The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

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1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 Clinical Trial Synopsis, NCT Title of Study: A Study of the Safety of Ramelteon in Subjects with Moderate to Severe Chronic Obstructive Pulmonary Disease Protocol Number: Name of Sponsor: Takeda Global Research & Development Center, Inc. Brand Name/Active Ingredient Name: ROZEREM TM /TAK-375 (ramelteon) Publication (reference): None Study Period (years): 03 April 2006 to 06 November 2006 Phase of Development: Phase 4 OBJECTIVES Primary: To determine whether ramelteon has respiratory depressant effects in subjects with moderate to severe chronic obstructive pulmonary disease (COPD). Secondary: To evaluate the safety and tolerability of ramelteon in subjects with moderate to severe COPD. To evaluate the effects of ramelteon on sleep by means of subjective and objective assessments. METHODOLOGY This was a double-blind, randomized, placebo controlled, single-dose, 2-way crossover study in adult subjects with moderate to severe COPD. One dose of single-blind placebo medication was administered during Screening; following Screening, subjects were randomized on Day 1 to 1 of 2 crossover treatment sequences, to receive 1 dose each of 8 mg ramelteon and matching placebo during the Crossover Treatment Periods 1 and 2, respectively (or vice-versa). A 5- to 10- day Washout Period occurred between doses. One follow up visit was completed approximately 1 week after the final treatment period. Number of Subjects: Planned: 24 subjects randomized, with a minimum of 16 subjects with severe COPD included. Analyzed: Completer Analysis Set 25 subjects; Full Analysis Set 25 subjects. Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been male or nonpregnant, nonlactating females; aged 40 or older; with a body mass index between 18 and 34, inclusive; able to comprehend and willing to sign an informed consent form. The subjects must have had a clinical history of COPD and a confirmatory diagnosis based on pulmonary function tests (PFTs) performed at the Outpatient Screening Visit, with moderate to severe airflow limitation defined by: Moderate: forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) less than 70%; FEV1 50% to 80% of the predicted value. Page 1 of 7

3 Severe: FEV1/FVC less than 70%; FEV1 less than 50% of the predicted value Subjects must also have had a post-bronchodilator FEV1 change from Baseline of less than 12% and not exceeding 200 ml at the Outpatient Screening Visit; an oxygen saturation (SaO2) during wakefulness greater than 90% (both supine and sitting) as assessed by pulse oximetry at the Outpatient Screening Visit; an SaO2 during sleep of greater than or equal to 80% for at least 75% of the recording period with no more than 5 continuous minutes less than 80%; and no SaO2 readings less than 70% as assessed by pulse oximetry at the Inpatient Screening Visit. Test Product, Dose and Mode of Administration: Batch/Lot Number Ramelteon 8 mg tablet, oral Z Placebo tablet, oral Z Albuterol, inhalation aerosol ACZ54A Duration of Treatment: The study duration was up to 42 days and consisted of Screening, 2 Treatment Periods and a Final Visit. The Screening Period included 1 Outpatient and 1 overnight Inpatient Screening Visit between Study Days -21 and -7. The single-blind placebo dose was administered in the evening during the Inpatient Screening Visit. There were 2 randomized, double-blind Crossover Treatment Periods of 1 night each separated by a Washout Period of 5 to 10 days, and a Final Visit 7 days (±2 days) after sleep laboratory discharge from the Crossover Treatment Period 2. Reference Therapy, Dose and Mode of Administration, Batch Number: None Criteria for Evaluation: Primary Endpoint: Mean SaO2 during sleep for the entire night measured by pulse oximetry. Secondary Endpoints: Mean SaO2 calculated for each hour of the night measured by pulse oximetry. Mean SaO2 for Rapid Eye Movement (REM) and non-rem (NREM) sleep stages measured by pulse oximetry. Minutes for which SaO2 is less than 80% and minutes for which SaO2 is less than 90% as measured by pulse oximetry. Apnea Hypopnea Index (AHI) measured by pulse oximetry. Latency to persistent sleep (LPS), total sleep time (TST) and sleep efficiency as determined by polysomnography (PSG). Wake time after persistent sleep onset (WASO) as determined by PSG. Number of awakenings (NAW) after persistent sleep as determined by PSG. Percentage of time in REM sleep, stage 1, 2 and 3/4 NREM sleep as determined by PSG. Latency to REM as determined by PSG. Subjective sleep latency (ssl), subjective TST (stst), and subjective sleep quality as determined by a postsleep questionnaire. Subjective NAW (snaw) as determined by postsleep questionnaire. Safety: Safety variables included adverse events (AE), laboratory tests, vital signs, electrocardiogram (ECG) results and physical exam findings. Page 2 of 7

4 Statistical Methods: The completer set was the dataset analyzed for primary and efficacy analyses. The completer set consisted of all subjects who were randomized and received at least 1 dose of double-blind study medication with completed primary endpoint measurements. The full analysis set (FAS) was the dataset analyzed for safety analyses and consisted of all subjects who were randomized and received at least 1 dose of double-blind study medication. Analyses were performed for subpopulations based on baseline severity. The primary variable was mean SaO2 during sleep for the entire night measured by pulse oximetry. The primary analysis of this variable was performed for the completer analysis set. Comparisons between the ramelteon 8 mg and placebo treatment periods were made using 95% confidence intervals (CIs) for the treatment effect (difference between ramelteon and placebo) with least square means and standard errors obtained from the following analysis of variance (ANOVA) mixed model: Parameter = period + treatment + subject (sequence). The primary objective was met if the lower limit of 95% CI of the treatment effect (ramelteon placebo) lied above a clinically relevant difference of -1.5%. P-values for the primary outcome variable were reported, although they were not used in the interpretation of the results. Carry over effect was evaluated for the primary analysis. Secondary variables were analyzed similarly without assessing carry over effect. SUMMARY OF RESULTS Subject Disposition: A total of 25 subjects (15 male and 10 female; mean age of 64.0 years) were randomized in the study. Of the 25 randomized subjects, 9 had moderate COPD and 16 had severe COPD (diagnosis was confirmed at the Outpatient Screening Visit); the number of subjects was relatively evenly distributed among the 2 treatment sequences. All randomized subjects completed the study. Demographics and Baseline Characteristics The treatment groups were comparable regarding demographic and baseline characteristics (see table). Demographic and Baseline Characteristics COPD Severity, n (%) Ramelteon 8 mg/placebo N=13 Treatment Sequence Placebo/Ramelteon 8 mg N=12 Overall N=25 Moderate 4 (30.77) 5 (41.67) 9 (36.00) Severe 9 (69.23) 7 (58.33) 16 (64.00) Sex, n (%) Male 10 (76.9) 5 (41.7) 15 (60.0) Female 3 (23.1) 7 (58.3) 10 (40.0) Mean Age (SD) (yr) 64.4 (8.03) 63.5 (8.44) 64.0 (8.06) Race (a), n (%) Asian 0 (0.0) 1 (8.3) 1 (4.0) White 13 (100.0) 12 (100.0) 25 (100.0) Mean Weight (SD) (kg) 80.2 (14.54) 71.0 (10.23) 75.8 (13.25) Mean Height (SD) (cm) (8.02) (7.46) (8.47) Mean BMI (SD) (kg/m 2 ) 25.5 (3.53) 24.7 (3.14) 25.1 (3.30) (a) More than 1 race could be selected by a subject. Page 3 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. Because clinical trials are conducted under a variety of different conditions, the therapeutic effect observed in the clinical trials of a drug cannot be directly compared to the effects found in the clinical trials of other drugs, and may not reflect the therapeutic effects observed in practice. In the same way, therapeutic effects observed in a single clinical trial may not reflect the overall therapeutic effects observed in all clinical trials taken together. The efficacy information acquired from clinical trials does, however, provide a basis for identifying the potential effect a drug may have on subjects participating in the study. The results of the primary analysis for mean SaO2 (%) during sleep for the entire night by pulse oximetry (completer analysis set) are shown in the table below: Treatment Mean SaO2 (%) during Sleep during the Entire Night (by Pulse Oximetry) Placebo Ramelteon 8 mg (a) N Mean (SD) (2.866) (2.658) Minimum Maximum LS mean (SE) (b) (0.554) (0.554) LS mean difference from Placebo (SE) (0.414) 95% CI of difference (-1.09, 0.62) P-value (a) Mean SaO2 determined by pulse oximetry at the sleep laboratory for nights. (b) Least square (LS) means are from an ANOVA model with effects for period, treatment and subject ID (treatment sequence). Treatment with ramelteon 8 mg was clinically noninferior to placebo for the primary outcome variable, mean SaO2 for the entire night (the lower limit of the 95% CI of the treatment effect was above the clinically meaningful difference of -1.5%); the least square (LS) mean difference between treatments was not statistically significant (P=0.576). Page 4 of 7

6 A summary of the analysis of mean SaO2 (%) for each hour of the night (completer analysis set) is shown in the table below: Mean SaO2 (%) for Each Hour of the Treatment Night (by Pulse Oximetry) (a) Placebo (N=25) Ramelteon 8 mg (N=25) Hour 1 LS mean (SE) (b) (0.462) (0.462) LS mean difference from Placebo (SE) (0.281) 95% CI of difference (-1.13, 0.04) P-value Hour 2 LS mean (SE) (b) (0.523) (0.523) LS mean difference from Placebo (SE) (0.354) 95% CI of difference (-1.24, 0.22) P-value Hour 3 LS mean (SE) (b) (0.583) (0.583) LS mean difference from Placebo (SE) (0.470) 95% CI of difference (-1.90, 0.04) P-value Hour 4 LS mean (SE) (b) (0.539) (0.539) LS mean difference from Placebo (SE) (0.367) 95% CI of difference (-1.00, 0.52) P-value Hour 5 LS mean (SE) (b) (0.491) (0.491) LS mean difference from Placebo (SE) (0.380) 95% CI of difference (-1.25, 0.32) P-value Hour 6 LS mean (SE) (b) (0.451) (0.451) LS mean difference from Placebo (SE) (0.346) 95% CI of difference (-0.91, 0.52) P-value Hour 7 LS mean (SE) (b) (0.497) (0.497) LS mean difference from Placebo (SE) (0.361) 95% CI of difference (-1.04, 0.45) P-value Hour 8 LS mean (SE) (b) (0.499) (0.499) LS mean difference from Placebo (SE) (0.383) 95% CI of difference (-1.59, -0.01) P-value (a) Mean SaO2 determined by pulse oximetry at the sleep laboratory for nights. (b) LS means are from an ANOVA model with effects for period, treatment and subject identity (treatment sequence). Page 5 of 7

7 An analysis of the patients with moderate and severe COPD showed no difference in the SaO2 measured over an entire night between patients treated with ramelteon and those treated with placebo. In support of the primary analysis, mean SaO2 was similar between the ramelteon and placebo treatment periods for all 8 hours of the night. The lower limit of the 95% CI (of the treatment effect) was above the clinically meaningful difference of -1.5% for a majority of the hourly time points; exceptions included the lower limit of the 95% CI for Hour 3 (CI: -1.90, 0.04) and for Hour 8 (CI: -1.59, -0.01). The LS means for SaO2 for each measured stage of sleep (REM, NREM) were similar between the ramelteon and placebo treatment periods. The lower limit of the 95% CI for the REM stage of sleep was above the clinically meaningful difference of -1.5% (CI: -0.81, 1.29). The lower limit of the 95% CI for the NREM stage of sleep was less than the clinically meaningful difference (CI: -1.64, 0.19). There was no significant effect (all P 0.653) between treatments in the number of minutes of the night when SaO2 was less than 80% or less than 90%. The mean AHI was similar between the ramelteon and placebo treatment periods. There was no statistically significant difference (P=0.804) in AHI between the 2 treatments. There was no clinically meaningful treatment effect for mean SaO2 during sleep for the entire night between placebo and ramelteon 8 mg in subjects with severe COPD (N=16); the lower limit of the 95% CI was above the clinically meaningful difference of -1.5% (CI: -0.99, 1.13). The lower limit of the 95% CI for mean SaO2 in subjects with moderate COPD (N=9) was less than the clinically meaningful difference (CI: -2.56, 1.18). The LS mean difference between treatments was not statistically significant in either subpopulation (P 0.413). Sleep Assessments: For the objective sleep assessments by PSG, the LS mean for LPS was reduced in the ramelteon 8 mg treatment period (as compared with placebo); but this difference did not reach statistical significance (P=0.051). The LS means for both TST and sleep efficiency were both significantly greater (all P 0.019) in the ramelteon 8 mg treatment period (as compared with placebo). Although the LS mean for WASO was reduced in the ramelteon 8 mg treatment period (as compared with placebo), the difference between treatments was not statistically significant (P=0.276). The lack of statistical significance between treatments for both LPS and WASO was attributed to the small sample size and large variation of these parameters. The LS mean for NAW was comparable between treatments; the treatment difference was not significant (P=0.488). As measured subjectively by the postsleep questionnaire, the LS mean for stst was higher in the ramelteon 8 mg treatment group (as compared with placebo), whereas the LS means for ssl, snaw and subjective sleep quality were relatively similar between treatment groups. None of the LS mean differences for these subjective sleep variables was statistically significant (all P 0.074). The mean percentage of total sleep time in Stage 1, 2, 3/4 NREM, REM, and latency to REM was comparable between the ramelteon 8 mg and placebo treatment periods; none of the LS mean differences for these variables of sleep architecture was statistically significant (all P 0.098). Other 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. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs, and may not reflect the rates observed in practice. In the same way, the rates observed in a single clinical trial may not reflect the overall rates observed in all clinical trials taken together. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Page 6 of 7

8 Eight of the 25 subjects (32.0%) reported at least 1 AE during the study: 4 of 25 (16.0%) during the placebo treatment period and 4 of 25 subjects (16.0%) during the ramelteon 8 mg treatment period. Of 8 subjects, 5 had AEs that were considered treatment-related by the investigator (2 during placebo and 3 during ramelteon 8 mg treatment). All AEs reported during the study were rated as mild or moderate in intensity. In the placebo treatment period, the AEs included: fatigue (1 subject), hypercalcemia (1 subject), pain in jaw (1 subject), and road traffic accident (1 subject); the AEs of fatigue and hypercalcemia were judged by the investigator to be treatment-related. In the ramelteon 8 mg treatment period, the AEs were as follows: fatigue (1 subject), dizziness and photopsia (1 subject), respiratory tract congestion (1 subject), and supraventricular tachycardia (1 subject); all AEs except respiratory tract congestion were judged by the investigator to be treatment-related. There were no notable differences between treatment periods with respect to the severity, drug-relatedness, or other AE characteristics. No discontinuations due to AEs were reported, and no SAEs or deaths occurred during the study. There were no clinically important differences in incidence of changes for any laboratory parameters between treatments and there were no subjects who had markedly abnormal laboratory values for serum chemistry, or hematology laboratory tests. Although sporadic fluctuations in urinalysis and ECG results were reported, no trends were noted and no clinically important differences between treatments were observed. Date of Synopsis: 07 November 2008 Page 7 of 7