Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

Effect of Testosterone Solution 2% on Testosterone Concentration, Sex Drive and Energy in Hypogonadal Men: Results of a Placebo Controlled Study.

PURPOSE: We determined the effect of testosterone solution 2% on total testosterone level and the 2 symptoms of hypogonadism, sex drive and energy level. MATERIALS AND METHODS: This was a randomized, multicenter, double-blind, placebo controlled, 16-week study to compare the effect of testosterone and placebo on the proportion of men with a testosterone level within the normal range (300 to 1,050 ng/dl) upon treatment completion. We also assessed the impact of testosterone on sex drive and energy level measured using SAID (Sexual Arousal, Interest and Drive scale) and HED (Hypogonadism Energy Diary), respectively. A total of 715 males 18 years old or older with total testosterone less than 300 ng/dl and at least 1 symptom of testosterone deficiency (decreased energy and/or decreased sexual drive) were randomized to 60 mg topical testosterone solution 2% or placebo once daily. RESULTS: Of study completers 73% in the testosterone vs 15% in the placebo group had a testosterone level within the normal range at study end point (p <0.001). Participants assigned to testosterone showed greater baseline to end point improvement in SAID scores (low sex drive subset p <0.001 vs placebo) and HED scores (low energy subset p = 0.02 vs placebo, not significant at prespecified p <0.01). No major adverse cardiovascular or venous thrombotic events were reported in the testosterone group. The incidence of increased hematocrit was higher with testosterone vs placebo (p = 0.04). CONCLUSIONS: Once daily testosterone solution 2% for 12 weeks was efficacious in restoring normal testosterone levels and improving sexual drive in hypogonadal men. Improvement was also seen in energy levels on HED though not at the prespecified p <0.01. No new safety signals were identified.

A novel testosterone 2% gel for the treatment of hypogonadal males.

Testosterone replacement therapy (TRT) can improve the symptoms, signs, and well being of hypogonadal men by restoring serum testosterone concentrations to physiologic levels. This multicenter, open-label noncomparative trial of men with hypogonadism evaluated the pharmacokinetic profile and safety of a novel testosterone 2% gel (Fortesta™ Gel), administered once daily to the front and inner thighs at starting doses of 40 mg/d. The metered-dose delivery system allowed dose adjustments in 10-mg increments between 10 and 70 mg/d. Of the 149 patients enrolled, 138 patients (92.6%) completed the study and 129 patients (86.6%) were included in the efficacy analysis. On day 90, mean testosterone concentration (C(avg) [0-24 hours] ± SD) was 438.6 ± 162.5 ng/dL. Overall, 100 (77.5%) patients achieved serum total testosterone concentrations within the normal physiologic range (≥ 300 and ≤ 1140 ng/dL). On day 90, mean testosterone C(max) (± SD) was 827.6 ± 356.5 ng/dL. On day 90, a total of 122 patients (94.6%) had C(max) levels of 1500 ng/dL or less and 2 patients (1.6%) had values between 1800 and 2500 ng/dL. Similar results for C(avg) (0-24 hours) and C(max) were observed on day 35. All enrolled patients were included in the safety analysis. Testosterone 2% gel was generally well tolerated, with the most common adverse events (AE) being mild and moderate skin reactions. There were no serious AEs related to testosterone 2% gel. Once-daily testosterone 2% gel restored levels of testosterone in more than 75% of patients, with low risk of supraphysiologic testosterone levels. Patients may find this a suitable option for TRT because of its application site and low volume.

Retinal effects of 6 months of daily use of tadalafil or sildenafil.

OBJECTIVE: To assess changes in electroretinography (ERG) and other retinal function parameters during 6 months of daily use of tadalafil, sildenafil citrate, or placebo. METHODS: Subjects were randomized to use of a placebo (n=82), 5 mg of tadalafil (n=85), or 50 mg of sildenafil (n=77) daily for 6 months. Electroretinographs were recorded using the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol and standardized ERG equipment at all 15 study sites. Other tests of ocular anatomy and visual function were performed at each assessment. MAIN OUTCOME MEASURES: The primary outcome was the average mean change for both eyes from baseline to endpoint in ERG b-wave amplitude using dark-adapted combined standard response to a bright ISCEV standard flash. Secondary endpoints were other ERG parameter changes, visual acuity, number of errors in color discrimination testing, mean deviation in automated visual field testing, and intraocular pressure (IOP). RESULTS: No significant differences were found between treatment/placebo groups for the primary outcome, most other ERG variables, visual function, IOP, or anatomic assessments. The medications were well tolerated. CONCLUSIONS: No abnormalities in ERG or visual function and no treatment-related findings suggestive of drug toxicity are associated with daily administration of tadalafil or sildenafil for 6 months. APPLICATION TO CLINICAL PRACTICE: Assessed visual safety of tadalafil/sildenafil administered daily over a prolonged period. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00333281.