Covid-19 living Data

Losartan vs Standard care/Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2022-03-17

Studies description

Trial NCT04328012
Publication COVID MED - Freilich D, medRxiv (2022) (preprint)
Dates: 2021-04-06 to 2021-05-27
Funding: Public/non profit (Bassett Research Institute and Bassett Medical Center’s Department of Internal Medicine)
Conflict of interest: No

Trial NCT04340557
Publication Geriak M, Infect Dis Ther (2021) (published paper)
Dates: 2020-03-30 to 2020-07-04
Funding: Public/non profit ( Sharp Healthcare Foundation (San Diego, CA, USA))
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA Follow-up duration (days): 45
Inclusion criteria	Confirmed COVID-19 positive test result (RT-PCR) Mild to moderate respiratory symptoms of COVID-19 - hypoxia (SpO2 ≤ 96% on ≥ 1 L/min O2 by nasal cannula) but not on mechanical ventilation Systolic blood pressure ≥ 105 mmHg Screen within 3 days of a positive COVID-19 test Age ≥18 years old Access to a phone in the hospital room or an electronic device that is capable of receiving phone or video calls Able to read/write/speak English or Spanish fluently Subjects must have the capacity to provide consent or an appropriate LAR to provide informed consent Negative pregnancy test for women of childbearing potential.
Exclusion criteria	Severe allergy to any ARB or ACE-inhibitor, including angioedema In the intensive care unit at screening Home meds include any kind of ACE inhibitor or ARB Acute Kidney Injury (50% reduction in GFR from baseline at admission to any time during treatment in the study treatment arm) Hyperkalemia >5.0 mmol/L at baseline or any time during treatment in the study treatment arm Creatinine Clearance < 30 ml/min at baseline or any time during treatment in the study treatment arm.
Interventions
	Treatment Losartan 12.5 mg twice daily for up to 10 days. Dose could be escalated on judgement of treating physician.
	Control Standard care
Participants
	Randomized participants : Losartan =17 Standard care=15
	Characteristics of participants N= 32 Mean age : NR 19 males Severity : Mild: n=0 / Moderate: n=32 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Mechanical ventilation [ Time Frame: from date of patient admission to date of patient discharge or date of death, whichever came first, assessed up to 45 days ]
	In the report Receipt of mechanical ventilation or death before receiving ventilation (a composite of either receiving ventilation or the patient status changed to a do not resuscitate/do not intubate resulting in progressive respiratory failure and death).
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: 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	High
General comment	In addition to the published article, the trial registry was used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available. The authors report in the published article that the trial “was registered on clinicaltrials.gov (March 27, 2020; NCT04340557), inferring prospective registration. Clinicaltrials.gov reports the registration was first submitted on April 6, 2020, a week after start of recruitment. There were no differences between the registry and published article in population, procedures or interventions. There were some differences in the outcomes reported (receipt of mechanical ventilation or death before receiving ventilation, discharge without progression to ICU, ICU transfer, in-hospital mortality and length of hospital stay) and those in the registry (number requiring transfer into ICU for mechanical ventilation, number transferred from non-ICU bed to an ICU bed, number of days requiring oxygen therapy). Adverse events were not reported except for discontinuation due to tolerability/safety. Mortality was reported as in-hospital mortality. The study did not achieve its estimated sample size (n = 200; n = 32 randomized) and appears to have been terminated: “study enrollment dropped off consider- ably because of a rise in competing clinical trials”. The study was assessed to be at a high risk of bias due to some concerns in four of five domains.

Trial NCT04312009
Publication Puskarich M, medRxiv (2021) (preprint)
Dates: 2020-04-01 to 2021-02-28
Funding: Public/non profit (Bill and Melinda Gates Foundation, National Institutes of Health)
Conflict of interest: No

Methods
	RCT Blinding: quadruple blinding
	Location : Multicenter / USA Follow-up duration (days): 90
Inclusion criteria	1)>=18 years old 2) exhibiting at least one CDC-recognized symptom of COVID-19 3)positive clinical RT-PCR SARS-CoV-2 result 4)Hospitalized 5) respiratory sequential organ failure assessment score of at least 1 6)not already taking a renin angiotensin-aldosterone system (RAAS) inhibitor
Exclusion criteria	1) active outpatient treatment with an ACE-i, ARB, or aliskiren 2) prior adverse reaction to ACE-i/ARB 3)pregnancy, breastfeeding, or lack of contraception 4)history of dialysis, stage IV chronic kidney disease, or estimated glomerular filtration rate (eGFR) <30mL/min/1.73 m2 5) potassium >5.0 mmol/L 6)history of severe liver disease 7)enrollment in another blinded clinical trial for COVID-19 8)lack of informed consent 9)inability to randomize within 48 hours of admission or positive test 10)oxygen saturation at baseline 11)respiratory sequential organ failure assessment (SOFA) score of <1 (defined as P/F of <400, utilizing SaO2 if PaO2 is unavailable)
Interventions
	Treatment Losartan 50 mg orally twice a day if eGFR >60 mL/min/1.73 m2 for 10 days or until discharge; once a day if eGFR 30–60; discontinued if decreased eGFR <30, or if SAE suspected.
	Control Placebo
Participants
	Randomized participants : Placebo=104 Losartan =101
	Characteristics of participants N= 205 Mean age : NR 123 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Difference in Estimated (PEEP adjusted) P/F Ratio at 7 days
	In the report PaO2/FiO2 ratio on day 7
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: 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 pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available. The primary outcome in the article reflected that in the registry. Several secondary outcomes in the registry were not reported. The intervention treatment dosage is different in the registry from what was reported in the paper. The trial achieved its target sample size.

Methods
	RCT Blinding: quadruple blinding
	Location : Single center / USA Follow-up duration (days): 60
Inclusion criteria	Hospitalized >18 years-old laboratory-confirmed SARS-CoV-2 infection randomization within 72 hours of admission able to provide consent
Exclusion criteria	End-stage renal disease severe hepatic insufficiency nausea/vomiting/aspiration risk precluding oral medications unless can be given by nasogastric tube use of another SARS-CoV-2 medication pregnancy/breast feeding no contraception inability to obtain consent ARB allergy/intolerance taking ACEi/ARB hypotension hyperkalemia severe renal dysfunction severe volume depletion/AKI ascites aortic/mitral stenosis renal artery stenosis co-administration of CYP3A interacting drugs
Interventions
	Treatment Losartan Initially 25 mg orally twice daily; changed to 25 mg orally once daily (after other treatment arms stopped) for up to 14 days
	Control Placebo
Participants
	Randomized participants : Losartan =9 Placebo=4
	Characteristics of participants N= 13 Mean age : NR 8 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register National Institute of Allergy and Infectious Diseases COVID-19 Ordinal Severity Scale (NCOSS) [Time Frame: 60 days]
	In the report Improvement in the 7-point COVID-19 Ordinal Scale Score (COSS)
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: 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 preprint article, the study registry was used in data extraction and risk of bias assessment. Neither the protocol nor the statistical analysis plan was available. The sample size is very low; the study stopped early due to low enrollment and did not reach the target sample size (n=100)."