilizumab

Drug: Sarilumab

Anticoagulation Domain

Other group

Description:

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.

Treatment:

Drug: Local standard venous thromboprophylaxis

Drug: Continuation of therapeutic dose anticoagulation

Drug: Therapeutic dose anticoagulation

Drug: Conventional low dose thromboprophylaxis

Drug: Intermediate dose thromboprophylaxis

Immunoglobulin Domain

Other group

Description:

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.

Treatment:

Biological: Convalescent plasma

Other: No immunoglobulin

Biological: Delayed administration of convalescent plasma

Vitamin C Domain

Other group

Description:

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.

Treatment:

Other: No vitamin C

Drug: Vitamin C

Simvastatin Domain

Other group

Description:

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.

Treatment:

Other: No simvastatin

Drug: Simvastatin

Antiplatelet Domain

Other group

Description:

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.

Treatment:

Other: No antiplatelet

Drug: Aspirin

Drug: P2Y12 inhibitor

Mechanical Ventilation Domain

Other group

Description:

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

Treatment:

Procedure: Clinician-preferred mechanical ventilation strategy

Procedure: Protocolised mechanical ventilation strategy

COVID-19 Immune Modulation (2) Domain

Other group

Description:

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.

Treatment:

Other: No immune modulation for COVID-19

Drug: Eritoran

Drug: Apremilast

ACE2 RAS Domain

Other group

Description:

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.

Treatment:

Drug: Angiotensin converting enzyme inhibitor

Drug: Angiotensin Receptor Blockers

Other: No renin-angiotensin system inhibitor

Drug: ARB + DMX-200

Cysteamine Domain

Other group

Description:

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.

Treatment:

Other: No cysteamine

Drug: Cysteamine

Endothelial Domain

Other group

Description:

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.

Treatment:

Drug: Imatinib

Other: No endothelial modulator

Influenza Immune Modulation

Other group

Description:

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.

Treatment:

Other: No Immune Modulator for Influenza

Drug: Tocilizumab

Drug: Baricitinib

Drug: Tocilizumab

COVID-19 Antiviral (II) Domain

Other group

Description:

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

Treatment:

Drug: Nirmatrelvir/ritonavir + remdesivir

Drug: Nirmatrelvir/ritonavir

Drug: Remdesivir

Other: No antiviral agent for COVID-19

Other: No antiviral agent for COVID-19