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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Community-acquired Pneumonia, Influenza, COVID-19

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


Participation Criteria
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Eligibility Criteria
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REMAP-CAP PLATFORM INCLUSION CRITERIA: Adult patient admitted to an ICU for severe CAP within 48 hours of hospital admission with: symptoms or signs or both that are consistent with lower respiratory tract infection AND Radiological evidence of new onset consolidation (in patients with pre-existing radiological changes, evidence of new infiltrate) Up to 48 hours after ICU admission, receiving organ support with one or more of: Non-invasive or Invasive ventilatory support; Receiving infusion of vasopressor or inotropes or both PLATFORM EXCLUSION CRITERIA: Healthcare-associated pneumonia: Prior to this illness, is known to have been an inpatient in any healthcare facility within the last 30 days Resident of a nursing home or long term care facility 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 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 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 Patient is expected to be discharged from hospital today or tomorrow More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection. 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Antibiotic Domain<br>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<br>* The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.<br>Drug: Moxifloxacin or Levofloxacin<br>* The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.<br>Drug: Piperacillin-tazobactam<br>* The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.<br>Drug: Ceftaroline<br>* The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.<br>Drug: Amoxicillin-clavulanate<br>* The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.<br>|
| Other: Macrolide Duration Domain<br>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<br>* 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.<br>Drug: Extended course macrolide<br>* 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.<br>|
| Other: Corticosteroid Domain<br>Patients with community acquired pneumonia (CAP) 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. It remains open to patients with CAP without COVID-19. | Other: No systemic corticosteroid<br>* Patients are not to receive any systemic corticosteroids, including hydrocortisone, to study day 28 or hospital discharge (whichever occurs first).<br>Drug: Fixed-duration Hydrocortisone<br>* 50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.<br>Drug: Shock-dependent hydrocortisone<br>* 50mg IV hydrocortisone every 6 hours while the patient is in septic shock<br>Drug: Fixed-duration higher dose Hydrocortisone<br>* 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.<br>Drug: Fixed-duration dexamethasone<br>* 6 mg of IV or enteral dexamethasone will be administered daily for up to 10 days while in hospital.<br>|
| Other: Influenza Antiviral Domain<br>Patients with community-acquired pneumonia admitted to participating intensive care units with microbiological testing confirmed influenza infection will be randomised to one of six interventions. | Other: No antiviral agent for influenza<br>* No antiviral agent intended to be active against influenza infection is to be administered<br>Drug: Five-days oseltamivir<br>* Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first)<br>Drug: Ten-days oseltamivir<br>* Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first)<br>Drug: Baloxavir Marboxil<br>* Baloxavir marboxil administered on days 1 and 4 post-randomisation.<br>Drug: Five-days oseltamivir + baloxavir marboxil<br>* 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.<br>Drug: Ten-days oseltamivir + baloxavir marboxil<br>* 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.<br>|
| Other: COVID-19 Antiviral Domain<br>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<br>* No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered<br>Drug: Lopinavir / Ritonavir<br>* 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.<br>Drug: Hydroxychloroquine<br>* 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.<br>Drug: Hydroxychloroquine + lopinavir/ritonavir<br>* 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.<br>Drug: Ivermectin<br>* Ivermectin administered enterally at a dose of 0.2 mg/kg once daily with a maximum daily dose of 24mg/day.<br>|
| Other: COVID-19 Immune Modulation Domain<br>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<br>* No immune modulating agent intended to be active against COVID-19 is to be administered. Note: this intervention is now closed.<br>Drug: Interferon beta-1a<br>* 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.<br>* Other names: IFN-β1a;Drug: Anakinra<br>* 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.<br>Drug: Tocilizumab<br>* 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.<br>Drug: Sarilumab<br>* 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.<br>|
| Other: Anticoagulation Domain<br>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. | Drug: Local standard venous thromboprophylaxis<br>* 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.<br>Drug: Therapeutic dose anticoagulation<br>* 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.<br>Drug: Conventional low dose thromboprophylaxis<br>* 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.<br>Drug: Intermediate dose thromboprophylaxis<br>* 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.<br>Drug: Continuation of therapeutic dose anticoagulation<br>* 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.<br>|
| Other: Immunoglobulin Domain<br>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<br>* No immunoglobulin intended to be active against SARS-CoV-2 infection is to be administered. Note: this intervention is now closed.<br>Biological: Convalescent plasma<br>* 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.<br>Biological: Delayed administration of convalescent plasma<br>* Note: this intervention is now closed.<br>|
| Other: Vitamin C Domain<br>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<br>* No high dose intravenous vitamin C is to be administered<br>Drug: Vitamin C<br>* Intravenous Vitamin C 50mg/kg administered every 6 hours for 16 doses<br>|
| Other: Simvastatin Domain<br>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<br>* No simvastatin intended to be active against COVID-19 is to be administered<br>Drug: Simvastatin<br>* Simvastatin 80mg administered once daily via enteral route, while the patient remains in hospital up to 28 days after randomisation<br>|
| Other: Antiplatelet Domain<br>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. | Other: No antiplatelet<br>* No antiplatelet agent or NSAID to be administered. Note: this intervention is now closed.<br>Drug: Aspirin<br>* 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.<br>* Other names: acetylsalicylic acid;Drug: P2Y12 inhibitor<br>* 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.<br>* Other names: Ticagrelor;|
| Other: Mechanical Ventilation Domain<br>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<br>* Clinician-preferred ventilation strategy, including mode of ventilation and all ventilatory parameters<br>Procedure: Protocolised mechanical ventilation strategy<br>* Invasive mechanical ventilation strategy delivered as outlined in relevant protocol documents for this domain.<br>|
| Other: COVID-19 Immune Modulation (2) Domain<br>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: Placebo<br> <br> Drug: Eritoran<br>* 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<br>Drug: Apremilast<br>* Apremilast administered 30mg twice daily for 14 days or until hospital discharge, whichever occurs first. Note: this intervention is now closed.<br>|
| Other: ACE2 RAS Domain<br>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<br>* No RAS inhibitor (i.e. no ACEi or ARB) is to be administered up to the end of study day 10.<br>Drug: Angiotensin converting enzyme inhibitor<br>* Site-preferred ACEi agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.<br>* Other names: Captopril;Drug: Angiotensin Receptor Blockers<br>* Site-preferred ARB agent administered as directed by the treating clinician for 10 days or until hospital discharge, whichever occurs first.<br>* Other names: Olmesartan;Drug: ARB + DMX-200<br>* 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.<br>|
| Other: Cysteamine Domain<br>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. | Other: No cysteamine<br>* No cysteamine to be administered until the end of study day 10 or hospital discharge, whichever occurs first.<br>Drug: Cysteamine<br>* 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.<br>|
| Other: Endothelial Domain<br>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<br>* No endothelial modulator (imatinib or another tyrosine kinase inhibitor targeting the same pathway as imatinib) is to be administered.<br>Drug: Imatinib<br>* Enteral imatinib will be administered as a single 800mg loading dose (study day 1) followed by 400mg daily until study day 14 or discharge.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumonia, Lung Diseases, Respiratory Tract Diseases, Respiratory Tract Infections, Anti-Bacterial Agents, Moxifloxacin, Levofloxacin, Antibiotics, Hydrocortisone, Anti-Infective Agents, Ceftriaxone, Piperacillin-tazobactam, Ceftaroline, Amoxicillin-clavulanate, Oseltamivir, COVID-19, Influenza, Intensive care, Critical care, SARS-CoV-2, Vitamin C, Therapeutic Anticoagulation, Statin, Invasive Mechanical Ventilation, Convalescent plasma, Eritoran, Apremilast, DMX-200, Ivermectin