Design and Participants
This open label randomized controlled trial of effectiveness of ARB on COVID-19 disease was conducted between 20 April and 18 June 2020 in a teaching hospital of Iran University of medical Sciences (IUMS), Tehran, Iran. The current clinical trial was done in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization–Good Clinical Practice guidelines. The study protocol was approved by ethics committee of IUMS (IR.IUMS.RCT.1399.090) and registered in Iranian Registry of Clinical Trials (IRCT) with register number of IRCT20180725040596N2 on 18 April 2020 (URL: https://www.irct.ir/user/profile). The study protocol and reporting of results were adhered to Consolidated Standards for Reporting Trials (CONSORT).
Eligible patients were non pregnant women and men aged 18 years old or more with definite diagnosis of COVOD-19 by Real Time RNA specific Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) or computed tomography (CT) scan imaging (pneumonia), and oxygen saturation of 94% or less. The findings of CT were described as bilateral lung opacities and lobular and sub segmental areas of consolidation (10). The method of sampling was convenience from hospitalized patients who admitted to infectious ward of Firoozgar teaching hospital. We considered a significant level of 0.05 and 80% power to detect a moderate difference (Standardized difference =0.5) of hospitalization duration across two groups. Based on these criteria, the sample size was calculated as 50 per group (11).
Patients gave written informed consent according to regulations of ethics committee. Exclusion criteria included as: those who have a history of allergy to ARB class of drugs, abnormal liver or renal function, abnormal blood coagulation, ARB was used before inclusion, women who are nursing or pregnant and patients with severe heart disease.
Participants were assigned to the intervention or control groups using blocked randomization method. Envelopes were prepared for unmasking. The random allocation procedure was performed by an independent staff of the hospital of RCT setting. The project manager and other colleagues of our study enrolled and assigned participants to interventions.
In this trial patients with diagnosis of Covid-19 received either Hydroxychloroquine (400 mg just on first day) followed by 400 mg Kaletra (Lopinavir-ritonavir) BD or Hydroxychloroquine (400 mg BD on first day followed by 200 mg BD) followed by ARB (200 mg TDS) 7 to 14 days based on the severity of disease. The 100 mg capsule of ARB was used in this trial.
Patients monitored daily for adverse events, vital signs and change of signs and symptoms. The current trial was monitored by research branch of Food and Drug administration organization of Iran.
The primary outcome was hospitalization duration and clinical improvement 7 days after admission. The criteria of improvement were relief of cough, dyspnea and fever. Time to relieving fever was assessed across two groups too.
The secondary outcomes were death during 30 days of treatment, duration of hospitalization, changing laboratory tests during 7 days, changing of CT findings after 30 days and need to invasive mechanical ventilation.
We measures the age, gender, job, education status, underlying disease (history of diabetes, Ischemic heart disease, Hypertension, Asthma,..) and smoking status, as demographic variables. The fever, cough, dyspnea, nausea and vomiting, diarrhea, fatigue and weakness, and loss of appetite and taste were measured at the first day of admission. The saturation of peripheral oxygen, C-reactive protein (CRP), Complete Blood Cell Count (CBC), Erythrocyte Sedimentation Rate (ESR), Aspartate transaminase (AST), Alanine aminotransferase (ALT), White Blood Cell Count (WBC), Lymphocyte and Neutrophil count, Neutrophil Lymphocyte ratio, Total Bilirubin, Blood Na and K, Creatinine and Thyroid Stimulating Hormone (TSH) were measured at the first day of admission and 7 days after. The CT scan and chest X-ray were taken at the first day of admission and 30 days after. The PCR test was taken at admission and the time of discharge.
We categorized the patients to three groups based on severity of disease according to the CT scan and chest X-ray findings. Mild, moderate and severe categories were defined as involvement of base, less and more than 50% of the lung field respectively in CXR and CT scan.
Data analysis was carried out using SPSS version 24 software (SPSS Inc., IL, USA). The normality of data was evaluated using Kolmogorov–Smirnov test. Descriptive statistics including mean, frequency, and standard deviation (SD) were calculated for all numeric variables and expressed as mean ± SD. Chi-square test was used to compare the qualitative variables across two groups. For normally distributed variables, independent sample and paired t-test were used across groups and before-after analysis respectively. We also used one way Analysis of Variance (ANOVA) to assess numeric variables across groups more than two category. Correlation analysis was used to evaluate the association between numeric variables. The B regression coefficients, with 95% confidence intervals (CI), were obtained using multiple linear regression analysis to assess the covariates associated with duration of hospitalization adjusted. All analyses were performed two-sided and significant level was considered at 0.05.