The REMAP-CAP Trial

Background

• Community-acquired pneumonia (CAP), that is of sufficient severity to require admission to an Intensive Care Unit (ICU), is associated with substantial mortality.
• In Australia, CAP is responsible for more than 7000 ICU admissions and 1400 deaths each year. The annual direct cost of ICU care of these patients is in the order of $200 million.
• All patients with severe pneumonia who are treated in an ICU will receive therapy that consists of a combination of multiple different treatments.
• The existing evidence-base, for treatment of patients with Severe CAP is limited, reflected in variation in Australian and international guidelines as well as variation in practices including choice of antibiotic, choice of ventilator strategy, and use of immune modulating agents.

Objectives

Primary

To determine the impact on 90-day mortality of:

• Alternative antibacterial strategies;
• Administration of azithromycin, acting as an immunomodulatory agent;
• Administration of a Corticosteroid;

A key benefit of the design is that additional questions can be asked over the lifetime of the platform.

Secondary

To provide Australia and New Zealand’s contribution to the pre-prepared global research response to future pandemics of Severe Acute Respiratory Illness (SARI) by seamlessly and rapidly (within days) adapting the platform to test the most promising interventions for pandemic infection and providing trial results during the first wave of a pandemic.

Methods

• The study will enrol adult patients with severe CAP who are admitted to ICUs using a design known as a REMAP, which is a type of platform trial.
• Eligible participants will be randomised to receive one intervention in each of one or more domains.
• This REMAP uses an adaptive design, relying on pre-specified criteria for adaptation, that:
  • avoids indeterminate results
  • concludes an answer to a question when sufficient data have accrued (not when a pre-specific sample is reached)
  • evaluates the effect of treatment options in pre-defined subgroups of patients (termed strata)
  • utilizes already accrued data to increase the likelihood that patients within the trial are randomized to treatments that are more likely to be beneficial
  • is multifactorial, evaluating multiple questions simultaneously
  • is intended to be perpetual (or at least open-ended), substituting new questions in series as initial questions are answered
  • can evaluate the interaction between interventions in different domains.
• Bayesian statistical methods will be used to establish the superiority, inferiority, or equivalence of interventions within a domain. Interventions determined to be superior will be incorporated into standard care within the ongoing REMAP. Interventions determined to be inferior will be discontinued.