This study has been transitioned to CTIS with ID 2023-507889-89-00 check the CTIS register for the current data. REMAP-CAP: The goal of the study is to investigate the best treatment regime for pneumonia patients. For non-pandemic pneumonia (…
ID
Source
Brief title
Condition
- Infections - pathogen unspecified
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint outside a pandemic is mortality at day 90 censored at
hospital discharge.
In case of a pandemic, this is retained as a secondary endpoint, and a new
pandemic primary endpoint is added: "days alive and without organ support at
day 21", where all subjects deceased before the end of follow up will be
denoted as -1 at that time.
Secondary outcome
ICU death, ICU admission duration, hospital admission duration, number of days
NOT on ventilator measured on day-28, number of days NOT on ventilator measured
on day-28, survival 6 months after data, health-related quality of life
assessment administered after 6 months , using EQ5D and a physical disability
assessment 6 months later using the World Health Organization Disability
Assessment Schedule (WHODAS).
See above: In a pandemic, the original primary endpoint is included as a
secondary endpoint.
Furthermore, because of the multiple domains, specific additional endpoints for
each domain are described in the DSA if necessary. We list these below:
COVID-19: Antiviral Therapy Domain - Serious Adverse Reactions (SAEs) as
defined in the Core Protocol. This domain is currently closed
COVID-19 Immuno Modulation Therapy Domain - It is currently closed.
COVID-19 Anti-coagulase domain:
• Confirmed Deep Vein Thrombosis
• Confirmed pulmonary embolism
• Confirmed ischemic cerebrovascular event
• Total number of red blood cell units transfused between randomization and the
end of study day 15
• Acute myocardial infarction
• Peak serum troponin between randomization and the end of study day 15
• Severe bleeding
• Other thrombotic events, including mesenteric ischemia and limb ischemia
• Serious Adverse Reactions (SAE) as defined in the Core Protocol
Vitamin C domain: this domain is currently on hold/closed
• Serious Adverse Reactions (SAE) as defined in the Core Protocol
Breathing domain:
• Serious Adverse Reactions (SAE) as defined in the Core Protocol
• Delivery of *rescue* therapy
• Barotrauma
Endothelial domain
From randomization in this domain, during the index hospitalization until the
end of study day 15:
• Severe thrombocytopenia (defined as <50 x 109/L)
- Severe neutropenia (defined as <1.0 x 109/L)
• Major bleeding (as defined by the ISTH criteria)
• Elevation of AST or ALT to 5 x ULN or bilirubin 3 x ULN
From randomization in this domain, during index hospitalization unless
otherwise noted, censored 90 days after enrollment:
• Confirmed proximal deep vein thrombosis
• Confirmed pulmonary embolism
• Acute myocardial infarction
• Confirmed ischemic cerebrovascular event
• Other thrombotic events
• Serious adverse reactions as defined in the core protocol
COVID-19 Simvastatin domain: This domain is currently closed
• Serious Adverse Reactions (SAE) as defined in the Core Protocol
COVID-19 Antiplatelet Drug Domain:
• Confirmed proximal deep vein thrombosis
• Confirmed pulmonary embolism
• Confirmed ischemic cerebrovascular event
• Total number of red blood cell units given between randomization and the end
of study day 15
• Mycardial infarction
• Severe bleeding
• Trobotic events, including mesenteric limb ischemia
• Serious Adverse Reactions (SAE) as defined in the core protocol
COVID-19 ACE2 RAS domain: This domain is currently closed
• acute kidney injury defined as KDIGO Stage >=2 acute kidney injury:
o Stage 2: serum creatinine increases 2-3x from baseline within 7 days
o Stage 3: increase in serum creatinine >=3x from baseline within 7 days, or
increase in serum creatinine by >=0.5 mg/dl (44 mmol/l) to >=4 mg/dl (353.6
mol/l) , or start of renal replacement therapy
• change from baseline to peak creatinine
• angioedema
• change in baseline to peak available AST, ALT and bilirubin during the
treatment period (14-day peak; these should be performed at least once within
blocks of post-randomization days 1-5, 6-10 and 11-14 ; preferably should be
these come from standard care labs, and if they are not available they must be
checked at least once within each of these time blocks)
• only in the ARB + **DMX-200 intervention:
o occurrence of suspected unexpected serious adverse reactions (SUSAR).
• Serious Adverse Reactions (SAE) as defined in the Core Protocol
COVID-19 Immunoglobulin domain
• All-cause mortality at 28 days censored at hospital discharge
• Confirmed Deep Vein Thrombosis
• Confirmed pulmonary embolism
• Confirmed ischemic stroke
• Confirmed acute myocardial infarction
• Other confirmed thrombotic events
• Serious Adverse Events (SAE) as defined in Core Protocol
Background summary
Pneumonia is an important and common health problem. Part of the patients will
be admitted to an ICU. These patients have severe pneumonia. 20-50% dies,
despite all available treatments. From the start of REMAP-CAP, we have aimed to
find the best treatment for these patients by investigating treatments
currently part of standard treatments across the globe, and finding the best
alternative for all patients.
Since 2020 there is a new, pandemic, cause of pneumonia: SARS-CoV-2. This
causes COVID-19 disease. Because early treatment could be beneficial, and
because there can be a differential treatment effect in different phases of the
disease, we include both hospitalized COVID-19 patients in the ICU as well as
the wards in REMAP-CAP if their pneumonia is caused by SARS-CoV-2. The study
was always designed to adapt in a pandemic, which facilitates this adjustment.
De treatment of patients with pneumonia is generally based on (international)
treatment guidelines. These are however based on very little high quality
evidence. There is a paucity of well conducted clinical trials. That is why we
investigate, in a randomized manner, the existing variation in standards of
care to see which treatment or treatments work best. We call this "from random
care to randomized care".
For pneumonia caused by Influenza virus (flu), it is known that many ICUs give
oseltamivir as part of the treatment, but if this is effective is unknown. But,
the results from mainly outpatient research cannot just be extrapolated to
severely ill ICU patients. That is why we investigate this specific therapy.
For COVID-19 patients, it's slightly different. This is a new disease for which
we had no treatment other than supportive care at the beginning of 2020, but
for which we now know that corticosteroids (such as dexamethasone) and IL-6
receptor antagonists work for some of the hospitalised patients. However,
mortality is still high and there are many outstanding questions. The type of
study we undertake, an Adaptive Platform Trial, is very suited to deal with
this dynamic situation. This is why we have a modular protocol. "Blocks"
(domains) can be added, removed or changed, without the need to set up a
complete new trial. If it is deemed necessary to make these changes, this is
filed as an amendment with the IRB, so COVID-19 patients can benefit from new
insights quickly.
The interventions we investigate in the subset of COVID-19 patients are
medications that have proven effective in animal or preclinical studies, with
which there is experience in other diseases, that have good safety profiles and
adequate availability. This is driven by the fact that completely new
treatments have not been developed yet, but also because relatively cheaper
medications with known side-effects and that have been used extensively are
preferred, if equally effective.
Study objective
This study has been transitioned to CTIS with ID 2023-507889-89-00 check the CTIS register for the current data.
REMAP-CAP: The goal of the study is to investigate the best treatment regime
for pneumonia patients. For non-pandemic pneumonia (including Influenza) we
investigate this in critically ill patients. For pneumonia caused by
SARS-CoV-2, we investigate the best treatment for all hospitalized patients.
Study design
Randomized Embedded, Multifactorial, Adaptive Platform (REMAP) trial.
Intervention
General information about the interventions in the trial:
a) Antibiotic domain: up to 5 different empirical AB strategies are compared.
Each hospital indicates what suits them in "standard" empirical therapy and
chooses 2 or more interventions (ceftriaxone+macrolide, amoxicillin/clavulanic
acid+macrolide, ceftaroline+macrolide, piperacillin/tazobactam+macrolide,
moxifloxacin/levofloxacin). Adjustments based on cultures or clinical
information are always allowed. Only IC patients are eligible for this.
b) Macrolide domain: a strategy with short-term macrolides (3-5 days) is
compared with 14 days macrolides. In case of indications for an atypical
causative agent, empty artis is of course treated. Only IC patients who have
been randomized in the AB domain for a macrolide strategy are eligible for this
(nested domain).
c) Steroid domain: We compare the non-administration of steroids with a
standard treatment of 7 days (hydrocortisone 4dd 50 mg) and treatment only when
the patient is in shock as part of the CAP treatment. Each hospital indicates
what suits them in "standard" empirical therapy and chooses 2 or more
interventions. Only ICU patients WITHOUT COVID-19 are eligible for this,
because since the publication of the RECOVERY trial data, dexamethasone is seen
as standard treatment for patients with O2 or ventilation and COVID-19 as the
cause of the CAP.
d) Influenza antiviral domain: We do not compare no antiviral treatment with
oseltamivir, with 5 and 10 days of treatment and/or Baloxavir. Each hospital
indicates what suits them in "standard" empirical therapy and chooses 2 or more
interventions. Only ICU patients with Influenza as the (presumed) causative
agent of their CAP are eligible for this.
e) Vitamin C domain: We do not compare Vitamin C with Vitamin C (50 mg/kg IV
every 6 hours for 16 doses). These interventions are available for both
moderately and severely ill patients. This domain is currently closed
f) Ventilation domain: We compare invasive artificial respiration according to
a protocol with ventilation directed by the individual physician. Only
seriously ill patients who receive invasive ventilation are eligible for this.
g) Endothelial domain. The use of imatinib. Lung damage can occur in patients
with severe pneumonia
The COVID-19 domains are only available for patients with SARS-CoV-2 as the
(presumed) causative agent of the pneumonia: Dot domain is only available for
critically ill patients
h) In the COVID-19 Antiviral domain we do or do not compare ivermectin
treatment against the COVID-19 virus. This domain is available for both
moderately and severely ill patients. This domain is currently closed
i) The COVID-19 Immunomodulation domain is currently closed.
j) In the COVID-19 Anticoagulant domain, only IC patients with organ support
are included, These interventions are only available for critically ill
patients. You can only participate in this part of the study if you do not
require a full dose of blood thinners for any other reason
k) In the COVID-19 Simvastatin domain, we do not compare Simvastatin with
Simvastatin. These interventions are available for both moderately and
critically ill patients. This domain is currently closed
l) In the COVID-19 Antiplatelet Drugs domain we compare 'no antiplatelet drugs'
with Asperin and P2Y12 inhibitor. The P2Y12 inhibitor is clopidogrel. This
intervention is only available for critically ill patients.
m) In the COVID-19 ACE2 RAS domain we compare Angiotensin receptor blockers
(ARB), Angiotensin receptor blockers in combination with
a chemokine receptor-2 (CCR2) inhibitor (ARB + **DMX-200), Angiotensin
Converting Enzyme (ACE) inhibitors and no specific treatment with a RAS
inhibitor. These interventions are available for both moderately and critically
ill patients. This domain is currently closed
n) The Immunoglobulin Domain. Use of convalescent plasma. Convalescent plasma
is plasma obtained from people who have had a COVID-19 infection and have been
cured. This plasma contains antibodies that could help fight the virus in
people who have not yet recovered from COVID-19. This domain is suitable for
both moderately and seriously ill patients
o) Immunomodulation domain for Influenza
Some agents might be effective against influenza because they affect the immune
system (and not the virus itself). We call these Immunomodulating agents. We do
compare no use of immunomodulating agents, tocilizumab and baricitinib. This
intervention is only available for critically ill patients.
In the data management system as well as in the trial administration, it is
established for each hospital in which domains and interventions they
participate.
Study burden and risks
The randomized treatments are partly variations in standards of care and are
part of daily clinical practice. The only difference is the randomized, instead
of random, choice for these treatments. Sites only choose interventions they
have clinical equipoise for. The risk is negligible.
For domains and interventions available to COVID-19 patients this is different.
This is a new disease where we look for new treatments. We prefer to use
medicines with known side effects, known dose, and PK/PD. Hence the choice to
investigate medicines commonly used in. other diseases. Risks in these domains
relate to the potential risk of side effects of these interventions. So, the
risk may be somewhat higher. However, the potential gain is also higher. If we
find an effective treatment we prevent mortality, days in hospital or days on
organ support like ventilation.
The design has many advantages over traditional RCTs. Firstly, we use response
adaptive randomization, randomizing more patients to the most promising
interventions. It is multifactorial, leaving almost no patients to receive no
active treatment at all. Also, data obtained are used to answer multiple
questions. As soon as an intervention is found to be futile it can be removed
from the study and no other patients are exposed to it. If a treatment proves
effective it can immediately be integrated as standard of care. The trial gives
a wealth of information about subgroup effects and interactions, compared to
traditional RCTs.
The robust design, excellent statistical team and international cooperation
make this a high quality study. This also ensures the highest chance of
achieving inclusion rates to obtain robust conclusions on potential effective
treatments and fast access to those treatments.
In summary, we find the burden and risks very limited, and definitely
proportional to the potential benefit.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
General REMAP-CAP:
1. Adult patient admitted to an ICU for acute severe CAP within 48 hours of
hospital admission with
a. symptoms or signs or both that are consistent with lower respiratory tract
infection AND
b. Radiological evidence of new onset infiltrate of infective origin (in
patients with pre-existing radiological changes, evidence of new infiltrate)
2. Up to 48 hours after ICU admission, receiving organ support with one or more
of:
a. Non-invasive or invasive ventilatory support;
b. Receiving infusion of vasopressor or inotropes or both
For the COVID-19 domains:
1. COVID-19 infection is suspected by the treating clinician or has been
confirmed by microbiological testing (i.e. PISOP stratum)
2. Microbiological testing for SARS-CoV-2 infection of upper or lower
respiratory tract secretions or both has occurred or is intended to occur
If applicable, domain and/or intervention-specific inclusion criteria listed in
the DSA.
Exclusion criteria
General REMAP-CAP Exclusion Criteria:
1. Healthcare-associated pneumonia:
a. Prior to this illness, is known to have been an inpatient in any
healthcare facility within the last 30 days
b. Resident of a nursing home or long-term care facility.
2. 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.
3. Previous participation in this REMAP within the last 90 days
For subjects suspected or proven to have COVID-19, the 48 hour time window does
not apply, due to the nature of the disease process.
There are specific exclusion criteria (if needed) for every domain or
intervention within a domain in the trial, listed in each DSA.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-507889-89-00 |
| EudraCT | EUCTR2015-002340-14-NL |
| ClinicalTrials.gov | NCT02735707 |
| CCMO | NL53818.041.15 |