List of Angiotensin-receptor blocker (ARB) trials for COVID-19:
- Do Angiotensin Receptor Blockers Mitigate Progression to Acute Respiratory Distress Syndrome With SARS-CoV-2 Infection. Intervention: losartan 12.5mg bid, can be increased based on SBP.
- Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease. Intervention: valsartan titrated based on BP, maximum of 160mg bid.
- Status: trial terminated, transformed into REMAP-CAP RAS domain.
- COVID MED Trial - Comparison Of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 (COVIDMED). Intervention: losartan, 25 mg po QD X 5-14 days "depending on availability."
- Results: "Of 432 screened patients, 14 were enrolled (3.5%), 9 received losartan and 5 combined control..Treatment with losartan was not associated with a difference in NCOSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan."
- Preprint of results.
- Study of Open Label Losartan in COVID-19. Intervention: losartan 25mg qd, escalated to 50mg od.
- Results: "On losartan, 24/30 (80%) experienced an adverse event as opposed to 29/30 (97%) of controls, with a lower average number of adverse events on losartan relative to control (2.2 vs 3.3). Using Poisson regression and controlling for age, sex, race, date of enrollment, disease severity at enrollment, and history of high-risk comorbidities, the incidence rate ratio of adverse events on losartan relative to control was 0.69 (95% CI: 0.49 - 0.97)
Conclusions: Losartan appeared safe for COVID-19-related acute respiratory compromise. To assess true efficacy, randomized trials are needed." - Results: "An Open Label Trial to Assess Safety of Losartan for Treating Worsening Respiratory Illness in COVID-19"
- Results: "On losartan, 24/30 (80%) experienced an adverse event as opposed to 29/30 (97%) of controls, with a lower average number of adverse events on losartan relative to control (2.2 vs 3.3). Using Poisson regression and controlling for age, sex, race, date of enrollment, disease severity at enrollment, and history of high-risk comorbidities, the incidence rate ratio of adverse events on losartan relative to control was 0.69 (95% CI: 0.49 - 0.97)
- Losartan for Patients With COVID-19 Requiring Hospitalization. Intervention: losartan 50mg bid.
- Results: "From April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]."
- Paper: preprint available on medrxiv.
- Losartan for Patients With COVID-19 Not Requiring Hospitalization. Intervention: losartan 25mg bid.
- Results: From April-November 2020, 117 participants were randomized 58 to losartan and 59 to placebo. The primary outcome did not differ significantly between the two arms based on Barnard’s test [losartan arm: 3 events (5.2%; 95% CI 1.8-14.1%) versus placebo arm: 1 event(1.7% 95% CI 0.01-9.0%); proportion difference -3.5% (95% CI -12.7-4.5%); p=0.32]. Functional status, self-reported dyspnea, maximum daily temperatures, and viral load were not significantly different between treatment groups. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early.
- Paper: paper on Preprints with The Lancet.
- Telmisartan for Treatment of COVID-19 Patients. Intervention: Telmisartan 80mg bid.
- Results: "..Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79–4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08–2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79–3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44–1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30." -- Results paper.
- "Renin Angiotensin System Inhibition as treatment for Covid-19?" - Commentary on the telmisartan trial in EClinicalMedicine.
- Treatments to Decrease the Risk of Hospitalization or Death in Elderly Outpatients With Symptomatic SARS-CoV-2 Infection (COVID-19) (COVERAGEfrance) and Early Treatment of Vulnerable Individuals With Non-Severe SARS-CoV-2 Infection (COVERAGE-A). Intervention: telmisartan 20mg od.
- Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease (CLARITY). Intervention: ARB, dose/medication not specified.
- CLARITY 2.0. Intervention: ARB, dose/medication unknown, plus CCR2-inhibitor, DMX-200.
- Chloroquine + Losartan Compared to Chloroquine Alone for the Treatment of COVID-19 Pneumonia. Intervention: losartan 25mg bid.
- Status: trial was cancelled after "evidence showed chloroquine is not effective against COVID-19" (per clinicaltrials.gov)
- Early Treatment With Ivermectin and LosarTAN for Cancer Patients With COVID-19 Infection (TITAN). Intervention: losartan 50mg od.
- Austrian CoronaVirus Adaptive Clinical Trial (COVID-19) (ACOVACT). Intervention: candesartan 4mg od, titrated up based on BP.
- Pilot Clinical Trial of the Safety and Efficacy of Telmisartan for the Mitigation of Pulmonary and Cardiac Complications in COVID-19 Patients. Intervention: telmisartan 40mg od.
- Host Response Mediators in Coronavirus (COVID-19) Infection (ARBS CORONA I). Intervention: observational study of existing ACEi/ARB users.
- Host response mediators in Coronavirus (COVID-19) infection - Is there a protective effect of ARBs on outcomes of Coronavirus infection? (ARBs CORONA II). Intervention: losartan 25mg, then 24 hours later 50mg, then 24 hours later 100mg.
- The McGill RAAS-COVID-19 Randomized Controlled Trial (RAAS-COVID). Intervention: observational study of existing ACEi/ARB users. Will suspend or hold ACEi/ARB.
- Telmisartan in Respiratory Failure Due to COVID-19 (STAR-COVID). Intervention: telmisartan 40mg od.
- Evaluation of the effects of Losartan in patients with corona virus disease 2019. Intervention: losartan 25mg bid.
- This was a small randomized controlled trial (N = 80) testing de novo initiation of either 25mg bid losartan or 5mg / day amlodipine in COVID-19 positive, hospitalized patients that presented with hypertension who did not have a history of taking an ACEi or ARB.
- Results: No statistically significant difference in the primary or secondary outcomes between the groups were seen. The small trial may have been unpowered to detect benefits of losartan, as there appeared to be non-statistically significant improvements in the losartan group. Additionally, as noted by the authors, in an observational study, amlodipine was associated with improved outcomes in COVID-19.
- Paper: results paper in IJCP paper here.
- The COVID-RASi Trial (COVID-19). Intervention: ACEi or ARB of choice (unspecified).
- Losartan and Spironolactone Treatment for ICU Patients With COVID-19 Suffering From ARDS (COVIDANCE). Intervention: losartan 50mg od, Spironolactone 25mg od.
- Combination Therapies to Reduce Carriage of SARS-Cov-2 and Improve Outcome of COVID-19 in Ivory Coast: a Phase Randomized IIb Trial (INTENSE-COV). Intervention: Lopinavir/ritonavir + telmisartan. Telmisartan 40mg od for 10 days.
- INvestigating TELmisartin Study (INTEL). Intervention: telmisartan 80mg
- Using the blood pressure medication losartan to improve outcomes for patients with SARS CoV-2. Intervention: losartan 25mg od or losartan 50mg od depending on systolic blood pressure at randomization.
- Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study. This was a prospective cohort study comparing de novo initiation of losartan in hospitalized hypertensive COVID-19 patients to a retrospective cohort of hospitalized hypertensive COVID-19 patients already on losartan. Intervention: losartan 25mg od, titrated daily by 25mg until 100mg od.
- Results: "In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension...There were suggestions of lung protection with losartan use, including the observation of an improvement in S/F ratio during hospitalization in the prospective cohort, however these findings would need validation through a properly designed randomized clinical trial (RCT)"
- Paper: results paper in PLOS ONE.
- Planned meta-analysis (Cochrane Reviews). A Cochrane Reviews meta analysis of renin-angiotensin inhibitors for COVID-19 is planned.
ACE inhibitor trials:
- Ramipril for the Treatment of COVID-19 (RAMIC). Intervention: ramipril 2.5 od.
- Efficacy of Captopril in Covid-19 Patients With Severe Acute Respiratory Syndrome (SARS) CoV-2 Pneumonia (CAPTOCOVID) (CAPTOCOVID). Intervention: captopril 25mg od.
- Efficacy of Aerosol Combination Therapy of 13 Cis Retinoic Acid and Captopril for Treating Covid-19 Patients Via Indirect Inhibition of Transmembrane Protease, Serine 2 (TMPRSS2). Intervention: captopril 25mg alongside "aerosolized 13 cis retinoic acid plus Inhalation administration by nebulization."
Other trials of renin-angiotensin modulation for COVID-19:
- Treatment of Angiotensin Peptide (1-7) for COVID-19
- Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial (ATCO)
- Angiotensin 1-7 in the Therapy of Covid19
- TXA COVID-19 Clinical Trial
- Angiotensin (1-7) for the Treatment of COVID-19 in Hospitalized Patients
- Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (APN01-COVID-19)
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"The primary endpoint of the trial was a composite endpoint of all-cause death or invasive mechanical ventilation up to 28 days or until hospital discharge. The data showed that fewer patients treated with APN01 (n=9) died or received invasive ventilation compared to placebo (n=12), although statistical significance was not achieved due to the low total number of events. Standard of care has improved dramatically since study initiation, resulting in fewer deaths and less use of nvasive mechanical ventilation than at the time of design of the study.
Secondary objectives included mechanical ventilator-free days, change in viral RNA load, improvements according to the WHO 11-Point score system and the evaluation of relevant biomarker changes following treatment with APN01. Treatment with APN01 was safe and well tolerated and no drug-related severe adverse events were observed during the study. The data demonstrated a statistically significant improvement in mechanical ventilator-free days in alive patients and reduction in viral load in the group treated with APN01 compared to placebo. APN01 also demonstrated a positive impact on key biomarkers of the renin angiotensin system (RAS), demonstrating in vivo efficacy of the drug."
- Results: press release from Aperion.
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- Testing the Efficacy and Safety of BIO101 for the Prevention of Respiratory Deterioration in COVID-19 Patients (COVA)
- RAS and Coagulopathy in COVID19. Trial of AT1R agonist TRV027.
- Safety and Efficacy of C21 in Subjects With COVID-19. Intervention: AT2R agonist C21, 100mg bid.
- Results: 106 patients underwent randomization (51 in the C21 group and 55 in the placebo group). At day 14 after start of treatment, the proportion of patients still requiring supplemental oxygen was significantly reduced by 90% in the C21 group compared to the placebo group (p=0.003). Moreover, fewer patients required mechanical ventilation (one C21 patient and four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one and three deaths in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. --Trial results paper.
- Follow up study of lung imaging in a subset of patients in the ATTRACT C21 study: "The C21-treated patients (n=17) displayed reduced pathological abnormalities compared to the placebo-treated group (n=16); in the C21 group, on average 10.3% of the lung was affected compared to 19.2% in the placebo group."
- A Trial to Investigate Recovery From COVID-19 With C21 in Adult Subjects (ATTRACT-3). Intervention: AT2R agonist C21, 50mg bid.
- REPLACE COVID was an open-label trial of continuation versus discontinuation of renin–angiotensin system inhibitors in hospialized COVID-19 patients. Building on the results of BRACE CORONA, it found: "Continuation of ACEI or ARB therapy among patients admitted to hospital with COVID-19 had no overall effect on severity of COVID-19 disease course." According to trial investigator Jordana B Cohen, MD, "consistent with society recommendations considering the observational evidence, our findings support that ACEIs & ARBs can be safely continued in patients who are hospitalized with COVID-19. Ongoing studies are evaluating if de novo introduction of ARBs is helpful to treat COVID-19."
- Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR). Intervention: TXA127 (Mas receptor agonist), TRV027 (AT1 receptor selective agonist).
- Use of Angiotensin-(1-7) in COVID-19. Intervention: Angiotensin-(1-7) given I.V.
- REMAP-CAP RAS domain. Adaptive platform trial with a RAS arm. Details on the RAS domain protocol can be found in the REMAP-CAP RAS domain protocol paper.
