This was a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study.

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GSK (Gabapentin Enacarbil) Study Number: RXP Title: A Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, Parallel-Group Study to Compare the Efficacy, Tolerability, and Safety of 3 Doses of Gabapentin Enacarbil (GSK ) With Placebo in the Treatment of Subjects With Moderate-to-Severe Primary Restless Legs Syndrome (RLS) Rationale: The New Drug Application (NDA ) for gabapentin enacarbil (GEn) for the treatment of moderate-to-severe primary RLS in adults was approved on 06 April With the approval of the NDA, the FDA requested GlaxoSmithKline (GSK) to conduct a randomized, placebo-controlled, double-blind, parallel-group clinical trial of GEn at 600, 450, and 300 mg/day in adult subjects with moderate-to-severe primary RLS as a postmarketing commitment (PMC ). This Phase IV study is adequately powered to demonstrate statistically significant benefit for treatment with GEn at the doses tested against placebo. The study also investigates the safety and tolerability of GEn at doses of 600, 450, and 300 mg/day in adult subjects with moderate-to-severe primary RLS. Phase: IV Study Period: 25-Jun-12 to14-nov-13 Study Design: This was a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study. Eligible subjects (18 years of age) must have had the following: A diagnosis of moderate-to-severe primary RLS according to the International Restless Legs Syndrome Study Group [IRLSSG] Diagnostic Criteria A history of RLS symptoms for at least 15 nights in the prior month or, if on treatment, this frequency of symptoms before treatment was started Documented RLS symptoms for at least 4 of the 7 consecutive evenings/nights during the Screening Period and a total RLS severity score of at least 15 on the International Restless Legs Syndrome (IRLS) Rating Scale at the screening and baseline visits The study included 9 visits over approximately 14 weeks for eligible subjects, including a 1-week Screening Period, a 12-week Treatment Period, and a 1-week Follow-up Period. Screening occurred within 1 week of the first scheduled dose of study medication. Each subject s participation in the study was approximately 14 weeks unless he or she was withdrawn early from the study. For subjects who completed the study, Visit 9 (which could have occurred between Days 86 and 92) was considered their End-of-Study visit. The total duration of the study, from the first subject enrolled to the last subject completed, was approximately 1.5 years. Centres: This study was conducted at 52 centers in the United States, 48 of which randomly assigned subjects. Indication: Moderate-to-severe primary RLS Treatment: Gabapentin enacarbil (GEn); 300 mg, 450 mg, 600 mg and matching placebo 1

2 Objectives: The primary objective of the study was to assess the efficacy of (GEn) at doses of 600, 450, and 300 mg daily compared with placebo in adult subjects with moderate-to-severe primary RLS. The secondary objective of the study was to assess the safety and tolerability of GEn at doses of 600, 450, and 300 mg daily compared with placebo in adult subjects with moderate-to-severe primary RLS. Primary Outcome/Efficacy Variable: The co-primary efficacy endpoints were: The change from Baseline to the end of treatment (EOT) in the IRLS Rating Scale total score The proportion of subjects responding to treatment, where a response was a report of much improved or very much improved on the Clinical Global Impression of Improvement [CGI-I] at the EOT Secondary Outcome/Efficacy Variable(s): AEs and SAEs, including PSRAEs Physical examination findings (including height and weight), vital sign measurements (blood pressure, pulse rate, and respiratory rate), 12-lead ECG readings (Screening only) pregnancy testing, and clinical laboratory evaluations (at Screening only) Approximately 498 subjects were planned for random assignment to study medication, which assuming a dropout rate of approximately 14% over the first 12 weeks of the study should have provided 428 evaluable subjects assigned in a 1:1:1:1 ratio. At least 107 subjects per treatment group allowed for statistical comparison of each active GEn dose versus placebo (3 dose comparisons, following a prespecified testing sequence at the experiment-wise 2-sided -level of 0.05, for each of the 2 primary endpoints, with a minimum overall power of 86%): For the change from Baseline in IRLS Rating Scale total score at the EOT, a sample size of 107 subjects per treatment group had 90% power to detect a difference in means of ;- 3.5, assuming a standard deviation (SD) of 7.9 For the proportion of subjects responding to treatment based on the CGI-I at the EOT, a sample size of 107 subjects per treatment group had 96% power to detect a difference between a placebo response rate of 45% and a GEn response rate of 70% No sample size re-estimations were performed. The actual withdrawal rate for the study was 22%; 501 subjects were randomly assigned to treatment. The following analysis populations were defined: Randomized Population: included all subjects who were randomly assigned to study 2

3 medication All Subjects Population: included all subjects who were randomly assigned or who, prior to being randomly assigned, reported an SAE that was considered to be related to study participation. The All Subjects Population was used to summarize pretreatment SAEs, fatal SAEs, nonfatal SAEs, Columbia-Suicide Severity Rating Scale (C-SSRS) scores, and PSRAEs Safety Population: included all subjects who received at least 1 dose or any portion of a dose of study medication. Subjects who were dispensed study medication at Baseline and did not return to the site after, did not have any AEs or vital sign information collected, and did not return the originally dispensed kit were excluded from the Safety Population as these subjects did not show they had received any portion of a dose. Also, subjects who were dispensed study medication and returned the originally dispensed kit with no pills missing were excluded from the Safety Population. The Safety Population was the primary population for evaluation of safety parameters Modified Intent-to-Treat (mitt) Population: included all randomly assigned subjects who received at least 1 dose (or any portion of a dose) of study medication as defined for the Safety Population, had a baseline IRLS Rating Scale total score, and had at least 1 on-treatment IRLS Rating Scale total score. An on-treatment IRLS Rating Scale total score was collected after the first dose of study medication and within 1 day of the last dose of study medication. The mitt Population was the primary population for evaluation of efficacy parameters Per Protocol (PP) Population: included all mitt subjects who had no major protocol deviations. The PP Population was not analyzed if this population comprised more than 95% or less than 50% of the mitt Population. The analysis of the PP Population provided supportive evidence for the analysis of the mitt Population All major protocol deviations were reviewed and determined prior to database freeze and unblinding. Study Population: Key Inclusion Criteria: Men or women who were at least 18 years of age at the time of consent and had: RLS, based on the IRLSSG Diagnostic Criteria Reported history of RLS symptoms for at least 15 nights in the prior month or, if on treatment, this frequency of symptoms before treatment was started Documented RLS symptoms, using the 7-day RLS Symptom Record, for at least 4 of the 7 consecutive evenings/nights during the Screening Period Total RLS severity score of 15 or greater on the IRLS Rating Scale at Visit 1 and at Visit 2 Discontinuation of dopamine agonists and/or gabapentin at least 2 weeks prior to Baseline Discontinuation of other treatments for RLS (e.g., opioids, benzodiazepines) at least 2 weeks prior to Baseline Key Exclusion Criteria: 3

4 A sleep disorder (e.g., sleep apnea) that might have significantly affected the assessment of RLS A history of RLS symptom augmentation or end-of-dose rebound with previous dopamine agonist treatment Neurologic disease or movement disorder (e.g., diabetic neuropathy, Parkinson s disease, multiple sclerosis, dyskinesias, or dystonias) Other medical conditions (e.g., poorly controlled diabetes [i.e., glycosylated hemoglobin >7.5% by history in the last 6 months], iron deficiency anemia) or drug therapy (e.g., sedative-hypnotics) that could have affected RLS efficacy assessments Had taken gabapentin or pregabalin for the treatment of conditions other than RLS. Subjects were eligible provided that (1) their total exposure to gabapentin or pregabalin had been less than 3 months during the preceding 12 months, and (2) the subject had discontinued gabapentin or pregabalin for at least 3 months prior to Baseline Had previously taken gabapentin or pregabalin for the treatment of primary RLS or, at enrollment, were taking any drug therapy that could affect RLS efficacy assessments including levodopa/carbidopa, dopamine agonists, gabapentin, sedative-hypnotics, opioids, or benzodiazepines. Subjects who had taken these drugs may have been eligible provided that they had discontinued these drugs at least 2 weeks prior to Baseline. Other previously prescribed medications were permitted provided that the treatment regimen had been stable for 3 months prior to enrollment and remained stable throughout the study Had active suicidal plan/intent or had had active suicidal thoughts in the previous 6 months; had a history of suicide attempt Had clinically significant or unstable medical conditions (e.g., history of cancer [with the exception of basal cell carcinoma], cardiovascular disease, hepatic or renal disease, immunocompromised, or psychiatric illness) Summary of Demographic and Baseline Characteristics mitt Population Placebo (N=117) GEn 300 mg (N=111) GEn 450 mg (N=112) GEn 600 mg (N=119) Total (N=459) Age (years), n Mean (SD) 52.1 (13.01) 52.0 (14.51) 52.1 (12.22) 49.2 (12.92) 51.3 (13.20) Min-max Sex, n Female, n 64 (55) 71 (64) 69 (62) 73 (61) 277 (60) Male, n 53 (45) 40 (36) 43 (38) 46 (39) 182 (40) Race, n Nonwhite, n 8 (7) 14 (13) 15 (13) 7 (6) 44 (10) White, n 109 (93) 95 (87) 97 (87) 112 (94) 413 (90) Primary Efficacy Results: Summary of the Analysis of Change From Baseline in IRLS Total Score at End-of-Treatment (LOCF With Baseline Carried Forward Data) mitt Population Week 12 (End-of-Treatment) Placebo (N=117) GEn 300 mg (N=111) GEn 450 mg (N=112) GEn 600 mg (N=119) 4

5 n Adjusted mean (SE) (0.753) (0.745) (0.767) (0.764) Treatment difference % CI (-3.63, 0.53) (-4.68, -0.54) (-4.62, -0.52) p-value Summary of the Analysis of Change from Baseline in IRLS Total Score at End-of-Treatment (LOCF with Baseline Carried Forward Data/PP Population and OC Data/mITT Population) LOCF data PP Population OC data mitt Population Placebo, N n Adjusted mean (SE) (0.783) (0.783) GEn 300 mg, N n Adjusted mean (SE) (0.827) (0.816) Treatment difference (relative to placebo) 95% CI (-3.87, 0.54) (-3.95, 0.44) GEn 450 mg, N n Adjusted mean (SE) (0.811) (0.791) Treatment difference (relative to placebo) 95% CI (-4.64, -0.29) (-4.35, -0.06) GEn 600 mg, N n Adjusted mean (SE) (0.781) (0.810) Treatment difference (relative to placebo) 95% CI (-4.78, -0.52) (-4.66, -0.32) 5

6 Number and Proportion of Responders by the Investigator-Rated CGI-I Scale at End-of-Treatment (LOCF Data) mitt Population Placebo (N=117) GEn 300 mg (N=111) GEn 450 mg (N=112) GEn 600 mg (N=119) Week 12 (End-of-Treatment) n Proportion of responders, n 59 (50) 75 (68) 75 (67) 80 (67) Odds ratio % CI (1.27, 3.94) (1.23, 3.77) (1.30, 3.95) p-value Number and Proportion of Responders by the Investigator-Rated CGI-I Scale at End-of-Treatment (LOCF Data/PP Population and OC Data/mITT Population) LOCF data PP Population OC data mitt Population Placebo, N n Proportion of responders, n 56 (51) 57 (56) GEn 300 mg, N n Proportion of responders, n 67 (68) 68 (73) Odds ratio (relative to placebo) 95% CI (1.28, 4.29) (1.21, 4.33) GEn 450 mg, N n Proportion of responders, n 67 (66) 72 (73) Odds ratio (relative to placebo) 95% CI (1.15, 3.75) (1.23, 4.27) GEn 600 mg, N n Proportion of responders, n 75 (68) 67 (70) Odds ratio (relative to placebo) 95% CI (1.33, 4.24) (1.09, 3.75) 6

7 Safety Results: Most Frequent 5 Adverse Events on Therapy (in Each Treatment Group) Safety Population Number of Subjects Preferred Term Placebo GEn 300 mg GEn 450 mg GEn 600 mg (N=121) (N=121) (N=123) (N=122) Any TEAE 66 (55) 64 (53) 73 (59) 68 (56) Somnolence 8 (7) 12 (10) 20 (16) 13 (11) Headache 12 (10) 10 (8) 9 (7) 11 (9) Dizziness 5 (4) 5 (4) 8 (7) 15 (12) Lethargy 0 3 (2) 4 (3) 2 (2) Nausea 7 (6) 3 (2) 4 (3) 5 (4) Upper Respiratory Tract Infection 7 (6) 3 (2) 10 (8) 6 (5) Fatigue 7 (6) 0 5 (4) 5 (4) Arthralgia 4 (3) 1 (<1) 3 (2) 3 (2) Insomnia 1 (<1) 4 (3) 1 (<1) 1 (<1) Dry Mouth 2 (2) 3 (2) 2 (2) 3 (2) Diarrhoea 0 3 (2) 4 (3) 1 (<1) Flatulence 1 (<1) 3 (2) 0 0 Gastroenteritis viral 1 (<1) 3 (2) 0 1 (<1) Nasopharyngitis 2 (2) 2 (2) 5 (4) 4 (3) Vomiting 1 (<1) 0 5 (4) 2 (2) Serious Adverse Events - On-Therapy Placebo (N=121) GEn 300 mg (N=121) GEn 450 mg (N=123) GEn 600 mg (N=122) Subjects with fatal SAEs, n Subjects with non-fatal SAEs, n 1 (<1) 2 (2) 0 0 SAEs considered by the Investigator to be related to study medication, n Coronary Artery Disease 0 1 (<1) 0 0 Alcohol Withdrawal Syndrome 0 1 (<1) 0 0 Pulmonary Embolism 1 (<1) Post-Treatment SAE Ligament Rupture (<1) Conclusion: Twelve-week treatment with GEn was statistically significant compared to placebo in the treatment of adults with moderate-to-severe primary RLS at doses of 600 and 450 mg, when assessed by mean change from Baseline in the IRLS Rating Scale total score and the proportion of responders on the investigator-rated CGI-I. The 300-mg dose of GEn did not achieve a statistically significant improvement over placebo when assessed by mean change from Baseline in the IRLS Rating Scale total score. The 300-mg dose of GEn was statistically different from placebo for the proportion of responders on the investigator-rated CGI-I. 7

8 The 3 most frequent AEs on therapy regardless of treatment were somnolence, dizziness, and headache. The only AE on therapy leading to withdrawal in more than 1 subject in a single treatment group was insomnia, which was reported by 2 subjects in the GEn 300-mg treatment group. A total of 3 subjects (1 subject in the placebo treatment group, 2 subjects in the GEn 300-mg treatment group) experienced nonfatal SAEs during the treatment period; none of them were considered related to treatment by the investigator. One additional subject in the GEn 600-mg group experienced a nonfatal SAE during the post-treatment period (preferred term: ligament rupture) none of them were considered related to treatment by the investigator. No deaths occurred during this study. 8