Clinical Bioequivalence of OT329 SOLIS and ADVAIR DISKUS in Adults with Asthma.

RATIONALE: OT329 SOLIS is a generic candidate for the branded asthma treatment, ADVAIR DISKUS (fluticasone propionate/salmeterol xinafoate), and, as such, the manufacturer is required to provide evidence of clinical "bioequivalence" as a condition for regulatory approval. OBJECTIVES: The objective of the current study was to determine if SOLIS and DISKUS provided bioequivalent improvements in lung function at two time points: Day 1 and Week 4. METHODS: This study was a randomized, multiple-dose, placebo-controlled, parallel-group design conducted in the United States (NCT02260492) with a 2-week run-in followed by a 4-week treatment period. Consenting patients were randomized to treatment with OT329 SOLIS 100/50, ADVAIR DISKUS 100/50, or placebo. Lung function was measured predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the first dose to test equivalence of the ß-agonist salmeterol component based on FEV1 area under the curve (0-12 h). After 4 weeks of twice-daily dosing, trough (predose) FEV1 was measured to evaluate equivalence of the fluticasone propionate corticosteroid component. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of the products fell within 80-125%. MEASUREMENTS AND MAIN RESULTS: Of the 1,524 screened, 879 patients with asthma were randomized to treatment (n = 418 SOLIS, 419 DISKUS, 42 placebo). OT329 SOLIS and ADVAIR DISKUS were bioequivalent at Day 1, with an FEV1 area under the curve (0-12 h) test/reference ratio of 108% (90% CI = 94-122%). Likewise, the products were bioequivalent at Week 4 with a trough FEV1 test/reference ratio of 105% (90% CI = 90-119). Both active treatments were superior to placebo (P < 0.05) at both time points. CONCLUSIONS: The data support a conclusion of clinical bioequivalence of OT329 SOLIS to ADVAIR DISKUS. Clinical trial registered with www.clinicaltrials.gov (NCT02260492).

Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies.

BACKGROUND: Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Ralpha receptor complexes. METHODS: In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV1) over 4-10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV(1) over 4-10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with ClinicalTrials.gov, numbers NCT00535028 and NCT00535031. FINDINGS: No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17.1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23.1% in the placebo group (difference 6%, 95% CI -4.37 to 16.32; p=0.243). In study 2, there was a 4.4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15.9% in the placebo group (3.7 [95% CI 2.08-6.25] times lower in the pitrakinra group; p=0.0001). There were fewer asthma-related adverse events (p=0.069) and fewer adverse events requiring beta-agonist rescue (p=0.031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events. INTERPRETATION: Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.

Force enhancement by PEG during ramp stretches of skeletal muscle.

We have investigated the effects of a stronger actomyosin bond on force (Ps) during rapid stretch of active permeabilized rabbit psoas muscle fibers as a function of temperature from 5 to 30 degrees C. The strength of the actomyosin bond is enhanced by addition of polyethylene glycol (PEG), especially in pre-powerstroke states [Chinn et al. (2000) Biophys J 49: 437-451]. We have hypothesized that such states produce much of the force when activated muscles are stretched [Getz et al. (1998) Biophys J 75: 2971-2983]. Addition of PEG to activated fibers produced a small increase in isometric tension, Po (50-90 kN/m2), which was approximately independent of temperature. In contrast PEG produced a dramatic increase in Ps at low temperatures (200-300 kN/m2), but a modest increase at higher temperatures (70-90 kN/m2). We also measured Ps and Po in solutions containing the phosphate analog aluminum fluoride (AlF4) with and without PEG. In the absence of PEG, AlF4 reduced Po much more than Ps. Addition of PEG did not enhance Po, but enhanced Ps significantly. The contrasting effects of PEG on Ps and Po, and the effect of temperature can be explained by a model in which stretch force is produced by pre-powerstroke cross-bridges whose maximum distension is increased by PEG, and isometric force is produced by strongly bound cross-bridges whose bond strength is also enhanced by PEG, but to a lesser extent.