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Background: Lersivirine is a nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. Objective: The goal of this study was to investigate the safety and tolerability of multiple oral doses of lersivirine administered to healthy male subjects to assist in the planning of longer term studies. Methods: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter, Phase I clinical study in fasting, healthy male volunteers. Subjects were randomly assigned in a ratio of 7:7:4:4 to receive lersivirine 500 mg BID, lersivirine 750 mg once daily, efavirenz 600 mg once daily, or placebo once daily for 28 days. Safety and tolerability were assessed throughout the study by continuous collection of adverse events (AEs), including adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, and clinically significant changes in physical examination findings. Vital sign measurements and ECGs were performed at screening; on day 1 (predose and 2, 3, and 4 hours postdose); on days 7, 14, 21, and 28 (predose); at discharge; and at follow-up. Safety laboratory tests (including hematology, chemistry, and urinalysis) were performed at screening; days 0, 7, 14, 21, and 27; and at follow-up. Results: Of the 66 healthy male subjects enrolled (age range, 21–51 years; body mass index, 18.1–29.9 kg/m 2), 40 were white, 22 were Asian, 3 were black, and 1 was of mixed race. There were no clinically significant laboratory abnormalities, including changes in lipid profile, liver or renal function test results, or ECG findings. Overall, 86% (18/21) of subjects in the lersivirine 500-mg BID group, 81% (17/21) in the lersivirine 750-mg once-daily group, 92% (11/12) in the efavirenz 600-mg once-daily group, and 92% (11/12) in the placebo group experienced at least one treatment-related AE. Eight subjects were permanently discontinued from the study; 4 subjects in the efavirenz group (3 of whom participated in the trial at the Brussels study center) were permanently discontinued due to AEs considered to be treatment related. No subjects receiving lersivirine permanently discontinued the study due to treatment-related AEs, although one subject temporarily discontinued treatment. In addition, 4 subjects withdrew consent (2 subjects [1 of whom was at the Brussels study center] receiving lersivirine 750 mg once daily and 2 subjects [1 of whom was at the Brussels study center] receiving efavirenz). There were no deaths or serious AEs in any of the study groups. Conclusion: Lersivirine appeared to be well tolerated after 28 days of continuous dosing in this small, selected group of young, healthy male volunteers.

Background. The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection. Methods. Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed. Results. The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n=721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of −10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above −10% for each end point. Conclusions. Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293).

Abstract Background An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814—the prodrug (lufotrelvir) and its active moiety (PF-00835231)—is a potent inhibitor of the SARS-CoV-2 3CL protease. Method Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167. Single and multiple ascending PF-07304814 (lufotrelvir) infusions were generally safe and well tolerated in participants hospitalized with COVID-19. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250 and 500 mg/d, respectively.

Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population. We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP) to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study. Twenty-five adults (20-70 years of age) with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1) pregabalin followed by placebo or (2) placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5-15). In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint) were significantly reduced for pregabalin versus placebo, with a mean treatment difference of -0.81 (95% confidence interval: -1.45 to -0.17; P = 0.015). The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain.