Clinical Trial Synopsis Title of Study: A Phase III, Open-Label, Fixed-Dose Study to Determine the Safety of Long-Term Administration of TAK-375 in Subjects With Chronic Insomnia Protocol Number: Name of Sponsor: Takeda Global Research and Development Brand Name/Active Ingredient Name: ROZEREM /TAK-375 (ramelteon) Page 1 of 5 NCT Number: NCT00671086 Publications based on the study: See ClinicalStudyResults.org posting for current publications Study Period: 26 February 2003 through 23 September 2004 Phase of Development: Phase 3 OBJECTIVES Primary: The objective of this study was to assess the long-term safety of regular use of TAK-375. Secondary: None METHODOLOGY Subjects were instructed to take a single oral dose of ramelteon at bedtime and to maintain sleep diaries for 1 year after having completed a 7-day Baseline Lead-in Period during which they completed a sleep diary and a menstrual diary (menstruating women only). Throughout the study, subjects returned to the clinic for safety assessments (including evaluation of adverse events, concomitant medications, sleep diaries, and menstrual diaries [menstruating women only]). At the end of dosing, subjects completed a 3-night Placebo Run-out Period. All study participants received placebo during this period, and all study participants, but not investigators, were blinded to treatment during this run-out period, which was designed to assess the potential for rebound insomnia upon withdrawal of ramelteon. Number of Subjects: Planned: 1000 subjects; Enrolled: 1213 subjects; Analyzed: 1213 subjects Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have 1) been 18 years of age or older 2) had a body mass index (BMI) between 18 and 34, 3) been willing to sign an informed consent, 4) participated previously in an allowed ramelteon study and had completed all Final Visit procedures from the previous study within 21 days of the Treatment Initiation Visit (or been ramelteon naïve), 5) required long-term treatment for insomnia, 6) had a diagnosis of primary insomnia as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR ) for at least 3 months and a history of daytime complaint(s) associated with disturbed sleep, 7) 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 Baseline Lead-in Period, based on the subject s sleep diary, 8) had an habitual bedtime between 8:30 PM and 12:00 AM, and 9) not had any sleep schedule changes required by employment (eg, shift worker) within 3 months prior to Day 1 of study medication, or had flown across more than 3 time zones within 7 days prior to Screening.
Test Product, Dose and Mode of Administration Ramelteon 8 mg, oral tablet: Ramelteon 16 mg, oral tablet: Placebo 8 mg, oral tablet: Placebo 16 mg, oral tablet: Duration of Treatment: The treatment duration was approximately 1 year. Reference Therapy, Dose and Mode of Administration: Not applicable Page 2 of 5 Lot Number: Z5159021, Z5159031, Z515K011, Z515K031 Z515A031, Z515L011, Z515L021 Z515H011 Z515J011 Criteria for Evaluation: Safety: The primary endpoints of this study were adverse events and changes in vital signs, laboratory tests, electrocardiograms (ECGs), physical examination findings, and menstrual diary results over the course of treatment. Efficacy: The secondary endpoints of this study were subjective sleep assessments (including stst and ssl) collected from subjects diaries over the week preceding each visit. Additional secondary endpoints were the results from clinicians Clinical Global Impression (CGI) scales. Measures of ssl were used to assess rebound insomnia. Statistical Methods: For continuous variables, descriptive statistics included the number of subjects, mean, standard deviation or standard error (as appropriate), minimum, median, and maximum. For categorical data, frequency counts and percentages were presented. Rebound insomnia and safety evaluations were based on observed data only. Summaries of efficacy variables were based on last observation carried forward (LOCF) data. Subject Sets Analyzed: The intent-to-treat (ITT) population was analyzed for safety and efficacy. The ITT population consisted of all subjects who received at least 1 dose of open-label study medication. In practice, analysis for a given variable included only subjects who had a measurement for that variable. Subjects were evaluated according to the actual treatment they received. Summaries of disposition, exposure, compliance, and safety data were presented for subjects who completed 24 (6 months) and 48 weeks (1 year) of dosing. Subjects were considered to be compliant with dosing if they took an average of at least 3 doses per week. In order to be considered compliant subjects in the 24-week group had to have taken at least 72 tablets at the Month 6 Visit and subjects in the 48-week group had to have taken at least 144 tablets at the Month 12 Visit. Data presentations that summarize the ITT Population are synonymous with all subjects; the 24-Week Compliant population is synonymous with the population of subjects who took ramelteon for 6 months; and the 48-Week Compliant population is synonymous with the population of subjects who took ramelteon for 1 year. SUMMARY OF RESULTS Subject Disposition: A total of 1213 subjects enrolled from 123 clinical sites in the United States; 597 completed 6 months of dosing with ramelteon and 472 completed 1 year of dosing with ramelteon. Overall, 473 subjects completed the open-label portion of the trial and 740 discontinued participation in the study. The main reasons subjects discontinued from the study were lack of efficacy (239 subjects, 19.7%), adverse events (148 subjects, 12.2%), and withdrawal of consent (144 subjects, 11.9%). Of the 597 subjects who completed 6 months of dosing with ramelteon, 125 (20.9%), withdrew or were withdrawn from the study before they completed 1 year of dosing with ramelteon. The main reasons given
were withdrawal of consent (34 subjects, 5.7%), lack of efficacy (22 subjects, 3.7%), and adverse event (19 subjects, 3.2%), protocol deviations (17 subjects, 2.8%), and lost to follow-up (17 subjects, 2.8%). The mean age of subjects in this trial was 51.6 years; 501 men and 712 women were enrolled. Efficacy Results: 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. ssl (Observed Data): Following regular dosing with ramelteon for both elderly adult and nonelderly adult subjects, ssl improved over the course of the study. At 6 months, the mean ssl was less than 50 minutes (approximately 35 minutes less than Baseline, which was between 85 and 89 minutes); this improvement in ssl was seen as early as at 2 to 3 months. At 1 year, improvements in ssl were sustained and mean ssl was approximately 42 minutes. ssl (LOCF data): Clinically meaningful reductions in ssl from Baseline occurred by month 2 (58.4 minutes for elderly subjects and 60.0 minutes for adult subjects) and month 3 (59.9 minutes for elderly and 58.7 minutes for adult) in both elderly and adult subjects with nightly dosing of ramelteon. At 6 months of nightly dosing, reductions in ssl were sustained and mean ssl were 60.2 minutes for elderly subjects and 58.1 minutes for adult subjects. Following 1 year of nightly dosing, reductions in ssl continued and mean ssl was 59.0 minutes for elderly subjects and 58.3 minutes for adult subjects. stst (Observed Data): The mean observed duration of stst improved over the course of the study. At 6 months, the mean improvement in stst was approximately 1 hour. At 1 year, improvement in stst was sustained and mean stst was approximately 72 to 75 minutes. As demonstrated in mean reduction of ssl, increases in mean stst were seen as early as months 2 and 3. stst (LOCF data): Clinically meaningful increases in stst from Baseline occurred by month 2 for elderly subjects (334.7 minutes) and adult subjects (350.0 minutes) with nightly dosing of ramelteon. At 6 months of nightly dosing with ramelteon for both elderly and adult subjects, improvements in stst were sustained and mean stst was 333.4 minutes for elderly subjects and 352.6 for adult subjects. At 1 year, increases in stst from Baseline continued and mean stst was 335.8 minutes for elderly subjects and 352.1 minutes for adult subjects. Mean results from CGI indices indicated that: Based on investigators assessment, subjects insomnia condition improved from Baseline at 6 months (global rating of change of condition); this change was sustained at 1 year. There was a moderate and sustained improvement in the severity of illness at 6 months and 1 year. Investigators reported that there was a moderate therapeutic effect of ramelteon at 6 months and 1 year. The results for elderly and adult were similar for all efficacy outcomes. No rebound insomnia occurred in this study, even after 1 year of exposure to ramelteon. Page 3 of 5
Safety Results: 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. The most common adverse events (ie, occurring in greater than or equal to 5% of the ITT population) reported by all subjects, 24-Week Compliant subjects, and 48-Week Compliant subjects were headache, somnolence, nasopharyngitis, and upper respiratory tract infection. The most common adverse events reported by all subjects were headache (8.7%), somnolence (8.0%), nasopharyngitis (7.9%), upper respiratory tract infection (5.9%) and fatigue (5.1%); by 24-Week Compliant subjects were nasopharyngitis (13.4%), headache (10.9%), upper respiratory tract infection (9.2%), somnolence (7.9%), sinusitis (5.7%), and influenza (5.0%); and by 48-Week Compliant subjects were nasopharyngitis (13.9%), headache (10.9%), upper respiratory tract infection (10.3%), somnolence (8.4%), sinusitis (6.5%), diarrhea (5.3%), and influenza (5.1%). Subjects who took ramelteon for at least 6 months and 1 year had a higher incidences of drug-related (per the investigator) adverse events under the system organ class (SOC) Investigations (10.4% and 9.7%, respectively) than all subjects (6.7%); many adverse events in this category were laboratory results. Subjects who took ramelteon for at least 6 months and 1 year had a lower incidences of events under the Psychiatric Disorders SOC (4.5% and 3.8%, respectively) than all subjects (6.4%). The incidence of abnormal dreams, nightmares and exacerbated insomnia was less in subjects who took ramelteon for at least 6 months and 1 year compared to all subjects. Two subjects died during the study; both subjects were in the ramelteon 16 mg adult group and died as the result of motor vehicle accidents. Neither death was considered by the investigator or the sponsor s medical monitor to be related to study medication. Thirty-eight subjects experienced serious adverse events (SAEs) during the study. Three subjects in the ITT population, 3 subjects in the 24-week Compliant group, and 1 subject in the 48-week Compliant group experienced SAEs that were considered drug-related by the investigator. These events included cerebral vascular accident (8 mg elderly group), syncope (16 mg adult group), and prolactinoma (16 mg adult group). One-hundred forty-seven (12%) subjects experienced treatment-emergent adverse events that led to study drug discontinuation. Three percent of those who completed 6 months of dosing with ramelteon withdrew due to adverse events. Clinical Chemistry For subjects who took ramelteon for 6 months and for 1 year, group mean clinical chemistry values and mean changes from Baseline were unremarkable. Shift changes occurred for a small number of subjects, and almost always, it was less than 2% of subjects for any analyte in either direction. In addition, there did not appear to be any changes in a number of analytes that might reflect systemic diseases or health conditions (eg, increased BUN and creatinine, with alterations in serum protein and albumin might suggest renal disease). The greatest numbers of subjects who had markedly abnormal clinical chemistry values, without regard to whether they had normal values at Baseline occurred for alanine aminotransferase (ALT) (n=8), aspartate aminotransferase (AST) (n=9), gamma glutamyl transferase (GGT) (n=11), blood urea nitrogen (BUN) (n=36), uric acid (n=27), and fasting serum glucose (n=36). The differences between the incidences of subjects with markedly abnormal clinical chemistry results between subjects who took ramelteon for 6 months and for 1 year was small and, when it was different, there were always fewer subjects among those with 1 year of drug exposure compared to those with at least 6 months exposure. Page 4 of 5
Hematology Mean hematology values, mean changes from Baseline, and the distribution of the values around the means were contained within the range of normal for all analytes. Mean changes from Baseline at 6 months and at the Final Visit were not clinically important for any value. At Month 6, there were no clinically important differences in the hematology and WBC differential shift results between all subjects and subjects who took ramelteon for 6 months. There also were no clinically relevant changes in these shifts between all subjects at their Final Visit and between all subjects and subjects who took ramelteon for 1 year. The differences between the incidences of subjects with markedly abnormal hematology and WBC results between subjects who took ramelteon for 6 months and for 1 year was small and, as for clinical chemistry results, when it was different there were always fewer subjects among those with 1 year of drug exposure compared to those with at least 6 months exposure. Urinalysis There were no clinically important differences between the results for all subjects and for subjects who completed 6 months and 1 year of dosing with ramelteon. The only shifts in urinalysis values occurred with specific gravity. These findings did not appear to be clinically relevant in the absence of significant clinical findings such as dehydration, for example. The number of subjects who had markedly abnormal urinalysis values and took ramelteon for 1 year was less than for those who took ramelteon for 6 months. Endocrine Tests No clinically important changes in endocrine laboratory parameters were identified. Vital Signs, ECGs, Physical Findings, and Menstrual Diaries Mean vital sign values and changes from Baseline were not considered clinically meaningful at any timepoint or for any analysis performed in this study. There were no major findings as a result of physical examinations. Three subjects had ECGs that became abnormal and clinically important during the trial at 6 months, and 1 subject had an ECG that was abnormal (but not clinically important) that became clinically important during treatment. Four subjects had abnormal and clinically important ECGs that normalized during treatment with ramelteon and 1 that was abnormal and clinically important improved during treatment (ie, no longer clinically important). At the Final Visit, the ECG results were similar; 7 subjects ECGs improved from abnormal and clinically important to normal or abnormal and not clinically important. Five subjects ECGs deteriorated from normal or abnormal (but not clinically important) to abnormal and clinically important. At least 80% of menstruating women reported that their menses were normal at the first, sixth, and twelfth menses during the study. There was a normal distribution in the results for each menses. There did not appear to be any clinically important differences in this distribution for the first, sixth, and twelfth menses compared to the Baseline distribution. Date of Synopsis: 30 September 2008 Page 5 of 5