Mahnaz Asgharnejad

A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents.

Objective. To compare the efficacy and tolerability of sumatriptan nasal spray (NS; 5 mg, 10 mg, and 20 mg) with placebo for the treatment of acute migraine in adolescents. Methods. A randomized, double-blind, placebo-controlled, single-attack study was conducted in 653 US adolescents (12–17 years of age). Patients with at least a 6-month history of migraine, who met International Headache Society criteria for migraine (with or without aura) were eligible for participation. Headache relief 2 hours postdose, complete relief, presence or absence of associated symptoms, headache recurrence, and use of rescue medications were recorded. The primary efficacy endpoint was headache relief 2 hours postdose sumatriptan NS (20 mg) versus placebo. Safety and tolerability were assessed by examining adverse events, changes in electrocardiograms, vital signs, physical examinations, and clinical laboratory tests. Results. Headache relief 1 hour postdose was significantly greater for patients using 10 mg (56%) and 20 mg (56%) of sumatriptan NS compared with placebo (41%). Headache relief 2 hours postdose was significantly greater for patients using 5 mg of sumatriptan NS (66%) compared with placebo (53%), and approached statistical significance for 20 mg (63%) compared with placebo (53%). Complete relief 2 hours postdose was significantly greater for patients using 20 mg of sumatriptan NS compared with placebo (36% vs 25%, respectively). Each dose of sumatriptan (5 mg, 10 mg, and 20 mg) was superior to placebo with respect to the cumulative percentages of patients first reporting headache relief within 2 hours of dosing (Kaplan-Meier). The sumatriptan 20-mg dose was superior to placebo with respect to the cumulative percentages of patients first reporting complete relief within 2 hours of dosing (Kaplan-Meier). Photophobia and phonophobia were significantly reduced 2 hours postdose for sumatriptan NS (20 mg), compared with placebo (36% vs 48% and 25% vs 44%, respectively). Taste disturbance was the most commonly reported adverse event (2%, 19%, 30%, and 26% for placebo, 5 mg, 10 mg, and 20 mg, respectively). No drug-related serious adverse events or clinically relevant changes in laboratory parameters, electrocardiograms, or vital signs were reported. Conclusions. Sumatriptan NS is effective and well-tolerated for the treatment of acute migraine in adolescents, with the 20-mg dose providing the best overall efficacy and tolerability profiles.

Naratriptan is effective and well tolerated in the acute treatment of migraine Results of a double-blind, placebo-controlled, crossover study

The efficacy and tolerability of naratriptan tablets (2.5 mg, 1 mg, and 0.25 mg) compared with placebo in the acute treatment of migraine were evaluated in a randomized, double-blind, four-period crossover study. Five hundred eighty-six assessable patients received naratriptan 2.5 mg, 595 received 1 mg, 591 received 0.25 mg, 602 received placebo. Headache relief(moderate or severe pain reduced to mild or none) 4 hours postdose was reported in 68% of patients after treatment with naratriptan 2.5 mg compared with 57% after 1 mg, 39% after 0.25 mg, and 33% after placebo (p< 0.001 naratriptan 2.5 mg and 1 mg versus placebo and 1 mg and 2.5 mg versus 0.25 mg). Headache relief was maintained 8, 12, and 24 hours postdose with no use of rescue medication or a second dose of study medication by significantly (p < 0.001) greater percentages of patients after treatment with naratriptan 2.5 mg or 1 mg compared with naratriptan 0.25 mg or placebo. Naratriptan was also more effective than placebo in reducing clinical disability and the incidences of nausea, photophobia, and phonophobia. The overall incidence of adverse events and the incidences of specific adverse events did not differ in the naratriptan groups compared with placebo. No clinically relevant changes in ECG, blood pressure, or laboratory findings were reported. These data demonstrate that naratriptan is effective and well tolerated for the acute treatment of migraine. The 2.5-mg dose was associated with superior efficacy, whereas its adverse event profile was similar to that of placebo.

A Randomized Controlled Exploratory Pilot Study to Evaluate the Effect of Rotigotine Transdermal Patch on Parkinson's Disease-Associated Chronic Pain

Pain is a troublesome nonmotor symptom of Parkinsons disease (PD). This double‐blind exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a dopamine agonist on PD‐associated pain as primary outcome. Patients with advanced PD (ie, receiving levodopa) and at least moderate PD‐associated chronic pain (≥3 months, ≥4 points on 11‐point Likert pain scale) were randomized to rotigotine (optimal/maximum dose ≤16 mg/24h) or placebo and maintained for 12 weeks. Primary efficacy variable was change in pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables included percentage of responders (≥2‐point Likert pain scale reduction), Kings PD Pain Scale (KPPS) domains, and PD Questionnaire (PDQ‐8). Statistical analyses were exploratory. Of 68 randomized patients, 60 (rotigotine, 30; placebo, 30) were evaluable for efficacy. A numerical improvement in pain was observed in favor of rotigotine (Likert pain scale: least‐squares mean [95%CI] treatment difference, −0.76 [−1.87 to 0.34]; P = .172), and proportion of responders was 18/30 (60%) rotigotine vs 14/30 (47%) placebo. An ∼2‐fold numerical improvement in KPPS domain “fluctuation‐related pain” was observed with rotigotine vs placebo. Rotigotine improved PDQ‐8 vs placebo (−8.01 [−15.56 to −0.46]; P = .038). These results suggest rotigotine may improve PD‐associated pain; a large‐scale confirmatory study is needed.

ICARUS study: Prevalence and clinical features of impulse control disorders in Parkinson's disease

Background Impulse control disorders/other compulsive behaviours (‘ICD behaviours’) occur in Parkinson’s disease (PD), but prospective studies are scarce, and prevalence and clinical characteristics of patients are insufficiently defined. Objectives To assess the presence of ICD behaviours over a 2-year period, and evaluate patients’ clinical characteristics. Methods A prospective, non-interventional, multicentre study (ICARUS (Impulse Control disorders And the association of neuRopsychiatric symptoms, cognition and qUality of life in ParkinSon disease); SP0990) in treated Italian PD outpatients. Study visits: baseline, year 1, year 2. Surrogate primary variable: presence of ICD behaviours and five ICD subtypes assessed by modified Minnesota Impulsive Disorder Interview (mMIDI). Results 1069/1095 (97.6%) patients comprised the Full Analysis Set. Point prevalence of ICD behaviours (mMIDI; primary analysis) was stable across visits: 28.6% (306/1069) at baseline, 29.3% (292/995) at year 1, 26.5% (245/925) at year 2. The most prevalent subtype was compulsive eating, followed by punding, compulsive sexual behaviour, gambling and buying disorder. Patients who were ICD positive at baseline were more likely to be male, younger, younger at PD onset, have longer disease duration, more severe non-motor symptoms (including mood and sexual function), depressive symptoms, sleep impairment and poorer PD-related quality of life. However, they did not differ from the ICD-negative patients in their severity of PD functional disability, motor performance and cognitive function. Conclusions Prevalence of ICD behaviours was relatively stable across the 2-year observational period. ICD-positive patients had more severe depression, poorer sleep quality and reduced quality of life.

Impulse control disorder related behaviours during long-term rotigotine treatment: a post hoc analysis

Dopamine agonists in Parkinsons disease (PD) are associated with impulse control disorders (ICDs) and other compulsive behaviours (together called ICD behaviours). The frequency of ICD behaviours reported as adverse events (AEs) in long‐term studies of rotigotine transdermal patch in PD was evaluated.

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome

Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinsons disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotines high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist–receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotines efficacy, safety, and tolerability in patients with early‐ and advanced‐stage PD, including improvements in motor symptoms and off‐time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate‐to‐severe primary RLS. This review examines rotigotines developmental history for transdermal administration leading to its approval for the treatment of early‐ and advanced‐stage PD and moderate‐to‐severe primary RLS.

Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease

ABSTRACT Objective: To evaluate the dopamine receptor agonist, rotigotine, for improving depressive symptoms in patients with Parkinson’s disease (PD). Methods: Patients were randomized 1:1 to rotigotine or placebo, titrated for ≤7 weeks, and maintained at optimal/maximum dose for 8-weeks. Primary efficacy variable: 17- item Hamilton Depression Rating Scale (HAM-D 17) total score change from baseline to end-of-maintenance. Secondary variables: changes in Beck Depression Inventory-II, Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living [ADL]) and III (motor) subscores, UPDRS II+III total, patient-rated Apathy Scale (AS), and Snaith-Hamilton Pleasure Scale. Results: Of 380 patients randomized, 149/184 (81.0%) rotigotine-treated and 164/196 (83.7%) placebo-treated patients completed the study. Patients: mean (±SD) age 65.2 (±8.5) years; time since PD-diagnosis 2.74 (±3.08) years; 42.6% male. The treatment difference (LS mean [95% CI]) in change from baseline HAM-D 17 was −1.12 (−2.56, 0.33; p = 0.1286). UPDRS II, III, II+III and AS scores improved numerically with rotigotine versus placebo. Common adverse events with higher incidence with rotigotine: nausea, application/instillation site reactions, vomiting, and pruritus. Forty-one (10.8%) patients discontinued owing to adverse events (25 rotigotine/16 placebo). Conclusions: No statistically significant improvement in depressive symptoms were observed with rotigotine versus placebo. ADL, motor function, and patient-rated apathy improved numerically. ClinicalTrials.gov: NCT01523301

Comparing the incidence of falls/fractures in Parkinson's disease patients in the US population

Patients with Parkinson’s disease (PD) may experience falls and/or fractures as a result of disease symptoms. There are limited data available from long-term studies estimating the incidence of falls/fractures in patients with PD. The objective was to compare the incidence rate of falls/fractures in PD patients with non-PD patients in a US population. This was a retrospective study using a US-based claims database (Truven Health MarketScan®) that compared the incidence rate of falls/fractures in PD subjects with non-PD subjects. The study period included the 12 months prior to index date (defined as earliest PD diagnosis [International Classification of Diseases, Ninth Revision, Clinical Modification code 332.0]) and a postindex period to the end of data availability. Fractures were defined by inpatient/outpatient claims as a principal or secondary diagnosis and accompanying procedure codes during the postindex period. Incidence rates and 95% CIs for falls/fractures were calculated as the number of events per 10,000 person-years of follow-up using negative binomial or Poisson regression models. Twenty-eight thousand two hundred and eighty PD subjects were matched to non-PD subjects for the analysis (mean [SD] age, 71.4 [11.8] years; 53% male). A higher incidence rate (adjusted for comorbidities and medications) of all fall/fracture cases and by fall and fracture types was observed for PD subjects versus non-PD subjects; the overall adjusted incidence rate ratio comparing PD to non-PD subjects was 2.05; 95% CI, 1.88–2.24. The incidence rate of falls/fractures was significantly higher in subjects with PD compared with non-PD subjects in a US population.

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome: post hoc analysis of patients with early Parkinson’s disease with mild symptom severity

Objective: Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson’s disease (PD) with mild symptom severity. Background: Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson’s Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716). Methods: Post hoc analysis of patients at Hoehn and Yahr 1–2; groups defined by treatment received in 6-month double-blind studies: ‘Rotigotine–Rotigotine’ received rotigotine (n = 221), ‘Placebo–Rotigotine’ received placebo (n = 125). Results: At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: −8.5 ± 10.6 ‘Rotigotine–Rotigotine’, −7.7 ± 9.0 ‘Placebo–Rotigotine.’ After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in ‘Rotigotine–Rotigotine’, and ∼ 21 months in ‘Placebo–Rotigotine.’ At the time mean UPDRS II + III had crossed baseline in ‘Placebo–Rotigotine’ (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to ‘Rotigotine–Rotigotine’ change from baseline was −3.89 (95% CI −6.94, −0.84); p = 0.013. Conclusions: In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.

Efficacy of Rotigotine at Different Stages of Parkinson’s Disease Symptom Severity and Disability: A Post Hoc Analysis According to Baseline Hoehn and Yahr Stage

Background: The efficacy of rotigotine has been demonstrated in studies of patients with early (i.e. not receiving levodopa) and advanced (i.e. not adequately controlled on levodopa; average 2.5 h/day in ‘off’ state) Parkinson’s disease (PD). Objective: To further investigate the efficacy of rotigotine transdermal patch across different stages of PD symptom severity and functional disability, according to baseline Hoehn and Yahr (HY) staging. Methods: Post hoc analysis of six placebo-controlled studies of rotigotine in patients with early PD (SP506, SP512, SP513; rotigotine ≤8 mg/24 h) or advanced-PD (CLEOPATRA-PD, PREFER, SP921; rotigotine ≤16 mg/24 h). Data were pooled and analyzed according to baseline HY stage (1, 2, 3 or 4) for change from baseline to end of maintenance in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), UPDRS III (motor) and UPDRS II+III; statistical tests are exploratory. Results: Data were available for 2057 patients (HY 1 : 262; HY 2 : 1230; HY 3 : 524; HY 4 : 41). Patients at higher HY stages were older, had a longer time since PD diagnosis and higher baseline UPDRS II+III scores vs patients at lower HY stages. Rotigotine improved UPDRS II+III versus placebo for each individual HY stage (p < 0.05 for each HY stage), with treatment differences increasing with increasing HY stages. Similar results were observed for UPDRS II and UPDRS III. Conclusions: This post hoc analysis suggests that rotigotine may be efficacious across a broad range of progressive stages of PD symptom severity and functional disability (HY stages 1–4).