Thrombogenicity evaluation in 221 patients with haemophilia B treated with nonacog alfa.

: Risk for thrombotic events with factor IX replacement therapy in patients with haemophilia B remains a concern for patients, those who treat them, and regulatory agencies, based on experience with early use of prothrombin complex concentrates. The current post hoc analysis assessed the incidence of thrombotic events and changes in prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer in 221 patients with haemophilia B who received nonacog alfa in clinical studies. Thrombotic event and coagulation marker data were collected from 8 interventional studies utilizing on-demand, prophylactic, and preventive regimens in patients with haemophilia B. Mean age was 25 years (min-max, 0-69), with 51 (23%) patients aged less than 12 years and 15 (7%) aged less than 2 years. None tested positive for inhibitors. Mean time on study was 60.9 ±â€Š32 weeks and mean number of exposure days was 69.3 (min-max, 1-496). Sixty-nine (31%) patients regularly received infusions that were approximately 100 IU/kg as part of a routine prophylaxis regimen, and 29 (13%) patients underwent surgical procedures. No clinical thrombotic events were reported, and no patient experienced clinically significant changes in coagulation markers between baseline and end-of-study testing. These collective data support the low thrombotic risk associated with nonacog alfa in paediatric, adult, and surgical patients with haemophilia B receiving different treatment regimens, including doses of approximately 100 IU/kg. Although careful thrombotic clinical evaluation is important, regular coagulation marker monitoring does not appear to be warranted in patients with haemophilia B.

A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia.

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.

A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder.

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.

A comparison of sumanirole versus placebo or ropinirole for the treatment of patients with early Parkinson's disease.

To assess the safety and efficacy of sumanirole, a highly selective dopamine agonist, versus placebo and demonstrate its noninferiority to ropinirole, 614 patients with early Parkinson's disease (PD) were treated with sumanirole, 1 to 16 mg/day; ropinirole, 0.75 to 24 mg/day; or placebo. Primary end point in this flexible-dose, double-blind, double-dummy, parallel-group study of 40 weeks was the change in total sum of the United Parkinson's Disease Rating Scale (UPDRS) Parts II + III scores from baseline to end of maintenance. Approximately half the subjects in the sumanirole and placebo groups withdrew early from the study, most (51.8% and 68.5%, respectively) due to lack of efficacy. Of the ropinirole subjects who withdrew (50.5%), most discontinued because of adverse events. In sumanirole and ropinirole groups, mean changes from baseline of -2.48 and -5.20 in UPDRS II + III mean scores were significant versus 0.38 in the placebo group (P

Efficacy and tolerability of sumanirole in restless legs syndrome: a phase II, randomized, double-blind, placebo-controlled, dose-response study.

OBJECTIVE: To compare the efficacy, safety and tolerability of sumanirole with placebo in patients with idiopathic restless legs syndrome (RLS). METHODS: In this double-blind, placebo-controlled, randomized, parallel-group, dose-response study, 270 patients with idiopathic RLS were enrolled and randomized to receive sumanirole 0.5, 1.0, 2.0, or 4.0mg, or placebo. The primary efficacy endpoint was mean change of the total score of the International Restless Legs Scale (IRLS-10), a 10-item scale, from baseline to end of maintenance. Secondary assessments included polysomnography (PSG) variables. RESULTS: Treatment with sumanirole was well tolerated. Mean change in IRLS-10 showed no statistically significant change compared with placebo at any dose, although the mean change with the 4.0-mg dose was numerically greater than the other doses and placebo. PSG variables, specifically the periodic leg movements during sleep, showed statistically significant dose-related improvement in favor of sumanirole. Consistent with earlier multinational, multicenter studies in RLS, high placebo response rates were seen with IRLS-10 but not with PSG variables. CONCLUSIONS: Given data published in Parkinson's disease, the dose range of sumanirole selected here may have been too low. Alternatively, dopamine D(2) selective agents could be intrinsically less effective than agonists with combined D(2)/D(3) activity. Sumanirole demonstrated an excellent safety profile.

Sumanirole versus placebo or ropinirole for the adjunctive treatment of patients with advanced Parkinson's disease.

The aims of this study were to assess the safety, tolerability, and efficacy of sumanirole, a highly selective D(2) dopamine receptor agonist, versus placebo in subjects with advanced Parkinson's disease (PD), and to demonstrate noninferiority of sumanirole to ropinirole. In this flexible-dose, randomized, double-blind, double-dummy, parallel-group study, 948 subjects were treated with sumanirole 1 to 48 mg/day, ropinirole 0.75 to 24 mg/day, or placebo. Treatment consisted of 13 weeks of dose escalation, 26 weeks of maintenance, and 1 week of tapering. Approximately 70% of subjects treated with either sumanirole or ropinirole completed the study. Statistical significance (P < 0.0001) was achieved when both sumanirole and ropinirole groups were compared with placebo, with mean differences of -7.7 and -8.8 on combined sum of the Unified Parkinson's Disease Rating Scale (UPDRS) part II (average on and off) and part III total scores at the end of maintenance. Noninferiority of sumanirole to ropinirole was also demonstrated, with a sumanirole minus ropinirole difference of 1.17 (90% CI: -0.56 to 2.89). Both dopamine agonists, sumanirole and ropinirole, were statistically superior compared with placebo as adjunctive therapy for patients with advanced Parkinson's disease, based on UPDRS II + III total score. Noninferiority of sumanirole to ropinirole was established, with comparable tolerability profiles.