Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV).

BACKGROUND: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. METHODS: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). RESULTS: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%). CONCLUSIONS: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.

Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV).

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high-dose oral ivermectin (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin, the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower (95% confidence interval [CI] -27.2% to +11.8%; n=45) than in the no drug arm (n=41), whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster (95% CI +7.0% to +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well-tolerated method of assessing SARS-CoV-2 antiviral therapeutics in vitro. Funding: 'Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)' is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Clinical trial number: NCT05041907.

Efficacy and safety of ivermectin in the treatment of mild to moderate COVID-19 infection: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The emergent outbreak of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emphasized the requirement for therapeutic opportunities to overcome this pandemic. Ivermectin is an antiparasitic drug that has shown effectiveness against various agents, including SARS-CoV-2. This study aimed to assess the efficacy of ivermectin treatment compared with the standard of care (SOC) among people with mild to moderate COVID-19 symptoms. METHODS: In this randomized, double-blind, placebo-controlled, single-center, parallel-arm, superiority trial among adult hospitalized patients with mild to moderate COVID-19, 72 patients (mean age 48.57 ± 14.80 years) were randomly assigned to either the ivermectin (n=36) or placebo (n=36) group, along with receiving standard care. We aimed to compare the negativity of reverse transcription polymerase chain reaction (RT-PCR) result at days 7 and 14 of enrolment as the primary outcome. The secondary outcomes were duration of hospitalization, frequency of clinical worsening, survival on day 28, and adverse events. RESULTS: At days 7 and 14, no differences were observed in the proportion of PCR-positive patients (RR 0.97 at day 7 (p=0.759) and 0.95 at day 14 (p=0.813). No significant differences were found between the groups for any of the secondary endpoints, and no adverse events were reported. CONCLUSION: No difference was found in the proportion of PCR-positive cases after treatment with ivermectin compared with standard care among patients with mild to moderate COVID-19 symptoms. However, early symptomatic recovery was observed without side effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT05076253. Registered on 8 October 2021, prospectively.

The efficacy of Thai capsaicin in management of overactive bladder and hypersensitive bladder.

This paper has been generated to provide information on the effectiveness of capsaicin treatment among patients with overactive or hypersensitive bladder. The evaluation process required approximately 14 (overactive bladder) and 11 (hypersensitive bladder and primary detrusor instability) participants who received capsaicin intravesically. The solution consisted of capsaicin (concentration = 1 mM/L) diluted in 30 per cent ethanol solution 100 ml. All participants went through at least 1 urodynamic test 1 month before and after receiving capsaicin intravesical instillation. The capsaicin treatment for overactive and hypersensitive bladders was very effective. On the average, (overactive bladder) participants' voiding needs decreased from 16.5 +/- 4.8 times/day to 8.6 +/- 2.5 times/day, leakage from 9.7 +/- 8.1 times/day to 2.4 +/- 4.3 times/day, bladder capacity from 160.1 +/- 123.3 ml to 236.9 +/- 146.1 ml, and detrusor contraction from 71.1 +/- 29.2 cm/H2O to 57.3 +/- 27.2 cm/H2O. On average, (hypersensitive bladder and primary detrusor instability) participants' voiding needs decreased from (Day time) 19.45 +/- 17.99 times to 12.00 +/- 8.91 times/day, (Night time) 7.09 +/- 6.03 times to 4.09 +/- 3.8 times, bladder capacity from 197.40 +/- 156.06 ml to 323.45 +/- 129.46 ml, and detrusor contraction from 32.64 +/- 22.77 cm/H2O to 36.64 +/- 19.22 cm/H2O. Capsaicin efficiency was rated very high for both overactive and hypersensitive bladder and primary detrusor instability. In Thailand, it has been possible to produce capsaicin using local chili supplies, thus the price of the drug itself is very economical. When considering the efficiency and the inexpensive cost of capsaicin, this treatment would be another great alternative for overactive and hypersensitive bladder cure.