Safety, Tolerability and Efficacy Study of V117957 in Subjects With Insomnia Associated With Alcohol Cessation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and efficacy of V117957 in subjects with alcohol use disorder (AUD) who experience insomnia associated with alcohol cessation, compared to placebo.

Official Title
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A Phase 2, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of V117957 in Subjects With an Alcohol Use Disorder Who Are Experiencing Insomnia Associated With Alcohol Cessation

Conditions
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Insomnia

Intervention / Treatment
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* Drug: V117957 tablets
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria include: Male or female, 18-64 years of age with a body weight of 50-100 kg (110-220 lbs) and a body mass index (BMI) of 18-32 kg/m2. Otherwise healthy as determined by medical evaluation that includes: medical history, physical examination, neurological exam, laboratory tests, vital signs, and cardiac monitoring. History of moderate or severe alcohol use disorder (AUD) categorized based on Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria, as follows: Moderate as defined by presence of 4-5 of the 11 criteria Severe as defined by the presence of ≥ 6 of the 11 criteria. At least 3 weeks and not more than 6 months since last alcoholic beverage intake at the time of study screening. Any subject who completed an alcohol detoxification program must be at least 7 days from completion of the program at the time of screening. Persistent insomnia that emerged or worsened during AUD period, or during or after alcohol cessation characterized by a study-specific sleep diary. A female participant is eligible to participate if she is not pregnant and not breastfeeding. Both females of childbearing potential and nonsurgically sterilized males with a sexual partner of childbearing potential must be willing to use adequate and reliable contraception throughout the study. Willing to refrain from a behavioral or other treatment program for insomnia during participation in the study. Key Exclusion Criteria include: Current diagnosis of a sleep-related breathing disorder including obstructive sleep apnea (with or without continuous positive airway pressure (CPAP) treatment), periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder or narcolepsy. An apnea-hypopnea index (AHI) score of >10 or a periodic limb movement arousal index (PLMAI) score of > 15 recorded during the screening period PSG. Documented history of insomnia prior to onset of the alcohol use disorder (AUD), which did not worsen during the AUD period or during or after alcohol cessation. Comorbid conditions which interfere with normal sleep pattern or the evaluation of next day residual effects. Any lifetime history of suicidal ideation or behavior. History of or any current conditions that might interfere with drug absorption, distribution, metabolism, or excretion (including any surgical interventions for weight loss). Any history of seizures (except related to alcohol withdrawal) or head trauma with sequelae. Known history of testing positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV). History of diagnosed, active liver disease or elevated liver enzymes/bilirubin. History of kidney stones or renal insufficiency or abnormal kidney function at screening. Uncontrolled hypertension (> 140 mm Hg systolic / 90 mm Hg diastolic). Use of any medication that affects sleep and/or wake function during the week before starting the screening period. Subjects currently undergoing treatment of other addictions in addition to alcohol. Excessive caffeine consumption. Positive urine drug screen for prohibited substances, except for cannabis on a case-by-case basis. History of drug use disorder over the past year, other than alcohol/nicotine/caffeine/cannabis. Plans to travel across more than 3 time zones in the 2 weeks before screening, or during study participation. Night or rotating shift worker. Any history and/or current evidence of other medical (eg, cardiac, respiratory, gastrointestinal, renal, malignancy other than basal cell carcinoma), neurological, or psychiatric conditions that, in the opinion of the investigator, could affect the subject's safety or interfere with the study. Other protocol-specific inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V117957 1 mg<br>V117957 tablets taken orally at bedtime | Drug: V117957 tablets<br>* V117957 tablets taken orally at bedtime<br>|
| Experimental: V117957 2 mg<br>V117957 tablets taken orally at bedtime | Drug: V117957 tablets<br>* V117957 tablets taken orally at bedtime<br>|
| Placebo Comparator: Placebo<br>Placebo to match V117957 tablets taken orally at bedtime | Drug: Placebo<br>* Tablets to match V117957<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Wakefulness After Sleep Onset (WASO) Measured by Polysomnography (PSG) | Wakefulness After Sleep Onset, as measured by PSG, was defined as wake time after persistent sleep (wake time during sleep plus wake time after sleep, expressed in minutes). Nights 1 / 2 is the average of the PSG measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the PSG measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Sleep Efficiency (SE) | Sleep efficiency, as measured by PSG, is defined as Total Sleep Time (TST), divided by total recording time, multiplied by 100. Nights 1 / 2 is the average of the PSG measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the PSG measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Mean Latency to Persistent Sleep (LPS) | Latency to onset of persistent sleep (LPS), as measured by PSG, is defined as time from lights-off to the first of 20 consecutive periods of non-wake sleep stages. Latency to persistent sleep is reported in minutes. Nights 1 / 2 is the average of the PSG measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the PSG measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Mean Total Sleep Time (TST) | Total sleep time, as measured by PSG, is the duration of rapid eye movement (REM) plus NREM (stages N1 + N2 + N3) during time in bed. Nights 1 / 2 is the average of the PSG measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the PSG measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Mean Number of Awakenings (NAW) | Sleep component as measured by PSG. Number of awakenings is determined from persistent sleep to lights-on. An awakening is defined as a PSG recording of at least 2 consecutive wake periods. Nights 1 / 2 is the average of the PSG measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the PSG measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Sleep Quality (sSleep) | Self-reported sleep outcome measured by subject diary data. Scores have a range of 1 to 5, with 1 being equal to Very Poor and 5 being equal to 'Very Good. Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Total Sleep Time (sTST) | Self-reported sleep outcome measured by subject diary data. Total sleep time is reported in minutes. Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Wakefulness After Sleep Onset (sWASO) | Self-reported sleep outcome measured by subject diary data. WASO is defined as wake time after persistent sleep (wake time during sleep plus wake time after sleep, expressed in minutes). Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Sleep Onset Latency (sSOL) | Self-reported sleep outcome measured by subject diary data. Sleep onset latency (SOL) is the time it takes to fall asleep after turning the lights out. Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Sleep Efficiency (sSE) | Self-reported sleep outcome measured by subject diary data. Sleep efficiency (SE) is calculated by dividing the time asleep by the total time in bed multiplied by 100 (SE is reported as percent). Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Number of Awakenings (sNAW) | Self-reported sleep outcome measured by subject diary data. The subject recorded the number of awakenings in the diary. Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Change From Baseline in Subjective Morning Sleepiness on Awakening | Self-reported sleep outcome measured by subject diary data. Individual scores have a range of 1 to 5, with 1 being equal to Not at All Rested and 5 being equal to Very Well Rested. Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Baseline, Nights 1 / 2, Nights 20 / 21 | 
| Proportion of Responders to V117957 1 mg and 2 mg Compared to Placebo | The proportion of responders is based on subjects meeting or exceeding WASO (wakefulness after sleep onset) 15 minute threshold as derived from polysomnography (PSG). Nights 1 / 2 is the average of the measurements taken during the first two nights of study drug exposure. Nights 20 / 21 is the average of the measurements taken during nights 20 and 21 of study drug exposure. | Nights 1 / 2, Nights 20 / 21 | 
| Occurrence of Rebound Insomnia During the Washout/Follow-up Period | Rebound insomnia is defined as a worsening of sleep compared with pretreatment. The comparison is based on the Wakefulness After Sleep Onset (WASO) measured by PSG of the Washout/Follow-up Period versus Baseline. If the LS means for WASO for the Washout/Follow-up Period is lower than Baseline, then no rebound insomnia was suggested. Nights 22 / 23 is the average of the measurements taken during nights 22 and 23 (Washout Period). | Baseline Compared to Washout/Follow-up Period (Nights 22 / 23) | 
| Next Day Residual Effects as Determined by Digit Symbol Substitution Test (DSST). | The DSST explores attention and psychomotor speed by measuring total correct responses. The maximum score is 165. Higher scores represent better outcome/improvement. | Baseline, Night 2, Night 21 | 
| Next Day Residual Effects as Determined by Karolinska Sleepiness Scale (KSS) | The KSS is a 9-point Likert scale (range: 1 = extremely alert to 9 = very sleepy) that measures level of sleepiness. | Baseline, Night 2 (9- and 10-hours postdose), Night 21 (9- and 10-hours postdose) | 
| Next Day Residual Effects as Determined by Profile of Mood States (POMS) - Brief | The POMS-Brief contains 30 questions that assess mood states. Scores for each question range 0 = not at all to 4 = extremely. Total mood disturbance assessment is the total of the subject's subscales scores on anger/hostility, confusion/bewilderment, depression/dejection, fatigue/inertia, tension/anxiety, and vigor/activity. Total scores range from 0-120 and a higher total score indicates more mood disturbance. | Baseline, Night 2, Night 21 |