TABLE 1.
Characteristics of ongoing clinical trials on the continuation or suspension of RAAS blockers in patients with COVID-19, and on the efficacy of ACE inhibitors, ARBs, angiotensin 1-7, and ACE2 for COVID-19.
| Clinical trial number | Clinical phase | Study design | Arms | Estimated enrollment | Primary outcome | Estimated study completion date |
|---|---|---|---|---|---|---|
| NCT04351581 | Not specified | •Randomized, single mask, parallel assignment trial | • Experimental: Continuation. The enrolled patients will continue their prescribed ACEi/ARB in the same dose. The clinicians will be encouraged to continue the medication throughout the hospital admission but it will be permissible for the clinician to stop treatment if necessary e.g., due to hypotension. | 215 | 1. Days alive and out of hospital within 14°days after recruitment | December 2020 |
| • Experimental: Discontinuation. The enrolled patients will discontinue their prescribed ACEi/ARB. If hypertensive treatment is necessary during hospital admission the clinicians will first be encouraged to start non-ACEi/non-ARB treatment. | ||||||
| NCT04353596 | 4 | • Randomized, open label, parallel assignment trial | • Experimental arm: Stopping/replacing ACEI/ARB. Chronic treatment with ACEI or ARB will be stopped or replaced. | 208 | 1. Combination of maximum sequential organ failure assessment (SOFA) score and death at 30°days | May 15, 2022 |
| • Control arm: No intervention, which means further treatment with ACEI or ARB. | 2. Composite of admission to an intensive care unit (ICU), the use of mechanical ventilation, or all-cause death at 30°days | |||||
| NCT04329195 | 3 | • Randomized, open label, parallel assignment trial | • Experimental arm: discontinuation of RAAS blocker therapy. | 554 | 1. Time to clinical improvement from day 0 to day 28 (improvement of two points on a seven-category ordinal scale, or live discharge from the hospital, whichever comes first) | August 9, 2020 |
| • Active Comparator arm: continuation of RAAS blocker therapy | ||||||
| NCT04351724 substudy | 2/3 | • Randomized, open label, parallel assignment trial | • Experimental arm: candesartan at 4 mg once daily and titrated to normotension | 500 | 1. Sustained improvement (>48°h) of one point on the WHO Scale within 29°days (daily evaluation) | December 31, 2020 |
| • Active Comparator arm: non-RAAS antihypertensive agents titrated to normotension. Those with normal blood pressure may be controlled without further treatment. | ||||||
| NCT04312009 | 2 | • Randomized, quadruple mask, parallel assignment trial | • Experimental arm: losartan (50 mg daily, oral) | 200 | 1. Difference in Estimated Positive End-expiratory Pressure (PEEP adjusted) P/F Ratio at 7°days. Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2: FiO2 ratio). PaO2 is preferentially used if available. A correction is applied for endotracheal intubation and/or positive end-expiratory pressure. Patients discharged prior to day 7 will have a home pulse oximeter send home for measurement of the day 7 value, and will be adjusted for home O2 use, if applicable. Patients who died will be applied a penalty with a P/F ratio of 0 | April 1, 2021 |
| • Control arm: placebo (microcrystalline methylcellulose, gelatin capsule, oral) | ||||||
| NCT04311177 | 2 | • Randomized, quadruple mask, parallel assignment trial | • Experimental arm: losartan (25 mg daily, oral) | 580 | 1. Hospital Admission within 15°days. Outcome reported as the number of participants per arm admitted to inpatient hospital care due to COVID-19-related disease within 15°days of randomization | April 1, 2021 |
| • Comparator arm: placebo (microcrystalline methylcellulose, gelatin capsule, oral) | ||||||
| NCT04328012 | 2/3 | • Randomized, quadruple mask, parallel assignment trial | • Experimental arm: lopinavir/ritonavir (400 mg/200 mg, oral, BID X 5–14°days depending on availability) | 4000 | 1. National Institute of Allergy and Infectious Diseases COVID-19 Ordinal Severity Scale (NCOSS) at 60°days. Difference in NCOSS scores between the different treatment groups | April 1, 2021 |
| • Experimental arm: hydroxychloroquine (400 mg BID on Day 0, and 200 mg BID Days 1–4, days 1–13 if available) | ||||||
| • Experimental arm: losartan (25 mg, oral, daily X 5–14°days depending on availability) | ||||||
| • Comparator arm: placebo (BID X 14°days) | ||||||
| NCT04335786 | 4 | • Randomized, quadruple mask, parallel assignment trial | • Experimental arm: valsartan for 14°days at a dosage and frequency titrated to blood pressure with 80 mg or 160 mg tablets up to a maximum dose of 160 mg b.i.d | 651 | 1. First occurrence of intensive care unit admission, mechanical ventilation or death within 14°days. Death is defined as all-cause mortality | December 2021 |
| • Comparator arm: placebo for 14°days (matching 80 mg or 160 mg placebo tablets at a dosage and frequency titrated to systolic blood pressure) | ||||||
| NCT04360551 | 2 | • Randomized, triple mask, parallel assignment trial | • Experimental arm: telmisartan (40 mg, oral, daily X 21°days) | 40 | 1. Maximum clinical severity of disease over the 21°day period of study. Based on a modified World Health Organization (WHO) COVID-19 7-point ordinal scale | June 30, 2021 |
| • Comparator arm: placebo (once daily X 21°days) | ||||||
| NCT04428268 | 2 | • Randomized, double mask, parallel assignment trial | •Experimental: chloroquine phosphate 450 mg orally every 12°hrs plus losartan 25 mg orally every 12°hrs | 20 | 1. All-cause mortality up to 28°days after randomization in Non-Critically ill Patients with SARS-COV-2 Pneumonia | August 30, 2020 |
| • Comparator arm: chloroquine phosphate 450 mg every 12 h orally | ||||||
| NCT04643691 | 2 | • Randomized, open label, parallel assignment trial | • Experimental arm: losartan 50 mg and spironolactone 25 mg (oral) | 90 | 1. Organ failures assessed on the SOFA score on day 7 post-inclusion | October 30, 2022 |
| • Comparator arm: usual care of COVID-19 infection in intensive care | ||||||
| NCT04606563 | 3 | • Randomized, open label, parallel assignment trial | • Experimental arm: losartan 25 mg oral increased to 50 mg after 24 h and then increased to a max dose of 100 mg after another 24 h, dependent on tolerance (for up max of 3°months) | 1372 | 1. Mortality at 28°days | June 30, 2021 |
| • Comparator arm: usual care for duration of hospitalization for up to 3°months if still hospitalized | ||||||
| NCT04447235 | 2 | • Randomized, double mask, parallel assignment trial | • Experimental arm: a single dose of 12 mg of ivermectin on the day of the confirmed diagnosis of COVID-19, followed by losartan 50 mg orally once daily for 15 consecutive days | 176 | 1. Incidence of severe complications due COVID-19 infection at 28°days | February 2021 |
| • Comparator arm: ivermectin-placebo single dose on the day of confirmed diagnosis of COVID-19, followed by losartan-placebo daily for 15°days | ||||||
| NCT04340557 | 4 | • Randomized, open label, parallel assignment trial | • Experimental arm: standard of care plus losartan to be taken orally twice daily for up to 10°days or until discharged from the hospital, whichever occurs first. Investigator may increase dose on days 210 if confident the subject will tolerate | 200 | 1. Number of subjects requiring transfer into ICU for mechanical ventilation due to respiratory failure at 45°days | December 31, 2020 |
| • Comparator arm: standard of care | ||||||
| NCT04335123 | 1 | • Open label, single group trial | • Experimental arm: losartan 25 mg once daily on study day 0. If parameters are met the dose of losartan will be increased to 50 mg once daily on study day 3. Participants will continue losartan until they experience resolution of respiratory failure (normal oxygen levels on room air), are discharged from the hospital, meet stoppage criteria or complete 14°days of therapy | 50 | 1. Number of participants with treatment-related adverse events as assessed by protocol definition of adverse event at 14°days | August 17, 2020 (results not published yet) |
| NCT04355936 | 4 | • Randomized, open label, parallel assignment trial | • Experimental arm: 80 mg telmisartan twice daily plus standard care | 400 | 1. Serum C rective protein levels at days 5 and 8 | November 30, 2020 (results not published yet) |
| • Comparator arm: standard care | ||||||
| NCT04359953 | 3 | • Randomized, open label, parallel assignment trial | • Experimental arm: 200 mg of hydroxychloroquine twice a day during 14°days | 1600 | 1. Two-weeks survival rate | June 1, 2021 |
| • Experimental arm: 250 mg of azithromycin twice a day during 14°days | ||||||
| • Experimental arm: 40 mg of telmisartan twice a day during 14°days | ||||||
| • Comparator arm: usual Care (no intervention) | ||||||
| NCT04510662 | 2 | • Randomized, open label, parallel assignment trial | • Experimental arm: telmisartan 40 mg daily plus standard care | 60 | 1. Death as all-cause mortality at 30°days. | April 2021 |
| • Comparator arm: standard care | 2. Occurrence of mechanical ventilation at 14°days | |||||
| NCT04466241 | 2/3 | • Randomized, open label, parallel assignment trial | • Experimental arm: lopinavir boosted by ritonavir 200°mg/50°mg (2 tablets morning and evening from Day 1 to Day 10) plus telmisartan 40 mg (1 tablet daily from Day 1 to Day 10)) | 294 | 1. Proportion of patients with undetectable nasopharyngeal swab SARS-CoV-2 PCR and C-reactive protein (CRP) < 27 mg/L at Day 11 | March 26, 2021 |
| • Experimental arm: lopinavir boosted by ritonavir 200°mg/50°mg (2 tablets morning and evening from Day 1 to Day 10) plus atorvastatin 20 mg (1 tablet daily from Day 1 to Day 10) | ||||||
| • Comparator arm: lopinavir boosted by ritonavir 200°mg/50°mg (2 tablets morning and evening from Day 1 to Day 10 | ||||||
| NCT04356495 | 2/3 | • Randomized, open label, parallel assignment trial | • Experimental arm: telmisartan (20 mg) during 10°days | 615 | 1. Proportion of participants who had a Grade 3 or 4 adverse event at day 14 | August 31, 2021 |
| • Experimental arm: ciclesonide (160 µg) during 10°days | 2. Proportion of participants with an occurrence of death at day 14 | |||||
| • Comparator arm: vitamin supplement during 10°days | 3. Proportion of participants who had an indication for oxygen therapy at day 14 | |||||
| 4. Proportion of participants who had an indication for hospitalization at day 14 | ||||||
| NCT04583228 | 1 | • Randomized, quadruple mask, sequential assignment trial | • Experimental arm (sequence 1): HLX71 2.5 mg/kg (IV, single dose), or placebo (IV, single dose) of which 2 receive intravenous injections of placebo and 8 receive intravenous injections of the HLX71 | 40 | 1. Number of participants with adverse events, serious adverse event and infusion-related reactions as assessed by CTCAE v5.0 at 28° days | May 31, 2021 |
| • Experimental arm (sequence 2): HLX71 5 mg/kg (IV, single dose), or placebo (IV, single dose) of which 2 receive intravenous injections of placebo and 8 receive intravenous injections of the HLX71 | 2. The proportion of subjects undergoing DLT events in each dose cohorts during the DLT observation period a days 1–7 | |||||
| • Experimental arm (sequence 3): HLX71 10 mg/kg (IV, single dose), or placebo (IV, single dose) of which 2 receive intravenous injections of placebo and 8 receive intravenous injections of the HLX71 | ||||||
| • Experimental arm (sequence 4): HLX71 15 mg/kg (IV, single dose), or placebo (IV, single dose) of which 2 receive intravenous injections of placebo and 8 receive intravenous injections of the HLX71 | ||||||
| NCT04332666 | 2/3 | • Randomized, triple mask, parallel assignment trial | • Experimental arm: A1-7 infusion (venous) of 0.2°mcg/Kg/h for 48°h | 60 | 1. Composite outcome of mortality and necessity of mechanical ventilation at 28°days | June 15, 2021 |
| • Comparator arm: placebo | ||||||
| NCT04605887 | 2 | • Randomized, triple mask, parallel assignment trial | • Experimental arm: A1-7 subcutaneously 500°mcg/kg/day | 120 | 1. Need for mechanical ventilation from randomization to 30°days | April 2024 |
| • Comparator arm: NaCl 0.9% subcutaneously 2.0°cc once a day | ||||||
| NCT04401423 | 2 | • Randomized, triple mask, parallel assignment trial | • Experimental arm: A1-7 at one 3°h dosage (0.5 mg/kg), intravenously, for 10°days consecutively | 100 | 1. Change of serum creatinine at day 1 and day 10 | December 2021 |
| • Comparator arm: placebo at one 3°h dosage (0.5 mg/kg), intravenously, for 10°days consecutively | 2. Number of participants requiring intubation and ventilatory support at day 10 | |||||
| NCT04570501 | 1/2 | • Randomized, double mask, parallel assignment trial | • Experimental arm: A1-7 for 7°days, administered by continuous intravenous (IV) infusion | 160 | 1. Time to recovery up to 29°days | June 2021 |
| • Comparator arm: placebo for 7°days | ||||||
| NCT04633772 | 1/2 | • Randomized, quadruple mask, parallel assignment trial | • Experimental arm: A1-7 intravenous | 130 | 1. Supplemental oxygen-free days (SOFDs) at 28°days | February 28, 2021 |
| • Comparator arm: placebo (NaCl 0.9%) | ||||||
| NCT04364893 | Not reported | • Randomized, open label, parallel assignment trial | • Experimental arm: maintenance of ARBs and ACE-inhibitors | 700 | 2. Median days alive and out of the hospital at 30°days | December 1, 2020 |
| • Comparator arm: suspension of ARBs and ACE-inhibitors |