Randomised controlled trial to compare efficacy of standard care alone and in combination with homoeopathic treatment of moderate/severe COVID-19 cases.

BACKGROUND & OBJECTIVES: No definite treatment is known for COVID-19 till date. The objective of this study is to assess the efficacy of customized Homoeopathic medicines, when used as an add-on treatment to Standard of Care (SOC), in patients suffering from moderate to severe COVID-19 infection. METHODS: This was a randomized, controlled, single-blind, parallel-group trial where 214 COVID19-positive patients were screened for moderate and severe cases of COVID-19. Adjuvant homoeopathic medicines were given in the treatment group and SOC was given to both groups. The duration of oxygen support was compared as the primary outcome. Subjects were followed for 28 days or till the end-point of mechanical ventilation/ death. RESULTS: Of 129 subjects included, 57 and 55 were severe; and 8 and 9 were moderate cases in Homoeopathy and SOC arms, respectively. In all, 9 (15.2%) participants in Homoeopathy and 20 (32.2%) participants in SOC arms eventually expired (p<0.05). Oxygen support was required for 9.84±7.00 and 14.92±7.549 days in Homoeopathy and SOC arms, respectively (p<0.005). Subjects receiving Homoeopathy (12.9±6.days) had a shorter hospitalization stay than in SOC (14.9±7.5 days). Homoeopathy arm (10.6±5.7 days) also showed statistically significant mean conversion time of of Realtime-Polymerase Chain Reaction (RT-PCR) from positive to negative than the SOC arm (12.9±5.6 days). The mean score of Clinical Outcome Ordinal Scale (COOS) was lower in the Homoeopathy arm. Laboratory markers [Interleukins (IL)-6, C-reactive protein (CRP), Neutrophils-Lymphocytes ratio (NLR)]were normalized earlier in Homoeopathy arm. CONCLUSION: Homoeopathy, as add-on therapy with SOC for COVID-19 management, demonstrates a reduction in mortality and morbidity, by reduced requirement of oxygen and hospitalization. Some laboratory markers are normalized at an earlier time. Hence, there is overall control over the disease. Registry: The study was registered on the http://ctri.nic.in/Clinicaltrials website under identifier number: CTRI/2020/12/029668 on 9th December 2020.

Immunogenicity and safety of Biological E's CORBEVAX™ vaccine compared to COVISHIELD™ (ChAdOx1 nCoV-19) vaccine studied in a phase-3, single blind, multicentre, randomized clinical trial.

Optimum formulation of Biological-E's protein subunit CORBEVAX™ vaccine was selected in phase-1 and -2 studies and found to be safe and immunogenic in healthy adult population. This is a phase-3 prospective, single-blinded, randomized, active controlled study conducted at 18 sites across India in 18-80 year-old subjects. This study has two groups; (i) immunogenicity-group, participants randomized either to CORBEVAX™ (n = 319) or COVISHIELD™ arms (n = 320). (ii) Safety-group containing single CORBEVAX™ arm (n = 1500) and randomization is not applicable. Healthy adults without a history of COVID-19 vaccination or SARS-CoV-2 infection were enrolled into immunogenicity arm and subjects seronegative to SARS-CoV-2 infection were enrolled into the safety arm. The safety profile of CORBEVAX™ vaccine was comparable to the comparator vaccine COVISHIELD™. Majority of reported AEs were mild in nature in both arms. The CORBEVAX™ to COVISHIELD™ GMT-ratios at day-42 time-point were 1·15 and 1·56 and the lower limit of the 95% confidence interval for the GMT-ratios was determined as 1·02 and 1·27 against Ancestral and Delta strains of SARS-COV-2 respectively. Both COVISHIELD™ and CORBEVAX™ vaccines showed comparable seroconversion post-vaccination against anti-RBD-IgG response. The subjects in CORBEVAX™ cohort also exhibited higher interferon-gamma secreting PBMC's post-stimulation with SARS-COV-2 RBD-peptides than subjects in COVISHIELD™ cohort.

Evaluation of the Safety and Efficacy of Favipiravir in Adult Indian Patients with Mild-to-Moderate COVID-19 in a Real-World Setting.

Purpose: To evaluate the safety and efficacy of favipiravir, which is prescribed for the treatment of patients with mild-to-moderate coronavirus disease 2019 (COVID-19) in India. Patients and Methods: This was a prospective, open-label, multicenter, single-arm postmarketing study conducted in India. Patients with mild-to-moderate COVID-19 received favipiravir (3600 mg [1800 mg orally twice daily] on the first day, followed by 800 mg orally twice daily, up to a maximum of 14 days) as a part of their treatment. The primary endpoints were to evaluate the safety of favipiravir by assessing the number of adverse events (AEs) and treatment-related AEs. The secondary endpoints were to evaluate the efficacy of favipiravir by assessing time to clinical cure, rate of clinical cure, time to pyrexia resolution, rate of oxygen requirement, and all-cause mortality. Results: A total of 1083 patients were enrolled in this study from December 2020 to June 2021. Adverse events were reported in 129 patients (11.9%), 116 (10.7%) of whom had mild AEs. Dose modification or withdrawal of favipiravir treatment was reported in four patients (0.37%). The median time to clinical cure and pyrexia resolution was 7 and 4 days, respectively. A total of 1036 patients (95.8%) exhibited clinical cure by day 14. Oxygen support was required by 15 patients (1.4%). One death was reported, which was unrelated to favipiravir. Conclusion: In the real-world setting, favipiravir was well-tolerated, and no new safety signals were detected.

Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India.

BACKGROUND: ZyCoV-D, a DNA-based vaccine, showed promising safety and immunogenicity in a phase 1/2 trial. We now report the interim efficacy results of phase 3 clinical trial with ZyCoV-D vaccine in India. METHODS: We conducted an interim analysis of a multicentre, double-blind, randomised, placebo-controlled phase 3 trial at 49 centres in India. Healthy participants aged at least 12 years were enrolled and randomly assigned (1:1) to receive either ZyCov-D vaccine (Cadila Healthcare; 2 mg per dose) or placebo. An interactive web response system was used for randomisation (blocks of four) of participants as well as to enrol those aged 60 years and older with or without comorbid conditions, and those aged 12-17 years. It was also used to identify 600 participants for immunogenicity (blocks of six). Participants, investigators, and outcome assessors were masked to treatment assignment. Three doses of vaccine or placebo were administered intradermally via a needle-free injection system 28 days apart. The primary outcome was the number of participants with first occurrence of symptomatic RT-PCR-positive COVID-19 28 days after the third dose, until the targeted number of cases (interim analysis n=79, full analysis n=158) have been achieved. The analysis was done in the per-protocol population, which consisted of all participants with negative baseline SARS-CoV-2 status who received three doses of vaccine or placebo. Assessment of safety and tolerability was based on the safety population, which consisted of all enrolled participants who were known to have received at least one dose of study vaccine or placebo. This trial is registered with Clinical Trial Registry India, CTRI/2021/01/030416, and is ongoing. FINDINGS: Between Jan 16, and June 23, 2021 (data cutoff), 33 194 individuals were screened, of whom 5241 did not meet screening criteria and 27 703 were enrolled and randomly assigned to receive ZyCoV-D (n=13 851) or placebo (n=13 852). Per-protocol, 81 cases were eligible and included in efficacy analysis (20 of 12 350 in the ZyCoV-D group and 61 of 12 320 in placebo group). The ZyCoV-D vaccine efficacy was found to be 66·6% (95% CI 47·6-80·7). The occurrence of solicited adverse events was similar between the treatment groups (623 [4·49%] in the ZyCoV-D group vs 620 [4·47%] in the placebo group). There were two deaths (one in each group) reported at the data cutoff, neither of which was considered related to the study treatments. INTERPRETATION: In this interim analysis, ZyCoV-D vaccine was found to be efficacious, safe, and immunogenic in a phase 3 trial. FUNDING: National Biopharma Mission, Department of Biotechnology, Government of India and Cadila Healthcare, Ahmedabad, Gujarat India.

Efficacy and Safety of a Phytopharmaceutical Drug Derived from Cocculus hirsutus in Adults with Moderate COVID-19: a Phase 2, Open-label, Multicenter, Randomized Controlled Trial.

INTRODUCTION: There is an urgent need for an effective, oral therapy for COVID-19. Purified aqueous extract of Cocculus hirsutus (AQCH) has shown robust antiviral activity in in vitro studies. We aimed to evaluate the efficacy and safety of AQCH plus standard of care in hospitalized patients with moderate COVID-19. METHODS: In an open-label, multicenter, randomized controlled trial conducted in India, eligible patients (aged 18-75 years) were randomized (1:1) to receive AQCH 400 mg orally three times a day plus standard of care (AQCH group) or standard of care alone (control group) for 10 days. Primary endpoint was the proportion of patients showing clinical improvement by day 14. Time to clinical improvement, time to viral clearance, and duration of hospitalization were secondary endpoints. RESULTS: A total of 210 patients were randomized. By day 14 most patients in both groups showed clinical improvement [difference - 0.01 (95% CI - 0.07 to 0.05); p = 1.0]. Median time to clinical improvement was 8 days (IQR 8-11) in the AQCH group versus 11 days (IQR 8-11) in the control group [HR 1.27 (95% CI 0.95-1.71); p = 0.032]. Time to viral clearance and duration of hospitalization were also significantly shorter in the AQCH group (p = 0.0002 and p = 0.016, respectively). AQCH was well tolerated, with no safety concerns identified. CONCLUSIONS: AQCH significantly reduced time to clinical improvement, time to viral clearance, and duration of hospitalization. In a pandemic, this has significant potential to decrease healthcare resource utilization and increase hospital bed availability. Further investigation of the therapeutic potential of AQCH in patients with COVID-19 is warranted. TRIAL REGISTRATION: Clinical Trials Registry - India (CTRI/2020/05/025397).

Safety and Immunogenicity of a novel three-dose recombinant nanoparticle rabies G protein vaccine administered as simulated post exposure immunization: A randomized, comparator controlled, multicenter, phase III clinical study.

BACKGROUND: Rabies vaccines are lifesaving in human post animal exposure. However, the compliance to the complete course of vaccine is found to be only 60%. Hence, there is a need for safe and immunogenic, shorter course vaccine that can enhance the compliance and effectively prevent the disease. OBJECTIVES: To establish a noninferiority of a novel three-dose recombinant rabies G protein vaccine to be administered as simulated postexposure prophylaxis when compared to five-dose WHO prequalified vaccine for better safety and immunogenicity. METHODS: A multi-centric, open label, assessor blind, center-specific block randomized, parallel design, phase III clinical study was conducted among 800 subjects. The eligible subjects were randomized in 2:1 ratio for recombinant rabies G protein vaccine and the reference vaccine. Subjects in recombinant rabies G protein vaccine arm received three doses of vaccine on days 0, 3, and 7, while subjects in reference vaccine arm received five doses of WHO prequalified vaccine on days 0, 3, 7, 14, and 28. RESULTS: The socio-demographic characteristics of the two arms were comparable. About 9.9% subjects in recombinant rabies G protein vaccine arm and 17.2% subjects in reference arm reported adverse events. The sero-protection on day 14 was found to be 99.24% and 97.72% in recombinant rabies G protein vaccine arm and reference vaccine arm respectively and the difference was statistically nonsignificant. CONCLUSION: The novel three-dose recombinant rabies G protein vaccine administered as simulated postexposure prophylaxis was noninferior to five dose WHO prequalified vaccine in terms of safety and immunogenicity.

Effect of Saccharomyces boulardii CNCM-I 3799 and Bacillus subtilis CU-1 on Acute Watery Diarrhea: A Randomized Double-Blind Placebo-Controlled Study in Indian Children.

PURPOSE: To assess the effect of combination probiotic Saccharomyces boulardii CNCM-I 3799 and Bacillus subtilis CU-1 in outpatient management of acute watery diarrhea in children. METHODS: A randomized double-blind placebo-controlled study was conducted in 180 participants aged six months to five years with acute mild to moderate diarrhea. All were enrolled from six centers across India and centrally randomized to receive S. boulardii CNCM-I 3799 and B. subtilis CU-1 or a placebo along with oral rehydration salts and zinc supplementation. Each participant was followed up for three months to assess recurrence of diarrhea. RESULTS: The mean duration of diarrhea in the probiotic and placebo groups were 54.16 hours and 59.48 hours, respectively. The difference in the duration of diarrhea in those administered with probiotic or placebo within 24 hours of diarrhea onset was 25.21 hours. Furthermore, the difference in duration of diarrhea was 13.84 hours (p<0.05) for participants who were administered with probiotics within 48 hours. There were no significant differences in the stool frequencies between the two arms. After three months, 15% in the probiotic group and 18.5% in the placebo group reported episodes of diarrhea. The mean duration of diarrhea was considerably lower in the probiotic group, 31.02 hours versus 48 hours in placebo (p=0.017). CONCLUSION: S. boulardii CNCM-I 3799 and B. subtilis CU-1 combination was effective in reducing the duration of diarrhea when administered within 48 hours of diarrhea onset. Similarly, it reduced recurrence of diarrhea and its intensity in the subsequent three months.

Efficacy and safety of pegylated interferon-α2b in moderate COVID-19: a phase 3, randomized, comparator-controlled, open-label study.

OBJECTIVE: To evaluate the efficacy and safety of pegylated interferon alpha-2b (PEG IFN-α2b) administered in conjunction with the standard of care (SOC) in subjects with moderate coronavirus disease-19 (COVID-19). METHODS: In this study, adult subjects with confirmed moderate COVID-19 were randomized in a 1:1 ratio to receive either PEG IFN-α2b + SOC or SOC alone. The primary endpoint was a two-point improvement in clinical status on Day 11, measured by the World Health Organization's seven-point ordinal scale. RESULTS: Of 250 subjects, 120 were randomized to the PEG IFN-α2b + SOC arm and 130 were randomized to the SOC arm. The results for the PEG IFN + SOC arms vs the SOC arm for the proportion of subjects with a two-point improvement in the seven-point ordinal scale were 80.36% vs 68.18% (P=0.037) on Day 8, 91.60% vs 92.56% (P=0.781) on Day 11, and 94.12% vs 95.93% (P=0.515) on Day 15. There was a time-dependent decrease in the biomarkers in both arms, and no clinically significant changes in laboratory parameters. The safety profile was similar in both arms. CONCLUSION: PEG IFN-α2b induced early viral clearance, improved the clinical status, and decreased the duration of supplemental oxygen. It provides a viable treatment option and can limit the spread of severe acute respiratory syndrome coronavirus-2.

A drug utilization study of psychotropic drugs prescribed in the psychiatry outpatient department of a tertiary care hospital.

BACKGROUND: Psychiatric disorders are one of the major causes of morbidity. Development of newer drugs like SSRIs and atypical antipsychotics has altered the treatment paradigms. Various factors like cost of drugs, local paradigms, etc. play a role in the selection of drug therapy and hence, affect the outcome. Keeping this in mind, we conducted a study to delineate the various drugs used in psychiatric disorders, to find discrepancies, if any, between the actual and the ideal prescribing pattern of psychotropic drugs and to conduct a cost analysis. MATERIAL AND METHODS: After our institutional ethics committee approved, a retrospective cross sectional drug utilization study of 600 prescriptions was undertaken. Preparation of the protocol and conduct of the study was as per the WHO - DUS and the STROBE guidelines. RESULTS: Drug use indicators - In 600 prescriptions, 1074 (88.25%) were psychotropic drugs. The utilization from the National and WHO EML was 100% and 90%, respectively. Average number of psychotropic drugs per prescription was 1.79 ± 1.02 (SD). 22.5% of the prescriptions contained psychotropic FDCs. 76.01% of drugs were prescribed by generic name. Percentage of psychotropic drugs prescribed from the hospital drug schedule and psychotropic drugs actually dispensed from the hospital drug store were 73.1% and 62.3%, respectively. Drug utilization pattern in different psychiatric disorders - Most commonly prescribed drugs for schizophrenia, bipolar disorders, depression and anxiety disorders were trifluoperazine + trihexiphenydyl (63.9%), carbamazepine (17.2%), amitriptyline (34.9%), and diazepam (23.8%), respectively. The least commonly prescribed drugs were levosulpiride (1.7%), lithium (1.3%), bupropion (4.7%) and clozapine (1.9%), respectively. The PDD/DDD ratio of three drugs - haloperidol, pimozide and amitriptyline - was equal to one. The cost borne by the hospital was 116, i.e., 65.2% of the total cost. The cost index of clozapine was 11.2. CONCLUSION: Overall, the principles of rational prescribing were followed. The hospital drug schedule should include more SSRIs. The practice of using 1(st) generation/ typical anti-psychotics as the first line was as per current recommendations. Anti-cholinergics should be used only in selected cases of patients on anti-psychotics. The use of diazepam should be curtailed and it should be used for short term only.