Long-term, open-label, safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease.

Long-term safety of once-daily ropinirole extended/prolonged release (ropinirole XL/PR) was evaluated in subjects with early and advanced Parkinson's disease (PD) in this study, 101468/248. Subjects (n = 419) who completed one of three prior studies evaluating ropinirole XL/PR for the treatment of PD were enrolled in this open-label, multicenter, extension study, and were to be followed for up to 73 months. Ropinirole XL/PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/d). Levodopa (L-dopa) and other nondopamine agonist PD medications were permitted. Safety outcomes that were investigated included frequency of adverse events (AEs). Subjects' preference regarding once daily versus three times daily study medication regimens was also investigated in a subset of the study population. The median duration of ropinirole XL/PR exposure was 1275 d. Most subjects (87%) reported at least one AE, with the most common (≥ 10%) AEs being, back pain (14%), hallucinations (13%), somnolence (11%) and peripheral edema (11%). Twenty-five percent of subjects discontinued the study prematurely due to an AE during the treatment period. Long-term treatment with ropinirole XL/PR was not associated with any new or unexpected safety concerns in patients with early and advanced PD, and a majority of subjects preferred the once-daily dosing regimen.

A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy.

BACKGROUND: Gabapentin enacarbil (GEn), a transported prodrug of gabapentin, provides sustained, dose-proportional gabapentin exposure. The purpose of this study was to investigate the dose response of GEn to select the optimal dose(s) for clinical use in subsequent diabetic peripheral neuropathy (DPN) trials. METHODS: This was a multicenter, randomized, double-blind, double-dummy, parallel group, placebo-controlled trial with a study duration of approximately 20 weeks (Clinicaltrials.gov database, Identifier ! NCT00643760). Pregabalin (PGB) (Lyrica(®) ; Pfizer Inc.) was used as an active control to provide assay sensitivity of the trial. A total of 421 adult subjects with DPN were randomized in a ratio of 2:1:1:1:2 to receive oral GEn 3,600 mg/day, GEn 2,400 mg/day, GEn 1,200 mg/day, PGB 300 mg/day, or matching placebo, respectively. The primary efficacy endpoint was change from baseline to end of maintenance treatment with respect to the mean 24-hour average pain intensity score based on an 11-point Pain Intensity Numerical Rating Scale (PI-NRS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, electrocardiograms (ECG), neurological examination, and pedal edema. RESULTS: The adjusted mean difference vs. placebo at the end of maintenance treatment with respect to the mean 24-hour average PI-NRS pain intensity score for GEn 1,200 mg (-0.35; [95% CI: -1.02, 0.31]; P = 0.295), GEn 2,400 mg (-0.02; [95% CI: -0.71, 0.66]; P = 0.946), and GEn 3,600 mg (-0.55; [95% CI: -1.10, 0.01]; P = 0.105) was not statistically significant. The active control, PGB (300 mg/day), did not differentiate from placebo. CONCLUSION: Overall, none of the GEn treatment groups differentiated from placebo. Analyses of the secondary endpoints showed comparable results across treatment groups. However, the majority of the endpoints, including all of the pain endpoints, showed the largest numerical treatment difference was between GEn 3,600 mg and placebo. The active control, PGB (300 mg/day), did not differentiate from placebo.

Long-term, open-label study of once-daily ropinirole prolonged release in early Parkinson's disease.

Long-term safety and efficacy of once-daily ropinirole prolonged release (PR) were evaluated in subjects with early Parkinson's disease (PD). Subjects (n = 83) who completed one of two studies were enrolled in this open-label, multicenter, extension study, and followed for up to 78 months. Ropinirole PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/day). L-dopa and other non-dopamine agonist PD medications were permitted. Safety outcomes included adverse events (AEs). Efficacy outcomes included Unified Parkinson's Disease Rating Scale (UPDRS) II and III scores, and Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I) scores. The median duration of ropinirole PR exposure was 1,069 days. Most subjects (97.6%) reported at least one AE, most commonly (≥ 30%) nausea (42.2%), dizziness (41.0%), peripheral edema (38.6%), back pain (33.7%), and headache (31.3%). Seventeen (20.5%) subjects discontinued due to an AE. UPDRS and CGI scores indicated that the clinical status of subjects was maintained throughout the treatment period. In patients with early PD, long-term treatment with once-daily ropinirole PR was not associated with any new safety concerns, and was effective in maintaining clinical status. These results support the extended use of ropinirole PR for treatment of PD.

A Retrospective, Pooled Suicidality Evaluation of Ropinirole Immediate Release and Controlled Release for the Treatment of Restless Legs Syndrome.

PURPOSE: Based on an internal request, GlaxoSmithKline conducted a retrospective pooled analysis of randomized controlled trials to compare suicidality in adult subjects with restless legs syndrome (RLS) who were being treated with ropinirole. The objective was to proactively evaluate the incidence of potentially suicidal thoughts or behaviors (suicidality) among patients with RLS treated with ropinirole immediate release (IR) or controlled release (CR). METHODS: The US Food and Drug Administration approved methods previously used for the retrospective analysis of suicidality with antidepressants and anticonvulsants. Potential cases of suicidal thoughts and behavior were identified from searches of treatment-emergent adverse event preferred and verbatim terms; a review of serious adverse events; and searches of a priori-identified free text comment fields in the case report forms. Blinded case reports for these potential cases, in addition to all serious adverse events, were categorized by using the Columbia Classification Algorithm of Suicide Assessment. FINDINGS: The dataset for this study comprised 1799 patients who received ropinirole (either formulation) and 1258 patients who received placebo. No signal for suicidality was detected for ropinirole in the treatment of patients with RLS. IMPLICATIONS: The pooled datasets in this study were not designed to prospectively assess for suicidal ideation or behavior. Any future studies in this area should include the collection of prespecified, detailed information regarding suicidality.

Evaluation of antidepressant properties of the p38 MAP kinase inhibitor losmapimod (GW856553) in Major Depressive Disorder: Results from two randomised, placebo-controlled, double-blind, multicentre studies using a Bayesian approach.

Pro-inflammatory cytokines (PICs) may play important pathophysiological roles in some forms of Major Depressive Disorder (MDD). The p38 MAPK inhibitor losmapimod (GW856553) attenuates the pro-inflammatory response in humans by reducing PIC production. Losmapimod (7.5 mg BD) was administered for 6 weeks in two randomised, placebo-controlled trials in subjects with MDD enriched with symptoms of loss of energy/interest and psychomotor retardation (Studies 574 and 009). Primary efficacy endpoints were the Bech 6-item depression subscale of the HAMD-17 (the 'Bech,') for Study 009; and the Bech, Inventory of Depressive Symptomatology-Clinician Rated (IDS-C), HAMD-17, and Quick Inventory of Depressive Symptomatology (self-rated) (QIDS-SR) for Study 574. Key cytokine biomarker levels were also measured. Study 574 (n=24) was terminated prematurely in light of emerging data from an internal study in rheumatoid arthritis. Efficacy results available at termination favoured losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = -4.10; 95% CI, -7.36, -0.83; p=0.017). A subsequent study, Study 009 (n=128), designed using a Bayesian approach based on a prior derived from Study 574, showed no advantage for losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = 1.11; 95% credible interval, -0.22, 2.50). Biomarker data showed no significant changes. In conclusion 7.5 mg BID losmapimod was not effective in MDD.

Study Site Experiences and Attitudes Toward Prospective Assessments of Suicidal Ideation and Behavior in Clinical Trials: Results of an Internet-based Survey.

OBJECTIVE: The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Working Group conducted an online survey regarding clinical trial site experiences and attitudes toward suicidal ideation and behavior data collection following the 2010 release of the initial United States Food and Drug Administration draft guidance on prospective assessment of suicidal ideation and behavior in clinical trials. Sites that had participated in at least one central nervous system clinical trial in the prior two years (N=6,058) were invited, via email, to complete a 20-item online assessment survey. RESULTS: Nine hundred and seventy-nine evaluable responses were collected (42% United States). Respondents included principal investigators (36%), raters (28%), coordinators (25%), and others (10%). The majority were psychiatrists (43%) and reported using suicidal ideation and behavior assessments across many indications. Most respondents (80%) personally conducted suicidal ideation and behavior assessments. Overall, respondents indicated that suicidal ideation and behavior assessments were readily incorporated into the conduct of clinical trials and improved subject safety. The greatest challenge was obtaining an accurate baseline lifetime history (51%), while the greatest benefit was identifying subjects at risk of suicide (84%). Approximately a quarter of respondents reported implementation challenges such as training. Differences based on geographical region, respondents' roles, and responsibility for assessments were observed. Open-ended responses revealed additional challenges, e.g., use in cognitively impaired populations. CONCLUSION: Prospective suicidal ideation and behavior monitoring was generally viewed positively, though specific challenges were identified. Limitations include self-report survey methodology and recruitment of only central nervous system clinical trials sites. These findings may help guide development of better methodologies for suicidal ideation and behavior assessment in clinical trials.