Active Flow Control on Vertical Tail Models.

Active flow control (AFC) subscale experiments were conducted at the Lucas Wind Tunnel of the California Institute of Technology. Tests were performed on a generic vertical tail model at low speeds. Fluidic oscillators were used at the trailing edge of the main element (vertical stabilizer) to redirect the flow over the rudder and delay or prevent flow separation. Side force increases in excess of 50% were achieved with a 2% momentum coefficient (C µ ) input. The results indicated that a collective C µ of about 1% could increase the side force by 30-50%. This result is achieved by reducing the spanwise flow on the swept back wings that contributes to early flow separation near their tips. These experiments provided the technical backdrop to test the full-scale Boeing 757 vertical tail model equipped with a fluidic oscillator system at the National Full-scale Aerodynamics Complex 40-by 80-foot Wind Tunnel, NASA Ames Research Center. The C µ is shown to be an important parameter for scaling a fluidic oscillator AFC system from subscale to full-scale wind tunnel tests. The results of these tests provided the required rationale to use a fluidic oscillator AFC configuration for a follow-on flight test on the Boeing 757 ecoDemonstrator.

Meta-analysis of clinical trial safety data in a drug development program: answers to frequently asked questions.

BACKGROUND: Meta-analyses of clinical trial safety data have risen in importance beyond regulatory submissions. During drug development, sponsors need to recognize safety signals early and adjust the development program accordingly, so as to facilitate the assessment of causality. Once a product is marketed, sponsors add postapproval clinical trial data to the body of information to help understand existing safety concerns or those that arise from other postapproval data sources, such as spontaneous reports. PURPOSE: This article focuses on common questions encountered when designing and performing a meta-analysis of clinical trial safety data. Although far from an exhaustive set of questions, they touch on some basic and often misunderstood features of conducting such meta-analyses. METHODS: The authors reviewed the current literature and used their combined experience with regulatory and other uses of meta-analysis to answer common questions that arise when performing meta-analyses of safety data. RESULTS: We addressed the following topics: choice of studies to pool, effects of the method of ascertainment, use of patient-level data compared to trial-level data, the need (or not) for multiplicity adjustments, heterogeneity of effects and sources of it, and choice of fixed effects versus random effects. LIMITATIONS: The list of topics is not exhaustive and the opinions offered represent only our perspective; we recognize that there may be other valid perspectives. CONCLUSIONS: Meta-analysis can be a valuable tool for evaluating safety questions, but a number of methodological choices need to be made in designing and conducting any meta-analysis. This article provides advice on some of the more commonly encountered choices.

Characterizing 16-Week Responder Profiles Using Group-Based Trajectory Modeling in Over 4300 Clinical Trial Participants Receiving Pharmaceutical Treatment for Moderate to Severe Osteoarthritis.

INTRODUCTION: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo. METHODS: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression. RESULTS: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments. CONCLUSIONS: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188).

The efficacy of pregabalin for the treatment of neuropathic pain in Japanese subjects with moderate or severe baseline pain.

PURPOSE: Although analyses of pooled clinical trial data have reported how international populations respond to pregabalin by baseline neuropathic pain (NeP) severity, no studies have evaluated this specifically in patients from Japan. Thus, this post hoc pooled analysis evaluated the efficacy of pregabalin in Japanese subjects for treating moderate or severe baseline NeP. PATIENTS AND METHODS: Data were pooled from three placebo-controlled trials enrolling Japanese subjects with postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and spinal cord injury (SCI). The efficacy of pregabalin was evaluated by baseline pain severity (moderate or severe NeP). The trials on PHN and DPN included a 1-week titration of pregabalin from 150 mg/day to 300 or 600 mg/day; the SCI trial included a 4-week dose optimization phase (150 mg/day, titrated up to 600 mg/day). Treatment durations were 13-16 weeks (excluding 1-week taper periods), and pregabalin was administered in two divided doses per day. RESULTS: Mean baseline pain scores and demographic characteristics were comparable between treatment cohorts. Pregabalin treatment significantly reduced pain scores from baseline to endpoint compared with placebo in subjects with both moderate (P<0.001) and severe (P<0.05) baseline pain. Significant improvements in mean sleep scores from baseline to endpoint were associated with pregabalin compared with placebo in subjects with both moderate and severe baseline pain (both P<0.0001). A greater proportion of subjects in both pain cohorts achieved a ≥30% reduction in pain from baseline with pregabalin vs placebo (P<0.05). Higher proportions of pregabalin-treated vs placebo-treated subjects shifted to a less severe pain category at endpoint. Consistent with the known safety profile of pregabalin, common adverse events included dizziness, somnolence, weight gain, and peripheral edema. CONCLUSION: Pregabalin demonstrated efficacy for pain relief and sleep improvement with a consistent safety profile in Japanese subjects with either moderate or severe baseline pain severity. CLINICALTRIALSGOV IDENTIFIERS: NCT0039490130, NCT0055347522, NCT0040774524.

Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies.

INTRODUCTION: Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN. METHODS: Data were integrated from nine randomized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined "what if" scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive-moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging. RESULTS: Final pain levels were significantly different depending on dose changes (P < 0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0-1 dose change, and 15.2% had ≥ 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from ≥ 2 dose changes. Patient satisfaction with tolerability (range 90.3-96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns. CONCLUSION: Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonresponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability. FUNDING: Pfizer, Inc.

Annualized was found better than absolute risk reduction in the calculation of number needed to treat in chronic conditions.

BACKGROUND AND OBJECTIVE: Recent studies have calculated number needed to treat (NNT) estimates based on annualized rates; however, the ramifications of altering the NNT statistic have not yet been explored in the literature. Here we introduce the concept of annualized NNT (ANNT), and apply it to data from randomized controlled trials (RCTs). METHODS: Incidence rates from RCTs for serious adverse events for three medicines were compared to an older class of drugs. NNT and ANNT were calculated from the event rates for these events. RESULTS: Based on the data, the NNT to prevent one adverse event a year vs. older medications was drug A, ANNT = 88; drug B, ANNT = 77; drug C, ANNT = 68. Equivalent calculations based on Bayesian statistics are drug C, ANNT = 54; drug B, ANNT = 49. Drug A produced a bimodal distribution, with one mode within the NNT range and the other in the number needed to harm range. CONCLUSIONS: NNT can erroneously inflate differences between treatments when based on absolute and not differential safety. We propose that NNT be limited to acute conditions with short-term, well-defined treatment courses, and that ANNT be used for chronic conditions.

A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures.

PURPOSE: This study assessed the comparative efficacy of pregabalin for refractory partial seizures. METHODS: Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day. RESULTS: During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. DISCUSSION: Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease.

OBJECTIVE: This subanalysis of a large, double-blind, placebo-controlled trial examined the prevalence of behavioral symptoms in moderate to severe Alzheimer's disease (AD), and the effect of treatment with donepezil. METHODS: Two hundred ninety patients with moderate to severe AD (standardized Mini-Mental State Examination scores 5-17) were randomized to receive 24 weeks of once-daily doses of donepezil 5 mg/day for 28 days, and 10 mg/day thereafter per the clinician's judgment (n = 144), or placebo (n = 146). The outcome measure of interest was the 12-item Neuropsychiatric Inventory (NPI). RESULTS: Baseline demographics were similar between the treatment groups. Least squares mean (+/- SE) baseline NPI 12-item total scores were 19.55 +/- 1.48 and 19.30 +/- 1.45, respectively. At baseline, the most common symptoms were apathy/indifference (67%), aberrant motor behavior (53%), depression/dysphoria (52%), anxiety (49%), and agitation/aggression (45%). NPI individual item change from baseline scores at Week 24 using a last observation carried forward (LOCF) analysis showed benefits with donepezil treatment compared with placebo for all items, with significant treatment differences for depression/dysphoria, anxiety, and apathy/indifference (p < .05). Symptoms present at baseline that improved significantly for donepezil- compared with placebo-treated patients at Week 24 LOCF included anxiety, apathy/indifference, and irritability/lability (p < .05). When patients who were not receiving psychoactive medications at baseline were analyzed separately, significant improvements in NPI (continued) 12-item total score were observed with donepezil compared with placebo at most visits and at Week 24 LOCF (p < .05). CONCLUSIONS: Behavioral symptoms of the magnitude observed in this moderate to severe AD population improved with donepezil.