Pharmacokinetic and Safety of Ramelteon Between Adolescents With Insomnia and Healthy Adults

Study Overview
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Brief Summary
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The purpose of this study is to determine the pharmacokinetic profile, safety, and tolerability of ramelteon in adolescents with insomnia, children with Attention Deficit Hyperactivity Disorder (ADHD) associated with insomnia and gender- and race-matched healthy adults.

Detailed Description
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Ramelteon is a treatment for insomnia approved for use in the United States (US) in July 2005 and in the Philippines and Indonesia in 2008. It is currently under development in the European Union (EU) and Japan. Ramelteon is marketed in the US as ROZEREM® for the treatment of insomnia characterized by difficulty with sleep onset in patients over 18 years of age. In adolescents, the form of sleep onset and/or sleep maintenance insomnia, defined as psychophysiologic insomnia, is similar to adults, and more appropriate for treatment with pharmacological intervention when compared to insomnia in children younger than 12 years of age. In psychophysiologic insomnia, the individual develops conditioned anxiety around difficulty falling or staying asleep, which leads to heightened physiologic and emotional arousal and further compromises the ability to sleep. In children over the age of 12, insomnia is more likely to be persistent and have identifiable consequences. In addition, there is less variability in normative sleep data for this age group than in younger children. Sleep disturbances are also common in children. Specifically, insomnia associated with ADHD in children is very common with a reported prevalence of 28% in medication-free children with ADHD. This study is to characterize the pharmacokinetics (PK) and safety profile of a 4 or 8 mg dose of ramelteon in adolescents who are between 12 to 17 years of age (prior to the 18th birthday) with insomnia characterized by difficulty with sleep initiation, and in pediatrics who are between 6 to 11 years of age who have insomnia associated with ADHD. These profiles will be compared with those of healthy adults aged 18 to 50 years who are matched by race and gender receiving an 8 mg dose of ramelteon. This open-label study is designed in accordance with the recommendations of the FDA and ICH guidances for pediatric PK studies.

Official Title
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A Comparative Single Dose Pharmacokinetic and Safety Study of 4 mg or 8 mg Ramelteon in Adolescents With Insomnia Characterized by Difficulty With Sleep Onset, Children With Insomnia Associated With ADHD, and Healthy Adults.

Conditions
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Insomnia

Intervention / Treatment
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* Drug: Ramelteon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for adolescent and pediatric participants only: Is male or female between 12 and 17 years of age (less than 18 years of age on Day 1) with complaints of insomnia characterized by difficulty with sleep initiation OR a male or female between 6 to 11 years of age (less than 12 years of age on Day 1) with complaints of insomnia characterized by difficulty with sleep initiation associated with ADHD. Has a body mass index within the 5th to 95th percentile of the appropriate body mass index designated charts based on stature-for-age and weight-for-age and by gender. In the age group of 12 to 17 years, has a history of primary insomnia characterized by difficulty initiating sleep as defined by the Pharmacologic Management of Insomnia in Children and Adolescents: Consensus Statement OR in the age group of 6 to 11 years, has a history of insomnia characterized by difficulty with sleep initiation (as defined by the Pharmacologic Management of Insomnia in Children and Adolescents: Consensus Statement associated with ADHD). There is agreement in the participant's parent or caregiver's opinion with the following: The complaint involves significant difficulty in initiating sleep The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or parasomnia. The disturbance does not occur exclusively during the course of another mental disorder (eg, Major Depressive Disorder, Generalized Anxiety Disorder, and Delirium). The disturbance is not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication) or a general medical condition. Based on sleep history, reports a subjective sleep latency greater than or equal to 45 minutes for at least 1 month. If taking concomitant medications, he/she has been on a stable dose or regimen of his/her medication for at least 30 days prior to Screening. Inclusion criteria for gender- and race-matched adult participants only: Weighs at least 50 kg (110 pounds) and has a Screening body mass index between 18 and 30 kg/m^2, inclusive. Inclusion criteria for all participants: A female of childbearing potential (defined as females aged ≥12 years old and younger girls who, at the discretion of the investigator, are deemed to be of reproductive potential) and males who are sexually active agree to routinely use adequate contraception from Screening throughout the duration of the study and through 30 days following the last dose of study medication. Must have a negative urine test result for selected substances of abuse (including alcohol) at Screening and Day 1. Has clinical laboratory results (including clinical chemistry, hematology, and complete urinalysis [fasted] within the reference range for the testing laboratory unless the results are deemed not clinically meaningful by the investigator or sponsor. Has a negative test result for hepatitis B surface antigen and hepatitis C virus antibody, and no known history of human immunodeficiency virus. Exclusion Criteria: Is participating in another investigational study or has taken an investigational drug within 30 days (or 5 half-lives, whichever period is longer) prior to study Screening. Has received ramelteon within 30 days of Screening. Is a study site employee, or is an immediate family member (ie, spouse, parent, child, sibling) of a study site employee, involved in conduct of this study. Has abnormal hematological parameters of hemoglobin and/or hematocrit (if these exceed +/- 2 points of the normal range for the age and sex appropriate values), or erythrocytes at Screening. Has a known hypersensitivity to ramelteon or related compounds including melatonin. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as consumption of more than 4 alcoholic drinks per day) within 1 year prior to study Day 1. Has had an acute, clinically significant illness within 30 days prior to Screening. Has autistic spectrum disorders or other pervasive developmental disorder. Has a history or clinical manifestations of significant metabolic (including diabetes mellitus, hypercholesterolemia, or dyslipidemia), hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urologic, immunologic, musculoskeletal, or psychiatric disorder unless currently controlled and stable with protocol-allowed medication for at least 30 days prior to Screening (except for ADHD in the age group of 6 to 11 years). Has sleep schedule changes required by employment, school and/or extra curricular activity (eg, shift worker) within 3 months prior to Screening, or has flown across greater than 3 time zones within 7 days prior to Screening. Has a history or clinical manifestations of depression, seizures, sleep apnea, restless leg syndrome, or periodic leg movements during sleep. Has a history of abdominal surgery (except laparoscopic cholecystectomy or uncomplicated appendectomy) or thoracic or nonperipheral vascular surgery within 6 months prior to study Day 1. Has a history of cancer, other than basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to study Day 1. Has used any tobacco (ie, nicotine) products (including but not limited to cigarettes, pipe, cigar, chewing tobacco, nicotine patch, or nicotine gum) within 6 weeks prior to Screening, or is unwilling to abstain from these products for the duration of the study. Has poor peripheral venous access. Has any clinically important abnormal finding as determined by a medical history, physical examination, electrocardiography (ECG), or clinical laboratory tests, as determined by the investigator. Participants with clinically significant abnormalities being considered for the study must be approved by both Takeda medical monitor or designee and the Principal Investigator. Has any additional condition(s) that in the Investigator's opinion would: a) affect sleep/wake function, b) prohibit from completing the study, or c) not be in the best interest of to participate in the study.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Children Ramelteon 4 mg<br>Children 6 to 11 years of age who had insomnia associated with ADHD received a single 4 mg oral dose of ramelteon. | Drug: Ramelteon<br>* Ramelteon tablets, orally for one day only.<br>* Other names: Rozerem;|
| Experimental: Children Ramelteon 8 mg<br>Children 6 to 11 years of age who had insomnia associated with ADHD received a single oral 8 mg dose of ramelteon. | Drug: Ramelteon<br>* Ramelteon tablets, orally for one day only.<br>* Other names: Rozerem;|
| Experimental: Adolescents Ramelteon 4 mg<br>Adolescents 12 to 17 years of age with insomnia received a single oral dose of 4 mg ramelteon. | Drug: Ramelteon<br>* Ramelteon tablets, orally for one day only.<br>* Other names: Rozerem;|
| Experimental: Adolescents Ramelteon 8 mg<br>Adolescents 12 to 17 years of age with insomnia received a single oral dose of 8 mg ramelteon. | Drug: Ramelteon<br>* Ramelteon tablets, orally for one day only.<br>* Other names: Rozerem;|
| Active Comparator: Healthy Adult Ramelteon 8 mg<br>Healthy adults (18 to 50 years old) received a single oral dose of 8 mg ramelteon. | Drug: Ramelteon<br>* Ramelteon tablets, orally for one day only.<br>* Other names: Rozerem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) | Maximum observed serum concentration (Cmax) is the peak serum concentration of ramelteon and its metabolite (M-II) after administration, obtained directly from the serum concentration-time curve. | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Time to Reach Maximum Serum Concentration (Tmax) | Tmax: Time to reach the maximum serum concentration (Cmax) of ramelteon and its metabolite M-II, equal to time (hours) to Cmax. | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Area Under the Serum Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]) | Area under the serum concentration-time curve from time 0 to time of last quantifiable concentration (tlqc) of ramelteon and its metabolite M-II, calculated using the linear trapezoidal rule. | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) | Area under the serum concentration-time curve from time zero extrapolated to infinity for ramelteon and its metabolite M-II. The terminal area from the last quantifiable concentration (lqc) to infinity is calculated by approximation: lqc / terminal elimination rate constant (λz). | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Apparent Clearance After Oral Administration (CL/F) | Apparent oral clearance of drug from the serum calculated as: CL/F = Dose / Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC[0-inf]). | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Terminal Elimination Rate Constant (λz) | The rate at which ramelteon and its metabolite M-II are eliminated from the body, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Terminal Elimination Half-life (T1/2) | Terminal phase elimination half-life (T1/2) for ramelteon and its metabolite M-II is the time required for half of the drug to be eliminated from the serum, calculated as T1/2 = natural logarithm of 2 (ln[2]) / Terminal elimination rate constant (λz). | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 
| Apparent Volume of Distribution (Vz/F) | Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as Vz/F = Apparent oral clearance (CL/F) / Terminal elimination rate constant (λz). | Day 1: predose (within 1 hour prior to dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product; it did not necessarily have to have a causal relationship with this treatment. The different categories of intensity (severity) were characterized as follows: Mild: The event was transient and easily tolerated by the participant. Moderate: The event causes the participant discomfort and interrupted usual activities. Severe: The event causes considerable interference with the participant's usual activities. | Day 1 to Day 15 | 
| Number of Participants With Clinically Significant Laboratory Findings | Laboratory samples were collected at Screening, Check-in (Day 1), and Day 2 or Early Termination for assessment of hematology, chemistry, and urinalysis. | Screening, Day 1, Day 2 and Day 4 | 
| Number of Participants With Clinically Significant Vital Signs | Vital signs included oral body temperature, pulse and blood pressure (taken after 5 minutes in the sitting position). Vital signs measurements were determined to be clinically significant according to predefined criteria. | Screening, Day 1, Day 2 and Day 4 | 
| Number of Participants With Clinically Significant Electrocardiogram Findings | A standard 12-lead electrocardiogram (ECG) was recorded at Screening, Day 2, and at Final Visit (Day 4). The investigator interpreted the ECG using one of the following categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically significant. | Screening, Day 2 and Day 4 | 
| Number of Participants With Clinically Significant Physical Examination Results | A complete physical examination was performed for each participant at Screening, Check-in (Day 1), Day 2, and Final Visit (Day 4) or Early Termination. The examination consisted of a review of the following body systems: eyes; ears, nose, and throat; respiratory; gastrointestinal; extremities; musculoskeletal; cardiovascular; nervous; and dermatological. | Screening, Day 1, Day 2 and Day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep Initiation and Maintenance Disorders, Drug Therapy