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Study design:Double-blind, placebo-controlled, flexible-dose study.Objective:To evaluate the efficacy, safety and tolerability of oral sildenafil in women with female sexual arousal disorder as a result of SCI (paraplegia/tetraplegia).Setting:The study was conducted at clinical practice sites in North America (n =23), 11 European countries (n =23), Australia (n =4) and South Africa (n =2).Methods:129 women were randomized and treated with sildenafil or matching placebo. A 4-week baseline period was followed by 12 weeks of treatment, which could be increased from 50 to 100 mg or decreased to 25 mg once during the treatment period, depending on efficacy and tolerability. By use of an event log, sexual activity was monitored between screening and the end of treatment. The Sexual Function Questionnaire, the Sexual Quality of Life Questionnaire-Female, a global efficacy question and Sexual Distress Question were also assessed.Results:Sildenafil-treated women and placebo-treated women had an increase in their percentage of sexual activities throughout the course of the study, with no statistically significant difference between groups in the percentage of successful sexual activities at end of treatment versus baseline. There were also no statistically significant differences between sildenafil- and placebo-treated women on the aforementioned measures. The most common adverse events included headache and vasodilatation.Conclusion:The results of this study are similar to other reports regarding a lack of clinically meaningful benefit of sildenafil in other populations of women.Sponsorship:This study was sponsored by Pfizer Inc. [ABSTRACT FROM AUTHOR]

Background: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH., Methods: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population., Results: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P <0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P <0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P =0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil., Conclusions: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487., Competing Interests: Disclosures M.M.H. is a paid consultant and speaker of pharmaceutical companies including Actelion, Acceleron, AOP Health, Bayer, Ferrer, Gossamer, Janssen, Keros, and MSD. R.E. is a paid consultant for advisory boards and scientific lectures from Janssen, Boehringer Ingelheim, AOP, United Therapeutic, Novartis, AstraZeneca, and OMT. P.J. is a paid consultant and speaker for numerous pharmaceutical companies and has received financial grant for Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Orphan, Bayer Healthcare, MSD, and Arena Pharmaceuticals Inc. Y.S. is an employee of NSC MD Strazhesko Institute of Cardiology, Clinical and Regenerative Medicine of the National AMS of Ukraine. A.S. is a paid consultant of pharmaceutical companies including Gossamer Bio, AOP Orphan, and Medison Pharma, and is paid as a speaker for KRKA, Altavant Sciences. C.B. is currently employee of Pfizer and hold stocks in Pfizer and Viatris. S. Hackley is a former employee of Pfizer and current employee of Viatris and hold stocks in Viatris. S.V. is an employee of MEDA Pharma GmbH & Co KG (A Viatris Company). P.A. hold shares of Pfizer. S. Haughie hold stocks in Viatris. T.H. is currently employee of Viatris and hold stocks of Viatris. R.J.O. is a principal investigator in studies and attends ad hoc advisory boards sponsored by Aerovate, Gossamer Bio, Janssen, Keros, Merck, and United Therapeutics. He is a paid speaker for Janssen and United Therapeutics.

A recent study reported that the high-dose quadrivalent influenza vaccine provided superior immunogenicity and efficacy versus the standard-dose quadrivalent vaccine in the elderly. However, we need to view these results in terms of public health benefits as well. The Number Needed to Vaccinate (NNV) is an important tool to measure the benefit of a given vaccine. Further, NNV evaluates the benefits of a vaccine in preventing and controlling communicable diseases. Considering the target of vaccination and coverage of 75% not met in the elderly in Europe, it is important not to prioritize one vaccine over the other, but rather to increase the vaccine coverage with all the available vaccines.

Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model ("Superbatch") or included as a fixed or random effect ("Fixed Batch Effect," "Random Batch Effect"). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study ("Targeted Batch"). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits., (© 2021. The Author(s).)

Background: Wixela ® Inhub ® is a dry powder inhaler approved as a generic equivalent to Advair ® Diskus ® (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. Methods: This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV 1 ]) of FP/salmeterol (100/50 μg) after inhaled delivery via T and R. Results: Randomized patients ( N  = 1127) received T ( n  = 512), R ( n  = 512), or placebo ( n  = 103). T and R significantly increased day 1 FEV 1 area under the effect curve over 12 hours of the change from baseline (AUC [0-12] ) and day 29 trough FEV 1 over placebo, indicating that these endpoints were sufficiently sensitive for evaluation of bioequivalence. On day 1, T and R each increased FEV 1 AUC (0-12) over placebo (3.134 L•h [T], 2.677 L•h [R]; each p  < 0.0001). Following twice-daily dosing for 28 days, T and R also each increased trough FEV 1 (measured on day 29) over placebo (235 mL [T], 215 mL [R]; each p  < 0.0001). Least-squares mean T/R ratios (90% confidence intervals) for day 1 FEV 1 AUC (0-12) and day 29 trough FEV 1 were 1.120 (1.016-1.237) and 1.069 (0.938-1.220), respectively, indicating that T and R were bioequivalent for both co-primary endpoints. FP/salmeterol was well tolerated when administered via either T or R. Conclusions: These results demonstrate that the therapeutic effects of Wixela Inhub are bioequivalent to Advair Diskus in the lung. Wixela Inhub represents a therapeutically equivalent new FP/salmeterol treatment option for use in the treatment of asthma and COPD.

Background: Wixela ® Inhub ® was developed to deliver inhaled fluticasone propionate/salmeterol (FP/S) combination as a substitutable generic equivalent to Advair ® Diskus ® . These studies aimed to confirm the pharmacokinetic bioequivalence (BE) of FP/S after single doses of Wixela Inhub (test [T]) and Advair Diskus (reference [R]). Methods: Three open-label, randomized, two-way crossover, single-dose studies in healthy subjects ( N  = 66 each) compared the systemic exposure of FP and salmeterol after inhalation from three dose strengths of FP/S (100/50, 250/50, or 500/50 μg) delivered from T and R. Primary BE endpoints were the area under the plasma concentration-time curve from time = 0 to the last measurable concentration (AUC (0-t) ) and the maximum observed plasma concentration (C max ) for both FP and S. The BE acceptance criteria specified that the 90% confidence intervals (CIs) of the geometric mean T/R ratios for AUC (0-t) and C max can be contained within 0.80-1.25 for both FP and salmeterol. Results: Wixela Inhub met the acceptance criteria for BE for FP and salmeterol at each dose strength. Estimated AUC (0-t) and C max geometric mean ratios (T/R [90% CI]) for FP were, respectively, 1.04 (1.00-1.08) and 0.92 (0.87-0.96) for 100/50 μg FP/S, 1.07 (1.02-1.13) and 1.01 (0.95-1.07) for 250/50 μg, and 0.97 (0.92, 1.00) and 0.90 (0.86-0.93) for 500/50 μg. Estimated AUC (0-t) and C max ratios for salmeterol were, respectively, 1.08 (1.04-1.11) and 1.00 (0.94-1.04) for 100/50 μg FP/S, 1.03 (0.99-1.07) and 0.93 (0.87-1.00) for 250/50 μg, and 1.00 (0.96-1.04) and 0.86 (0.81-0.91) for 500/50 μg. FP/S at all doses via both T and R was comparably well tolerated. Conclusions: Wixela Inhub was bioequivalent to Advair Diskus at all three dose strengths for both FP and S, providing direct evidence of equivalent systemic safety and indirect evidence for equivalent pulmonary deposition.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair ® Diskus ® . Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 μg), FPS (100/50 or 200/100 μg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC 20 ). Study entry required screening PC 20 ≤8 mg/mL, with a greater than fourfold increase (and PC 20 ≤128 mg/mL) after 180 μg albuterol. Results: Both albuterol (90 and 180 μg) and FPS (100/50 and 200/100 μg) significantly increased PC 20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC 20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (F eNO ) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated F eNO (≥45 parts per billion). Methods: Thirty-four patients received three of five treatments: FPS 100/50 μg once daily (QD), FPS 100/50 μg twice daily (BID), FPS 250/50 μg BID, FPS 500/50 μg BID, or placebo, each for 2 weeks separated by 14-day washout. F eNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards. Results: FPS treatments decreased F eNO compared with placebo, with the largest differentiation between doses noted on day 14; the mean decreases from days 1 to 14 ranged from -46.6% to -64.5% with FPS versus -9.1% with placebo. The dose-response plateaued at 200 μg/day (FPS 100/50 μg BID). Linear regression analysis revealed significant slopes between FPS doses, with the steepest between 100/50 μg QD and 100/50 μg BID (-0.0039, p  = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80-1.25 and 0.67-1.50 bioequivalence limits, respectively). However, as the slope between BID FPS doses was shallow, a larger SS may be needed if only an approved dose regimen was used. Conclusion: F eNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable.

Aims: Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva ® HandiHaler ® (HH). The ratio of tiotropium lung-to-oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics, and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block., Methods: A seven-period, single-dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation., Results: PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 μg tiotropium) lung deposition was similar to Spiriva HH (18 μg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The C max and AUC 0-0.5h of Spiriva HH with and without charcoal block were bioequivalent; however, Spiriva HH AUC 0-8h was lower when gastrointestinal absorption was inhibited with oral charcoal administration., Conclusions: Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC 0-t than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract., (© 2018 The British Pharmacological Society.)

Context: Meta-analyses are regularly used to inform healthcare decisions. Concerns have been expressed about the quality of meta-analyses and, in particular, about those supported by the pharmaceutical industry., Objective: The objective of this study is to compare the quality of pharmaceutical-industry-supported meta-analyses with academic meta-analyses and of meta-analyses published before and after companies started to disclose their data., Data Sources: We identified industry-supported meta-analyses by searching the Scopus bibliographic database, using author affiliations. We matched each industry-supported meta-analysis with an academic meta-analysis using high-level MeSH terms in PubMed., Study Selection: We included meta-analyses of randomized trials assessing the efficacy or safety of any pharmaceutical intervention in humans, published in 2002-2004 or 2008-2009. Cochrane reviews were excluded. Two individuals independently selected papers, with discrepancies resolved by two further individuals., Assessment: We developed and piloted a quality-assessment tool, consisting of 43 questions in four domains, with a key summary question covering each domain. Two individuals independently assessed each meta-analysis., Results: We examined 126 meta-analysis publications in 63 matched pairs. The average quality was low, with fewer than 50% adequate in three of the four domains. Industry-supported meta-analyses less often demonstrated adequate methods for locating studies and assessing their quality (odds ratio 0.44, 95% confidence interval 0.21 to 0.92), for analysing the included studies (0.52, 0.25 to 1.06), for undertaking meta-analyses (0.82, 0.40 to 1.68) and in reaching sound conclusions (0.62, 0.30 to 1.28). Quality generally improved over time, particularly for some aspects of industry reports., Conclusions: Academic meta-analysis papers are generally of higher quality than industry-supported ones. This is largely due to less detailed reporting in industry-supported meta-analyses and a tendency for them to take the included studies at face value, probably arising from the implicit assumption that these studies already have high methodological standards to meet licensing requirements. The improved quality over time does not appear to be due to the use of data disclosed by industry. The main limitations of this study are the small sample of papers and the subjective nature of some of the assessment processes., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Because meta-analyses are increasingly prevalent and cited in the medical literature, it is important that tools are available to assess their methodological quality. When performing an empirical study of the quality of published meta-analyses, we found that existing tools did not place a strong emphasis on statistical and interpretational issues., Methods: We developed a quality-assessment tool using existing materials and expert judgment as a starting point, followed by multiple iterations of input from our working group, piloting, and discussion. After having used the tool for our empirical study, agreement for four key items in the tool was measured using weighted kappa coefficients., Results: Our tool contained 43 items divided into four key areas (data sources, analysis of individual studies, meta-analysis methods, and interpretation), and each area ended with a summary question. We also produced guidance for completing the tool. Agreement between raters was fair to moderate., Conclusions: The tool should usefully inform subsequent initiatives to develop quality-assessment tools for meta-analysis. We advocate use of consensus between independent raters when assessing statistical appropriateness and adequacy of interpretation in meta-analyses., (Copyright © 2013 John Wiley & Sons, Ltd.)

Introduction: We previously described dynamic, noncontrast magnetic resonance imaging (MRI) of the female genitalia as a reproducible, nonintrusive, objective means of quantifying sexual arousal response in women without sexual difficulties. These studies showed an increase in clitoral engorgement ranging from 50 to 300% in healthy women during sexual arousal., Aim: This study sought to evaluate the genital arousal response in women with female sexual arousal disorder (FSAD) after administration of sildenafil and placebo. We performed a multicenter, double-blind, placebo-controlled, cross-over study to assess the clitoral engorgement response using dynamic MRI in women with FSAD after administering sildenafil and placebo followed by audiovisual sexual stimulation (AVSS)., Methods: Nineteen premenopausal women with FSAD underwent two MRI sessions. Subjects were randomized to receive either (i) sildenafil 100 mg during the first session followed by placebo during the second session, or (ii) placebo followed by sildenafil. During each session, baseline MR images were obtained while subjects viewed a neutral video. Subjects then ingested sildenafil or placebo. After 30 minutes, a series of MRIs were obtained at 3-minute intervals for 10 time points while subjects viewed AVSS., Main Outcome Measures: A positive sexual arousal response was achieved if clitoral volume increased ≥50% from baseline., Results: Thirteen of 19 (68%) subjects achieved a ≥50% increase in clitoral engorgement from baseline when administered sildenafil or placebo 30 minutes after dose administration. At 60 minutes after administration, 17/19 (89%) subjects receiving sildenafil and 16/19 (84%) subjects receiving placebo had responded (P value 0.3173)., Conclusions: Sildenafil did not augment the genital response in women with FSAD. Secondarily, a majority of women in this study did not have impaired clitoral engorgement as measured by MRI, suggesting that FSAD is not predominantly a disorder of genital engorgement., (© 2012 International Society for Sexual Medicine.)

Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (-0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.

Objectives: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor, UK-369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED)., Patients and Methods: This was a multicentre, double-blind, placebo-controlled, parallel-group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥ 18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥ 8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK-369,003; or placebo once a day) for 12 weeks. The primary study endpoints were those derived from the bladder diary that recorded the number of voluntary urinary voids, volume of urine per void, leaks and urgency episodes over a 72-h period, before baseline and again at 2, 4 and 12 weeks. Secondary efficacy measures included the International Prostate Symptom Score (total and storage and voiding subscores), International Index of Erectile Function-Erectile Function domain (IIEF-EF), questions 5 and 6 of the Quality of Erection Questionnaire (QEQ), the Overactive Bladder Questionnaire Short Form, the Patient Perception of Bladder Condition, the International Consultation on Incontinence Questionnaire-Male LUTS, and the patient-reported treatment impact questionnaire., Results: Overall, there were no clinically relevant treatment differences in voiding frequency, mean voided volume, urgency episode frequency, or nocturia frequency for any dose of UK-369,003 MR compared with placebo. In the subset of patients with ED there were improvements in the IIEF-EF and QEQ scores in all UK-369,003 treatment groups compared with placebo., Conclusions: These data provide no evidence of efficacy for UK-369,003 in the treatment of storage LUTS in men (based on classic OAB eligibility criteria). However, although the endpoints on these classic OAB efficacy variables were negative, there is evidence to suggest a greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Objectives: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men with and without erectile dysfunction (ED)., Patients and Methods: This was a multicentre, double-blind, placebo- and active-controlled, parallel-group study conducted across 45 centres in North and South America, Europe, and Australia. In all, 418 men aged ≥ 40 years with a clinical diagnosis of BPH, an International Prostate Symptom Score (IPSS) of ≥ 13, and maximum urinary flow rate (Q(max) ) of 5-15 mL/s for a voided volume of > 150 mL were stratified into two groups (with and without ED) and randomized to one of seven treatment groups, i.e. UK-369,003 at 10, 25, 50 or 100 mg modified release (MR), UK-369,003 40 mg immediate release (IR), tamsulosin 0.4 mg prolonged release, or placebo, for 12 weeks. The primary study endpoint was the change in total IPSS after 12 weeks of treatment. Secondary efficacy measures were IPSS storage and voiding subscores, Q(max) , International Index of Erectile Function-Erectile Function domain, questions 5 and 6 of the Quality of Erection Questionnaire, the International Consultation on Incontinence Questionnaire-Male LUTS, the patient-reported treatment-impact questionnaire, and a bladder diary in which patients recorded the number of voluntary urinary voids, volume of urine voided per micturition, leaks, and urgency episodes., Results: The mean change in the IPSS from baseline at week 12 for UK-369,003 100 mg MR and 40 mg IR was -2.91 and -2.50 better than placebo, respectively. There was increasing efficacy with increasing dose of the MR formulation. For UK-369,003 100 mg MR, Q(max) improved by 2.10 mL/s compared with 0.84 mL/s in the placebo group., Conclusions: UK-369,003 had clinically meaningful efficacy and was well tolerated in men with LUTS associated with BPH. The Bayesian statistical analysis gave high posterior probabilities for true differences between UK-369,003 100 mg MR and placebo. There was greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Purpose: To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies., Materials: Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. Simulations were performed to evaluate the expected clinical response in patients with FSAD., Results: The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women., Conclusion: A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.

Aim: To determine if the validated Sexual Function Questionnaire (SFQ), developed to assess efficacy in female sexual dysfunction (FSD) clinical trials, may also have utility in identifying target populations for such studies., Methods: Data from five clinical trials and two general population surveys were used to analyze the utility of the SFQ as a tool to discriminate between the presence of specific components of FSD (i.e., hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and dyspareunia)., Results: Sensitivity/specificity analysis and logistic regression analysis, using data from all five clinical studies and the general population surveys, confirmed that the SFQ domains have utility in detecting the presence of specific components of FSD and provide scores indicative of the presence of a specific sexual disorder., Conclusions: The SFQ is a valuable new tool for detecting the presence of FSD and identifying the specific components of sexual functions affected (desire, arousal, orgasm, or dyspareunia).

Objectives: Premature ejaculation (PE) is the most common ejaculatory dysfunction. We assessed the efficacy of sildenafil to increase the time to ejaculation, improve ejaculatory control, and decrease the postejaculatory erectile refractory time in men with PE., Design and Methods: The main study was an 8-week, double-blind, placebo-controlled, parallel group study in men between 18 and 65 years of age with diagnosed PE. A substudy was also conducted using a subset of patients (two-way crossover, one center) before entry to the main study. The primary study measured intravaginal ejaculatory latency (IELT) and responses to the Index of Premature Ejaculation (IPE) questionnaire. The substudy measured vibrotactile stimulation ejaculatory latency time (VTS-ELT) and postejaculatory erectile refractory time. Differences between treatment groups were determined by ancova at the 5% level of significance., Results: The change in IELT (1.6 +/- 6.08 vs. 0.6 +/- 2.07 minutes) and VTS-ELT (2.9 +/- 0.4 vs. 2.4 +/- 0.4 minutes) were higher after taking sildenafil, compared with placebo, but did not reach statistical significance. However, patients who took sildenafil (vs. placebo) reported significantly (P < 0.05) increased ejaculatory control (1.8 +/- 0.3 vs. 1.5 +/- 0.3), increased ejaculatory confidence (2.2 +/- 0.2 vs. 1.9 +/- 0.2), and improved overall sexual satisfaction scores (3.1 +/- 0.2 vs. 2.8 +/- 02) on the IPE, and had a decreased postejaculatory erectile refractory time (3.2 +/- 0.7 vs. 6.4 +/- 0.7 minutes). The most common adverse events for sildenafil (vs. placebo) were headache (15% vs. 1%), flushing (15% vs. 0%), dyspepsia (5% vs. 1%), abnormal vision (5% vs. 0%), and rhinitis (5% vs. 0%)., Conclusions: Although IELT and VTS-ELT were not significantly improved, sildenafil increased confidence, the perception of ejaculatory control, and overall sexual satisfaction, and decreased the refractory time to achieve a second erection after ejaculation in men with PE.

We briefly outline the importance of statistical input into clinical trial research in the pharmaceutical industry and in interactions with regulatory agencies, with particular concentration on the role of the statistician in projects on sexual health during Phases 2 and 3 of clinical trials required in bringing new drugs to the market.

Purpose: We evaluated the efficacy and safety of sildenafil citrate in spontaneously or surgically postmenopausal women with female sexual arousal disorder (FSAD)., Materials and Methods: Sildenafil (a 50 mg dose adjustable to 100 or 25 mg) was evaluated in a 12-week, double-blind, placebo controlled study in 202 postmenopausal women with FSAD who had protocol specified estradiol and free testosterone concentrations, and/or were receiving estrogen and/or androgen replacement therapy. Patients were excluded if emotional, relationship or historical abuse issues contributed significantly to sexual dysfunction. Primary end points were questions 2 (increased genital sensation during intercourse or stimulation) and 4 (increased satisfaction with intercourse and/or foreplay) from the Female Intervention Efficacy Index (FIEI). Secondary end points were the remaining questions from this index, the Sexual Function Questionnaire and sexual activity event log questions., Results: Significant improvements in FIEI questions 2 (p = 0.017) and 4 (p = 0.015) were noted with sildenafil compared with placebo. For women with FSAD without concomitant hypoactive sexual desire disorder (HSDD) sildenafil was associated with significantly greater improvement in 5 of 6 FIEI items compared with placebo (p <0.02). No significant improvements were shown for women with concomitant HSDD. Most adverse events were mild to moderate with headache, flushing, rhinitis, nausea and visual symptoms reported most frequently., Conclusions: Sildenafil was effective and well tolerated in postmenopausal women with FSAD without concomitant HSDD or contributory emotional, relationship or historical abuse issues. All patients had protocol specified estradiol and free testosterone concentrations or were receiving estrogen and/or androgen replacement therapy.