Randomized Controlled Trial

. 2023 Nov;40(11):4805-4816.

doi: 10.1007/s12325-023-02618-7. Epub 2023 Aug 24.

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Daniel Q Huang^#^{1

2

3}, Veeral Ajmera^#^{1

4}, Christian Tomaszewski⁵, Andrew LaFree⁵, Ricki Bettencourt¹, Wesley K Thompson⁶, Davey M Smith^{7

8}, Atul Malhotra⁹, Ravindra L Mehta¹⁰, Vaishal Tolia¹¹, Jeffrey Yin¹², Paul A Insel^{13

14}, Stone Leachman¹, Jinho Jung¹, Summer Collier⁴, Lisa Richards¹, Kristin Woods¹⁵, Maral Amangurbanova¹, Archana Bhatt¹⁵, Xinlian Zhang¹⁶, Oana M Penciu¹⁷, Stuart Zarich¹⁸, Tamrat Retta¹⁹, Michelle S Harkins²⁰, J Pedro Teixeira²⁰, Brian Chinnock²¹, Netanya S Utay²², Jordan E Lake²³, Rohit Loomba^{24

25

26}

Affiliations

¹ NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA.
² Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³ Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
⁴ Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁵ Department of Emergency Medicine, University of California, San Diego and the El Centro Regional Medical Center, San Diego, CA, USA.
⁶ Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
⁷ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Veteran Affairs Medical Center, San Diego, CA, USA.
⁹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹⁰ Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹¹ Department of Emergency Medicine, University of California San Diego, La Jolla, CA, USA.
¹² Department of Pharmacy, University of California San Diego, La Jolla, CA, USA.
¹³ Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
¹⁴ Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA.
¹⁵ Clinical & Translational Research Institute, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA, USA.
¹⁷ Beverly Hospital, Montebello, CA, USA.
¹⁸ Section of Cardiovascular Medicine, Yale New Haven Health Bridgeport Hospital, Bridgeport, CT, USA.
¹⁹ Department of Internal Medicine, Howard University, Washington, DC, USA.
²⁰ Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
²¹ Department of Emergency Medicine, University of California San Francisco-Fresno Medical Education Program, Fresno, CA, USA.
²² Division of Infectious Diseases and Geographic Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²³ Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
²⁴ NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA. roloomba@ucsd.edu.
²⁵ Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. roloomba@ucsd.edu.
²⁶ Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA. roloomba@ucsd.edu.

^# Contributed equally.

PMID: 37615850
PMCID: PMC10709987
DOI: 10.1007/s12325-023-02618-7

Randomized Controlled Trial

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Daniel Q Huang et al. Adv Ther. 2023 Nov.

. 2023 Nov;40(11):4805-4816.

doi: 10.1007/s12325-023-02618-7. Epub 2023 Aug 24.

Authors

Affiliations

¹ NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA.
² Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³ Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
⁴ Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁵ Department of Emergency Medicine, University of California, San Diego and the El Centro Regional Medical Center, San Diego, CA, USA.
⁶ Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
⁷ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Veteran Affairs Medical Center, San Diego, CA, USA.
⁹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹⁰ Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹¹ Department of Emergency Medicine, University of California San Diego, La Jolla, CA, USA.
¹² Department of Pharmacy, University of California San Diego, La Jolla, CA, USA.
¹³ Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
¹⁴ Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA.
¹⁵ Clinical & Translational Research Institute, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA, USA.
¹⁷ Beverly Hospital, Montebello, CA, USA.
¹⁸ Section of Cardiovascular Medicine, Yale New Haven Health Bridgeport Hospital, Bridgeport, CT, USA.
¹⁹ Department of Internal Medicine, Howard University, Washington, DC, USA.
²⁰ Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
²¹ Department of Emergency Medicine, University of California San Francisco-Fresno Medical Education Program, Fresno, CA, USA.
²² Division of Infectious Diseases and Geographic Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²³ Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
²⁴ NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA. roloomba@ucsd.edu.
²⁵ Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. roloomba@ucsd.edu.
²⁶ Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, CA, USA. roloomba@ucsd.edu.

^# Contributed equally.

PMID: 37615850
PMCID: PMC10709987
DOI: 10.1007/s12325-023-02618-7

Abstract

Introduction: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19.

Methods: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14.

Results: Between 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m². Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19.

Conclusion: De novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19.

Trial registration: Clinicaltrials.gov NCT04366050.

Keywords: COVID-19; Coronavirus; Ramipril; Therapy.

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Figures

**Fig. 1**
Trial profile. *COVID-19* coronavirus disease 2019, *NSAIDS* non-steroidal anti-inflammatory drugs, *ALT* alanine aminotransferase, *AST* aspartate aminotransferase, *ULN* upper limit of normal, BP blood pressure

See this image and copyright information in PMC

References

1. WHO. WHO coronavirus (COVID-19) dashboard. https://covid19.who.int Accessed Feb 1, 2022.
1. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052–9. - PMC - PubMed
1. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782–93. - PubMed
1. Li J, Huang DQ, Zou B, et al. Epidemiology of COVID-19: a systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes. J Med Virol. 2020;93(3):1449–58. - PMC - PubMed
1. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605–10. - PubMed

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Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Affiliations

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous