Clinical Trial Synopsis TL , NCT#

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1 Clinical Trial Synopsis, NCT# Title of Study: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Single-Dose Study of TAK-375 in Healthy Adult Volunteers in a Sleep Lab Model of Transient Insomnia Protocol Number: Name of Sponsor: Takeda Pharmaceuticals North America, Inc. Brand Name/Finished Product Name: ROZEREM /TAK-375 (ramelteon) Publication (reference): Zammit G, Schwartz H, Roth T, Wang-Weigand S, Sainati S, Zhang J. The effects of ramelteon in a firstnight model of transient insomnia. Sleep Med PMID: Study Period (years): 06 Jan 2003 to 09 May 2003 Investigator(s): 15 investigators in the United States Phase of Development: Phase III Study Sites : 15 in the United States OBJECTIVES: The primary objective of this study was to evaluate the safety and efficacy of ramelteon after single-dose, night-time administration of 8 and 16 mg compared to placebo in normal, healthy subjects who were naïve to a sleep-laboratory environment. METHODOLOGY: This was a double-blind, randomized, placebo-controlled, single-dose, parallel-group, multicenter study in 289 healthy adult volunteers who were naïve to a sleep laboratory (transient insomnia model). Subjects were randomized to receive a single dose of 8 or 16 mg of ramelteon or placebo. Number of Subjects: Planned: 270 subjects; Analyzed: Intent-to-treat (ITT) population, 289 subjects; per-protocol (PP) set, 276 subjects Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been healthy men or women aged 18 to 64 years, inclusive. Women must have been nonpregnant and nonlactating; women of childbearing potential were required to use appropriate birth control during the study. Women who were not of childbearing potential must have been postmenopausal for at least 1 year or had a history of hysterectomy or oophorectomy. Subjects must have been capable of understanding and willing to comply with the protocol and had signed an informed consent document at Screening, prior to any study-related procedures being performed. Subjects must have been fluent in English (speaking, writing, and reading). Subjects body mass index (BMI) must have been between 18 and 34, inclusive, and their habitual bedtime must have been between 8:30 PM and 12:00 AM. Subjects must have reported sleep 6.5 to 8 hours per night and a subjective sleep latency (ssl) of 30 minutes or less. Test Product, Dose and Mode of Administration: 8 mg tablet, oral 16 mg tablet, oral Placebo tablet, oral Lot Number Z Z515A031 Z Duration of Treatment: The treatment duration was a single night-time dose on Day 1. Reference Therapy, Dose and Mode of Administration: None. Page 1 of 5

2 Criteria for Evaluation: The primary efficacy variable was the latency to persistent sleep (LPS) from the 1 night of polysomnography (PSG) recording in a sleep laboratory. The secondary efficacy variables were as follows: total sleep time (TST), sleep efficiency, wake time after persistent sleep onset (WASO), and number of awakenings after persistent sleep (NAW), all determined by PSG. Secondary efficacy variables of ssl, subjective total sleep time (stst), subjective wake time after sleep onset (swaso), subjective number of awakenings (snaw), sleep quality, and subjective ease of falling back to sleep after awakening were assessed by the Postsleep Questionnaire and included subjective endpoints. Secondary efficacy variables also included of Stage 1, 2, and 3/4 nonrapid eye movement (NREM) sleep, latency to rapid eye movement (REM) sleep, and percentage of total sleep time in REM sleep were determined from sleep architecture study. Residual pharmacological effect variables included the Digit-Symbol Substitution Test (DSST), Memory Recall Test scores (Immediate Recall and Delayed Recall), and visual analog scales (VAS) of Mood and Feelings. Subjects also rated their levels of alertness and ability to concentrate as collected by the Postsleep Questionnaire. Safety variables included adverse events, laboratory tests, vital signs, electrocardiogram (ECG) results, and physical examination findings. Statistical Methods: The primary measure of efficacy was LPS from the polysomnography (PSG) recording. The primary analysis of this variable was performed in the ITT population. Comparisons between the 2 ramelteon dose groups and placebo were made with least-squares (LS) means and SE obtained from the analysis of variance (ANOVA) model with effects for treatment and pooled center. P-values for pairwise comparisons were obtained using t-tests from the ANOVA model of the overall treatment comparison. Treatment-by-center interaction was evaluated for the primary efficacy variable. Log transformation and nonparametric analyses (using overall ranks) of the primary efficacy variable were performed as confirmatory analyses. Analysis of the primary efficacy variable in the PP population was also performed using the model described above for the ITT analysis. Pre-determined important secondary efficacy variables (Total Sleep Time [TST], sleep efficiency, Wake time After Sleep Onset [WASO], Number of Awakenings after Persistent Sleep Onset [NAW], subjective sleep latency [ssl], Subjective Total Sleep Time [stst], and subjective sleep quality) were analyzed in the same way as the primary efficacy variable in the ITT population, with a stepwise application of Fisher protected least significant difference (LSD) testing procedure to interpret the results. The residual pharmacological effect variables (Digit-Symbol Substitution Test [DSST], Word List Memory Test, visual analog scale [VAS] for Mood, and VAS for Feelings) were collected both in the evening before dosing and in the morning. The score for Day 1 was used as a covariate for the analysis of the Day 2 score. Subjective level of alertness and subjective ability to concentrate, as well as the sleep architecture variables, were analyzed using the same statistical methods as described for the efficacy variables. Page 2 of 5

3 SUMMARY OF RESULTS Demographics: A summary of subjects demographics and baseline characteristics follows. Characteristic Gender, n (%) Placebo n=97 Treatment 8 mg n=98 16 mg n=94 N=289 Male 40 (41.2) 43 (43.9) 45 (47.9) 128 (44.3) Female 57 (58.8) 55 (56.1) 49 (52.1) 161 (55.7) Mean Age (SD)(yr) 29.8 (9.17) 28.5 (9.07) 28.1 (9.40) 28.8 (9.21) Race, n (%) Caucasian 64 (66.0) 60 (61.2) 69 (73.4) 193 (66.8) Asian 7 (7.2) 5 (5.1) 2 (2.1) 14 (4.8) Black 4 (4.1) 10 (10.2) 4 (4.3) 18 (6.2) Hispanic 21 (21.6) 22 (22.4) 19 (20.2) 62 (21.5) Other 1 (1.0) 1 (1.0) 0 (0.0) 2 (0.7) Mean weight (SD)(kg) (15.832) (13.860) (14.600) (14.749) Mean height (SD)(cm) (9.407) (10.423) (10.114) (9.968) Mean BMI (SD) (kg/m 2 ) (3.896) (4.177) (3.941) (3.994) Subject Disposition: A total of 289 subjects were randomized to treatment in the study. Ninety-seven subjects received placebo, 98 subjects received ramelteon 8 mg, and 94 received ramelteon 16 mg. All subjects completed the study with the exception of 1 woman in the placebo group, who discontinued due to adverse events of agitation and increased sweating. 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 shown in the table below, compared to the placebo group, shortened LPS was observed in the ramelteon 8 mg and 16 mg groups; however, the treatment effect was not statistically significant for the 16 mg group. Placebo 8 mg 16 mg LS mean (SE) 19.7 (1.87) 12.2 (1.88) 14.8 (1.93) P-value LS mean difference from placebo (SE) -7.6 (2.62) -4.9 (2.65) % CI of difference (-12.7, -2.4) (-10.1, 0.3) Pairwise P-value Results of secondary PSG efficacy variable of TST, sleep efficiency, WASO, and NAW are presented in the following table. The TST from PSG was statistically significantly longer for subjects receiving ramelteon 8 and 16 mg than for subjects receiving placebo. In addition, sleep efficiency was statistically significantly greater with ramelteon 8 mg than with placebo. WASO and NAW in the treatment groups were not statistically significantly different from placebo. Page 3 of 5

4 Total sleep time (minutes) Placebo 8 mg 16 mg P-value LS mean (SE) (4.66) (4.70) (4.82) LS mean difference from placebo (SE) 17.1 (6.55) 13.5 (6.62) % CI of difference (4.2, 30.0) (0.4, 26.5) Pairwise P-value Sleep efficiency (%) LS mean (SE) 87.9 (0.90) 91.1 (0.91) 90.3 (0.93) LS mean difference from placebo (SE) 3.3 (1.26) 2.4 (1.28) % CI of difference (0.8, 5.7) (-0.1, 5.0) Pairwise P-value WASCO (minutes) LS mean (SE) 38.8 (3.29) 33.8 (3.32) 36.3 (3.40) LS mean difference from placebo (SE) -5.0 (4.62) -2.5 (4.68) % CI of difference (-14.1, 4.1) (-11.7, 6.7) Pairwise P-value NAW LS mean (SE) 6.7 (0.47) 7.3 (0.47) 7.2 (0.48) LS mean difference from placebo (SE) 0.5 (0.66) 0.5 (0.66) % CI of difference (-0.7, 1.8) (-0.8, 1.8) Pairwise P-value There was no statistically significant treatment effect on the secondary efficacy variables of ssl, stst, swaso, snaw, ease of falling back to sleep, and sleep quality obtained from the Postsleep Questionnaire. Sleep architecture variables (percentage of TST in REM sleep, Stage 1, 2, and 3/4 NREM sleep, and latency to REM as determined by PSG) were not statistically significantly different in the ramelteon 8 or 16 mg groups when compared to the placebo group. Residual pharmacological effect variables (VAS for Mood, VAS for Feelings, DSST, Word List Memory Test [Immediate Recall and Delayed Recall], subjective level of alertness, and subjective ability to concentrate) were not statistically significantly different in the ramelteon 8 or 16 mg groups when compared to the placebo group. 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. Page 4 of 5

5 A total of 31 of 289 subjects (10.7%) experienced 1 or more adverse events during the Treatment Period. Most adverse events were rated as mild or moderate in severity; only 1 subject in the ramelteon 8 mg group experienced adverse events considered to be severe., the incidence of adverse events was similar between the placebo group (12.4%) and the ramelteon 8 mg group (13.3%) and lower in the ramelteon 16 mg group (6.4%). Somnolence was the most commonly reported adverse event, reported for 2.1%, 3.1%, and 3.2% of subjects, respectively, in the placebo, ramelteon 8 mg, and ramelteon 16 mg groups. No serious adverse events (SAEs) were reported, and no deaths occurred during the study; 1 subject in the placebo group did not complete the PSG due to AEs of agitation and increased sweating that began approximately 2 hours after study drug administration. These adverse events were considered by the investigator to be moderate in severity and probably related to the study drug. Date of Synopsis: 04 December 2008 Page 5 of 5