An Efficacy Study of Compound LY2624803 in the Treatment of Patients With Chronic Insomnia

Study Overview
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Brief Summary
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The purpose of this study is to compare an investigational drug (LY2624803) with placebo and with zolpidem in the treatment of outpatients with chronic insomnia.

Detailed Description
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Outpatients with chronic insomnia who participate in this study will be treated in each of four 2-week treatment periods with bedtime doses of either placebo, zolpidem, LY2624803 1 mg, or LY2624803 3 mg. Neither patients nor investigators will be told what treatments are being given in any treatment period. A patient who completes all four treatment periods will be treated with placebo in 1, 2, or 3 of the periods; with zolpidem in 0, 1, or 2 of the periods; and with LY2624803 in either 1 or 2 of the periods. No patient will receive placebo for all four of the 2-week treatment periods. All patients will receive LY2624803 for at least one of the four 2-week treatment periods. During each treatment period, patients will record information each morning about their sleep the night before, and each evening about their functioning since waking up. Patients will also wear wrist actigraphy devices to record their physical activity. At the conclusion of each treatment period, patients will answer questions about their sleep, functioning, health, and relative preference for treatments.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo- and Active-Comparator-Controlled Study of the Safety and Efficacy of LY2624803 in Outpatients With Insomnia

Conditions
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Primary Insomnia, Secondary Insomnia

Intervention / Treatment
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* Drug: LY2624803
* Drug: LY2624803
* Drug: Placebo
* Drug: zolpidem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be between 18 and 85 years of age, with a stable living situation Clinical diagnosis of either primary insomnia or secondary insomnia (comorbid with depression, anxiety, and/or medical illness) Insomnia systems must be at least moderate in severity within the month prior to study entry, and must include difficulty staying asleep and/or problems with awakening earlier than desired Psychiatric and medical conditions present must be stable over the 3 months prior to study entry, and not expected to worsen significantly or require hospitalization during participation in the study Ongoing treatments for psychiatric and medical conditions present must have been stable for the 3 months prior to study entry, and must be expected to remain stable during participation in the study Patients must be willing to abstain from taking medications (other than study drug) to help them sleep during participation in the study Patients must be willing to consistently spend at least 7 hours each night either sleeping or trying to sleep during participation in the study Patients must be able to speak and read English and be capable of using a computer with a web browser (computers with internet connections will be provided to patients who need them) Exclusion Criteria: Unusual or unstable sleep/wake schedule, such as with rotating shift work Severe or unstable psychiatric or medical illness Suicidal ideation Substance abuse Known obstructive sleep apnea, restless leg syndrome, or periodic limb movement disorder History of seizures Body Mass Index > 33 Clinically significant abnormality in clinical chemistry, hematology, urinalysis, and/or electrocardiogram Anticipated inability to regularly use a medication which might reduce motor or cognitive functioning during sleeping hours, such as a person who might often need to be on call, drive a car, or be responsible for the care of another person during sleeping hours Contraindication to zolpidem History of breast cancer An estimated glomerular filtration rate (GFR; an index of renal function) that is <30 mL/min at study entry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Period A<br>2-week double-blind placebo lead-in period. Period A is the first of four 2-week treatment periods. | Drug: Placebo<br>* matching placebo (capsule or tablet), once nightly before bedtime<br>|
| Experimental: Period B<br>Patients will receive LY2624803, zolpidem or placebo in a sequence of four 2-week treatment periods. Period B is the second of four 2-week treatment periods. | Drug: LY2624803<br>* 1 mg, oral capsule, once nightly before bedtime<br>Drug: LY2624803<br>* 3 mg, oral capsule, once nightly before bedtime<br>Drug: Placebo<br>* matching placebo (capsule or tablet), once nightly before bedtime<br>Drug: zolpidem<br>* 5 or 10 mg, oral tablet, once nightly before bedtime<br>|
| Experimental: Period C<br>Patients will receive LY2624803, zolpidem or placebo in a sequence of four 2-week treatment periods. Period C is the third of four 2-week treatment periods. | Drug: LY2624803<br>* 1 mg, oral capsule, once nightly before bedtime<br>Drug: LY2624803<br>* 3 mg, oral capsule, once nightly before bedtime<br>Drug: Placebo<br>* matching placebo (capsule or tablet), once nightly before bedtime<br>Drug: zolpidem<br>* 5 or 10 mg, oral tablet, once nightly before bedtime<br>|
| Experimental: Period D<br>Patients will receive LY2624803, zolpidem or placebo in a sequence of four 2-week treatment periods. Period D is the fourth of four 2-week treatment periods. | Drug: LY2624803<br>* 1 mg, oral capsule, once nightly before bedtime<br>Drug: LY2624803<br>* 3 mg, oral capsule, once nightly before bedtime<br>Drug: Placebo<br>* matching placebo (capsule or tablet), once nightly before bedtime<br>Drug: zolpidem<br>* 5 or 10 mg, oral tablet, once nightly before bedtime<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Nightly Total Sleep Time at Week 4 (Week 2 of Period B) Endpoint | Total Sleep Time is defined as time in bed minus total time awake. Minimum would be 0; no defined maximum (except if as defined as time in bed). The higher the number, the more time asleep. Calculated in minutes from participant-reported daily sleep questionnaire averaged across study Period B (2 weeks). Change score subtracts Period B average from Period A average (baseline). Analysis of covariance (ANCOVA) Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Unwanted Time Awake at Week 4 (Week 2 of Period B) Endpoint | Unwanted time awake (minutes awake [MA] before sleep [between turning off the lights to first falling asleep], MA during sleep, MA after sleep before getting out of bed). Minimum would be 0; no defined maximum. The higher the number, the more the unwanted time awake. Calculated in minutes from participant-reported daily sleep questionnaire averaged (Avg.) across Period B. Change score subtracts Period B Avg. from Period A Avg. (baseline). ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group, and insomnia type. | Baseline, 2 weeks | 
| Change From Baseline in Number of Awakenings During Sleep at Week 4 (Week 2 of Period B) Endpoint | Elicited from participant-reported daily sleep questionnaire averaged across study Period B (2 weeks). Change score subtracts Period B average from Period A average (baseline). ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Change From Baseline in Total Time Awake at Week 4 (Week 2 of Period B) Endpoint | Calculated in minutes from participant-reported daily sleep questionnaire averaged across study Period B (2 weeks). Change score subtracts Period B average from Period A average (baseline). ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Change From Baseline in Sleep Efficiency at Week 4 (Week 2 of Period B) Endpoint | Calculated as (TIB-TTA)/TIB where TIB is time in bed and TTA is total unwanted time awake. Higher score indicates better sleep efficiency. ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Change From Baseline in Assessment of Sleep Quality at Week 4 (Week 2 of Period B) Endpoint | Assessment of Sleep Quality (ASQ) scale is asked in the participant-reported daily sleep questionnaire; 8 items on 4 point Likert scale with a range of 0 to 24. Sleep experience score ranges from 0-9; awakening experience ranges from 0-15. The higher the score, the better the sleep. Scale is averaged across study Period B (2 weeks). Change score subtracts Period B average from Period A average (baseline). ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Change From Baseline in Participants' Impression of Daytime Functioning Measured by Daily Consequences of Insomnia Questionnaire (DCIQ) at Week 4 (Week 2 of Period B) Endpoint | DCIQ scale is asked in the participant-reported daily evening questionnaire; 5 point Likert scale with minimum of 0 and maximum of 44 (the higher the score, the more consequences of insomnia). Scale is averaged across study Period B (2 weeks). Change score subtracts Period B average from Period A average (baseline). ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Change From Baseline in the Insomnia Severity Index (ISI) at Week 4 (Week 2 of Period B) Endpoint | The ISI is a brief self-report instrument that measures a participant's perception of his or her insomnia. 7 questions on 5-point Likert scale with minimum of 0 and maximum of 28. The higher the score, the more severe the insomnia. It was collected at the bi-weekly office visits. ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Change From Baseline in Physical and Mental Component Scores as Measured by the Short Form 12 (SF-12) Version 2 at Week 4 (Week 2 of Period B) Endpoint | The SF-12 is a subset of 12 items from the Medical Outcomes Study 36-Item Short Form Survey (SF-36) and was collected at the bi-weekly office visits. Each score ranges from 0-100. The components measure physical and mental health, respectively. Higher scores are indicative of better function. ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary) | Baseline, 2 weeks | 
| Change From Baseline in Health-related Quality of Life as Measured by European Quality of Life (EuroQol) at Week 4 (Week 2 of Period B) Endpoint | The EuroQoL Questionnaire-5 Dimension (EQ-5D) is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood. The score ranges 0-100. The higher score indicates a better health state perceived by the participant. ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, age group (<65 or ≥65), and insomnia type (primary vs. secondary). | Baseline, 2 weeks | 
| Treatment Satisfaction as Measured by the Participant Drug Preference Question | After study Periods A, and B, participants were asked to rate their experience with the treatment they had just completed. Data are presented as percentage of participants preferring the treatment received in Period A (placebo) or treatment received in Period B. | Baseline (Period A) and 2 weeks (Period B) | 
| Clinical Global Impression of Improvement (CGI-I) in Insomnia at Week 4 (Week 2 of Period B) Endpoint | Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment. Scores range from 1 (very much improved) to 7 (very much worse). Data are presented as percentage of participants in each category. | 2 weeks | 
| Patient Global Impression of Improvement (PGI-I) in Insomnia at Week 4 (Week 2 of Period B) Endpoint | A scale that measures the participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much improved) to 7 (very much worse). Data are presented as percentage of participants in each category. | 2 weeks | 
| Change From Baseline in Total Sleep Time at Week 4 (Week 2 of Period B) Endpoint Based on Insomnia Type | Total Sleep Time is defined as time in bed minus total time awake. Minimum would be 0; no defined maximum (except if as defined as time in bed). The higher the number, the more time asleep. Analyses were not performed by insomnia type (primary versus secondary) as originally planned because of insufficient number of secondary insomnia participants. | Baseline, 2 weeks | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Based on Insomnia Type | Number of participants with AEs and SAEs. Analyses were not performed by insomnia type (primary versus secondary) as originally planned because of insufficient number of secondary insomnia participants. | Baseline through 8 weeks | 
| Change From Baseline in Total Sleep Time at Week 4 (Week 2 of Period B) Endpoint Based on Age Group | Total Sleep Time is defined as time in bed minus total time awake. Minimum would be 0; no defined maximum (except if as defined as time in bed). The higher the number, the more time asleep. Analyses were not performed by age group (under age 65 versus over age 65) as originally planned because of insufficient number of elderly participants. | Baseline, 2 weeks | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Based on Age Group | Number of participants with AEs and SAEs. Analyses were not performed by age group (under age 65 versus over age 65) as originally planned because of insufficient number of elderly participants. | Baseline through 8 weeks | 
| Number of Participants With Treatment Emergent Adverse Events (TEAE) | Treatment Emergent Adverse Events (TEAEs) are defined as AEs that first occurred or worsened during the treatment period. TEAEs are summarized by study period and treatment group. TEAEs do not distinguish whether the events were deemed serious. A summary of non-serious AEs is located in the Reported Adverse Event module. | Baseline through 8 weeks | 
| Number of Participants With Serious Adverse Events (SAEs) | SAEs do not distinguish whether the events are treatment-emergent. A summary of SAEs is located in the Reported Adverse Event module. | Baseline through 8 weeks | 
| Change From Baseline in Blood Pressure (BP) at Each 2-Week Treatment Endpoint | Change from baseline to the end of each of the 2-week treatment periods (Periods B, C, and D) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) are presented. Least Squares Mean (LSMean) values were adjusted for baseline and treatment. | Baseline, 2 weeks of treatment over 8 weeks | 
| Change From Baseline in Pulse Rate at Each 2-week Treatment Endpoint | Change from baseline to the end of each of the 2-week treatment periods (Periods B, C, and D) for pulse rate are presented. Least Squares Mean (LSMean) values were adjusted for baseline and treatment. | Baseline, 2 weeks of treatment over 8 weeks | 
| Change From Baseline in Weight at Each 2-week Treatment Endpoint | Change from baseline to the end of each of the 2-week treatment periods (Periods B, C, and D) for body weight are presented. Least Squares Mean (LSMean) values were adjusted for baseline and treatment. | Baseline, 2 weeks of treatment over 8 weeks | 
| Number of Participants With Abnormal Laboratory Analytes at Each 2-Week Treatment Endpoint | Summary of number of participants with abnormal clinical chemistry, hematology and urinalysis laboratory results. A participant is included in the abnormal category if he/she experienced a result outside the normal reference ranges based on Lilly's reference range in the current period. All analytes have both lower and upper limits. The abnormal number includes both low (below normal range) and high (above normal range). | 2 weeks of treatment over 8 weeks | 
| Change From Baseline in Heart Rate as Measured by Electrocardiogram (ECG) at Each 2-week Treatment Endpoint | Change from baseline to the end of each of the 2-week treatment periods (Periods B, C, and D) for heart rate are presented. Least Squares Mean (LSMean) values were adjusted for baseline and treatment. | Baseline, 2 weeks of treatment over 8 weeks | 
| Change From Baseline in QT Interval Corrected Using Fridericia Formula (QTcF) as Measured by Electrocardiogram (ECG) at Each 2-week Treatment Endpoint | QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTcF is the QT interval corrected for heart rate using Fridericia formula. Least Squares Mean (LSMean) values were adjusted for baseline and treatment. | Baseline, 2 weeks of treatment over 8 weeks |