Adjusted Mean Treatment Difference Research Articles

Dose Response of Gabapentin Enacarbil versus Placebo in Subjects with Moderate-to-Severe Primary Restless Legs Syndrome

The efficacy and tolerability of gabapentin enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg. The objective of this study was to evaluate key efficacy and safety outcomes in subjects with RLS treated with once-daily gabapentin enacarbil 600 mg, 1200 mg, 1800 mg and 2400 mg, providing supportive evidence of the efficacy of gabapentin enacarbil 600 mg compared with higher doses and placebo. Integrated post hoc analysis of three 12-week, randomized, double-blind, placebo-controlled trials in subjects with RLS. The three studies were carried out at multiple centres in the US. In total, 760 subjects were included in the pooled analysis (placebo, n = 245; gabapentin enacarbil 600 mg, n = 163; gabapentin enacarbil 1200 mg, n = 269; gabapentin enacarbil 1800 mg, n = 38; gabapentin enacarbil 2400 mg, n = 45). In all studies, gabapentin enacarbil or placebo was administered once daily at approximately 5 p.m. with food. Gabapentin enacarbil was initiated at a dose of 600 mg with subsequent titration in 600 mg increments every 3 days up to the randomized dose. The efficacy endpoints analysed for the purpose of this integrated analysis were change from baseline in International Restless Legs Scale (IRLS) total score and the proportion of responders (subjects rated as 'much' or 'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety endpoints assessed were the incidence of treatment-emergent adverse events (AEs) and serious AEs. Gabapentin enacarbil 600 mg significantly improved IRLS total score compared with placebo (adjusted mean [standard error] change in IRLS total score from baseline to week 12 last observation carried forward: -13.6 [0.71] vs -9.3 [0.55]; adjusted mean treatment difference: -4.3; 95% CI -6.01, -2.52; p < 0.0001). A significantly higher proportion of subjects was rated as responders on the investigator-rated CGI-I scale with gabapentin enacarbil 600 mg compared with placebo (70.2% vs 42.2%; adjusted odds ratio 3.1; 95% CI 1.96, 4.89; p < 0.0001). Similar treatment benefits were seen with both efficacy endpoints for the three higher doses. The AEs reported most frequently were somnolence and dizziness; there was a dose-response relationship to these AEs. No new or unexpected safety issues were identified by this integrated analysis. The lowest dose of gabapentin enacarbil evaluated (600 mg) significantly improved RLS symptoms compared with placebo. The safety profile was consistent with that described previously in the literature.

Abstract 763: A phase 1 open-label study to investigate the potential drug-drug interaction (DDI) between single-dose (SD) dacomitinib (PF-00299804; DC) and steady-state (SS) paroxetine (PX) in healthy volunteers (HVs)

Abstract Introduction: DC, a small molecule, pan-HER inhibitor, is partly metabolized by cytochrome P450 (CYP) 2D6. Concomitant administration with therapeutic agents that are inhibitors of CYP2D6 could potentially cause DDIs. This study evaluated the effect of PX, a potent CYP2D6 inhibitor, on the pharmacokinetics (PK) of DC in HVs who were extensive CYP2D6 metabolizers. The safety and tolerability of SD DC was also assessed when given alone and co-administered with PX. Methods: In this Phase 1, single fixed-sequence, 2-period study, 14 HVs received a 45 mg SD of DC alone (Period 1). After a 21-day washout, 30 mg of PX was given daily for 10 days (Period 2) and on Day 4, a 45 mg SD of DC was co-administered with PX. Blood samples were collected up to 240 h post DC dose in both periods and analyzed for DC, its CYP2D6 metabolite PF-05199265, and PX using validated high performance liquid chromatographic tandem mass spectrometric methods. PK parameters were calculated using noncompartmental methods. Analysis of variance was performed on natural log transformed AUC and Cmax to estimate adjusted mean treatment differences and 90% confidence intervals (CI) which were exponentiated to produce the adjusted geometric mean ratio (GMR) and 90% CI of the ratios. Results: 14 males (median age 41 [23-54] yrs; 9 black, 5 Caucasian) were evaluated for PK and safety. The GMR and 90% CI of AUCinf and Cmax for DC when given as DC + PX vs DC alone was 137.2% (109.1%, 172.6%) and 110% (82.9%, 145.1%), respectively. Median Tmax of DC was 8 and 10 h post dose, and its half-life was 96 and 90 h, in the presence and absence of PX, respectively. Total exposure (AUC240) to PF-05199265 was decreased in the presence of SS PX (33.5 vs 322 ng.hr/mL). There were no serious adverse events (AEs), severe AEs, or deaths during the study. The majority of AEs were mild (including all 14 events reported during DC treatment alone) and resolved. Conclusions: PX inhibited DC metabolism resulting in 90% reduction in exposure (AUC240) of the CYP2D6 metabolite, PF-05199265. No meaningful change in absorption was observed when DC was given with SS concentrations of PX. DC seems to present a low extraction profile and high variability during the absorption phase, the latter probably due to its physicochemical characteristics (BCS Class II). In the presence of PX, there was an approximate 37% increase in DC exposure (AUCinf) with a wide CI, reflecting large intra-subject variability. The DC change in exposure reported in this study is likely to be less in the clinical setting (45 mg QD). As the exposure of DC reported in the presence of PX is within the range shown to be tolerated and efficacious, no dose adjustment is recommended for DC when administered concomitantly with a CYP2D6 inhibitor, such as PX. SD DC administered alone and in combination with PX was well tolerated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 763. doi:1538-7445.AM2012-763

Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined (mixed) dyslipidaemia

To compare the long-term efficacy and safety of pitavastatin with atorvastatin in patients with type 2 diabetes and combined (mixed) dyslipidaemia. Randomised, double-blind, active-controlled, multinational non-inferiority study. Patients were randomised 2 : 1 to pitavastatin 4 mg (n = 279) or atorvastatin 20 mg (n = 139) daily for 12 weeks. Patients completing the core study could continue on pitavastatin 4 mg (n = 141) or atorvastatin 20 mg (n = 64) [40 mg (n = 7) if lipid targets not reached by week 8] for a further 44 weeks (extension study). The primary efficacy variable was the change in low-density lipoprotein cholesterol (LDL-C). Reductions in LDL-C were not significantly different at week 12 between the pitavastatin (-41%) and atorvastatin (-43%) groups. Attainment of National Cholesterol Education Program and European Atherosclerosis Society targets for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) was similarly high for both treatment groups. Changes in secondary lipid variables (e.g. HDL-C, apolipoprotein B and triglycerides) were similar between treatments. Post hoc analysis showed that adjusted mean treatment differences for pitavastatin vs. atorvastatin were within the non-inferiority margin at weeks 16 (+0.11%; 95% confidence interval (CI), -5.23 to 5.44) and 44 (-0.02%; 95% CI, -5.46 to 5.41) of the extension study. Both treatments were well tolerated; atorvastatin increased fasting blood glucose from baseline (+7.2%; p < 0.05), whereas pitavastatin had no significant effect (+2.1%). Reductions in LDL-C and changes in other lipids were not significantly different in patients treated with pitavastatin 4 mg or atorvastatin 20 or 40 mg. Pitavastatin may, however, have a more favourable effect on the glycaemic status.

Comparative efficacy of pitavastatin and simvastatin in high-risk patients: a randomized controlled trial

Despite the proven efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in lowering total and low-density lipoprotein cholesterol (LDL-C), many patients do not reach recommended lipid targets. This study compared pitavastatin, a new and highly effective statin, and simvastatin in patients at high risk of coronary heart disease (CHD). The primary objective was to demonstrate noninferiority of pitavastatin to simvastatin. The study was a phase 3, randomized, double-blind, double-dummy, parallel-group, active-controlled study conducted at 37 centers in five European countries. Following a dietary run-in period of 6-8 weeks, patients with primary hypercholesterolemia or combined dyslipidemia and at least two CHD risk factors were randomized 2:1 to receive pitavastatin 4 mg or simvastatin 40 mg once daily for 12 weeks. The primary efficacy variable was the change in LDL-C from baseline. In total, 355 patients were randomized, 236 to pitavastatin and 119 to simvastatin; 330 patients (223 and 107, respectively) completed the study. In the pitavastatin group, mean (± SD) reduction in LDL-C concentrations from baseline was -44.0 ± 12.8% compared with -43.8 ± 14.4% in the simvastatin group. The adjusted mean treatment difference (simvastatin--pitavastatin) was 0.31% (95% confidence interval -2.47, 3.09; P = 0.829), which was within the predefined noninferiority range. More than 80% of patients in each group reached recommended LDL-C targets. Pitavastatin provided a greater increase in high-density lipoprotein cholesterol (HDL-C; 6.8% vs. 4.5%; P = 0.083) and a significantly greater decrease in triglycerides (-19.8% vs. -14.8%; P = 0.044) than simvastatin. Both treatments were well tolerated. Pitavastatin 4 mg is as effective as simvastatin 40 mg in lowering LDL-C in dyslipidemic patients at high risk of CHD, with additional effects on HDL-C and triglycerides. Therefore, pitavastatin may be appropriate for the management of dyslipidemic patients at high cardiovascular risk.

Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease

The 24-week, double-blind Efficacy and Safety Evaluation in PD-Adjunct (EASE-PD Adjunct) study randomized patients with advanced Parkinson's disease (PD) suboptimally controlled with levodopa to once-daily placebo or adjunctive ropinirole prolonged release (2-24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake 'off' time, reduced night-time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Once-daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance.

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Gabapentin Enacarbil in Subjects with Restless Legs Syndrome

To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS). This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events. 325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: -3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo-treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg). GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated.

Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome

We assessed the efficacy and tolerability of gabapentin enacarbil in the treatment of moderate to severe primary restless legs syndrome and associated sleep disturbance. This was a multicenter, randomized, double-blind, placebo-controlled, 2-period crossover polysomnography study of gabapentin enacarbil 1200 mg or placebo taken once daily. Subjects were randomized 1:1 to a sequence of gabapentin enacarbil:placebo or placebo:gabapentin enacarbil, receiving each treatment for 4 weeks. The primary end point was the mean change from baseline at weeks 4 and 10 (4/10) last observation carried forward in wake time during sleep. The key secondary end point was the mean change from baseline at weeks 4/10 last observation carried forward in periodic limb movements associated with arousal per hour of sleep. Tolerability assessments included adverse events. One hundred thirty-six subjects were randomized (gabapentin enacarbil:placebo, 67; placebo:gabapentin enacarbil, 69), and 114 (gabapentin enacarbil:placebo, 53; placebo:gabapentin enacarbil, 61) completed the study. Gabapentin enacarbil 1200 mg significantly reduced wake time during sleep (mean change from baseline [adjusted mean treatment difference]: -26.0 minutes; P < .0001) and periodic limb movements associated with arousal per hour of sleep (adjusted mean treatment difference: -3.1 periodic limb movements with arousal/hour; P = .002) compared with placebo at weeks 4/10 last observation carried forward. The most commonly reported adverse events were dizziness (gabapentin enacarbil 20%, placebo 2%) and somnolence (gabapentin enacarbil 13%, placebo 2%). Gabapentin enacarbil 1200 mg once daily significantly reduces restless legs syndrome-associated sleep disturbance and periodic limb movements associated with arousal per hour of sleep and is generally well tolerated in adults with moderate to severe primary restless legs syndrome.

Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS patients: a multicentre, randomized, placebo-controlled study

Comorbid depressive symptoms in restless legs syndrome (RLS) remain a treatment challenge, as some antidepressants aggravate RLS symptoms. Preliminary data in depressive patients suggest antidepressant properties of ropinirole. The present study investigates the effects of ropinirole immediate release (IR) on depressive symptoms and RLS severity. A multicenter, placebo-controlled, double-blind randomized (3:1) study was performed including patients with moderate to severe idiopathic RLS and at least mild depressive symptoms. Ropinirole IR (in flexible doses up to 4 mg/day) or placebo was given for 12 weeks including an uptitration phase of 7 weeks. Visits were scheduled at screening, baseline, and weeks 1, 4, and 12 with additional telephone contacts for dosing decisions. The modified intent to treat population comprised 231 patients (171 ropinirole, 60 placebo). The MADRS (Montgomery-Asberg Depression Rating Scale) scores decreased from baseline to week 12 from 18.8 to 8.7 in the ropinirole group and from 18.4 to 12.1 in the placebo group (primary endpoint, adjusted mean treatment difference -3.6 (95% CI: -5.6 to -1.6, significance in favor of ropinirole: P < 0.001). The superiority of ropinirole compared to placebo was confirmed by the Hamilton Scale for Depression and Beck Depression Inventory-II scores. RLS severity scores (IRLS) decreased by 14.7 (ropinirole) and by 9.9 (placebo, P < 0.001) points. Three out of four subdomains of the Medical Outcomes Study Sleep Scale improved significantly. The findings indicate that mild to moderate depressive symptoms should not be treated before sufficient therapy for RLS. Antidepressant medication can be necessary if depression symptoms still persist even if RLS symptoms are ameliorated.

Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Antagonist, SB-742457, in Alzheimers Disease

This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of the 5-HT6 receptor antagonist, SB-742457, in subjects with mild-to-moderate probable Alzheimer's disease (AD). Participating subjects had a Mini-Mental State Examination (MMSE) score of 12 to 26 after a 4-week, single-blind, placebo run-in phase, and were randomized (2:1:1:2) to receive placebo, SB-742457 5 mg, 15 mg, or 35 mg once daily for 24 weeks. Coprimary efficacy endpoints were the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score at Week 24, in the intent-to-treat (ITT) population. A model-based design provided 90% power to detect a linear trend in treatment response across increasing doses and > or =90% power to compare SB-742457 35 mg with placebo. 371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB-742457 vs 15% for placebo. SB-742457 was generally safe and well tolerated and may be efficacious in AD.

Early treatment benefits of ropinirole prolonged release in Parkinson's disease patients with motor fluctuations

We performed a retrospective analysis of the Efficacy And Safety Evaluation in Parkinson's Disease (EASE-PD) Adjunct Study, assessing the minimum time to symptom improvement after initiation of ropinirole prolonged release (2-24 mg/day) versus placebo in patients with moderate-to-advanced PD not optimally controlled with levodopa. Ropinirole prolonged release was superior to placebo at Week 2 for change from baseline in "off" time (adjusted mean treatment difference [AMTD] - 0.7 hours; 95% confidence interval [CI], -1.1, -0.2; P = 0.0029), and "on" time without troublesome dyskinesia (0.4 hours; 95%CI, 0.01, 0.88; P = 0.0444). At Week 4, improvements were seen in change from baseline in Unified Parkinson's Disease Rating Scale total motor score (AMTD, -3.1; 95%CI, -4.4, -1.8; P < 0.0001), activities of daily living score (AMTD, -1.1; 95%CI, -1.7, -0.5; P = 0.0004), and the cardinal symptoms of PD compared with placebo. These analyses indicate that once-daily, adjunctive ropinirole prolonged release can offer PD symptom control 2 weeks after treatment initiation.

Gabapentin Enacarbil in Restless Legs Syndrome

Assess the efficacy and tolerability of gabapentin enacarbil (GEn), a transported prodrug of gabapentin with improved gabapentin exposure, in adults with moderate-to-severe primary restless legs syndrome. This 14-day, double-blind, randomized, controlled trial of GEn at 1200 or 600 mg or placebo taken once daily, evaluated the mean change from baseline International Restless Legs Scale (IRLS) total score at end of treatment (day 14:primary comparison, GEn at 1200 mg vs placebo). Secondary end points included Clinical Global Impression-Improvement scale outcomes at day 14. Ninety-five subjects were randomized (GEn: 1200 mg, n = 33 and 600 mg, n = 29; placebo, n = 33); 2 subjects (GEn at 1200 mg) withdrew because of adverse events. At day 14,the mean (SD) change from baseline IRLS total score was significantly greater with GEn at 1200 mg (-16.1 [7.93]) compared with placebo (-8.9 [7.72]; adjusted mean treatment difference, -7.2; P < 0.0001). Investigator-rated Clinical Global Impression-Improvement scale responses also significantly favored GEn at 1200 mg compared with placebo (P G 0.0001).The mean (SD) change from baseline IRLS total score with GEn at 600 mg at day 14 was -9.1 (5.95), similar to placebo. The most commonly reported treatment-emergent adverse events were somnolence (GEn: 1200 mg, 36% and 600 mg, 14%; placebo,15%) and dizziness (GEn: 1200 mg, 18% and 600 mg, 14%; placebo, 3%), most of which were rated mild or moderate in intensity. Gabapentin enacarbil at 1200 mg significantly improved restless legs syndrome symptoms compared with placebo. Efficacy outcomes for GEn at 600 mg were similar to placebo. Both GEn doses were generally well tolerated.

Gabapentin enacarbil improves mood, quality of life and functioning in subjects with moderate-to-severe primary Restless Legs Syndrome

Restless Legs Syndrome (RLS) symptoms may negatively impact patients' mood, quality of life (QoL), and daily functioning. Gabapentin enacarbil is a non-dopaminergic therapy under investigation for the treatment of primary RLS. The 12-week, double-blind, multicenter study (XenoPort XP052) randomized subjects with moderate-to-severe primary RLS to gabapentin enacarbil 1200 mg (n = 114) or placebo (n = 108), once daily at 5pm with food. Results demonstrated that 1200mg gabapentin enacarbil significantly improved mean International Restless Legs Scale total score versus placebo at Week 12 LOCF compared with baseline (adjusted mean treatment difference [AMTD]: –4.0; 95%CI: –6.2, –1.9; p = 0.0003) and significantly more subjects were Clinical Global Impression – Improvement scale responders (rated as ‘very much’ or ‘much’ improved; 76% vs 39%; adjusted odds ratio: 5.1; 95% CI: 2.8, 9.2; p<0.0001) (co-primary endpoints).

Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials

Cardiovascular risk is subject to circadian variation, with peak morning incidence of myocardial infarction and stroke correlating with the early morning blood pressure (BP) surge (EMBPS). Ideally, antihypertensive therapy should maintain control of BP throughout the 24-h dosing cycle. In two sister studies, Prospective, Randomized Investigation of the Safety and efficacy of Micardis vs Ramipril Using ABPM (ambulatory BP monitoring) (PRISMA) I and II, BP control was compared in patients with essential hypertension (24-h mean baseline ambulatory BP approximately 148/93 mm Hg) randomized to the angiotensin receptor blocker, telmisartan (80 mg; n=802), or the angiotensin-converting enzyme inhibitor, ramipril (5 or 10 mg; n=811), both dosed in the morning. The primary end point was the change from baseline in mean ambulatory systolic BP (SBP) and diastolic BP (DBP) during the final 6 h of the 24-h dosing cycle. The adjusted mean treatment differences in the last 6-h mean ambulatory SBP/DBP were -5.8/-4.2 mm Hg after 8 weeks and -4.1/-3.0 mm Hg after 14 weeks, in favour of telmisartan (P<0.0001 for all four comparisons). Secondary end point results, including the mean 24-h ambulatory BP monitoring, day- and night-time BP and 24-h BP load, also significantly favoured telmisartan (P<0.0001). Both treatments were well tolerated; adverse events, including cough, were less common with telmisartan. These findings suggest that telmisartan is more effective than ramipril throughout the 24-h period and during the EMBPS; this may be attributable to telmisartan's long duration of effect, which is sustained throughout the 24-h dosing period.

Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, non-inferiority crossover study

ABSTRACTObjective: This study compares once-daily ropinirole 24-h prolonged release and three-times-daily ropinirole immediate release in patients with early Parkinson's disease.Methods: This multicentre, double-blind, non-inferiority crossover study involved 161 patients randomized to one of four formulation sequences: (1) immediate release–immediate release–prolonged release; (2) immediate release–prolonged release–prolonged release; (3) prolonged release–prolonged release–immediate release; (4) prolonged release–immediate release–immediate release. During a 12-week dose-titration period, ropinirole immediate release was titrated according to the approved labelling; titration of ropinirole 24-h prolonged release started at a higher dose and was more rapid. Patients then entered three consecutive, flexible-dose, 8-week maintenance periods. At the end of the first maintenance period, half of the patients in each formulation group switched to the same or closest dose of the alternative formulation; remaining patients switched at the end of the second maintenance period.Results: At the end of titration, before the first dose switch, there were substantial reductions in mean Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. During maintenance periods, both groups showed similar efficacy on the UPDRS motor score. Overall mean (standard error) change from period baseline was −0.1 (0.28) for ropinirole 24-h prolonged release, and 0.6 (0.30) for ropinirole immediate release (adjusted mean treatment difference −0.7; 95% confidence interval [CI]: −1.51, 0.10; p = 0.0842). The upper limit of the 95% CI was less than the predefined threshold of 3 points for non-inferiority. Ropinirole 24-h prolonged release was well-tolerated when titrated more rapidly than ropinirole immediate release; overnight switching between formulations was also well-tolerated. Study limitations included complexity of the non-inferiority study design and the forced dose-titration schedule.Conclusion: Ropinirole 24-h prolonged release was effective and well-tolerated in patients with early Parkinson's disease.

Two-Year Pulmonary Safety and Efficacy of Inhaled Human Insulin (Exubera) in Adult Patients With Type 2 Diabetes

OBJECTIVE—The purpose of this study was to evaluate the 2-year pulmonary safety of inhaled human insulin (Exubera [EXU]) in 635 nonsmoking adults with type 2 diabetes.RESEARCH DESIGN AND METHODS—Patients were randomly assigned to receive prandial EXU or subcutaneous insulin (regular or short-acting) plus basal (intermediate- or long-acting) insulin. The primary end points were the annual rate of decline in forced expiratory volume in 1 s (FEV1) and carbon monoxide diffusing capacity (DLCO).RESULTS—Small differences in FEV1 favoring subcutaneous insulin developed during the first 3 months but did not progress. Adjusted treatment group differences in FEV1 annual rate of change were −0.007 l/year (90% CI −0.021 to 0.006) between months 0 and 24 and 0.000 l/year (−0.016 to 0.016) during months 3–24. Treatment group differences in DLCO annual rate of change were not significant. Both groups sustained similar reductions in A1C by month 24 (last observation carried forward) (EXU 7.7–7.3% vs. subcutaneous insulin 7.8–7.3%). Reductions in fasting plasma glucose (FPG) were greater with EXU than with subcutaneous insulin (adjusted mean treatment difference −12.4 mg/dl [90% CI −19.7 to −5.0]). Incidence of hypoglycemia was comparable in both groups. Weight increased less with EXU than with subcutaneous insulin (−1.3 kg [−1.9 to −0.7]). Adverse events were comparable, except for a higher incidence of mild cough and dyspnea with EXU.CONCLUSIONS—Two-year prandial EXU therapy showed a small nonprogressive difference in FEV1 and comparable sustained A1C improvement but lower FPG levels and less weight gain than seen in association with subcutaneous insulin in adults with type 2 diabetes.

Reduction in magnetic resonance imaging T2 burden of disease in patients with relapsing-remitting multiple sclerosis: analysis of 48-week data from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study

BackgroundThe EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study was an international, randomized, open-label, assessor-blinded, parallel-group study assessing the efficacy and tolerability of interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), and IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw), in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this analysis was to assess whether reductions in T2 burden of disease (BOD) were greater for patients receiving IFN beta-1a, 44 mcg sc tiw, than for those treated with IFN beta-1a, 30 mcg im qw, and to assess the impact of neutralizing antibodies (NAbs).MethodsA post-hoc analysis was performed on magnetic resonance imaging (MRI) data collected prospectively from the EVIDENCE study. The analysis included all patients with evaluable T2 MRI scans at the start of dosing and at week 48, and those who received at least one drug dose (n = 553). Lesions were identified by a radiologist blinded to treatment codes and the total volume of T2 lesions (BOD) was reported in mm3.ResultsBoth median percentage decreases and absolute reduction in BOD were greater in the IFN beta-1a, 44 mcg sc tiw, treatment group. The adjusted mean treatment difference in percentage change in BOD from baseline to week 48 showed a significant treatment benefit for patients treated with IFN beta-1a, 44 mcg sc tiw, over those treated with IFN beta-1a, 30 mcg im qw (-4.6%; standard error: 2.6%; p = 0.002). The presence of NAbs reduced the effect of IFN beta-1a 44, mcg sc tiw, on BOD, but BOD changes were still similar to those seen with IFN beta-1a, 30 mcg im qw.ConclusionPatients with RRMS treated with IFN beta-1a, 44 mcg sc tiw, had greater reduction in T2 BOD after 48 weeks than those treated with IFN beta-1a, 30 mcg im qw, which is consistent with other clinical and MRI outcome measures in the EVIDENCE study. In patients testing positive for NAbs (NAb+) to IFN beta-1a 44 mcg sc tiw, changes in BOD were smaller than in NAb negative (NAb-) patients, but similar to those receiving IFN beta-1a, 30 mcg im qw.

A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24-month results from FACTS-International

To compare alendronate 70 mg once weekly (OW) with risedronate 35 mg OW with respect to change in bone mineral density (BMD), biochemical markers and upper gastrointestinal (UGI) tolerability over 24 months. This was a 12-month extension to the Fosamax Actonel Comparison Trial international study (FACTS). Postmenopausal women with osteoporosis randomly assigned to either alendronate 70 mg OW or risedronate 35 mg OW for the 12-month base study continued taking the same double-blind study medication. Efficacy measurements were BMD at the hip trochanter, lumbar spine, total hip, and femoral neck and levels of four bone turnover markers at 24 months. The primary hypothesis was that alendronate would produce a greater mean per cent increase from baseline in hip trochanter BMD at 24 months. Trochanter BMD increased significantly from baseline to month 24 in both groups, with a significantly larger increase with alendronate: adjusted mean treatment difference of 1.50% (95% confidence interval: 0.74%, 2.26%; p < 0.001). Similar results were seen at all BMD sites. Significant geometric mean per cent decreases (p < 0.001) from baseline were seen for all four bone turnover markers in both groups, with significantly larger decreases (p < 0.001) with alendronate: adjusted mean treatment differences ranged from 8.9% to 25.3%. No significant differences were seen in incidence of UGI or other adverse events. Alendronate 70 mg OW yielded significantly greater BMD gains and larger decreases in bone turnover marker levels than risedronate 35 mg OW over 24 months, with no difference in UGI tolerability.

Two-Year Safety and Efficacy of Inhaled Human Insulin (Exubera) in Adult Patients With Type 1 Diabetes

The purpose of this study was to evaluate the long-term (2-year) safety and efficacy of inhaled human insulin (Exubera [insulin human (rDNA origin)] inhalation powder) (EXU) in adult patients with type 1 diabetes. Patients were randomly assigned to receive EXU (n = 290) or subcutaneous (s.c.) insulin (n = 290), plus basal (intermediate- or long-acting) insulin. The primary end point was the annual rate of decline in pulmonary function (forced expiratory volume in 1 s [FEV1] and carbon monoxide diffusing capacity [DL(CO)]). The mean +/- SEM annual rates of change between months 0 and 24 were -0.051 +/- 0.005 l/year with EXU and -0.034 +/- 0.005 l/year with s.c. insulin (significant mean difference -0.017 +/- 0.007 l/year [90% CI -0.028 to -0.005]) for FEV1 and -0.437 +/- 0.073 ml x min(-1) x mmHg(-1) x year(-1) with EXU and -0.287 +/- 0.065 ml x min(-1) x mmHg(-1) x year(-1) with s.c. insulin (nonsignificant mean difference -0.150 ml x min(-1) x mmHg(-1) x year(-1) [-0.310 to 0.011]) for DL(CO). The mean annual rates of change in FEV1 between months 3 and 24 were -0.041 +/- 0.005 and -0.031 +/- 0.006 l/year in the EXU and s.c. insulin groups, respectively (nonsignificant mean difference -0.011 l/year [-0.023 to 0.002]), indicating that the significant difference between the treatment groups in FEV1 developed during the first 3 months and was not progressive thereafter. Adverse event profiles were similar except for a higher incidence of cough (usually mild and unproductive) in patients receiving EXU (37.6 vs. 13.1%) that decreased to 1.3% by month 24. Glycemic control was sustained in both groups (adjusted mean treatment difference in change from baseline A1C at month 24 0.25 +/- 0.07% [0.13-0.37]). Although the overall hypoglycemic events were comparable between groups (4.0 vs. 3.8 events/subject-month), the incidence of severe hypoglycemic events was lower with EXU than with s.c. insulin (2.8 vs. 4.1 events/100 subject-months, risk ratio 0.67 [0.57-0.79]). Body weight increased to a significantly lesser extent with EXU (adjusted mean treatment difference -1.25 +/- 0.36 kg [-1.85 to -0.66]). Treatment group differences in lung function between EXU and s.c. insulin in adult patients with type 1 diabetes are small, develop early, and are nonprogressive for up to 2 years of therapy.

2.237 Ropinirole 24-hour prolonged release improves sleep disturbance, but does not increase daytime somnolence in patients with advanced Parkinson's disease when administered as adjunctive therapy

Objective: A new formulation, ropinirole 24-hour prolonged release, allows a simple, once-daily, dose-titration regimen with potential for enhanced compliance and tolerability in the treatment of Parkinson’s disease (PD). The effect of ropinirole 24-hour adjunctive therapy on sleep and daytime somnolence is presented. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, for 24 weeks. Initial dose was 2.0mg/day, titrated to a maximum of 24.0mg/day. At 8.0mg/day and at each subsequent increase, L-dopa dose reduction was required. Secondary endpoints included change in PD Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS) total scores. Primary endpoint was mean change from baseline in awake time spent “off” at Week 24 last observation carried forward (LOCF). Results: Baseline PDSS and ESS total scores were similar between treatment groups. At Week 24 LOCF, patients’ sleep, as measured by PDSS total score, was statistically significantly improved with ropinirole 24-hour versus placebo; adjusted mean change from baseline: 1.3 versus −3.3 (adjusted mean treatment difference [AMTD]: 4.7; 95% confidence interval [CI]: 0.8, 8.6; p = 0.0196). No statistically significant nor clinically relevant change in daytime somnolence was observed between ropinirole 24-hour and placebo, as measured by ESS total score, at Week 24 LOCF (AMTD: 0.3; 95%CI: −0.4, 1.1; p = 0.3692). At Week 24 LOCF, ropinirole 24-hour significantly reduced “off” time, compared with placebo (AMTD: −1.7 hours; 95%CI: −2.3, −1.1; p< 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at last visit was 18.8 (6.26)mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release leads to statistically significant improvements in sleep without increased ESSmeasured daytime somnolence, compared with placebo, in patients with PD not optimally controlled with L-dopa.

Ropinirole in the Treatment of Patients With Restless Legs Syndrome: A US-Based Randomized, Double-Blind, Placebo-Controlled Clinical Trial

To assess the efficacy, safety, and tolerability of the dopamine agonist ropinirole in the treatment of patients with moderate to severe primary restless legs syndrome (RLS). This multicenter, 12-week, double-blind, placebo-controlled, flexible-dose study enrolled US patients and was conducted between September 2003 and May 2004. Patients were randomized to ropinirole or placebo, 0.25-4.0 mg as needed and tolerated, once daily, 1 to 3 hours before bedtime. The primary end point was mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score. Key secondary efficacy measures included the Clinical Global Impression-Improvement scale. A total of 381 patients were enrolled; 164 (87.7%) of 187 patients randomized to ropinirole and 167 (86.1%) of 194 randomized to placebo completed the study. Significant treatment differences favoring ropinirole, compared with placebo, were observed for change in IRLS total score at week 12 (adjusted mean treatment difference, -3.7; 95% confidence interval, -5.4 to -2.0; P < .001) and for all 3 key secondary end points: mean change from baseline in IRLS total score at week 1 and proportion of patients who were much/very much improved on the Clinical Global Impression Improvement scale at weeks 1 and 12. Ropinirole was associated with significantly greater Improvements in subjective measures of sleep disturbance, quantity, and adequacy; quality of life; and anxiety. Although treatment differences favoring ropinirole in daytime somnolence were observed, they were not statistically significant (P = .10). Ropinirole was generally well tolerated, with an adverse-event profile consistent with other dopamine agonists. This study confirms that ropinirole improves RLS symptoms and subjective measures of sleep, quality of life, and anxiety and that it is generally well tolerated.