Systematic Review and Meta-Analysis to Estimate the Treatment Effect and Inform a Noninferiority Margin for a Phase 3 Noninferiority Trial in Uncomplicated Urogenital Gonorrhea.

BACKGROUND: Active-controlled noninferiority studies are used to investigate novel agents for uncomplicated urogenital gonorrhea (uUGC) as placebo-controlled trials are unethical. A systematic literature review and meta-analysis were conducted to estimate the ceftriaxone and proxy-for-placebo microbiological treatment effect and determine an appropriate noninferiority margin for phase 3 trials. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. To account for interstudy variability, a weighted, noniterative random-effects model was fitted using "R" software to estimate the microbiological response rate and 95% confidence intervals (CIs) for ceftriaxone and proxy-for-placebo (treatment with an antibiotic the isolate was subsequently confirmed resistant to, or spontaneous resolution without treatment). I2 , τ2 , and P values were computed and included in the meta-analysis forest plot. RESULTS: Seventeen studies were included in the meta-analysis; 14 reported ceftriaxone response in micro-intent-to-treat and microbiologically evaluable populations, and 3 reported proxy-for-placebo treatment response in uUGC (microbiologically evaluable population only). Microbiological treatment effect was estimated by subtracting the upper end of the CI for placebo from the lower end of the CI for ceftriaxone. Overall microbiological response was 98% (95% CI, 97-99) for ceftriaxone and 44% (95% CI, 34-54) for proxy-for-placebo, resulting in a microbiological treatment effect of 43%. A noninferiority margin of 15% preserved 65% of the ceftriaxone treatment effect, exceeding the 50% recommended per US Food and Drug Administration guidance for noninferiority studies. CONCLUSIONS: Results of this systematic literature review and meta-analysis could help inform the design, conduct, and analysis of future clinical studies in uUGC.

Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK.

PURPOSE: To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution. METHODS: Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B). RESULTS: TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect. CONCLUSIONS: Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial.

BACKGROUND: Oral CXC chemokine receptor 2 (CXCR2) antagonists have been shown to inhibit neutrophil migration and activation in the lung in preclinical and human models of neutrophilic airway inflammation. A previous study with danirixin, a reversible CXCR2 antagonist, demonstrated a trend for improved respiratory symptoms and health status in patients with COPD. METHODS: This 26-week, randomised, double-blind, placebo-controlled phase IIb study enrolled symptomatic patients with mild-to-moderate COPD at risk for exacerbations. Patients received danirixin 5, 10, 25, 35 or 50 mg twice daily or placebo in addition to standard of care. Primary end-points were the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms (Evaluating Respiratory Symptoms in COPD [E-RS:COPD] scores) and safety. Secondary end-points included the incidence of moderate-severe exacerbations, health status (COPD Assessment test, CAT) and health-related quality of life HRQoL (St. George Respiratory Questionnaire-COPD, SGRQ-C). RESULTS: A total of 614 participants were randomized to treatment. There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo; a larger than expected placebo effect was observed. There was an increased incidence of exacerbation in the danirixin-treated groups and an increased number of pneumonias in participants treated with danirixin 50 mg. CONCLUSIONS: The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov, NCT03034967.

Effects of umeclidinium/vilanterol on exercise endurance in COPD: a randomised study.

This multicentre, randomised, double-blind, placebo-controlled, two-period crossover study assessed the effect of umeclidinium/vilanterol (UMEC/VI) on exercise capacity in patients with chronic obstructive pulmonary disease (COPD) using the endurance shuttle walk test (ESWT). Patients were randomised 1:1 to one of two treatment sequences: 1) UMEC/VI 62.5/25 µg followed by placebo or 2) placebo followed by UMEC/VI 62.5/25 µg. Each treatment was taken once daily for 12 weeks. The primary end-point was 3-h post-dose exercise endurance time (EET) at week 12. Secondary end-points included trough forced expiratory volume in 1 s (FEV1) and 3-h post-dose functional residual capacity (FRC), both at week 12. COPD Assessment Test (CAT) score at week 12 was also assessed. UMEC/VI treatment did not result in a statistically significant improvement in EET change from baseline at week 12 versus placebo (p=0.790). However, improvements were observed in trough FEV1 (206 mL, 95% CI 167-246), 3-h post-dose FRC (-346 mL, 95% CI -487 to -204) and CAT score (-1.07 units, 95% CI -2.09 to -0.05) versus placebo at week 12. UMEC/VI did not result in improvements in EET at week 12 versus placebo, despite improvements in measures of lung function, hyperinflation and health status.

Correct usage, ease of use, and preference of two dry powder inhalers in patients with COPD: analysis of five phase III, randomized trials.

BACKGROUND: Handheld inhalers are used to deliver treatment for COPD. Incorrect usage leads to suboptimal disease control. Complex treatment regimens and use of multiple inhalers may reduce patient compliance. The Anoro Ellipta™ dry powder inhaler (DPI) simultaneously delivers umeclidinium bromide (UMEC) and vilanterol (VI) without coformulation being required. AIM: To assess the correct usage and ease of use of the Ellipta™ DPI administering UMEC/VI and to compare patient preference for Ellipta™ with the HandiHaler(®) through exploratory analyses of patient and observer questionnaires in five Phase III studies. METHODS: Two Phase III, 3-month double-blind, placebo-controlled studies assessed the correct usage of the Ellipta™ DPI at Day 1 and after 6 weeks, and ease of use of the Ellipta™ DPI using a nonvalidated patient questionnaire after 6 weeks or early withdrawal. In three 6-month, blinded double-dummy, active comparator studies (two Phase IIIa and one Phase IIIb), patients completed a COPD device preference questionnaire between the Ellipta™ DPI and the Handi-Haler(®) at Day 168 (Week 24) or early withdrawal. RESULTS: In the 3-month placebo-controlled studies, ≥98% of patients used the Ellipta™ DPI correctly and 99% of patients found the inhaler easy/very easy-to-use and the dose counter easy/very easy to read. Across the two Phase IIIa active comparator studies, patients consistently stated a preference for the Ellipta™ DPI over HandiHaler(®) regarding the number of steps to use (59% vs 17%), time taken to use (62% vs 14%), and ease of use (63% vs 15%) regardless of which inhaler contained active drug. Results were consistent in the Phase IIIb active comparator study. CONCLUSION: Delivery of UMEC/VI via the Ellipta™ DPI was considered easy-to-use, and patients with COPD demonstrated clear preference for this inhaler compared with HandiHaler(®).

A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 µg on health-related quality of life in patients with COPD.

BACKGROUND: The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting ß2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD). This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population. METHODS: This was a 12-week multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Eligible patients were randomized 1:1 to receive once-daily UMEC/VI 62.5/25 µg (via ELLIPTA(®) dry powder inhaler) or PBO for 12 weeks. The primary endpoint was St George's Respiratory Questionnaire (SGRQ) total score at day 84. Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1-12 and trough forced expiratory volume in 1 second on day 84. Adverse events were also assessed. RESULTS: A total of 496 patients were included in the intent-to-treat population in the UMEC/VI (n=248) and PBO (n=248) treatment groups. UMEC/VI 62.5/25 µg provided a significant and clinically meaningful improvement in SGRQ total score at day 84 versus PBO (difference between treatments in SGRQ total score change from baseline: -4.03 [95% confidence interval {CI}: -6.28, -1.79]; P<0.001). UMEC/VI 62.5/25 µg resulted in a statistically significant reduction in rescue albuterol use versus PBO (-0.7 puffs/day [95% CI: -1.1, -0.4]; P<0.001). UMEC/VI 62.5/25 µg provided a significant and clinically meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO (122 mL [95% CI: 71, 172]; P<0.001). The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 µg and PBO groups, respectively). CONCLUSION: The results of this study demonstrate that treatment with UMEC/VI 62.5/25 µg provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD.

Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: Results of two randomized studies.

OBJECTIVE: The aim of these studies (NCT01957163; NCT02119286) was to evaluate the efficacy and safety of umeclidinium (UMEC 62.5 µg and 125 µg) added to fluticasone furoate/vilanterol (FF/VI, 100/25 µg) in chronic obstructive pulmonary disease (COPD). METHODS: These were 12-week, double-blind, placebo-controlled, parallel-group, multicenter studies. Eligible patients were randomized 1:1:1 to treatment with once-daily blinded UMEC 62.5 µg (delivering 55 µg), UMEC 125 µg (delivering 113 µg) or placebo (PBO) added to open-label FF/VI (delivering 92/22 µg; N = 1238 [intent-to-treat population]). The primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 85; the secondary endpoint was 0-6 h post-dose weighted mean (WM) FEV1 at Day 84. Health-related quality of life was reported using St George's respiratory questionnaire (SGRQ). Adverse events (AEs) were also assessed. RESULTS: In both studies, trough FEV1 was significantly improved with UMEC + FF/VI (62.5 µg and 125 µg) versus PBO + FF/VI (range: 0.111-0.128 L, all p < 0.001 [Day 85]), as was 0-6 h post-dose WM FEV1 (range: 0.135-0.153 L, all p < 0.001 [Day 84]). SGRQ results were inconsistent, with statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI in one study only and with UMEC 62.5 µg only (difference in SGRQ total score from baseline between treatments: -2.16, p < 0.05). Across all treatment groups, the overall incidences of AEs were similar (30-39%), as were cardiovascular AEs of special interest (<1-3%) and pneumonia AEs (0-1%). CONCLUSION: Overall, the addition of UMEC to FF/VI therapy resulted in significant improvements in lung function compared with PBO + FF/VI in patients with COPD, with similar safety profiles, though SGRQ results were inconsistent. CLINICAL RELEVANCE: The results from these two studies demonstrate that the addition of umeclidinium (62.5 µg and 125 µg) to FF/VI (100/25 µg) provides statistically significant and clinically meaningful improvements in lung function compared with placebo + FF/VI in patients with COPD. Statistically significant improvements in quality of life with UMEC + FF/VI versus placebo + FF/VI were reported in one study only. Safety profiles were consistent across all treatment groups in both studies. These studies support the use of triple therapy in COPD, providing physicians with an alternative treatment option.

Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials.

OBJECTIVE: Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD). METHODS: Patients with COPD were randomized in two multicentre, double-blind, incomplete block crossover studies. Patients received two of six treatments in sequence (12 weeks each): placebo, umeclidinium (UMEC)/vilanterol (VI) (125/25 mcg or 62.5/25 mcg), VI (25 mcg) or UMEC (62.5 mcg or 125 mcg). Exercise endurance time (EET) and trough forced expiratory volume in 1 second (FEV1) (Week 12) were co-primary endpoints. Safety was monitored throughout. RESULTS: Both studies showed similar 3-hour post-dose EET improvements from baseline for UMEC/VI (Week 12). Significant EET improvements were observed with both UMEC/VI doses versus placebo at Week 12 in Study 418 (UMEC/VI 125/25 mcg: 65.8 s; p = 0.005; UMEC/VI 62.5/25 mcg: 69.4 s; p = 0.003), but not in Study 417, where a placebo effect was evident. Post hoc integrated data analysis showed significant but smaller EET improvements for both UMEC/VI doses versus placebo at Week 12 (UMEC/VI 125/25 mcg: 47.5 s; p = 0.002; UMEC/VI 62.5/25 mcg: 43.7 s; p = 0.001). Both studies showed trough FEV1 improvements at Week 12 for both UMEC/VI doses. The incidence of adverse events was similar between treatment groups within each study. CONCLUSIONS: UMEC/VI improved lung function and EET.

Efficacy and safety of once-daily GW870086 a novel selective glucocorticoid in mild-moderate asthmatics: a randomised, two-way crossover, controlled clinical trial.

OBJECTIVE: To assess the efficacy of inhaled, repeat doses (28 days) of the glucocorticoid agonist GW870086, which has been designed to inhibit gene transrepression of the glucocorticoid receptor while preserving its transactivation. METHODS: This was a randomised, placebo-controlled, two-way crossover study, approved by the independent ethics committees of the study centres. Subjects with FEV(1) 40-85% of the predicted normal value (n = 36) received GW870086 (1 mg, once-daily) and placebo. RESULTS: No significant change from baseline in forced expiratory volume in one second (FEV(1)) was seen following administration of GW8780086 1 mg relative to placebo; mean FEV(1) (day 28), relative to placebo, was (95% confidence intervals [CI]) -0.077 L (-0.192, 0.038). A moderate positive placebo response was observed on Days 14 and 28: Mean FEV(1) (95% CI) was 0.115 L (0.040, 0.189) and 0.115 L (0.019, 0.212), respectively. The placebo response was more notable in treatment period 1 and was larger than the response to GW870086 1 mg on day 28, irrespective of period. Peak expiratory flow rate results were consistent with FEV(1) and no difference was seen between the GW870086 and placebo for rescue medication usage. CONCLUSION: This total lack of effect suggests that repeat-dose GW8700861 mg has suboptimal efficacy in mild to moderate asthma.

Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.

BACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate. OBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism. METHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 µg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints. RESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 µg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 µg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens. CONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations.

Empirical assessment suggests that existing evidence could be used more fully in designing randomized controlled trials.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) provide the highest level of evidence regarding the effectiveness of interventions. Less is known about how they are used to inform the design and reporting of RCTs. METHODS: A sample of RCTs published in leading medical journals in 2007 was assessed to establish whether authors considered previous trials in the design of their trial. An approach to calculate the sample size required for a significant pooled effect in an updated meta-analysis was applied to a subsample of the RCTs to illustrate the ways in which the results of an existing meta-analysis can be incorporated into the planning and reporting of new RCTs. RESULTS: Six of the 27 trials assessed (22%) reported the use of previous trial(s) for sample size calculations. Meta-analyses relating the results of the trial to previous research were cited in 37% (10 out of 27) of the report discussion sections. Previous evidence is formally incorporated into retrospective sample size calculations for three of the trials. DISCUSSION/CONCLUSION: Consulting previous research before embarking on a new trial and basing decisions about future research on the impact on an updated meta-analysis will make the reporting of research more coherent and the design of new RCTs more efficient.

An encouraging assessment of methods to inform priorities for updating systematic reviews.

OBJECTIVE: To consider the use of statistical methods that aim to prioritize the updating of a collection of systematic reviews based on preliminary literature searches. STUDY DESIGN AND SETTING: A new simulation-based method estimating statistical power and the ratio of the weights assigned to the predicted new and old evidence, and the existing Barrowman n approach is considered. Using only information on the numbers of subjects randomized in the "new" trials, these were applied retrospectively, by removing recent studies, to existing systematic reviews from the Cochrane Infectious Diseases Group. RESULTS: Twelve systematic reviews were included. When the removed studies were reinstated, inferences changed in five of them. These reviews were ranked, in order of update priority, 1, 2, 3, 4, and 11 and 1, 2, 3, 4, and 12 by the Barrowman n and simulation-based power approaches, respectively. The low ranking of one significant meta-analysis by both methods was due to unexpectedly favorable results in the reinstated study. CONCLUSION: This study demonstrates the feasibility of the use of analytical methods to inform update prioritization strategies. Under conditions of homogeneity, Barrowman's n and simulated power were in close agreement. We encourage further, prospective, evaluation of these methods.

The relationship between tooth wear, habitat quality and late-life reproduction in a wild red deer population.

1. Molar tooth wear is considered an important proximate mechanism driving patterns of senescence in ungulates but few studies have investigated the causes of variation in molar wear or their consequences for reproductive success. 2. In this study, we assessed molar tooth wear at death among red deer Cervus elaphus of known age on the Isle of Rum, Scotland. 3. First molar height showed a decelerating decline with age. In females, the rates of molar wear with age varied with location of home range and individuals experiencing low resource competition showed reduced molar wear. We suggest that this spatial variation in molar wear is related to differences in the availability of high-quality grazing habitat and levels of resource competition. 4. There was no evidence that females with more heavily worn molars had reduced reproductive performance late in life or that first molar height was associated with reproductive senescence.

The rate of senescence in maternal performance increases with early-life fecundity in red deer.

Tradeoffs between reproduction and somatic maintenance are a frequently cited explanation for reproductive senescence in long-lived vertebrates. Between-individual variation in quality makes such tradeoffs difficult to detect and evidence for their presence from wild populations remains scarce. Here, we examine the factors affecting rates of senescence in maternal breeding performance in a natural population of red deer (Cervus elaphus), using a mixed model framework to control for between-individual variance. Senescence began at 9 years of age in two maternal performance traits. In both traits, females that produced more offspring in early life had faster rates of senescence. This tradeoff is evident alongside significant effects of individual quality on late life breeding performance. These results present rare evidence in support of the disposable soma and antagonistic pleiotropy theories of senescence from a wild vertebrate population and highlight the utility of mixed models for testing theories of ageing.