Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.

BACKGROUND: NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America. METHODS: We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed. RESULTS: Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose. CONCLUSIONS: NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).

Liraglutide effects in a paediatric (7-11 y) population with obesity: A randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics.

BACKGROUND: Childhood obesity is a major public health concern with limited treatment options. OBJECTIVE: The aim of this study was to assess safety, tolerability, pharmacokinetics, and pharmacodynamics during short-term treatment with liraglutide in children (7-11 y) with obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, 24 children received at least one dose of once-daily subcutaneous liraglutide (n = 16) or placebo (n = 8) starting at 0.3 mg with weekly dose escalations up to 3.0 mg or maximum tolerated dose, and 20 children completed the trial (14 in the liraglutide group and six in the placebo group). The primary endpoint was the number of adverse events. RESULTS: Baseline characteristics (mean ± standard deviation) included the following: age 9.9 ± 1.1 years, weight 71.5 ± 15.4 kg, and 62.5% male. Thirty-seven adverse events were reported in nine liraglutide-treated participants (56.3%) versus 12 events in five placebo-treated participants (62.5%). Most adverse events were mild in severity, three were of moderate severity, and none were severe. Gastrointestinal disorders were the most frequently reported events occurring in 37.5% of liraglutide-treated participants compared with placebo (12.5%). Six asymptomatic hypoglycaemic episodes occurred in five participants of whom four were liraglutide treated. Liraglutide exposure was consistent with dose proportionality. Body weight was the only covariate to significantly impact exposure. A significant reduction in body mass index (BMI) Z score from baseline to end of treatment (estimated treatment difference: -0.28; P = 0.0062) was observed. CONCLUSION: Short-term treatment with liraglutide in children with obesity revealed a safety and tolerability profile similar to trials in adults and adolescents with obesity, with no new safety issues.

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens.

This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412.

Self-reported sedation profile of quetiapine extended-release and quetiapine immediate-release during 6-day initial dose escalation in bipolar depression: a multicenter, randomized, double-blind, phase IV study.

BACKGROUND: A human-volunteer study reported lower sedation intensity during escalation of the extended-release formulation of quetiapine fumarate (quetiapine XR) than the immediate-release (IR) formulation. OBJECTIVE: To test the hypothesis that the profile of initial tolerability, including sedation, differs between the extended-release (XR) and immediate-release (IR) formulations of quetiapine in patients with bipolar depression. METHODS: In a randomized, double-blind, double-dummy, parallel-group, Phase IV study, male and female inpatients aged 18 to 50 years with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnosis of bipolar I or II depression were randomized after washout to receive placebo on day 1 and quetiapine XR or IR at escalating doses of 50, 100, 200, 300, and 300 mg once daily on the evenings of days 2 to 6, with hospital discharge on day 7. Sedation intensity was assessed by a self-reported modified Bond-Lader visual analog scale (VAS) score. RESULTS: Of 139 randomized patients, 134 completed the study. Mean patient age was 39.0 years; mean weight, 91.3 kg; and mean body mass index (calculated as weight in kilograms divided by height in meters squared), 31.0. Sedation intensity 1 hour after administration of the 50-mg dose (the primary study measure) was statistically significantly lower with quetiapine XR versus IR (mean [SD] VAS score: 33.4 [26.92] vs 44.0 [31.76]; least squares mean difference: 12.55, P = 0.009; modified intention-to-treat population). Sedation intensity was found in secondary analyses to be significantly lower with quetiapine XR than with quetiapine IR 1, 2, and 3 hours after each dose on days 2 to 6 (P ≤ 0.05), with similar sedation intensity between the treatment groups 4 to 14 hours postdose. Rates of treatment-related adverse events were 47.1% with quetiapine XR versus 59.4% with quetiapine IR. Three serious adverse events (4.3%) occurred in the quetiapine XR group. Adverse events led to study discontinuation in 1 patient (1.4%) in the quetiapine XR group and in 2 patients (2.9%) in the IR group. CONCLUSIONS: During the initial dose-escalation period studied, patients with bipolar depression reported statistically significantly lower sedation intensity in the 1 to 3 hours after taking quetiapine XR compared with the IR formulation. Overall tolerability for both formulations was consistent with the known profile of quetiapine. ClinicalTrials.gov identifier: NCT00926393.

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.

OBJECTIVE: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. METHODS: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. RESULTS: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). CONCLUSIONS: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine.

BACKGROUND: There is a need for a rapid-acting, non-injection, acute treatment for agitation. AIMS: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia. METHOD: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression-Improvement scale (CGI-I) score 2 h after dose one. RESULTS: Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS-EC score was evident 10 min after dose one with both 5 and 10 mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications. CONCLUSIONS: Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

Effect of raltegravir on the pharmacokinetics of methadone.

A randomized, placebo-controlled, 2-period crossover study in subjects on methadone maintenance therapy was conducted to assess the effect of the HIV-1 integrase inhibitor, raltegravir, on the pharmacokinetics of methadone. Twelve HIV-negative male and female subjects stabilized on an oral methadone program were enrolled. Subjects maintained their prescribed oral doses of methadone throughout the study and, in each of 2 periods, received either 400 mg of raltegravir or matching placebo every 12 hours on days 1 through 10 of each treatment period with a washout of 7 days between periods. Plasma samples for analysis of methadone pharmacokinetics were collected over 24 hours postdose on day 10 of each treatment period. Safety and tolerability were assessed throughout the study. The geometric mean ratio (90% confidence interval) for methadone when administered with raltegravir relative to methadone alone was 1.00 (0.93-1.09) for area under the methadone concentration time curve from time 0 to 24 hours and 1.00 (0.94-1.07) for maximal concentration. There were no serious clinical or laboratory adverse experiences. There were no discontinuations due to an adverse experience. Coadministration of raltegravir and methadone is generally well tolerated. Raltegravir has no clinically meaningful effect on methadone pharmacokinetics. No dose adjustment is required for methadone when coadministered with raltegravir.