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

• ClinicalTrials.gov Identifier: NCT02735707
• Recruitment Status: Recruiting
• First Posted: April 13, 2016
• Last Update Posted: March 30, 2020
• Sponsor: MJM Bonten
• 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

Tracking Information

• First Submitted Date: December 11, 2015
• First Posted Date: April 13, 2016
• Last Update Posted Date: March 30, 2020
• Actual Study Start Date: April 11, 2016
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 25, 2020)

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

Original Primary Outcome Measures (submitted: April 6, 2016)

Mortality (%) measured at day 60 after randomization of the patients included in this trial. [ Time Frame: 60 days ]

Mortality (%) measured at day 60 after randomization of the patients included in this trial for all different interventions.

Current Secondary Outcome Measures (submitted: March 25, 2020)

• ICU Mortality [ Time Frame: Day 90 ]
• ICU length of stay [ Time Frame: Day 90 ]
• Hospital length of stay [ Time Frame: Day 90 ]
• Ventilator free days [ Time Frame: Day 28 ]
• Organ failure free days [ Time Frame: Day 28 ]
• All-cause mortality [ Time Frame: 6 months ]
• Health-related Quality of life assessment [ Time Frame: 6 months ]
  EQ5D-5L and WHODAS 2.0 (not completed in all regions)
• Proportion of intubated patients who receive a tracheostomy [ Time Frame: Day 28 ]
• 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
• Readmission to the index ICU during the index hospitalization [ Time Frame: Day 90 ]

Original Secondary Outcome Measures (submitted: April 6, 2016)

• ICU length of stay of the patients included in this trial. [ Time Frame: Through study completion, average of 6 days ]
  ICU length of stay of the patients included in this trial, measured in number of days for all interventions
• Hospital length of stay of the patients included in this trial. [ Time Frame: Through study completion, average of 10 days ]
  Hospital length of stay of the patients included in this trial, measured in number of days for all interventions.
• Ventilator free days. [ Time Frame: Day 30 ]
  Measure the number of ventilator free days of the patients included in this trial at day 30.
• Ventilator free days. [ Time Frame: Day 60 ]
  Measure the number of ventilator free days of the patients included in this trial at day 60.
• Organ failure free days. [ Time Frame: Day 30 ]
  Measure the number of organ failure free days of the patients included in this trial at day 30.
• Organ failure free days. [ Time Frame: Day 60 ]
  Measure the number of organ failure free days of the patients included in this trial at day 60.

Current Other Pre-specified Outcome Measures (submitted: March 25, 2020)

• Occurrence of multi-resistant organism colonisation/infection [ Time Frame: Day 90, censored at hospital discharge ]
  Antibiotic Domain specific outcome
• Occurrence clostridium difficile [ Time Frame: Day 90, censored at hospital discharge ]
  Antibiotic Domain specific outcome
• 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.
• 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.
• 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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

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

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Community-acquired Pneumonia, Influenza, COVID-19

Intervention

• Drug: Fixed-duration Hydrocortisone
  50mg of intravenous hydrocortisone will be administered every 6 hours for up to 7 days.
• Drug: Shock-dependent hydrocortisone
  Patient will receive 50mg IV hydrocortisone every 6 hours while the patient is in septic shock
• 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.

  Ceftaroline is not available at commencement

• Drug: Amoxicillin-clavulanate
  The duration and dose of empiric antibiotics will be determined by the treating clinician and local guidelines or practice.
• 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
• 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
• 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)
• 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
• 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).
• 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).

• 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
• 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)

Study Arms

• Active Comparator: Corticosteroid Domain: fixed-duration Hydrocortisone
  The patient will receive Hydrocortisone 50 mg every 6 hours for up to 7 days.
  Intervention: Drug: Fixed-duration Hydrocortisone
• 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.
  Intervention: Drug: Shock-dependent hydrocortisone
• Active Comparator: Antibiotic Domain: Ceftriaxone + Macrolide
  Ceftriaxone and site preferred macrolide will be administered for empiric antibiotic therapy
  Intervention: Drug: Ceftriaxone
• Active Comparator: Antibiotic Domain: Moxifloxacin or Levofloxacin
  Moxifloxacin or levofloxacin will be administered for empiric antibiotic therapy
  Intervention: Drug: Moxifloxacin or Levofloxacin
• Active Comparator: Antibiotic Domain: Piperacillin-tazobactam + Macrolide
  Piperacillin-tazobactam and site preferred macrolide will be administered for empiric antibiotic therapy
  Intervention: Drug: Piperacillin-tazobactam
• Active Comparator: Antibiotic Domain: Ceftaroline + Macrolide
  Ceftaroline and site preferred macrolide will be administered for empiric antibiotic therapy
  Intervention: Drug: Ceftaroline
• Active Comparator: Antibiotic Domain: Amoxicillin-clavulanate + Macrolide
  Amoxicillin-clavunate and site preferred macrolide will be administered for empiric antibiotic therapy
  Intervention: Drug: Amoxicillin-clavulanate
• 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.
  Intervention: Drug: Macrolide administered for 3-5 days
• 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.
  Intervention: Drug: Macrolide administered for up to 14 days
• 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.
  Intervention: Drug: Five-days oseltamivir
• Active Comparator: 10-day course of oseltamivir
  The patient will receive a ten-day course of oseltamivir.
  Intervention: Drug: Ten-days oseltamivir
• 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.
  Intervention: Drug: Lopinavir/ritonavir
• Active Comparator: Hydroxychloroquine for COVID-19
  Patients will receive hydroxychloroquine intended to be active against SARS-CoV-2 infection.
  Intervention: Drug: Hydroxychloroquine
• 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.
  Intervention: Drug: Hydroxychloroquine + lopinavir/ritonavir
• 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.
  Intervention: Drug: Interferon-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.
  Intervention: Drug: Anakinra

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 16, 2018): 6800
• Original Estimated Enrollment (submitted: April 6, 2016): 4000
• Estimated Study Completion Date: June 2022
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Eligibility 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Cameron Green; info@remapcap.org

Contact: Wilma Van Bentum-Puijk, MSc; +31 (0) 88 755 5555; prepare_icu@umcutrecht.nl

• Listed Location Countries: Australia, Belgium, Canada, Croatia, Germany, Hungary, Ireland, Netherlands, New Zealand, Portugal, Romania, Spain, United Kingdom
• Removed Location Countries: France

Administrative Information

• NCT Number: 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- )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Responsible Party: MJM Bonten, UMC Utrecht
• Study Sponsor: MJM Bonten

Collaborators

• Berry Consultants
• Australian and New Zealand Intensive Care Research Centre
• Medical Research Institute of New Zealand
• Unity Health

Investigators

• 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

• PRS Account: UMC Utrecht
• Verification Date: March 2020