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Clinical Trial Synopsis, NCT#00671567 Title of Study: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Outpatient, Safety and Efficacy Study of TAK-375 in Adults With Chronic Insomnia Name of Sponsor: Takeda Pharmaceuticals North America, Inc. Name of Finished Product: Ramelteon (TAK-375) Investigators: 79 investigators Publication (reference): None Study Period (years): 09 January 2003 to 26 September 2003 Study Centers: 79 investigative sites (all in the United States) Phase of Development: Phase III Objectives: The primary objective of this study was to assess the safety and efficacy of ramelteon at doses of 8 and 16 mg, compared to placebo, in patients with chronic insomnia. Methodology: This was a randomized, double-blind, placebo-controlled, fixed-dose, parallel group, multicenter, outpatient study subjects with chronic primary insomnia. Subjects who met entry criteria completed a 7-night single-blind placebo lead-in period. Upon completing this period and meeting further eligibility criteria, subjects were randomized to ramelteon 8 mg, ramelteon 16 mg, or placebo and completed a 35-night double-blind treatment period. This was followed by a 7-night, single-blind placebo run-out period to evaluate for possible rebound insomnia and withdrawal effects. Throughout the course of the study, subjects were asked to maintain daily diaries and return to the clinic weekly for Clinical Global Impressions (CGIs) and review of diaries, concomitant medications, and adverse events. Number of Subjects: Planned: 810 subjects. Analyzed: Intent-to-treat (ITT) population 848 subjects; per protocol (PP) set 695 subjects; safety population 848 subjects Diagnosis and Main Criteria for Inclusion: Healthy male and nonpregnant, nonlactating, or postmenopausal female subjects, 18 to 64 years of age, inclusive. Subjects had primary insomnia as defined by the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR ) for at least 3 months and a history of daytime complaints associated with disturbed sleep. Subjects had a subjective sleep latency (ssl) greater than or equal to 45 minutes and a subjective total sleep time (stst) less than or equal to 6.5 hours per night for at least 3 nights during the week of the placebo lead-in period, based on the subject s diary. The subjects body mass index (BMI) was between 18 and 34, inclusive; and their habitual bedtime was between 8:30 PM and 12:00 AM. The subjects did not have had any significant medical or psychiatric disorder or had used any medications, which affected the central nervous system (CNS) or sleep/wake function within 1 week (or 5 half-lives [T1/2s]) prior to the first day of single-blind medication. Page 1 of 4
Test Product, Dose and Mode of Administration, Lot Number: Lot Numbers Ramelteon 8 mg tablet, oral Ramelteon 16 mg tablet, oral Placebo tablet, oral Z5159031; Z5159035 Z515A031; Z515A034 Z5157031; Z5157035 Duration of Treatment: The treatment duration was 7 nights of single-blind placebo run-in, 35 nights of double-blind treatment, then 7 nights of placebo run-out. Reference Therapy, Dose and Mode of Administration, Lot Number: None. Criteria for Evaluation: The primary efficacy variable was the mean subjective Sleep Latency (ssl), per subject diary, from Nights 1 through 7 of double-blind treatment. The secondary efficacy variables were: the mean ssl, per subject diary, over the week preceding the Day 15, Day 22, Day 29, and Day 36 Visits; subjective Total Sleep Time (stst); subjective number of awakenings (snaw), subjective ease of falling back to sleep after awakening, subjective sleep quality, and the clinician s clinical global impression (CGI). During the Single-Blind Placebo Run-out Period, ssl was used to assess rebound insomnia and the Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) was used to assess effects of withdrawal from study medication. Safety: Safety variables included adverse events, laboratory tests, vital signs, electrocardiogram (ECG) results, and physical examination findings. Statistical Methods: The primary measure of efficacy was the mean ssl over Nights 1 through 7 of double blind treatment. The primary analysis of this variable, mean ssl at Week 1, was performed in the ITT population. Comparisons between the 2 ramelteon doses and placebo were made using t-tests with least square (LS) means and SEs obtained from the analysis of covariance (ANCOVA) model with treatment and pooled center as fixed effects and the baseline value of the variable as a covariate. The treatment-by-center interaction was evaluated in the primary efficacy analysis. The efficacy of ramelteon was assessed using Fisher protected least significant difference (LSD) to control the Type I error. Pairwise treatment comparisons were interpreted as significant only when the overall treatment effect was significant at the 0.050 level. Log transformation and nonparametric analysis (using overall ranks) of the primary efficacy variable were performed as confirmatory analyses. Analysis of the primary efficacy variable in the per-protocol (PP) population was also performed using the model described above for the intent-to-treat (ITT) analysis. Pre-determined important secondary efficacy variables were analyzed in the same way as the primary efficacy variable in the ITT population, with a stepwise application of Fisher protected LSD testing procedure to interpret any significant results. Rebound insomnia and withdrawal effects using the BWSQ, were analyzed in the same way as the efficacy variables with baseline ssl and the score for Week 5 as covariates, respectively. Page 2 of 4
SUMMARY OF RESULTS Demographics and Baseline Characteristics: No significant differences were observed among the treatment groups for any demographic characteristic at Baseline. Demographics and baseline characteristics for all subjects are presented in the following table. Treatment Ramelteon Ramelteon Placebo 8 mg 16 mg Overall Characteristic n=287 n=277 n=284 N=848 Gender, n (%) Male 126 (43.9) 112 (40.4) 111 (39.1) 349 (41.2) Female 161 (56.1) 165 (59.6) 173 (60.9) 499 (58.8) Mean age (SD)(yr) 44.0 (12.38) 43.3 (12.3) 44.2 (11.99) 43.8 (12.22) Race, n (%) Caucasian 188 (65.5) 190 (68.6) 203 (71.5) 581 (68.5) Black 46 (16.0) 54 (19.5) 44 (15.5) 144 (17.0) Hispanic 45 (15.7) 21 (7.6) 26 (9.2) 92 (10.8) Asian 5 (1.7) 7 (2.5) 6 (2.1) 18 (2.1) Native American 1 (0.3) 1 (0.4) 0 2 (0.2) Other 2 (0.7) 4 (1.4) 5 (1.8) 11 (1.3) Mean weight (SD) (kg) 76.73 (14.787) 77.04 (15.285) 76.11 (15.063) 76.63 (15.031) Mean height (SD) (cm) 168.90 (9.435) 169.50 (9.075) 169.35 (9.910) 169.25 (9.475) Mean BMI (SD) (kg/m 2 ) 26.83 (4.204) 26.66 (3.878) 26.38 (3.752) 26.62(3.950) Subject Disposition: Of the 848 subjects who were enrolled in the study, 712 completed the Double-Blind treatment period and 708 completed the Single-Blind Placebo Run-Out period. During the Double-Blind treatment, 136 subjects were prematurely discontinued from the study (45, 45, and 46 subjects in the placebo and ramelteon 8 mg and 16 mg groups, respectively): 25 due to adverse events, 24 due to lack of efficacy, 25 due to protocol deviations, 31 withdrew informed consent, 21 were lost to follow-up, 9 withdrew for other reasons, and 1 subject was terminated from the study. During the Placebo Run-Out period, 4 subjects were prematurely discontinued from the study (1 due to AE, 1 due to protocol deviation, 1 was lost to follow-up, and 1 due to other reason). Efficacy Results: The therapeutic effect observed in clinical trials of a drug cannot be directly compared to the effects found in clinical trials of other drugs and may not reflect the therapeutic effects observed in practice. In addition, therapeutic effects observed in a single clinical trial may not reflect the overall therapeutic effects observed in all clinical trials of a drug. As presented in the following table, ssl did not show an incremental treatment effect of ramelteon when compared to placebo. Page 3 of 4
Baseline ssl (min) Placebo Ramelteon 8 mg Ramelteon 16 mg N 287 277 284 LS mean (SE) 85.5 (2.99) 85.2 (3.03) 92.5 (2.98) Week 1 Overall P-value N 283 270 276 0.602 LS mean (SE) 74.4 (2.17) 74.8 (2.20) 77.2 (2.17) LS mean difference from placebo (SE) 0.4 (3.01) 2.8 (3.00) 95% CI of difference (-5.5, 6.3) (-3.1, 8.7) Pairwise P-value 0.888 0.349 The secondary efficacy endpoints of ssl, stst, snaw, subjective ease of falling back asleep after awakening, subjective sleep quality and clinician s CGI Global Rating of Change of Condition did not demonstrate a consistent ability of ramelteon 8 or 16 mg groups to be distinguished from placebo at any of the timepoints specified. There was no statistically significant treatment effect for rebound insomnia or withdrawal effects at any analysis time point during the Placebo Run-out Period. Safety Results: Adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. In addition, the rates observed in a single clinical trial may not reflect the overall rates observed in all clinical trials of a drug. A total of 476 of 848 subjects experienced 1 or more adverse events. Adverse events were reported for 57% (164/287) of subjects in the placebo group, 56% (156/277) of subjects in the ramelteon 8 mg group, and 55% (156/284) of subjects in the ramelteon 16 mg group. Across all treatment groups, adverse events considered to be possibly, probably, or definitely related to study medication by the investigators were reported for 33% (95/287), 31% (86/277), and 33% (94/284) of subjects in the 3 treatment groups, respectively. Most adverse events were rated by the investigators as mild or moderate in severity. The most common adverse events in the placebo, ramelteon 8 mg, and ramelteon 16 mg group were headache (7%, 11%, and 10%, respectively), exacerbated insomnia (5%, 9%, and 9%, respectively), and somnolence (6%, 6%, and 10%, respectively). In addition to the above events, 3 subjects experienced 6 AEs that were not captured in the database and were reported as Amendment 1 to the clinical trial report. Five AEs considered possibly related to the study drug and all were either mild or moderate in severity. Five serious adverse events (SAEs) were reported: 1 in the placebo group, 1 in the ramelteon 8 mg group, and 3 in the ramelteon 16 mg group. No SAEs were reported as related to study medication. No deaths occurred during the study. Twenty-six subjects withdrew from the study due to adverse events (25 during the Double-Blind treatment period and 1 during the Single-Blind Placebo Run-Out period). The most common adverse events leading to discontinuations and judged to be related to study medication were somnolence, exacerbated insomnia, and nausea experienced by 3 or fewer subjects in any treatment group. Date of Synopsis: 20 November 2008 Page 4 of 4