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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02735707
Recruitment Status : Recruiting
First Posted : April 13, 2016
Last Update Posted : March 30, 2020
Sponsor:
Collaborators:
Berry Consultants
Australian and New Zealand Intensive Care Research Centre
Medical Research Institute of New Zealand
Unity Health
Information provided by (Responsible Party):
MJM Bonten, 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 ofon 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 resulting in critical illness.


Condition or disease Intervention/treatment Phase
Community-acquired Pneumonia, Influenza, COVID-19 Drug: Fixed-duration Hydrocortisone Drug: Shock-dependent hydrocortisone Drug: Ceftriaxone Drug: Moxifloxacin or Levofloxacin Drug: Piperacillin-tazobactam Drug: Ceftaroline Drug: Amoxicillin-clavulanate Drug: Macrolide administered for 3-5 days Drug: Macrolide administered for up to 14 days Drug: Five-days oseltamivir Drug: Ten-days oseltamivir Drug: Lopinavir/ritonavir Drug: Hydroxychloroquine Drug: Hydroxychloroquine + lopinavir/ritonavir Drug: Interferon-β1a Drug: Anakinra Phase 4

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6800 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia
Actual Study Start Date : April 11, 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Active Comparator: Corticosteroid Domain: fixed-duration Hydrocortisone
The patient will receive Hydrocortisone 50 mg every 6 hours for up to 7 days.
Drug: Fixed-duration Hydrocortisone
50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.

No Intervention: Corticosteroid Domain:No systemic corticosteroid (no placebo)
The patient will receive no systemic corticosteroid for the treatment of CAP or its direct complications, up until study day 28.
Active Comparator: Corticosteroid Domain: shock dependant Hydrocortisone
The patient will receive hydrocortisone (50mg IV every 6 hours) while the patient is in septic shock.
Drug: Shock-dependent hydrocortisone
Patient will receive 50mg IV hydrocortisone every 6 hours while the patient is in septic shock

Active Comparator: Antibiotic Domain: Ceftriaxone + Macrolide
Ceftriaxone and site preferred macrolide will be administered for empiric antibiotic therapy
Drug: Ceftriaxone
The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

Active Comparator: Antibiotic Domain: Moxifloxacin or Levofloxacin
Moxifloxacin or levofloxacin will be administered for empiric antibiotic therapy
Drug: Moxifloxacin or Levofloxacin
The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

Active Comparator: Antibiotic Domain: Piperacillin-tazobactam + Macrolide
Piperacillin-tazobactam and site preferred macrolide will be administered for empiric antibiotic therapy
Drug: Piperacillin-tazobactam
The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

Active Comparator: Antibiotic Domain: Ceftaroline + Macrolide
Ceftaroline and site preferred macrolide will be administered for empiric antibiotic therapy
Drug: Ceftaroline

The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

Ceftaroline is not available at commencement


Active Comparator: Antibiotic Domain: Amoxicillin-clavulanate + Macrolide
Amoxicillin-clavunate and site preferred macrolide will be administered for empiric antibiotic therapy
Drug: Amoxicillin-clavulanate
The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.

Active Comparator: Macrolide Duration Domain: Standard course macrolide
The patient will receive macrolide therapy for 3-5 days. This arm is nested within the Antibiotic Domain.
Drug: Macrolide administered for 3-5 days

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.
Other Name: Standard course macrolide

Active Comparator: Macrolide Duration Domain: Extended course macrolide
The patient will receive macrolide therapy for up to 14 days This arm is nested within the Antibiotic Domain.
Drug: Macrolide administered for up to 14 days

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 Name: Extended course macrolide

No Intervention: No antiviral agent active against influenza (no placebo)
The patient will receive no antiviral agent active against influenza, including oseltamivir.
Active Comparator: Five-day course of Oseltamivir
The patient will receive a five-day course of oseltamivir.
Drug: Five-days oseltamivir
Oseltamivir administered enterally twice daily for 5 days or until hospital discharge (whichever occurs first)

Active Comparator: 10-day course of oseltamivir
The patient will receive a ten-day course of oseltamivir.
Drug: Ten-days oseltamivir
Oseltamivir administered enterally twice daily for 10 days or until hospital discharge (whichever occurs first)

No Intervention: No antiviral for COVID-19
The patient will receive no antiviral agent intended to be active against SARS-CoV-2 infection.
Active Comparator: Lopinavir/ritonavir for COVID-19
Patients will receive lopinavir/ritonavir (kaletra) 400/100mg enterally every 12 hours intended to be active against SARS-CoV-2 infection.
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.
Other Name: Kaletra

Active Comparator: Hydroxychloroquine for COVID-19
Patients will receive hydroxychloroquine intended to be active against SARS-CoV-2 infection.
Drug: Hydroxychloroquine
Loading dose of 400mg administered enterally every 8 hours until 9 doses have been administered. Subsequently, 200mg hydroxychloroquine will be administered enterally every 12 hours until ICU discharge of end of study day 10 (whichever occurs first).

Active Comparator: Hydroxychloroquine + lopinavir/ritonavir for COVID-19
Patients will receive both hydroxychloroquine and lopinavir/ritonavir intended to be active against SARS-CoV-2 infection.
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 400mg hydroxychloroquine administered enterally every 8 hours until 9 doses have been administered. Subsequently, 200mg hydroxychloroquine will be administered enterally every 12 hours until ICU discharge of end of study day 10 (whichever occurs first).


No Intervention: No immune modulation for COVID-19
Patients will not receive any immune modulating therapy intended to be active against COVID-19.
Active Comparator: Interferon-β1a for COVID-19
Patients will receive Interferon-β1a daily for six days or until ICU discharge intended to be active against SARS-CoV-2 infection.
Drug: Interferon-β1a
IFN-β1a 10 μg will be diluted in 1 mL of sterile water. The diluted IFN-β1a will be administered as an intravenous bolus injection via a central or peripheral line. The injection will be followed with a 5 mL flush of sterile saline. IFN-β1a will be administered once daily for 6 days or until ICU discharge, whichever occurs first.
Other Name: IFN-β1a

Active Comparator: Anakinra (interleukin-1 receptor antagonist) for COVID-19
Patients will receive anakinra 300mg daily intended to be active against SARS-CoV-2 infection.
Drug: Anakinra

300mg anakinra administered as a bolus via central or peripheral line once daily.

In patients with renal impairment, anakinra will be administered on alternate days.

Other Name: Interleukin-1 receptor antagonist (IL-1Ra)




Primary Outcome Measures :
  1. All-cause mortality [ Time Frame: Day 90 ]
  2. Days alive and outside of ICU [ Time Frame: Day 21 ]
    Primary end-point for patients with suspected or proven pandemic infection


Secondary Outcome Measures :
  1. ICU Mortality [ Time Frame: Day 90 ]
  2. ICU length of stay [ Time Frame: Day 90 ]
  3. Hospital length of stay [ Time Frame: Day 90 ]
  4. Ventilator free days [ Time Frame: Day 28 ]
  5. Organ failure free days [ Time Frame: Day 28 ]
  6. All-cause mortality [ Time Frame: 6 months ]
  7. Health-related Quality of life assessment [ Time Frame: 6 months ]
    EQ5D-5L and WHODAS 2.0 (not completed in all regions)

  8. Proportion of intubated patients who receive a tracheostomy [ Time Frame: Day 28 ]
  9. Destination at time of hospital discharge [ Time Frame: Free text Day 90 ]
    Characterised as home, rehabilitation hospital, nursing home or long-term care facility, or another acute hospital

  10. Readmission to the index ICU during the index hospitalization [ Time Frame: Day 90 ]

Other Outcome Measures:
  1. Occurrence of multi-resistant organism colonisation/infection [ Time Frame: Day 90, censored at hospital discharge ]
    Antibiotic Domain specific outcome

  2. Occurrence clostridium difficile [ Time Frame: Day 90, censored at hospital discharge ]
    Antibiotic Domain specific outcome

  3. Occurrence of serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected death [ Time Frame: Day 90, censored at hospital discharge ]
    Macrolide Duration domain specific outcome, and COVID-19 Antiviral Domain specific outcome.

  4. Change from baseline influenza virus levels in upper and lower respiratory tract specimens [ Time Frame: Day 3, up to Day 7 ]
    Antiviral Domain specific outcome. Only required at selected sites.

  5. Serial detection of SARS-CoV-2 in upper or lower respiratory tract specimens (using only specimens collected for routine clinical testing) [ Time Frame: Day 90, censored at hospital discharge ]
    COVID-19 Antiviral Domain and COVID-19 Immune Modulation Domain specific endpoint



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

PLATFORM INCLUSION CRITERIA :

1. Adult patients admitted to an ICU for severe CAP within 48 hours of hospital admission with: i. symptoms or signs or both that are consistent with lower respiratory tract infection AND ii. Radiological evidence of new onset consolidation (in patients with pre-existing radiological changes, evidence of new infiltrate) 2. Requiring organ support with one or more of: i. Non-invasive ii. Invasive ventilatory support; iii. Receiving infusion of vasopressor or inotropes

PLATFORM EXCLUSION CRITERIA:

  1. Healthcare-associated pneumonia:

    i. Prior to this illness, has been an inpatient in any healthcare facility within the last 30 days ii. Resident of a nursing home or long term care facility

  2. Death is deemed to be imminent or inevitable admission within 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

DOMAIN-SPECIFIC ELIGIBLE CRITERIA:

Each domain may have additional eligibility criteria. Refer to the study website for more information (www.remapcap.org).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02735707


Contacts
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Contact: Cameron Green info@remapcap.org
Contact: Wilma Van Bentum-Puijk, MSc +31 (0) 88 755 5555 prepare_icu@umcutrecht.nl

Locations
Show Show 89 study locations
Sponsors and Collaborators
MJM Bonten
Berry Consultants
Australian and New Zealand Intensive Care Research Centre
Medical Research Institute of New Zealand
Unity Health
Investigators
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Study Chair: Steve Webb, Prof Monash University, Study Chair REMAP-CAP Australia
Study Chair: Colin McArthur, Dr Medical Research Institute of New Zealand, Study Chair REMAP-CAP New Zealand
Study Chair: Marc Bonten, Prof UMC Utrecht, Study Chair REMAP-CAP Europe
Study Chair: Lennie Derde, MD UMC Utrecht, Coordinating Investigator REMAP-CAP Europe
Study Chair: Marshall Marshall, Prof Unity Health Toronto

Additional Information:
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Responsible Party: MJM Bonten, Prof. Medical Microbiology, UMC Utrecht
ClinicalTrials.gov Identifier: NCT02735707    
Other Study ID Numbers: U1111-1189-1653
2015-002340-14 ( EudraCT Number )
602525 ( Other Grant/Funding Number: European Union, FP7-HEALTH-2013-INNOVATION-1, PREPARE )
16/631 ( Other Grant/Funding Number: Platform Trial Optimising Interventions in Severe Community Acquired Pneumonia Health Research Council, New Zealand) )
APP1101719 ( Other Grant/Funding Number: OPTIMISE-CAP, The National Health and Medical Research Council, Australia )
158584 ( Other Grant/Funding Number: Canadian Institute of Health Research, Strategy for Patient-Oriented Research (CIHR- )
First Posted: April 13, 2016    Key Record Dates
Last Update Posted: March 30, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by MJM Bonten, UMC Utrecht:
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
Additional relevant MeSH terms:
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Pneumonia
Respiratory Tract Infections
Respiratory Tract Diseases
Lung Diseases
Anti-Bacterial Agents
Amoxicillin
Moxifloxacin
Levofloxacin
Ofloxacin
Ceftriaxone
Tazobactam
Piperacillin
Clavulanic Acid
Clavulanic Acids
Ceftaroline fosamil
Piperacillin, Tazobactam Drug Combination
Amoxicillin-Potassium Clavulanate Combination
Antibiotics, Antitubercular
Interferons
Ritonavir
Antiviral Agents
Lopinavir
Oseltamivir
Interferon-beta
Interferon beta-1a
Hydroxychloroquine
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate