The Efficacy of Famotidine in Improvement of Outcomes in Hospitalized COVID-19 Patients: A Phase III Randomized Clinical Trial

Background & Aims : As the first randomized clinical trial, this study evaluated the effect of Famotidine on the improvement of outcomes of hospitalized patients with COVID-19. Materials & Methods : This phase III randomized clinical trial which was designed with two parallel arms, is a placebo-controlled, single-blind, and concealed allocation study, and recruited 20 patients (10 of them received Famotidine as treatment group and 10 received Placebo as control group). Oral Famotidine 160 mg four times a day was given to the COVID-19 patients until the discharge day or for a maximum of 14 days. Patients’ temperature, respiration rate, oxygen saturation, lung infiltration, lactate dehydrogenase (LDH) level, and complete blood count (CBC) were measured at the baseline (before the intervention) and on day 14 after the intervention or on discharge day. Length of stay in the hospital and length of stay in the ICU were also measured as secondary outcomes of the study. Results : The results showed a significant decrease in LDH (P=0.01), mean WBC (P=0.04) and length of stay (P=0.04) of patients with COVID-19 in the group treated with Famotidine compared to the control group. There was also a significant increase in oxygen saturation (P=0.01) in the group treated with Famotidine compared to the control group. Cough improvement was also higher in the oral Famotidine group compared to the control group (P=0.02). Conclusion : This was the first clinical trial on the effect of Famotidine on the improvement of hospitalized COVID-19 patients, which indicated that high-dose Famotidine improves patients’ clinical signs and reduces the severity of the disease and duration of hospitalization.


Introduction
Managing patients with COVID-19, which is caused by the SARS-CoV-2 virus, has become one of the challenges of healthcare systems today (1). Much research has recently focused on finding vaccines and medications for these patients (2). Famotidine is a lowcost, over-the-counter medication from histamine H2receptor antagonists (H2RAs) family, which is widely used for its antiacid properties (1)  Due to the lack of previous studies in this field, the sample size of 20 participants was considered for the study (7).

Inclusion criteria:
The main inclusion criteria before randomization were being infected with COVID-19 confirmed by a PCR test for SARS-Cov-2 and signing a written informed consent to participate in the study.

Exclusion Criteria:
The main exclusion criteria before randomization were suffering from immunodeficiency, end-stage renal

Description of blinding:
In this study, all participants were aware of participating in this study and entered the study with their consent. All participants were unaware of which group they were in, and received Famotidine if they were assigned to the treatment group, and placebo if they were assigned to the control group. The first author, healthcare personnel, data collectors, and those who assessed the outcomes were aware of the patient grouping. Those who drafted the article were unaware of the grouping if they were not involved in the above processes.

Intervention groups:
Group A received standard drug therapy according to the treatment protocols of the National Committee of COVID-19 plus oral Famotidine 160 mg (Chemi Darou Co.) four times a day until the discharge day or for a maximum of fourteen days. Also, the vital signs of the patients were frequently monitored at regular intervals ( Figure 1).

Primary outcomes:
Patients' temperature, respiration rate, oxygen saturation, lung infiltration, lactate dehydrogenase, and complete blood count were measured at the baseline (before the intervention) and on day 14 after the intervention or on the discharge day.
Secondary outcomes: Length of stay in the hospital and in the ICU were measured as secondary outcomes at the baseline (before the intervention) and on days 1 and 14 after the intervention or on the discharge day.

Statistical analysis:
IBM-SPSS version 22 software was used for data analysis; independent t-test and Mann-Whitney test were used to compare the means of quantitative data.
Chi-square and Fisher's test were used to compare qualitative variables.

Results
This study examined 20 patients with COVID-19.
Their mean age was 46±13 years while 12 patients were male and 8 were female.
Patients were divided into two groups of ten: Treatment group: They were treated with Famotidine in addition to standard COVID-19 treatment.
Control group: They were treated only with the COVID-19 standard treatment and placebo.
In this study, the mean age of patients in the treatment and the control groups were 47±14 and 48±12 years, respectively; there was no statistically significant difference between the two groups (P=0.2).
Regarding gender frequency, 60% of patients were male and 40% were female in the treatment group, and 70% of patients were male and 30% were female in the control group. There was no statistically significant difference between the two groups (P=0.1).

Comparison of laboratory findings and length of stay between the two groups:
The mean WBC on the discharge day was significantly lower in the treatment group (6550±2800) than that in the control group (10640±1600) (P=0.04).
LDH on the discharge day was significantly lower in the treatment group (584±158) than that in the control group (799±147) (P=0.01). Oxygen saturation on the discharge day was significantly higher in the treatment group (94±2%) than that in the control group (92±1%) (P=0.01) ( Table 1).
Length of stay was significantly shorter in the treatment group (6±3 days) than that in the control group (9±4 days) (P=0.04). Cough improvement was significantly higher in the treatment group (7 patients (70%)) than that in the control group (4 patients (40%)) (P=0.02) ( Table 1).
No death or ICU admission was reported in this study in either group.
There was no significant difference between the two groups in terms of comparing lung involvement on CT Scan of patients on the discharge day. In both groups, 50% of patients had over half of their lungs involved on the fifth day of admission (Table 1).  Our results regarding the gender of patients did not show a significant difference between the studied groups. We also examined lung involvement on CT Scan of patients and their age in both groups, which did not show a significant difference.
One of the limitations of our study was its small population, which presented itself in a decrease in statistical power in some tests, which did not reach a significant level. Also, it was impossible to follow up patients after discharge.

Conclusion
This was the first clinical trial on the effect of Famotidine on the recovery of inpatients with COVID-19, which indicated that high-dose Famotidine improves patients' clinical signs and reduces the severity of the disease and duration of hospitalization.

Declarations:
Ethics approval and consent to participate: