Clinical Trial Synopsis TL , NCT#

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1 Clinical Trial Synopsis, NCT# Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Ability of Ramelteon 1 mg, 4 mg, and 8 mg to Alleviate the Insomnia Symptoms Associated with Eastward-bound Jet Lag Across 5 Time Zones in Healthy Adult Volunteers Protocol Number: Name of Sponsor: Takeda Global Research & Development Center, Inc. Brand Name/Active Ingredient Name: ROZEREM /TAK-375 (ramelteon) Publication (Reference): None Study Period (years): 01 February 2007 to 07 August 2007 Phase of Development: Phase IV OBJECTIVES Primary: The primary objective was to evaluate the ability of ramelteon 1 mg, 4 mg, and 8 mg to alleviate the insomnia symptoms associated with rapid, eastward travel across 5 time zones. Secondary: The secondary objectives of the study were: To evaluate the safety of ramelteon 1 mg, 4 mg, and 8 mg. To evaluate the ability of ramelteon 1 mg, 4 mg, and 8 mg to alleviate other symptoms associated with rapid, eastward travel across 5 time zones. To determine whether ramelteon 1 mg, 4 mg, or 8 mg, compared with placebo, could facilitate restoration of normal circadian phase relationships as measured by salivary melatonin secretion offset time after imposition of a 5-hour phase advance. Page 1 of 7

2 METHODOLOGY This was a phase 4, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the ability of ramelteon 1 mg, 4 mg, and 8 mg to alleviate the insomnia symptoms associated with eastwardbound jet lag across 5 time zones in healthy adult volunteers. Approximately 110 subjects were screened and randomized in Hawaii and traveled to the East Coast of the United States for evaluation in a sleep laboratory. Once on the East Coast, subjects were confined to a sleep laboratory for 6 days and 5 nights, where they received study medication prior to bedtime on Nights 1 through 4 and underwent polysomnographic recordings while they slept. On Days 1 through 5, subjects responded to postsleep questionnaires (PSQs) and assessments to evaluate their insomnia symptoms and other jet lag symptoms. They also took tests to assess daytime alertness and function ability. On Day 6 the subjects returned to Hawaii and were escorted to their homes. Two days later, on Day 8, subjects received a telephone follow-up call to assess the status of their jet lag insomnia and other symptoms. Number of Subjects: Planned: 100 subjects (25 subjects per treatment group) Actually randomized: 110 subjects. Analyzed: Full Analysis Set (FAS) 110 subjects; Per Protocol Analysis Set (PPS) 103 subjects; Diagnosis and Main Criteria for Inclusion: To qualify for study participation subjects must have had a history of sleep disturbance associated with jet lag symptoms, with at least 2 occurrences in the last 3 years; aged 18 to 50 years, inclusive; been able to comprehend and willing to sign an informed consent form; been willing to travel from Hawaii to the East Coast with a minimum stay of 6 days; have lived in Hawaii for at least 12 months; and had not traveled outside of Hawaii for 4 consecutive days within 30 days prior to the Outpatient Screening Visit. The subject had to meet the following criteria based on sleep history during the past 3 months: habitual bedtime between 9:00 PM and 12:00 AM, subjective sleep latency (ssl) <30 minutes, and subjective total sleep time (stst) of 6.5 to 9 hours. The subject agreed to maintain a regular habitual bedtime during the screening period, defined as within 1 hour of the subject reported habitual bedtime on each night; a mean ssl of <30 minutes and a stst of 6.5 to 9 hours on at least 3 of 5 nights after the Outpatient Screening Visit as determined by PSQs; a sleep onset latency <30 minutes; and a total sleep time (TST) >6.5 hours as determined by PSQs. Subjects were excluded if they met any of the following criteria: a history of primary sleep disorders as determined by the Diagnostic and Statistical Manual, Edition 4, Text Revised within the past 6 months, treatment for a psychiatric disorder (including anxiety or depression) within the past 12 months, a history of seizures, sleep apnea, restless leg syndrome, periodic limb movement syndrome, chronic obstructive pulmonary disease, schizophrenia, bipolar disorder, mental retardation, cognitive disorder, sleep schedule changes required by employment (eg, shift worker) within 3 months prior to the administration of study medication, smoked >3 cigarettes per day or used tobacco products during nightly awakenings, high caffeine consumption (>600 mg daily), a known hypersensitivity to ramelteon or related compounds (including melatonin and melatonin-related compounds), or had used prescription or over-the-counter hypnotic medication (including melatonin) within 3 months of the screening visits. Test Product, Dose and Mode of Administration: Ramelteon 1 mg, tablets, orally Ramelteon 4 mg, tablets, orally Ramelteon 8 mg, tablets, orally Lot Number Z515C021 Z Z Duration of Treatment: The study ranged from 22 to 33 days, with a 5- to 10-day Outpatient Screening Period, a 2-night Inpatient Screening Visit, a 6- to 12-day Travel Preparation Period, departure from Hawaii with arrival in the East Coast (2 days), 4 nights of double-blind study medication treatment (followed by 4 days of postsleep assessments), departure from the East Coast and arrival at Hawaii (2 days), and a follow-up telephone call 2 days after arrival in Hawaii. Page 2 of 7

3 Reference Therapy, Dose and Mode of Administration/Lot Number: Placebo tablets, orally Page 3 of 7 Lot Number Z Criteria for Evaluation: The primary efficacy endpoint for the study was the average Latency to Persistent Sleep (LPS) of Night 2, Night 3, and Night 4 measured via polysomnography (PSG). The main secondary endpoint of this study was dim light melatonin secretion offset (DLMOff) in a subset of subjects defined as the time of the morning when the melatonin drops to below 3 pg/ml with a downward slope. DLMOff was determined using linear interpolation method using time points n-1 and n and the corresponding melatonin levels. DLMOff was collected at baseline, and the morning after treatment Night 2, Night 3, and Night 4. The secondary endpoints of the study as measured by PSG were: Sleep Efficiency (SE) on the N2, N3, and N4. Total Sleep Time (TST) on the N2, N3, and N4. Wake time After Sleep Onset (WASO) on the N2, N3, and N4. Number of awakenings on the N2, N3, and N4. The secondary endpoints of the study as measured in changes in various questionnaires were: Karolinska Sleepiness Scale (KSS) and Pittsburgh Sleep Quality Index (PSQI). Measurement of Daytime function will be assessed using Daytime Function Questionnaire (DTFQ) and Psychomotor Vigilance test (PVT). Next morning residual effects will be assessed using Daytime Function Questionnaire (DTFQ) and Psychomotor Vigilance Test (PVT). Next morning residual effects will be assessed using the Digit Symbol Substitution Test (DSST); Memory Recall Test (MRT); Visual Analogue Scale (VAS) for mood and feelings, level of alertness, ability to concentrate. Safety: All safety assessments including adverse events (AEs), clinical laboratory evaluations, vital signs, physical examination and medical history findings, and use of prior or concomitant medications were presented in the data listings and summarized with descriptive statistics, if appropriate. The date and time of study medication was presented in the data listings. Statistical Methods: For the primary analysis of the primary endpoint, an analysis of variance (ANOVA) was used to compare the treatment effect differences between ramelteon (1, 4, or 8 mg) and placebo. For secondary analyses, an analysis of covariance (ANCOVA) with Baseline as a covariate was used to compare the treatment effect differences between ramelteon (1 mg, 4 mg, and 8 mg) and placebo. For both ANOVA and ANCOVA models, treatment, Hawaii site, and East Coast site were included as class effects. Except for DLMOff, the light condition (ie, dim light vs natural light) was also included as class effect. No procedure was used to adjust for multiple testing. Exploratory analyses were conducted on the correlation between the circadian phase-shifting effect and the improvement of sleep quality, as well as between the sleep parameters measured via actigraphy and those measured via PSG. Since the East Coast observes summer daylight-saving time (DST) and Hawaii does not, the time difference between the 2 time zones was 6 hours in the summer and 5 hours in the winter. To ensure that all subjects experienced a 5-hour phase advance, the laboratory in the East Coast treated the subjects as if DST were not implemented. However, to account for the potential influence of other uncontrollable environmental factors

4 due to DST, the DST effect was tested in the ANCOVA model and removed from the model if not statistically significant. Subgroup analyses were performed by age, gender, and light conditions. SUMMARY OF RESULTS Subject Disposition: A total of 110 subjects (mean age of 30.1 years), including 58 male and 52 female subjects, were randomized in the study from the 144 subjects who were screened. One subject in the ramelteon 1 mg treatment group discontinued the study prematurely because of pregnancy; no other subject discontinued prematurely for any reason. Demographics and Baseline Characteristics: Baseline demographic characteristics for all subjects are summarized in the following table. No significant differences were observed among the treatment groups for demographic characteristics at Baseline. Characteristic Placebo (n=29) 1 mg (n=27) Ramelteon 4 mg (n=27) 8 mg (n=27) Total (n=110) Sex, n (%) Male 16 (55.2) 15 (55.6) 11 (40.7) 16 (59.3) 58 (52.7) Female 13 (44.8) 12 (44.4) 16 (59.3) 11 (40.7) 52 (47.3) Age (SD) (yr) 28.6 (7.25) 29.8 (9.98) 30.1 (9.95) 31.9 (10.20) 30.1 (9.34) Race, n (%) American 2 (6.9) 0 1 (3.7) 0 3 (2.7) Indian/Alaska Native Asian 2 (6.9) 2 (7.4) 5 (18.5) 5 (18.5) 14 (12.7) Black/African (3.7) 0 1 (0.9) American Native 1 (3.4) 2 (7.4) (2.7) Hawaiian/ Other Pacific Islander White 22 (75.9) 20 (74.1) 19 (70.4) 21 (77.8) 82 (74.5) Multiracial 2 (6.9) 3 (11.1) 1 (3.7) 1 (3.7) 7 (6.4) Weight (SD) (kg) 70.9 (15.18) 74.5 (14.62) 67.0 (10.94) 75.4 (14.14) 71.9 (14.05) Height (SD) (cm) (8.48) (8.73) (8.55) (8.70) (8.72) BMI (SD) (kg/m 2 ) 24.0 (3.76) 25.1 (3.81) 23.9 (3.30) 25.4 (3.57) 24.6 (3.63) Page 4 of 7

5 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. Primary Efficacy Variable: Average LPS of Nights 2, 3, and 4 Measured by PSG: As presented in the table below, treatment with ramelteon 1 mg significantly reduced average LPS over Nights 2, 3, and 4 compared with placebo from the ANOVA model, using the FAS (least squares [LS] mean difference from placebo= minutes, P=0.030). Results of the same analysis for the PPS were similar, with a significant reduction in LPS over Nights 2, 3, and 4 for the ramelteon 1 mg group compared with placebo (LS mean difference from placebo= minutes, P=0.036). There were no statistically significant differences from placebo for the ramelteon 4 mg and 8 mg treatment groups regarding average LPS over Nights 2, 3, and 4.. Full Analysis Set Placebo Ramelteon LPS (min) (n=29) 1 mg (n=27) 4 mg (n=27) 8 mg (n=27) Mean (SD) (29.61) (10.91) (12.56) (13.53) Median Minimum-Maximum LS mean (SE) (a) (3.40) (3.51) (3.56) (3.59) LS mean (SE) difference from (4.82) (4.83) (4.83) 95% CI of difference (a) (-20.20,-1.07) (-17.44, 1.71) (-18.52, 0.64) P-value for comparison with Per Protocol Analysis Set LPS (min) Placebo Ramelteon (n=28) 1 mg (n=26) 4 mg (n=25) 8 mg (n=24) Mean (SD) (30.06) (11.10) (12.66) (10.62) Median Minimum-Maximum LS mean (SE) (a) (3.41) (3.53) (3.63) (3.73) LS mean (SE) difference from (4.86) (4.91) (4.97) 95% CI of difference (a) (-19.97, -0.68) (-17.42, 2.08) (-19.46, 0.28) P-value for comparison with (a) LS means are from an ANOVA model with treatment, Hawaii site, East Coast site, and light as fixed factors. Page 5 of 7

6 The average LPS of Nights 2, 3, and 4 was also analyzed by gender, age, and light conditions. There was no significant difference for any ramelteon group compared with placebo with regard to the analysis by age; however, the analysis by gender and light conditions resulted in significant differences from placebo for female subjects and for subjects under dim light conditions for the ramelteon 1 mg and 8 mg groups. For female subjects on ramelteon 1 mg, the LS mean difference from placebo in LPS was minutes (P=0.043) and for female subjects in the ramelteon 8 mg group, the difference from placebo was minutes (P=0.044). When LPS was analyzed by light conditions, subjects in the ramelteon 1 mg group had a statistically significant improvement compared with placebo, with an LS mean difference of minutes (P=0.014). The LS mean differences from placebo for the ramelteon 4 mg and 8 mg groups under dim light conditions were (P=0.070) and minutes (P=0.082) respectively. Under natural light conditions, the LS mean differences from placebo were -2.34, -3.09, and -3.27, respectively, in the 1, 4, and 8 mg groups (P 0.404). The LS mean differences from placebo were , , and minutes, respectively, in the ramelteon 1 mg, 4 mg, and 8 mg dose groups for older subjects. In the subjects who were younger than the median age of 27, the LS mean differences from placebo in LPS were -2.59, -0.94, and minutes, respectively. Secondary Efficacy Variables: DLMOff: There were no significant differences in the change from Baseline of DLMOff for any ramelteon group compared with placebo. Objective Sleep Parameters Measured by PSG LPS: For LPS on Treatment Day 2, as measured by PSG, the LS mean difference from placebo in the ramelteon 1 mg group was minutes (P=0.044); at Treatment Day 4; in the ramelteon 8 mg group it was minutes (P=0.025). There were no significant differences in LPS as measured by PSG between placebo and the ramelteon 4 mg group. SE: For SE, there was no statistically significant improvement in the ramelteon groups compared with placebo. TST: There were no statistically significant increases in mean TST over placebo in the ramelteon groups WASO: There was no statistically significant improvement in the ramelteon groups compared with placebo. NAW: Number of awakenings decreased by 1.2, 0.6, and 3.2 in the ramelteon 4 mg group on Days 2, 3, and 4, respectively, and the difference at Day 4 was statistically significant (P=0.023). There were no other statistically significant improvements in the ramelteon groups compared with placebo. Subjective Sleep Parameters Assessed by Post Sleep Questionnaires There was no statistically significant improvement ssl, stst, or swaso in the ramelteon groups compared with placebo as measured by PSQs. Next morning residual effects were assessed using: Memory Recall Test Significantly fewer words were recalled by subjects in ramelteon-treated groups (1 mg, 4 mg, and 8 mg), compared with placebo at Day 4. The LS mean difference from placebo was -1.6 words in the ramelteon 1 mg group (P=0.010), -1.6 words in the ramelteon 4 mg group (P=0.012), and -2.0 words in the ramelteon 8 mg group (P=0.002). On other days, ramelteon-treated subjects generally remembered fewer words in both delayed and immediate memory modes but none of these differences were statistically significant. Digit-Symbol Substitution Test There were no statistically significant differences from placebo for any ramelteon treatment group (p 0.330). Visual Analogue Scale The VAS was divided into composite scores for mood and feeling. The higher the score, the more fatigued, slowed down, and weary a person felt on the mood component, and the more anxious, tense, and nervous a person was on the feeling component. There were no statistically significant differences for any ramelteon treatment group compared with placebo in the mood component. For the feeling component, there was a significant difference from placebo for the ramelteon 4 mg group compared with placebo at Treatment Days Page 6 of 7

7 2 and 3. The LS mean difference from placebo at Day 2 was -4.7 (P=0.018) and at Day 3 was, -4.1 (P=0.037). There were no other statistically significant improvements in the 1 mg and 8 mg groups. Daytime Function Questionnaire The lower the score on the DTFQ, the better the subject s ability to function during daytime; a higher score indicated poorer functioning. The ramelteon 4 mg group had results for 3 components of the DTFQ indicating significant improvement compared with placebo at various time points. For the Daytime Ability to Function score, the ramelteon 4 mg dose group had a lower mean score than placebo with an LS mean difference of -0.6, -0.5 (P=0.022), and -0.6 (P=0.015) at Treatment Days 2, 4, and 5, respectively. For the Daytime Alertness Score, the ramelteon 4 mg dose group had a lower mean score than placebo (indicating improvement) with an LS mean difference of -0.5 at Day 5 (P=0.040). For the Daytime Ability to Concentrate Score, the ramelteon 4 mg dose group had a lower mean score than placebo, with an LS mean difference of -0.5 (P=0.013) and -0.6 (P=0.020).The final component was the Nap Question (Have you taken any naps today?); all subjects responded no to this question at all time points (subjects were not permitted to nap), and so no analysis was conducted for this component of the DTFQ. There were no significant differences from placebo for the ramelteon 1 and 8 mg treatment groups for any component of the DTFQ. Karolinska Sleepiness Score The responses on the KSS range from 1 (very alert) to 9 (very sleepy), and a score of 7 indicates excessive sleepiness. At Baseline, mean morning scores ranged from 2.48 to 2.67 across all treatments. There were no statistically significant different changes in mean of morning and evening KSS scores or changes from Baseline to the average of mornings or evening sleepiness from placebo for any ramelteon treatment 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 A total of 58 out of 110 subjects experienced 1 or more AEs during treatment with study drug. Overall, the incidence of AEs was similar across treatment groups (55.6% to 58.6%), with the exception of the ramelteon 1 mg group which had a lower incidence (40.7%). The incidence of related AEs ranged from approximately 35% in the placebo group to 37% in the ramelteon 4 and 8 mg treatment groups, compared with 26% in the ramelteon 1 mg group. Most events were categorized as mild (43.6%). The most commonly occurring adverse events (occurring in at least 2% of all subjects) were headache (21.8%), back pain (8.2%), nausea (6.4%), and upper respiratory tract infection (5.5%). All other events occurred at a rate of less than 5%, and most events occurred in 1 subject only (0.9%). There were no adverse events that led to discontinuation, no serious adverse events, and no deaths during the study. Date of Synopsis: 06 November 2008 Page 7 of 7