Trial NCT04338009
Publication Cohen J, Lancet Respir Med, 2021 (published paper)
Dates: 2020-03-31 to 2020-08-20
Funding: Mixed (REPLACE COVID Investigators; REPLACE COVID Trial Social Fundraising Campaign; FastGrants)
Conflict of interest: Yes

Methods
RCT
Blinding: single blinding
Location : Multicenter / Argentina, Bolivia, Canada, Mexico, Peru, Sweden, USA
Follow-up duration (days): 28
Inclusion criteria1) Age 18 years or older;
2) Hospitalization with a suspected diagnosis of COVID-19, based on:
(a) A compatible clinical presentation with a positive laboratory test for SARS-CoV-2, or
(b) Considered by the primary team to be a Person Under Investigation due to undergo testing for COVID-19 in addition to compatible pulmonary infiltrates on chest x-ray (bilateral, interstitial or ground glass opacities);
3) Use of ACEI or ARB as an outpatient prior to hospital admission
Exclusion criteria1) Negative laboratory test for SARS-CoV-2;
2) Systolic blood pressure <100 mmHg;
3) Systolic blood pressure > 180 mmHg or >160 if unable to substitute ACEIs/ARBs for another antihypertensive class, per the investigator’s discretion;
4) Diastolic blood pressure > 110 mmHg;
5) Individuals with a history of heart failure in whom:
(a) left ventricular systolic function is not known (no EF assessment available);
(b) the EF is known to be <40% as per the last available 2D echo;
(c) in whom the EF was >40% as per the last available echocardiogram but the there was a significant interim clinical event likely to be associated with a reduction in LV EF (such as an ST-elevation myocardial infarction or chemotherapy with cardiotoxic drugs), as per investigator’s assessment;
6) Serum potassium >5.0 mmol/L on admission;
7) Known pregnancy or breastfeeding;
8) eGFR <30 mL/min/1.73m2;
9) ≥100% increase in creatinine (to a creatinine >177 μmol/L) compared to most recent creatinine in the past six months, if available;
10) Urine protein-to-creatinine ratio > 3 g/g or proteinuria > 3 g/24-hours within the past year;
11) Ongoing treatment with aliskiren or sacubitril-valsartan;
12) Inability to obtain informed consent from patient;
13) Inability to read and write or lack of access to a smart phone, computer or tablet device at the time of evaluation;
14) Prisoners/incarcerated individuals
Interventions
Treatment
Continue ARB/ACEI
Dose previously prescribed for routine care
Control
Discontinue ARB/ACEI
Participants
Randomized
152 participants (n1=75 / n2= 77)
Characteristics of participants
N=152
Mean age : 62
84 males
Severity : Mild: n=* / Moderate: n=*/ Severe: n=* Critical: n=*
Primary outcome
In the register
Hierarchical composite endpoint [ Time Frame: Up to 28 days ]
The primary endpoint of the trial will be a global rank score that ranks patient outcomes according to four factors:
(1) time to death,
(2) the number of days supported by invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO),
(3) the number of days supported by renal replacement therapy or pressor/inotropic therapy, and
(4) a modified sequential Organ Failure Assessment (SOFA) score.
The modified SOFA score will include the cardiac, respiratory, renal and coagulation domains of the SOFA score
In the report
Global rank score in which each participant was ranked against all other participants across four hierarchies of clinical outcomes collected over the duration of the hospitalisation: (1) days to death during the hospitalisation (ranked lowest to highest); followed by (2) days on invasive mechanical ventilation or extracorporeal membrane oxygenation (ranked highest to lowest); followed by (3) days on renal replacement therapy or inotropic or vasopressor therapy (ranked highest to lowest); followed by (4) area under the curve (AUC) of a modified SOFA score
Documents
available

Protocol

Yes. In English

Statistical plan

Yes

Data-sharing stated

Yes
Risk of bias
Overall
The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review
Some concerns
General comment In addition to the published article, the study registry and protocol were used in data extraction and risk of bias assessment. The target sample size specified in the registry was achieved. There were minor differences between the trial registry and the published article in blinding, but no substantive changes in population, procedures, interventions or outcomes.