RAMIC: Design of a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of ramipril in patients with COVID-19

Veeral Ajmera, Wesley K Thompson, Davey M Smith, Atul Malhotra, Ravindra L Mehta, Vaishal Tolia, Jeffrey Yin, Krishna Sriram, Paul A Insel, Summer Collier, Lisa Richards, Rohit Loomba, Veeral Ajmera, Wesley K Thompson, Davey M Smith, Atul Malhotra, Ravindra L Mehta, Vaishal Tolia, Jeffrey Yin, Krishna Sriram, Paul A Insel, Summer Collier, Lisa Richards, Rohit Loomba

Abstract

Background and aims: Retrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE).

Methods: RAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5 mg orally daily compared to placebo for 14 days. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7 days, glomerular filtration rate < 40 mL/min or a systolic blood pressure (BP) < 100 mmHg or diastolic BP < 65 mmHg. Patients are randomized 2:1 to receive ramipril (2.5 mg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually.

Conclusions: RAMIC is designed to assess the efficacy of treatment with ramipril for 14 days to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

Keywords: Covid-19; Mechanical ventilation; SARS-CoV2; Virtual visit.

Conflict of interest statement

Dr. Malhotra reports funding related to medical education from Livanova, Equillium and Corvus. ResMed provided a philanthropic donation to UCSD. Rohit Loomba: Potential conflict of interest for Rohit Loomba: Dr. Loomba serves as a consultant or advisory board member for Bird Rock Bio, Celgene, Enanta, GRI Bio, Madrigal, Metacrine, NGM, Sanofi, Arrowhead Research, Galmed, NGM, GNI, NovoNordisk, Merck, Siemens, Pfizer, Gilead. Glympsebio, In addition, his institution has received grant support from Allergan, BMS, BI, Daiichi-Sankyo Inc., Eli-Lilly, Galectin, Galmed, GE, Genfit, Intercept, Janssen Inc., Madrigal, Merck, NGM, Pfizer, Prometheus, Siemens, and Sirius. He is also co-founder of Liponexus Inc. Paul Insel is not currently but within the past 3 years has served as a consultant or received research support from Merck, Pfizer, and Bristol Myers Squibb. Davey Smith serves a consultant for Arena Pharmaceuticals, Nitto Pharmaceuticals and Bayer. He also serves on the Scientific Advisory Board of Safe Aloha and FluxErgy.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
RAMIC study design.
Fig. 2
Fig. 2
Remote Consent Process for RAMIC: A) Patient receives paper consent and sends a photograph or obtains impartial witness attestations or B) electronic consent and signature using IRB approved platform.

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