Efficacy, Safety, and Systemic Exposure of Once-Daily Indacaterol Acetate in Pediatric Asthma: A Randomized, Double-Blind, Controlled Dose-Finding Study.

BACKGROUND: Indacaterol acetate (IND), a long-acting ß2-agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma. METHODS: In this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥ 6 to < 12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV1) after two weeks of treatment. RESULTS: In total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 µg group and 25% patients in IND 150 µg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥ 0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile. CONCLUSIONS: Once-daily IND 75 µg and IND 150 µg via Breezhaler® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 µg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02892019; 08-Sep-2016).

A study on pharmacokinetics, pharmacodynamics and safety of lixisenatide in children and adolescents with type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon-like peptide-1 receptor agonist, lixisenatide, for the treatment of type 2 diabetes (T2D) in pediatric individuals. MATERIALS AND METHODS: In this Phase 1, multicenter, randomized, double-blind, placebo-controlled, parallel-group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once-daily lixisenatide in 2-week increments of 5, 10, and 20 µg (n = 18) or placebo (n = 5) for 6 weeks. RESULTS: Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti-drug antibody (ADA) status; however, mean lixisenatide concentrations and inter-subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post-prandial glucose, AUC0-4.5 , HbA1c , and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment-emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed. CONCLUSIONS: Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 µg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults.

Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine.

BACKGROUND: Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older. METHODS: In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-µg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose. RESULTS: A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3). CONCLUSIONS: A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.).

Immunological non-inferiority of a new fully liquid presentation of the MenACWY-CRM vaccine to the licensed vaccine: results from a randomized, controlled, observer-blind study in adolescents and young adults.

A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months.

BACKGROUND: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-µg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS: BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS: Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. METHODS: In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 µg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. RESULTS: A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

Efficacy of ABX196, a new NKT agonist, in prophylactic human vaccination.

We have assessed the immune-regulatory and adjuvant activities of a synthetic glycolipid, ABX196, a novel analog of the parental compound α-GalCer. As expected, ABX196 demonstrated a measurable and significant adjuvant effect in mice and monkeys with no appreciable toxicity at the doses used to promote immune responses. We performed a phase I/II dose escalation study of ABX196 in healthy volunteers, with the objectives to evaluate its safety profile, as well as its ability to be utilized as an adjuvant in the context of a prophylactic vaccine against hepatitis B. ABX196 was administered at three doses: 0.2, 0.4, and 2.0µg, in 44 subjects. In all the individuals injected with ABX196, peripheral blood NKT cells displayed hallmarks of activation, and 45% of them had measurable circulating IFN-γ 24h after the first administration. More importantly, the addition of ABX196 to the very poorly immunogenic HBs antigen resulted in protective anti-HBs antibody responses in majority of patients, demonstrating the adjuvant properties of ABX196 in human. Further analysis of the cohort of subjects receiving ABX196 with HBs antigen also indicates that a single injection appears sufficient to provide protection. A limited set of adverse events linked to the systemic delivery of ABX196 and access to the liver, is discussed in the context of formulation and the need to limit transport of ABX196 to secondary lymphoid tissues for maximal efficacy (Eudra-CT 2012-001566-15).

A randomized, double-blind, parallel-group, placebo-controlled trial of Extract Sceletium tortuosum (Zembrin) in healthy adults.

OBJECTIVES: The objective of the study was to evaluate the safety and tolerability of two doses (8 mg and 25 mg once daily) of a 2:1 standardized extract of the South African medicinal plant Sceletium tortuosum (L.) N.E. Br., trademarked Zembrin,(®) in healthy adult volunteers over a three-month period. DESIGN: This was a randomized, double-blind, parallel-group, placebo-controlled single center study. SETTING: Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, Cape Town, South Africa. PARTICIPANTS: The study took place between February 2 and July 27, 2009. Thirty-seven healthy adults were recruited from the general population. INTERVENTION: Participants were randomized to receive either one of two doses of study medication, or an identical placebo, taken once daily for 3 months. Of the 37 subjects, 12, 12, and 13 subjects received 8 mg extract Sceletium tortuosum (Zembrin), 25 mg extract Sceletium tortuosum (Zembrin), and placebo treatment, respectively. OUTCOME MEASURES: No efficacy variables were assessed. The safety and tolerability variables comprised of vital signs, physical examination, 12-lead electrocardiogram (ECG), laboratory assessments (hematology, biochemistry, and urinalysis), and the recording of adverse events (AEs). RESULTS: There were no apparent differences between the three treatments with regard to vital signs, 12-lead ECG, body weight, and physical examination from screening to the end of the 3-month treatment period. No significant changes were observed in hematology or biochemistry parameters between initial screening and the end of the study. Both doses of extract Sceletium tortuosum (Zembrin) were well-tolerated. The most commonly reported AE was headache, followed by abdominal pain and upper respiratory tract infections, all with greater incidence in the placebo group than in the treatment groups. Unsolicited positive effects on well-being were noted in patient diaries by some participants taking extract Sceletium tortuosum (Zembrin), including improved coping with stress and sleep. CONCLUSION: Both doses of extract Sceletium tortuosum (Zembrin) (8 mg and 25 mg) were well tolerated when used by healthy human subjects once daily for 3 months.

Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer.

AIM: To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS: An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 microm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 microg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K(+)) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS: The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K(+) revealed a significant dose-response with a non-significant T : R ratio. CONCLUSIONS: The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 microg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

Diagnostic value of post-bronchodilator pulmonary function testing to distinguish between stable, moderate to severe COPD and asthma.

OBJECTIVE: The GOLD guidelines suggest that the presence of a post-bronchodilator forced expiratory volume in one second (FEV1) < 80% of the predicted value in combination with a FEV1/forced vital capacity (FVC) < 70% confirms the diagnosis of COPD. Limited data exist regarding the accuracy of these criteria to distinguish between COPD and asthma. The aim of this study therefore was to investigate the diagnostic value of post-bronchodilator lung function parameters in obstructive lung disease. METHODS: The pulmonary function tests of 43 (22 = COPD, 21 = asthma) patients with similar baseline characteristics were evaluated (baseline FEV were 55.7% +/- 7.6%, and 59.3% +/- 8.4% predicted for COPD and asthma, respectively). Bronchodilator responsiveness (BDR) was calculated according to three recognized pulmonary function test criteria. RESULTS: The first criteria, post-bronchodilator FEV1 < 80% of the predicted value in combination with a post-bronchodilator FEV1/FVC ratio of < 70%, had an accuracy of 70% to diagnose COPD. This combination was very sensitive (100%) in diagnosing COPD, but it was not specific (38%). The second BDR criteria, defined as an increase of < 12% and 200 mL of initial FEV1 and criterion number 3, an increase of < 9% of predicted FEV1, were less sensitive (55% and 59%, respectively), but more specific (81% and 76% respectively) to diagnose COPD. Our findings suggest that the current recommended spirometric indices are not optimal in differentiating between COPD and asthma.

A randomized, double-blind, placebo-controlled trial of Lessertia frutescens in healthy adults.

OBJECTIVES: Indigenous medicines are widely used throughout Africa, despite a lack of scientific evidence for their safety or efficacy. The aims of this study were: (a) to conduct a pilot study of the safety of a common indigenous South African phytotherapy, Lessertia frutescens (Sutherlandia), in healthy adults; and (b) to contribute to establishing procedures for ethical and scientifically rigorous clinical trials of African indigenous medicines. DESIGN: A randomized, double-blind, placebo-controlled trial of Sutherlandia leaf powder in healthy adults. SETTING: Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, South Africa. PARTICIPANTS: 25 adults who provided informed consent and had no known significant diseases or allergic conditions nor clinically abnormal laboratory blood profiles during screening. INTERVENTION: 12 participants randomized to a treatment arm consumed 400 mg capsules of Sutherlandia leaf powder twice daily (800 mg/d). 13 individuals randomized to the control arm consumed a placebo capsule. Each participant received 180 capsules for the trial duration of 3 mo. OUTCOME MEASURES: The primary endpoint was frequency of adverse events; secondary endpoints were changes in physical, vital, blood, and biomarker indices. RESULTS: There were no significant differences in general adverse events or physical, vital, blood, and biomarker indices between the treatment and placebo groups (p > 0.05). However, participants consuming Sutherlandia reported improved appetite compared to those in the placebo group (p = 0.01). Although the treatment group exhibited a lower respiration rate (p < 0.04) and higher platelet count (p = 0.03), MCH (p = 0.01), MCHC (p = 0.02), total protein (p = 0.03), and albumin (p = 0.03), than the placebo group, these differences remained within the normal physiological range, and were not clinically relevant. The Sutherlandia biomarker canavanine was undetectable in participant plasma. CONCLUSION: Consumption of 800 mg/d Sutherlandia leaf powder capsules for 3 mo was tolerated by healthy adults.