Updated safety results from phase 3 lecanemab study in early Alzheimer's disease.

BACKGROUND: Alzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aß)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aß protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo. METHODS: Clarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally. RESULTS: Overall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3-6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%). CONCLUSIONS: Lecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care. TRIAL REGISTRATION: ClinicalTrials.gov numbers: Clarity AD NCT03887455).

Duration of response after DEB-TACE compared to lipiodol-TACE in HCC-naïve patients: a propensity score matching analysis.

OBJECTIVES: To retrospectively compare long-term outcomes of first-line drug-eluting particle (DEB)- transarterial chemoembolization (TACE) and lipiodol-TACE, in patients with unresectable hepatocellular (HCC). METHODS: We retrospectively reviewed our database to identify adult patients with treatment-naïve unresectable HCC, who underwent TACE from 2006 to 2013. Patients were excluded in the absence of complete medical records relative to first TACE, 1-month follow-up, and/or sufficient follow-up data. Periprocedural complications, duration of hospitalization, 1-month tumor response by mRECIST, time to tumor progression (TTP) and target tumor progression (TTTP), and overall survival (OS) were evaluated. RESULTS: Out of an initial series of 656 patients, 329 patients were excluded for unavailability of sufficient baseline and/or follow-up data. The remaining 327 patients underwent either lipiodol-TACE (n = 160) or DEB-TACE (n = 167). Patients treated with lipiodol-TACE had a significantly higher tumor burden. By propensity score, patients were matched according to baseline differences (BCLC stage, uninodular or multinodular HCC, and unilobar or bilobar HCC), resulting in 101 patients in each treatment group. Lipiodol-TACE was associated with a significantly higher incidence of adverse events (p = 0.03), and longer hospitalization (mean, 2.5 days vs 1.9 days; p = 0.03), while tumor response, TTP, and OS were comparable. In patients achieving 1-month complete response (CR) of target tumor, TTTP was significantly (p = 0.009) longer after DEB-TACE compared to lipiodol-TACE (median, 835 vs 353 days), resulting in a lower number of re-treatments during the entire follow-up (0.75 vs 1.6, p = 0.01). CONCLUSION: Compared to lipiodol-TACE, DEB-TACE offers higher tolerability, reduced hospitalization, and more durable target tumor response after CR. KEY POINTS: • Compared to lipiodol-TACE, DEB-TACE is better tolerated and has reduced side effects, which translates into shorter hospitalization. • When complete radiological response according to the mRECIST is obtained 1 month after the procedure, DEB-TACE offers a more durable local tumor control compared to lipiodol-TACE. • In these patients, the longer duration of response after DEB-TACE translates into a lower number of re-interventions.

Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study.

STUDY OBJECTIVES: To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment. METHODS: Adults and elderly subjects with insomnia disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition were enrolled in a multicenter, randomized, double-blind, placebo-controlled, Bayesian, adaptive, parallel-group study, receiving lemborexant (1, 2.5, 5, 10, 15, 25 mg) or placebo for 15 nights. Efficacy assessments included a utility function that combined efficacy (SE) and safety (residual morning sleepiness as measured by Karolinska Sleepiness Scale [KSS]), PSG measures, and sleep diary. Safety assessments included KSS, Digit Symbol Substitution Test, computerized reaction time tests, and adverse events (AEs). RESULTS: A total of 616 subjects were screened; 291 were randomized. Baseline characteristics were similar between lemborexant groups and placebo (∼63% female, median age: 49.0 years). The study was stopped for early success after the fifth interim analysis when the 15-mg dose met utility index/KSS criteria for success; 3 other doses also met the criteria. Compared with placebo, subjects showed significant improvements in SE, subjective SE, LPS, and subjective sleep onset latency at the beginning and end of treatment for lemborexant doses ≥ 5 mg (P < .05). WASO and subjective WASO showed numerically greater improvements for doses > 1 mg. AEs, mostly mild to moderate, included dose-related somnolence. CONCLUSIONS: Lemborexant doses ranging from 2.5-10 mg provided efficacy for the treatment of insomnia while minimizing next-morning residual sleepiness. CLINICAL TRIAL REGISTRATION: Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01995838; Identifier: NCT01995838.

Trans-Arterial Radioembolization for Hepatocellular Carcinoma.

This article offers an overview of a new therapeutic option in hepatocellular carcinoma using trans-arterial radioembolization. In particular, it covers practical aspects of the technique and the currently available preliminary data in terms of disease control. We explore the potentials of radioembolization both in early and advanced stages of the disease, as single treatment and as companion to targeted agents such as sorafenib.

Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives.

In the last decade trans-arterial radioembolization has given promising results in the treatment of patients with intermediate or advanced stage hepatocellular carcinoma (HCC), both in terms of disease control and tolerability profile. This technique consists of the selective intra-arterial administration of microspheres loaded with a radioactive compound (usually Yttrium(90)), and exerts its therapeutic effect through the radiation carried by these microspheres. A careful and meticulous selection of patients is crucial before performing the radioembolization to correctly perform the procedure and reduce the incidence of complications. Radioembolization is a technically complex and expensive technique, which has only recently entered clinical practice and is supported by scant results from phase III clinical trials. Nevertheless, it may represent a valid alternative to transarterial chemoembolization (TACE) in the treatment of intermediate-stage HCC patients, as shown by a comparative retrospective assessment that reported a longer time to progression, but not of overall survival, and a more favorable safety profile for radioembolization. In addition, this treatment has reported a higher percentage of tumor shrinkage, if compared to TACE, for pre-transplant downsizing and it represents a promising therapeutic option in patients with large extent of disease and insufficient residual liver volume who are not immediately eligible for surgery. Radioembolization might also be a suitable companion to sorafenib in advanced HCC or it can be used as a potential alternative to this treatment in patients who are not responding or do not tolerate sorafenib.

Safety and tolerability of zonisamide in paediatric patients with epilepsy.

BACKGROUND: Zonisamide has recently been approved in Europe for the adjunctive treatment of partial seizures (with or without secondary generalisation) in adolescents and children aged ≥6 years. AIM: To further assess the safety of adjunctive zonisamide in paediatric epilepsy patients. METHODS: A pooled analysis of data from 17 studies (including four randomised, double-blind trials) was conducted. The safety population comprised patients aged ≤16 years receiving at least one dose of study drug. Assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs and electrocardiography. RESULTS: The analysis included 398 patients treated with zonisamide (<12 years, n = 191; 12-16 years, n = 207). All but seven patients received zonisamide as adjunctive therapy. Mean duration of exposure was 318.7 days (mean dose, 253.1 mg/day). Most TEAEs were of mild or moderate intensity. The most frequently reported treatment-related TEAEs were decreased appetite (15.6%), somnolence (12.1%), fatigue (9.3%), dizziness (6.0%), decreased weight (5.8%), irritability (5.8%) and headache (5.3%). Incidence of serious zonisamide-related TEAEs was low (3.5% overall). TEAEs most commonly leading to discontinuation were lethargy (1.0%) and fatigue (1.0%). TEAEs of decreased weight and decreased appetite occurred in 28 (7.0%) and 78 (19.6%) patients, respectively. Twenty-eight patients had decreased bicarbonate levels, but there were no reports of respiratory alkalosis or metabolic acidosis. No changes in vital signs of clinical concern were observed and there were no reports of clinically significant electrocardiogram abnormalities with zonisamide treatment. CONCLUSION: Zonisamide demonstrated an acceptable safety profile when used as adjunctive treatment in paediatric patients.

Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy: results of a phase III, randomized, double-blind study.

OBJECTIVE: To investigate the long-term safety and maintenance of efficacy of monotherapy with once-daily zonisamide versus twice-daily controlled-release carbamazepine for partial seizures in adults with newly diagnosed epilepsy. METHODS: Long-term, double-blind, extension study, conducted in patients completing a phase III noninferiority trial comparing zonisamide and carbamazepine monotherapy. Patients continued their randomized treatment, with dosing adjusted according to tolerability/response (zonisamide 200-500 mg/day; carbamazepine 400-1,200 mg/day). Safety assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory parameters. Efficacy assessments included retention rate and the proportion of patients remaining seizure free for ≥24 months. RESULTS: Overall, 120 (87.6%) of 137 patients randomized to zonisamide and 134 (84.8%) of 158 patients randomized to carbamazepine completed the study. More than three-fourths of patients were exposed to >24 months of treatment. For zonisamide versus carbamazepine, incidences were similar for TEAEs (52.6% vs. 46.2%), serious treatment-related TEAEs (0.7% vs. 1.9%), and TEAEs leading to withdrawal (1.5% vs. 0.6%). The incidence of treatment-related TEAEs was 26.3% for zonisamide compared with 19.6% for carbamazepine, and the most frequently reported treatment-related TEAEs were decreased weight (5.1% vs. 0%), decreased appetite (3.6% vs. 0%), memory impairment (2.9% vs. 3.2%), and decreased hemoglobin level (1.5% vs. 3.2%). Most TEAEs were of mild or moderate intensity. There were no reports of Stevens-Johnson syndrome or toxic epidermal necrolysis in either group. Zonisamide was associated with small-to-moderate decreases in bicarbonate levels from baseline (mean -3.4 mm). There were no reports of metabolic acidosis. Retention rates were generally similar between treatment groups at all time points throughout the extension study. The proportion of patients remaining seizure free for ≥ 24 months was also similar for zonisamide (32.3%) and carbamazepine (35.2%). SIGNIFICANCE: Once-daily zonisamide monotherapy demonstrated favorable long-term safety and maintenance of efficacy in treating partial seizures in adults with newly diagnosed epilepsy. No new or unexpected safety findings emerged.

Adjunctive zonisamide therapy in the long-term treatment of children with partial epilepsy: results of an open-label extension study of a phase III, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To investigate the safety/tolerability and efficacy of long-term adjunctive zonisamide and its impact on growth and development in children (6-18 years) with partial epilepsy. METHODS: Open-label extension of a phase III, placebo-controlled trial. Started with double-blind transition period (2-11 weeks), during which patients on zonisamide continued at the same dose and those on placebo switched to zonisamide 1 mg/kg/day, up-titrated to 8 mg/kg/day (maximum 500 mg/day). During the subsequent open-label period (45-57 weeks), zonisamide dosing could be adjusted according to tolerability/response. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, and vital signs. Efficacy assessments included responder rate (primary assessment) and seizure freedom rate during the open-label period. Growth and development assessments comprised Tanner stages, hand x-rays, Child Behavior Checklist (CBCL 6/18), School Performance questionnaire, Physician and Parent/Guardian Global Impression of Change, and Controlled Oral Word Association Test (COWAT). RESULTS: One hundred forty-four children entered the study; 99 (68.8%) of 144 children completed it, and 108 (75.0%) of 144 received zonisamide for ≥1 year. TEAEs occurred in 39 (27.1%) of 144 patients. There were low incidences of serious TEAEs (2.1%) and TEAEs leading to discontinuation (2.8%). Bicarbonate level decreases >3.5 mm occurred in 64 patients (44.4%), and 24 patients (16.7%) had a weight decrease of ≥10% from baseline. During the open-label period, 81 (56.3%) of 144 patients were responders and 16 (11.1%) of 144 achieved seizure freedom. Tanner staging and skeletal development were as expected for the study population. Changes were minimal for CBCL 6/18 and School Performance scores. Most patients were "much improved"/"very much improved" on Physician (73.8%) and Parent/Guardian (75.4%) Global Impressions of Change. Median changes in COWAT Category and Letter Fluency scores were 2.0 and 0.5, respectively. SIGNIFICANCE: Adjunctive zonisamide was well tolerated and efficacious over a period of at least 1 year in children with partial epilepsy, with no unexpected safety concerns and no consistent detrimental effects on growth and development. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Ropinirole in patients with restless legs syndrome and baseline IRLS total scores ≥ 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension.

BACKGROUND: As with studies of other dopamine agonists, previously reported studies of ropinirole in restless legs syndrome (RLS) recruited patients with baseline International Restless Legs Scale (IRLS) total scores ≥ 15. The reported pooled analyses of clinical trials data suggest benefits of ropinirole in patients with IRLS total scores ≥ 24, but the effects of ropinirole have not been prospectively evaluated in this patient population. OBJECTIVE: The goal of this study was to evaluate the efficacy and tolerability of ropinirole in patients with RLS and baseline IRLS total scores ≥ 24. This study was conducted in part to fulfill a postlicensing commitment between the maker of ropinirole and the European Union's Committee for Medicinal Products for Human Use. METHODS: The protocol for this study comprised a randomized, double-blind, placebo-controlled, parallel-group, 26-week phase during which adults with baseline IRLS total scores ≥ 24 received a ropinirole dose from 0.25 to 4 mg (n = 197) or placebo (n = 207) followed by a 40-week, open-label phase during which all patients (n = 269) received ropinirole. The primary efficacy end point was the change from baseline in the IRLS total score at week 12. Tolerability measures included the incidence of adverse events, augmentation, and early morning rebound. Due to the possibility of a treatment-by-center group interaction (P = 0.04) in the IRLS analysis, further efficacy exploratory analyses were performed to assess the impact of the interaction on the overall assessment of efficacy. RESULTS: Demographic characteristics were comparable between groups (mean [SD] age: placebo, 56.1 [11.38] years; ropinirole, 56.5 [11.92] years; 63% female in both groups). All of the patients in the ropinirole group were white; 99% of the placebo group was white. Ropinirole was significantly better than placebo for change from baseline in the IRLS total score during both short- and long-term treatment, with mean treatment differences of -2.1 (P = 0.039) and -2.5 (P = 0.023) for weeks 12 and 26, respectively. A statistically significant treatment by center group interaction was observed (P = 0.040) for the change from baseline in IRLS total score, indicating variation of treatment effects among center groups; however, all center groups showed an improvement from baseline at both week 12 and week 26 for the ropinirole immediate-release group and the placebo group. The incidences of augmentation and early morning rebound were ≤ 4% for ropinirole. The adverse event profile of ropinirole was consistent with that reported in previous clinical trials. CONCLUSIONS: In this subset of patients with RLS and a baseline IRLS total score ≥ 24, ropinirole was effective and well tolerated compared with placebo. The incidence of augmentation and early morning rebound in this study was low.

A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy.

PURPOSE: To assess the efficacy and safety/tolerability of adjunctive zonisamide treatment in pediatric patients with partial epilepsy. METHODS: In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6-17 years) with partial epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥ 50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs). KEY FINDINGS: In total, 93 (86.9%) of 107 patients randomized to zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). SIGNIFICANCE: Adjunctive zonisamide treatment was shown to be effective and well tolerated in pediatric patients with partial epilepsy. No new or unexpected safety findings emerged.

Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.

BACKGROUND: Additional options are needed for monotherapy treatment of adults newly diagnosed with partial epilepsy. This trial compares the efficacy and tolerability of once-daily zonisamide with twice-daily controlled-release carbamazepine monotherapy for such patients. METHODS: In this phase 3, randomised, double-blind, parallel-group, non-inferiority trial, adults from 120 centres in Asia, Australia, and Europe, aged 18-75 years and newly diagnosed with partial epilepsy, were randomly assigned (in a 1:1 ratio, done with a computer-generated pseudorandom code) to receive zonisamide or carbamazepine. Patients, investigators, and sponsor personnel giving drugs, analysing outcomes, and interpreting data were masked to treatment allocation. After treatment initiation (zonisamide 100 mg/day vs carbamazepine 200 mg/day [given in two doses]) and up-titration (to 300 mg/day vs 600 mg/day), patients entered a 26-78 weeks flexible-dosing period (200-500 mg/day vs 400-1200 mg/day, according to response and tolerance). Once patients were seizure-free for 26 weeks they entered a 26-week maintenance phase. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00477295. FINDINGS: 583 patients were randomly assigned to treatment groups (282 zonisamide, 301 carbamazepine), of whom 456 were analysed for the primary endpoint (per-protocol population: 223 zonisamide, 233 carbamazepine). 177 of 223 (79·4%) patients in the zonisamide group and 195 of 233 (83·7%) patients in the carbamazepine group were seizure-free for 26 weeks or more (adjusted absolute treatment difference -4·5%, 95% CI -12·2 to 3·1). The incidence of treatment-emergent adverse events was 170 (60%) in the zonisamide group versus 185 (62%) in the carbamazepine group, of which 15 (5%) versus 17 (6%) were serious and 31 (11%) versus 35 (12%) led to withdrawal. INTERPRETATION: Zonisamide was non-inferior to controlled-release carbamazepine--according to International League Against Epilepsy guidelines--and could be useful as an initial monotherapy for patients newly diagnosed with partial epilepsy. FUNDING: Eisai Ltd.

PREPARED: Comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease.

BACKGROUND: PREPARED was a randomized, parallel-group, double-blind, multicenter study to evaluate the efficacy of adjunctive ropinirole prolonged release (PR) versus immediate release (IR) in patients with advanced Parkinson's disease (PD). METHODS: Patients received once-daily PR (2-24 mg/d; n = 177) or three-times-daily IR (0.75-24 mg/d; n = 173) for 24 weeks. The primary endpoint was the proportion of patients maintaining ≥ 20% reduction from baseline in "off" time over two consecutive visits at Week 24 last observation carried forward (LOCF). RESULTS: At Week 24 LOCF, PR significantly increased the proportion of patients maintaining ≥ 20% reduction in "off" time versus IR (adjusted odds ratio: 1.82; 95% CI: 1.16, 2.86; P = 0.009). Mean (SD) doses at Week 24 LOCF were: PR, 18.6 (6.5) mg/d; IR, 10.4 (6.4) mg/d; mean (SD) reductions from baseline in levodopa (L-dopa) dose were -162 (226) mg and -113 (138) mg, respectively. Adverse events (AEs) were reported by 72% of patients in the PR group and 61% in the IR group; 12% and 9% of patients, respectively, withdrew from the study due to an AE, and 6% and 5%, respectively, reported serious AEs. CONCLUSIONS: Adjunctive PR provided a significantly greater improvement in symptom control in terms of the odds of achieving ≥ 20% maintained reduction in time spent "off" compared with IR. Interpretation may be confounded by the higher doses of PR versus IR that were achieved, in combination with lower doses of L-dopa by the study end. Despite dosing differences, the PR titration regimen was generally well tolerated, with an AE profile similar to that of IR.

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

OBJECTIVE: 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.

Efficacy and tolerability of ropinirole in patients with restless legs syndrome and a baseline IRLS total score > or = 24 points--data from the ropinirole clinical trial programme.

OBJECTIVE: Results from one of the largest clinical trial programmes to date of a dopamine agonist in patients with primary restless legs syndrome (RLS) have demonstrated that ropinirole, 0.25-4.0 mg once daily 1-3 hours before bedtime, is associated with significant improvements in RLS symptoms, sleep parameters and quality-of-life measures, compared with placebo. Analyses were conducted in a subpopulation of patients with a baseline score on the International Restless Legs Scale (IRLS) of at least 24 points. RESEARCH DESIGN AND METHODS: Data was pooled from four, 12-week, pivotal studies: RESET PLM and TREAT RLS 1, 2 and US. MAIN OUTCOME MEASURES: Covariate analysis demonstrated that the magnitude of treatment difference between ropinirole and placebo for change in IRLS total score (a measure of RLS symptom severity) increased with increasing baseline IRLS total score. Mean treatment difference was > 3 points in patients with a baseline total score > or = 24. Among this population, ropinirole treatment was associated with significant reduction in RLS symptom severity compared with placebo, along with significant improvements in global symptoms and sleep measures. A treatment benefit was also observed for measures of quality of life. Ropinirole is well tolerated in this patient population. CONCLUSIONS: Patients with primary RLS and baseline IRLS total score > or = 24 gain clinically meaningful benefits from ropinirole treatment. As with the overall population in the ropinirole clinical trial programme, ropinirole was associated with improvements in RLS symptoms, global symptoms, sleep and quality of life and was well tolerated in patients with a baseline IRLS total score > or = 24.