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Neupro

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Neupro

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CLINICAL PHARMACOLOGY

Mechanism of Action

Rotigotine is a non-ergoline dopamine agonist. The precise mechanism of action of rotigotine as a treatment for Parkinson's disease is unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudateputamen in the brain. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine receptors.

Pharmacodynamics

Cardiac Electrophysiology

There is no indication of a QT/QTc prolonging effect of Neupro in doses up to 24 mg/24 hours. The effects of Neupro at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose) parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.

Pharmacokinetics

On average, approximately 45% of the rotigotine from the patch is released within 24 hours (0.2 mg/cm²). Rotigotine is primarily eliminated in the urine as inactive conjugates. After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.

Absorption and Bioavailability

When single doses of 8 mg/24 hours are applied to the trunk, there is an average lag time of approximately 3 hours until drug is detected in plasma (range 1 to 8 hours). Tmax typically occurs between 15 to 18 hours post dose but can occur from 4 to 27 hours post dose. However, there is no characteristic peak concentration observed. Rotigotine displays dose-proportionality over a daily dose range of 1 mg/24 hours to 24 mg/24 hours. In the clinical studies of rotigotine effectiveness, the transdermal system application site was rotated from day to day (abdomen, thigh, hip, flank, shoulder, or upper arm) and the mean measured plasma concentrations of rotigotine were stable over the six months of maintenance treatment. Relative bioavailability for the different application sites at steady-state was evaluated in subjects with Parkinson's disease. In a single trial conducted in patients with early-stage Parkinson's disease differences in bioavailability ranged from less than 1% (abdomen vs hip) to 46% (shoulder vs thigh) with shoulder application showing higher bioavailability.

Because rotigotine is administered transdermally, food should not affect absorption, and the product may be administered without regard to the timing of meals.

In a 14-day clinical study with rotigotine administered to healthy subjects, steady-state plasma concentrations were achieved within 2 to 3 days of daily dosing.

Figure 2 : Average (±95% CI) Neupro Plasma Concentrations in Patients with Early-stage Parkinson's Disease After Application of 8 mg/24 hours to 1 of 6 Application Sites (shoulder, upper arm, flank, hip, abdomen, or thigh) on 2 Different Days During the Maintenance Phase

Average (±95% CI) Neupro Plasma Concentrations - Illustration

Distribution

The weight normalized apparent volume of distribution, (Vd/F), in humans is approximately 84 L/kg after repeated dose administration.

The binding of rotigotine to human plasma proteins is approximately 92% in vitro and 89.5% in vivo.

Metabolism and Elimination

Rotigotine is extensively metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl -rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine.

After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.

Rotigotine is primarily excreted in urine (~71%) as inactive conjugates of the parent compound and N-desalkyl metabolites. A smaller proportion is excreted in feces (~23%). The major metabolites found in urine were rotigotine sulfate (16% to 22%of the absorbed dose), rotigotine glucuronide (11% to15%), and N-despropyl-rotigotine sulfate metabolite (14% to 20%) and N-desthienylethyl-rotigotine sulfate metabolite (10% to 21%). Approximately 11% is renally eliminated as other metabolites. A small amount of unconjugated rotigotine is renally eliminated ( <1% of the absorbed dose).

Drug Interaction Studies

CYP Interactions

In vitro studies indicate that multiple CYP-isoforms are capable of catalyzing the metabolism of rotigotine. In human liver microsomes, no extensive inhibition of the metabolism of rotigotine was observed when co-incubated with CYP isoform specific inhibitors. If an individual CYP isoform is inhibited, other isoforms can catalyze rotigotine metabolism.

Rotigotine, the 5-O-glucuronide and its desalkyl and monohydroxy metabolites were analyzed for interactions with the human CYP isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 in vitro. Based on these results, no risk for inhibition of CYP1A2, CYP2C9 and CYP3A4 catalyzed metabolism of other drugs is predicted at therapeutic rotigotine concentrations. There is a low risk of inhibition of CYP2C19 and CYP2D6 catalyzed metabolism of other drugs at therapeutic concentrations.

In human hepatocytes in vitro, there was no indication for induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4.

Rotigotine is metabolized by multiple sulfotransferases and two UDP-glucuronosyltransferases (UGT1A9 and UGT2B15). These multiple pathways make it unlikely that inhibition of any one pathway would alter rotigotine concentrations significantly.

Protein Displacement, Warfarin

In vitro, no potential for displacement of warfarin by rotigotine (and vice versa) from their respective human serum albumin binding sites was detected.

Digoxin

The effect of rotigotine on the pharmacokinetics of digoxin has been investigated in vitro in Caco-2 cells. Rotigotine did not influence the P-glycoprotein-mediated transport of digoxin. Therefore, rotigotine would not be expected to affect the pharmacokinetics of digoxin.

Cimetidine

Co-administration of rotigotine (up to 4 mg/24 hours) with cimetidine (400 mg b.i.d.), an inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4, did not alter the steady-state pharmacokinetics of rotigotine in healthy subjects.

Levodopa/Carbidopa

Co-administration of levodopa/carbidopa (100/25 mg b.i.d.) with rotigotine (4 mg/24 hours) had no effect on the steady-state pharmacokinetics of rotigotine; rotigotine had no effect on the pharmacokinetics of L-levodopa/carbidopa.

Oral Contraception

Co-administration of rotigotine (3 mg/24 hours) did not affect the pharmacodynamics and pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel).

Omeprazole

Co-administration of the CYP2C19 selective inhibitor omeprazole (40 mg/day) had no effect on the steady-state pharmacokinetics of rotigotine (4 mg/24 hours).

Pharmacokinetics in Special Populations

Hepatic Insufficiency

There were no relevant changes in rotigotine plasma concentrations in subjects with moderate hepatic impairment (Child Pugh classification – Grade B). No information is available on subjects with severe impairment of hepatic function.

Renal Insufficiency

There were no relevant changes in rotigotine plasma concentrations (up to end stage renal disease requiring hemodialysis). In subjects with severe renal impairment not on dialysis, (i.e., creatinine clearance 15 to <30 ml/min), exposure to conjugated rotigotine metabolites was doubled .

Gender

Female and male subjects and patients had similar plasma concentrations (body weight normalized).

Geriatric Patients

Plasma concentrations of rotigotine in patients 65 to 80 years of age were similar to those in younger patients, approximately 40 to 64 years of age. Although not studied, exposures in older subjects (>80 years) may be higher due to skin changes with aging.

Pediatric Patients

The pharmacokinetics of rotigotine in subjects below the age of 18 years has not been established.

Race

The pharmacokinetic profile was similar in Caucasians, Blacks, and Japanese. No dose adjustment is necessary based on ethnicity.

Adhesion

Adhesion was examined in subjects with Parkinson's disease when patches were applied to rotating sites. Similar results were observed for the 4 mg/24 hours (20 cm²), 6 mg/24 hours (30 cm²), and 8 mg/24 hours (40 cm²) patches. An adherence of ≥90% of the patch surface was observed in 71% to 82% of cases. A partial detachment of >10% was observed in 15% to 24% of cases. A complete detachment of the patch was observed in 3% to 5% of cases.

Animal Toxicology and/or Pharmacology

Retinal Pathology: Albino rats: Retinal degeneration was observed in albino rats in a 6-month toxicity study at the highest dose of rotigotine (plasma exposure [AUC] at least 15 times that in humans at the MRHD. Retinal degeneration was not observed in the 2-year carcinogenicity studies in albino rat (plasma AUCs up to 4-6 times that in humans at the MRHD) or albino mouse, or in monkeys treated for 1 year. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.

Clinical Studies

Parkinson's Disease

The effectiveness of Neupro in the treatment of the signs and symptoms of idiopathic Parkinson's disease was established in five parallel group, randomized, double-blind placebo-controlled trials conducted in the U.S. and abroad. Three of these five trials enrolled patients with early-stage Parkinson's disease (not receiving levodopa), and two enrolled patients with advanced-stage Parkinson's disease who were receiving levodopa. Depending on trial design, patients underwent a weekly titration of Neupro in 2 mg/24 hours increments to either the randomized dose or optimal dose. Back titrations by 2 mg/24 hours decrement of Neupro were permitted for intolerable adverse events. Patch application sites were changed on a daily basis.

Change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS), parts II + III, served as the primary outcome assessment measure in the early-stage studies. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV). Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. Part III is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.

Change from baseline in time spent “off” (hours) based on daily diaries was the primary outcome assessment in the two trials of advanced-stage Parkinson's disease (with levodopa).

Studies in Patients with Early-Stage Parkinson's Disease

Patients (N=649) in the three trials of early-stage Parkinson's disease had limited or no prior exposure to levodopa (off levodopa for at least 28 days prior to baseline or levodopa use for no more than 6 months). Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study.

PD-1

This trial was a multicenter, multinational dose-response study in which 316 early-stage Parkinson's disease patients were titrated over 4 weeks to their randomized treatment with either placebo or one of four fixed doses of Neupro (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours). The patches were applied to the upper abdomen and the sites of application were rotated on a daily basis.

Patients underwent a weekly titration (increasing the number of 2 mg/24 hours patches or placebo patches at weekly intervals) over 4 weeks such that the target doses of Neupro were achieved for all groups by the end of 3 weeks and were administered over the fourth week of the titration phase. Patients then continued on treatment for a 7 week maintenance phase followed by a down titration during the last week. Two back titrations by a single patch (i.e. 2 mg/24 hours decrement of Neupro or placebo) at a time were permitted for intolerable adverse events. The mean age of patients was approximately 60 years (range 33 to 83 years; approximately 36% were ≥ 65 years) and the study enrolled more men (62%) than women (39%). Most patients (85%) were Caucasian and most randomized patients ( ≥ 88%) completed the full treatment period.

Mean baseline combined UPDRS (Parts II + III) scores were similar among all treatment groups, between 27.1 and 28.5 for all groups. The mean change from baseline and difference from placebo for each treatment group is shown in Table 5. Statistically significant mean changes reflecting dose-related improvement were observed at the three highest doses, and the 6 mg/24 hours and 8 mg/24 hours doses had a similar effect.

Table 5 : PD-1: Mean Change in UPDRS (Parts II + III) from Baseline at End of Treatment for Intent-to-Treat Population

Treatment Mean Change from Baseline Difference from placebo
Placebo -1.4 NA
2 mg/24 hours -3.5 -2.1
4 mg/24 hours -4.5 -3.1
6 mg/24 hours -6.3 -4.9
8 mg/24 hours -6.3 -5

PD-2

This trial was a randomized, double-blind, multinational, flexible Neupro dose (2 mg/24 hours, 4 mg/24 hours, or 6 mg/24 hours), parallel group study in which 277 early-stage Parkinson's disease patients were assigned (2: 1 ratio) to treatment with Neupro or placebo for a period up to about 28 weeks. This trial was conducted in 47 sites in North America (U.S. and Canada). Patches were applied to different body parts including upper or lower abdomen, thigh, hip, flank, shoulder, and/ or upper arm and patch application sites were to be rotated on a daily basis. Patients underwent a weekly titration (consisting of 2 mg/24 hours increments at weekly intervals) over 3 weeks to a maximal dose of 6 mg/24 hours depending on efficacy and tolerability, and then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 4 days. Back/down titration by a single patch (i.e. 2 mg/24 hours decrement of Neupro or placebo) was permitted during the titration phase for intolerable adverse events but was not permitted during the maintenance phase (i.e., patients with intolerable adverse events had to leave the study). Primary efficacy data were collected after a treatment period of up to approximately 27 weeks.

The mean age of patients was approximately 63 years (range 32 to 86 years; approximately 45% were ≥65 years), approximately two-thirds of all patients were men, and nearly all patients were Caucasian. Approximately 90% of patients randomized to Neupro achieved a maximal daily dose of 6 mg/24 hours; 70% maintained this dose for most (>20 weeks) of the maintenance phase. Most enrolled patients ( ≥81 %) completed the full treatment period.

Mean baseline combined UPDRS (Parts II + III) was similar in both groups (29.9 Neupro group, 30.0 placebo). Neuprotreated patients experienced a mean change in the combined UPDRS (Parts II + III) from baseline to end of treatment (end of treatment week 27 or last visit for patients discontinuing early) of -4.0 (Table 6), and the difference from placebo was statistically significant.

Table 6 PD-2: Mean Change in UPDRS (Parts II + III) from Baseline at End of Treatment for Intent-to-Treat Population

Treatment Mean Change from Baseline Difference from placebo
Placebo +1.3 NA
Neupro up to 6 mg/24 hours -4.0 -5.3

PD-3

This study was a randomized, double-blind multinational, flexible Neupro dose (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours), three-arm, parallel-group study using a double-dummy treatment in which 561 early-stage Parkinson's disease patients were assigned to treatment with either placebo or Neupro or active oral comparator in a ratio of 1: 2: 2 for a period up to about 39 weeks. This study was conducted in up to 81 sites in many countries outside of North America. Patches were applied to different body parts including upper or lower abdomen, thigh, hip, flank, shoulder, and/ or upper arm and patch application sites were to be rotated on a daily basis. Treatment with a patch and placebo was given to all patients in a double-blinded manner such that no one would know the actual treatment (i.e. Neupro, comparator, or placebo).

Patients underwent a weekly dose escalation/titration of patch (consisting of 2 mg/24 hours increments of Neupro or placebo) and a dose escalation of capsules of comparator or placebo over 13 weeks (13 week titration was planned for the comparator treatment) up to a maximal dose of 8 mg/24 hours of Neupro depending on achieving optimal efficacy or intolerability at a lower dose. Patients randomized to Neupro achieved the maximal dose of 8 mg/24 hours after a 4 week titration if maximal efficacy and intolerability had not occurred over a 4 week titration period. Patients then received treatment over a 24 week maintenance phase followed by a de-escalation over a period up to 12 days. A single back titration by a single patch (i.e. 2 mg/24 hours decrement of Neupro or placebo) or capsule was permitted during the titration phase for intolerable adverse events but was not permitted during the maintenance phase (i.e. patients with intolerable adverse events had to discontinue from this study). Primary efficacy data were collected after a treatment period of up to approximately 37 weeks of randomized treatment.

The mean age of patients was approximately 61 years (range 30 -86 years; approximately 41% were ≥65 years), nearly 60% of all patients were men, and nearly all patients were Caucasian. About 73% of patients completed the full treatment period. The mean daily dose of Neupro was just less than 8 mg/24 hours and approximately 90% of patients achieved the maximal daily dose of 8 mg/24 hours.

Mean baseline combined UPDRS (Parts II + III) was similar across all groups (33.2 Neupro, 31.3 placebo, 32.2 comparator). Neupro-treated patients experienced a mean change in the combined UPDRS (Parts II + III) from baseline to end of treatment (end of treatment week 37 or last visit for patients discontinuing early) of -6.8 (Table 11), and the difference from placebo treated patients showed a mean change from baseline of –2.3 (see Table 7), a difference that was statistically significant.

Table 7 PD-3: Mean Change in UPDRS (Parts II + III) from Baseline at End of Treatment for Intent-to-Treat Population

Treatment Mean change from baseline Difference from placebo
Placebo -2.3 NA
Neupro up to 8 mg/24 hours -6.8 -4.5

Advanced-Stage Parkinson's Disease

Patients (N=658) in the three trials of Neupro in advanced-stage Parkinson's disease had to be experiencing “on-off” periods at baseline, despite treatment with optimal doses of levodopa. Patients continued concomitant levodopa during the trial; however, reductions in the dosage of levodopa were allowed if patients experienced adverse events that the investigator considered related to dopaminergic therapy. Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study. In the North American trial, COMT-inhibitors were not permitted.

PD-4 This trial was a multinational, three-arm, parallel group study in which 351 advanced-stage Parkinson's disease patients were titrated over 5 weeks to treatment with either placebo or Neupro (8 mg/24 hours or 12 mg/24 hours) and maintained treatment for 24 weeks followed by a down titration over the last week. This study was conducted in 55 sites in North America (U.S. and Canada).

Mean baseline “off” times were similar among all treatment groups (6.4, 6.8, and 6.3 hours for the placebo, Neupro 8 mg/24 hours and 12 mg/24 hours treatment groups, respectively). Neupro-treated patients experienced a mean change in “off” time from baseline to end of treatment of -2.7 hours for the 8 mg/24 hours treatment arm and -2.1 hours for the 12 mg/24 hours treatment arm (Table 8), and the difference from placebo was statistically significant for both Neupro doses (8 mg/24 hours, 12 mg/24 hours). Onset of treatment benefit began as early as the first week of treatment.

Table 8 PD-4: Mean Change in “off” time (hours) from Baseline at End of Treatment for Intent-to-Treat Population

Treatment Mean Change From Baseline Difference from placebo
Placebo -0.9 NA
8 mg/24 hours -2.7 -1.8
12 mg/24 hours -2.1 -1.2

PD-5

This trial was a multinational, flexible dose, three-arm, parallel-group study using a double-dummy treatment in which 506 advanced-stage Parkinson's disease patients were titrated over 7 weeks to treatment with either Neupro from a minimum dose of 4 mg/24 hours up to an optimal dose not exceeding 16 mg/24 hours, active oral comparator, or placebo and maintained treatment for 16 weeks followed by a down titration over 6 days. This study was conducted in 77 sites in many countries outside of North America.

Mean baseline “off” times were similar among all treatment groups (6.6, 6.2, and 6.0 hours for the placebo, Neupro, and comparator treatment groups, respectively). Neupro-treated patients experienced a mean 2.5 hour decrease change in “off” time from baseline to end of treatment (Table 9), and the difference from placebo was statistically significant. Onset of treatment benefit began as early as the first week of treatment. The optimal Neupro dose was established as 4 mg/24 hours for 2% of patients, 6 mg/24 hours for 6%, 8mg/24 hours for 8%, 10 mg/24 hours for 9%, 12 mg/24 hours for 16%, 14mg/24 hours for 11% and 16mg/24 hours for 44%.

Table 9 PD-5: Mean Change in “off” time (hours) from Baseline at End of Treatment for Intent-to-Treat Population

Treatment Mean Change From Baseline Difference from placebo
Placebo -0.9 NA
Up to 16 mg/24 hours -2.5 -1.6

Restless Legs Syndrome

The clinical program included 1309 patients with moderate to severe RLS. The efficacy of Neupro in the treatment of Restless Legs Syndrome (RLS) was primarily evaluated in 2 fixed-dose, randomized, double-blind, placebo-controlled trials with maintenance periods of 6 months duration. Patients received Neupro doses ranging from 0.5 mg/24 hours to 3 mg/24 hours or placebo once daily. In these 2 trials, the mean duration of RLS was 2.1 to 3.1 years, mean age was approximately 55 years (range of 19 to 78 years), approximately 68 % were women, and 97% were Caucasian. In both trials, patches were applied to different application sites including the abdomen, thigh, hip, flank, shoulder, and/or upper arm and patch application sites were rotated on a daily basis.

The two outcome measures used to assess the effect of treatment as co-primary efficacy endpoints were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7point scale.

RLS-1

This trial was a multicenter, 5-arm, parallel-group, fixed-dose trial of Neupro in subjects with moderate-to-severe RLS. A total of 505 subjects were randomized in this trial, participating at approximately 50 sites in the US. Subjects received placebo or Neupro (0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Subjects began treatment at a daily dosage of 0.5 mg/24 hours Neupro and were titrated over a 4 week period to their assigned daily dose followed by a 6 month maintenance period and 7 day down titration period.

Mean baseline IRLS sum score were similar among all treatment groups (23.5, 23.1, 23.2, 23.3, and 23.6 for the placebo, Neupro 0.5 mg/24 hours, 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 4 Neupro dose groups. The mean changes from baseline and differences from placebo in IRLS sum score and CGI Item 1 are shown for each treatment group in Table 10. The difference between the 2 highest treatment groups (2 mg/24 hours and 3 mg/24 hours) and placebo were statistically significant. Of the Neupro-treated patients, 23% had an IRLS score of 0 compared to 9.1% of placebo patients at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.

Table 10 RLS-1: ANCOVA Results for Co-primary Endpoints: Change from Baseline to End of Maintenance Period for Intent-to-Treat Population

Variable Treatment Mean Change From Baseline Difference from placebo
IRLS sum score Placebo -9 NA
0.5 mg/24 hours -11.1 -2.2
1 mg/24 hours -11.2 -2.3
2 mg/24 hours -13.5 -4.5
3 mg/24 hours -14.2 -5.2
CGI Item 1 Placebo -1.4 NA
0.5 mg/24 hours -1.8 -0.35
1 mg/24 hours -1.7 -0.32
2 mg/24 hours -2.1 -0.65
3 mg/24 hours -2.3 -0.9

RLS-2

This trial was a multicenter, 4-arm, parallel-group trial of Neupro in subjects with moderate-to-severe RLS. A total of 458 subjects were randomized in this trial, participating at approximately 50 sites in 8 European countries. Patients received placebo or Neupro (1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours). Patients began treatment at a daily dosage of 1 mg/24 hours Neupro and were titrated over a 3 week period to their assigned daily dose followed by a 6 month maintenance period and 7 day down-titration period.

Mean baseline IRLS sum score were similar among all treatment groups (28.1, 28.1, 28.2, and 28.0 for the placebo, Neupro 1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 3 Neupro dose groups. The mean changes from baseline and differences from placebo in IRLS sum score and CGI Item 1 are shown for each treatment group in Table 11. The difference between all 3 treatment groups (1 mg/24 hours, 2 mg/24 hours, and 3 mg/24 hours) and placebo were statistically significant. Of the Neupro-treated patients, 24% had an IRLS score of 0 compared to 12% of placebo patients at the end of the maintenance period. Onset of treatment benefit was seen with the 1 mg/24 hours dose.

Table 11 RLS-2: ANCOVA Results for Co-primary Endpoints: Change from Baseline to End of Maintenance Period for Intent-to-Treat Population

Variable Treatment Mean Change From Baseline Difference from placebo
IRLS sum score Placebo -8.6 NA
1 mg/24 hours -13.7  
2 mg/24 hours -16.2  
3 mg/24 hours -16.8  
CGI Item 1 Placebo -1.3 NA
1 mg/24 hours -2 -0.76
2 mg/24 hours -2.4 -1.07
3 mg/24 hours -2.5 -1.21

Last reviewed on RxList: 4/13/2012
This monograph has been modified to include the generic and brand name in many instances.

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