NCT02735707

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

• Status: Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 20,000 (estimated)
• Sponsor: UMC Utrecht · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Community-acquired Pneumonia, Influenza, COVID-19

Interventions

Type	Name	Description
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.
DRUG	Standard course macrolide	Standard course of macrolide therapy, discontinued between study day 3 and the end of study day 5. The dosing of and route of administration is not protocolised, the following guidance is provided: * Initial IV administration of a macrolide is strongly preferred * The preferred IV macrolide is azithromycin, but IV clarithromycin may be substituted. * The preferred enteral macrolide is azithromycin, but enteral clarithromycin or roxithromycin may be substituted.
DRUG	Extended course macrolide	Extended course of macrolide therapy discontinued at the end of study day 14 or hospital discharge (whichever occurs first). The dosing of and route of administration is not protocolised, the following guidance is provided: * Initial IV administration of a macrolide is strongly preferred * The preferred IV macrolide is azithromycin, but IV clarithromycin may be substituted. * The preferred enteral macrolide is azithromycin, but enteral clarithromycin or roxithromycin may be substituted.
OTHER	No systemic corticosteroid	Patients are not to receive any systemic corticosteroids, including hydrocortisone, to study day 28 or hospital discharge (whichever occurs first).
DRUG	Fixed-duration Hydrocortisone	50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days. 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.
OTHER	No antiviral agent for influenza	No antiviral agent intended to be active against influenza infection is to be administered
DRUG	Five-days oseltamivir	Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first)
DRUG	Ten-days oseltamivir	Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first)
OTHER	No antiviral agent for COVID-19	No antiviral agent intended to be active against SARS-CoV-2 infection is to be administered
DRUG	Lopinavir / Ritonavir	Lopinavir/ritonavir 400/100mg administered enterally, or 5ml 80/20mg per mL solution suspension via gastric tube, every 12 hours. Administered for a minimum of 5 days, including if discharged from ICU prior to end of study day 5. For patients discharged from ICU between study day 6 and study day 14, lopinavir/ritonavir is ceased at ICU discharge. Lopinavir/ritonavir is ceased at the end of study day 14 if the patient remains in ICU. Note: this intervention is now closed.
DRUG	Hydroxychloroquine	Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge (whichever occurs first). Note: this intervention is now closed.
DRUG	Hydroxychloroquine + lopinavir/ritonavir	Lopinavir/ritonavir 400/100mg administered enterally, or 5ml 80/20mg per mL solution suspension via gastric tube, every 12 hours. Administered for a minimum of 5 days, including if discharged from ICU prior to end of study day 5. For patients discharged from ICU between study day 6 and study day 14, lopinavir/ritonavir is ceased at ICU discharge. Lopinavir/ritonavir is ceased at the end of study day 14 if the patient remains in ICU. Loading dose of 800mg hydroxychloroquine administered enterally every 6 hours until 2 doses have been administered. Subsequently, 400mg hydroxychloroquine will be administered enterally every 12 hours for 12 doses or ICU discharge (whichever occurs first). Note: this intervention is now closed.
DRUG	Ivermectin	Ivermectin administered enterally at a dose of 0.2 mg/kg once daily with a maximum daily dose of 24mg/day. Note: this intervention 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.
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.
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	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	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	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.
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	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.
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.
PROCEDURE	Clinician-preferred mechanical ventilation strategy	Clinician-preferred ventilation strategy, including mode of ventilation and all ventilatory parameters
PROCEDURE	Protocolised mechanical ventilation strategy	Invasive mechanical ventilation strategy delivered as outlined in relevant protocol documents for this domain.
OTHER	No renin-angiotensin system inhibitor	No RAS inhibitor (i.e. no ACEi or ARB) is to be administered up to the end of study day 10. 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.
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.
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	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.
DRUG	Fixed-duration dexamethasone	6 mg of IV or enteral dexamethasone will be administered daily for up to 10 days while in hospital.
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	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	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	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.
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.

Timeline

• Start date: 2016-04-11
• Primary completion: 2026-02-01
• Completion: 2028-02-01
• First posted: 2016-04-13
• Last updated: 2024-07-12

Locations

408 sites across 29 countries: United States, Australia, Belgium, Canada, Colombia, Croatia, Czechia, Estonia, Finland, France, Germany, Hungary, India, Ireland, Israel, Italy, Japan, Nepal, Netherlands, New Zealand, Pakistan, Portugal, Romania, Saudi Arabia, Serbia, Slovenia, Spain, Switzerland, United Kingdom

Regulatory

• FDA-regulated drug study