This study is an open-label clinical trial conducted on patients with definitive diagnosis of COVID-19 (PCR testing from nasopharyngeal and oropharyngeal secretions or a clear view on the chest CT scan) (definitive evidence for SARS-CoV-2 in chest CT, Patchy Infiltiration appereance and ground-glass opacities in lungs) who had referred to Imam Khomeini Hospital Complex, Tehran, Iran This study was conducted from April 20 to June 4, 2020. In this study, multi-stage sampling was considered. In the first stage, 56 people were selected by accidental non-random sampling method. This sample size was subsequently divided into two groups by randomized block sampling (with a randomized block design, the experimenter divides subjects into subgroups called blocks, such that the variability within blocks is less than the variability between blocks. Then, subjects within each block are randomly assigned to treatment conditions.) (1:1). During the study, three patients left the case group (two patients lost to follow up, one patient discontinued intervention). These two groups included control (N=25) and case (N=28) arms. Their clinical symptoms were examined while taking these medicines in the disease course. (14-day follow-up for each patient). The inclusion criteria for the study were patients with age greater than or equal to 18 years, oral tolerance, and getting written informed consent from the patient and diagnosis of mild to moderate COVID-19 infection (Adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnoea, fast breathing) fatigue , anorexia , myalgias and Other non-specific symptoms, such as sore throat, nasal congestion, headache, diarrhoea, nausea and vomiting, have also been reported(1, 22-24) but should be without signs of severe pneumonia (including SpO2 ≥ 90% on room air, respiratory rate > 30 breaths/min; severe respiratory distress)(25) ),. The exclusion criterion was the patient’ basal Alanine aminotransferase (ALT) value greater than five times the normal range.( normal value for ALT in blood ranges from 29 to 33 units per liter (IU/L) for males and 19 to 25 IU/L for females)
The case group received hydroxychloroquine (HCQ) at a dose of 200 mg every 12 hours and Umifenovir at a dose of 200 mg every 8 hours for 10 days. The control group received the national treatment protocol proposed for COVID-19(26), including HCQ every 12 hours for 10 days and acetaminophen and Diphenhydramine oral syrup if needed.
With the exception of Umifenovir, all other standard interventions and treatments were the same for patients in both groups. Umifenovir was provided by the Center for Progress and Development (CPDI) of Iran Presidency and given to the infectious disease ward, and patients did not pay for it. Pharmstandard, one of the leading Russian pharmaceutical companies, is the manufacturer of this drug. Given the open-label nature of the trial, the department of pharmacotherapy was the research supervisor.
After obtaining written informed consent from the patients, demographic and clinical characteristics such as age, gender, BMI, history of underlying diseases including COPD, asthma, diabetes mellitus (DM), hypertension, malignancy, HIV, and taking immunosuppressive drugs were extracted and recorded from the patients’ medical history.
In the beginning, factors such as fever, heart rate, respiratory rate, oxygen saturation, and tests such as white blood cell count (WBC), C-reactive protein (CRP), liver enzymes, bilirubin, Creatine phosphokinase(CPK), and electrolytes including sodium, magnesium, and potassium were recorded.
Clinical symptoms of patients with COVID-19 infection, such as nausea, vomiting, diarrhea, cough, shortness of breath, fever, body aches, loss of appetite, and other symptoms were also monitored, and changes in symptoms in terms of improvement or worsening were reported on the 3rd day after start threatment in each groups as primary outcome, on the 7th day as secondary outcome, and on the 14th day as the final outcome.
The patients were also monitored for common side effects of Umifenovir, such as skin rashes and gastrointestinal symptoms such as nausea and vomiting, diarrhea or abdominal pain, jaundice, and bradycardia.
This study was approved by the Ethics Committee of Tehran University of Medical Sciences (TUMS) according to the 2013 Declaration of Helsinki. The written informed consent was obtained from all patients. The patients were informed that they could withdraw from the study at any time and continue their treatment according to the national protocol.
The Kolmogorov-Smirnov test was first used to assess whether the distribution of variables was normal. Continuous variables were expressed as median (interquartile range (IQR)) and their relationship was reported in the two groups using Mann-Whitney U test and Kruskal–Wallis test . Qualitative variables were expressed as numbers (percentages) and their relationship was analyzed using the Chi-square test and Fisher’s exact test. The Kaplan-Meier method was used to compare the improvement in disease symptoms during treatment between the two groups. The statistical analysis was performed using the SPSS software (version 25) and P-values<0.05 were considered statistically significant.