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

• V117957 tablets (Drug): V117957 tablets taken orally at bedtime
• Placebo (Drug): Tablets to match V117957

Primary outcomes

• Change From Baseline of Wakefulness After Sleep Onset (WASO) Measured by Polysomnography (PSG) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.

Secondary outcomes

• Change From Baseline in Mean Sleep Efficiency (SE) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Mean Latency to Persistent Sleep (LPS) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Mean Total Sleep Time (TST) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Mean Number of Awakenings (NAW) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Sleep Quality (sSleep) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Total Sleep Time (sTST) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Wakefulness After Sleep Onset (sWASO) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Sleep Onset Latency (sSOL) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Sleep Efficiency (sSE) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Number of Awakenings (sNAW) [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Change From Baseline in Subjective Morning Sleepiness on Awakening [Baseline, Nights 1 / 2, Nights 20 / 21]: 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.
• Proportion of Responders to V117957 1 mg and 2 mg Compared to Placebo [Nights 1 / 2, Nights 20 / 21]: 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.
• Occurrence of Rebound Insomnia During the Washout/Follow-up Period [Baseline Compared to Washout/Follow-up Period (Nights 22 / 23)]: 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).
• Next Day Residual Effects as Determined by Digit Symbol Substitution Test (DSST). [Baseline, Night 2, Night 21]: The DSST explores attention and psychomotor speed by measuring total correct responses. The maximum score is 165. Higher scores represent better outcome/improvement.
• Next Day Residual Effects as Determined by Karolinska Sleepiness Scale (KSS) [Baseline, Night 2 (9- and 10-hours postdose), Night 21 (9- and 10-hours postdose)]: The KSS is a 9-point Likert scale (range: 1 = "extremely alert" to 9 = "very sleepy") that measures level of sleepiness.
• Next Day Residual Effects as Determined by Profile of Mood States (POMS) - Brief [Baseline, Night 2, Night 21]: 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.

Sex: All, ages: 18 Years to 64 Years

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.

Participant flow

Outcome results

• Change From Baseline of Wakefulness After Sleep Onset (WASO) Measured by Polysomnography (PSG) (Primary), Mean, Minutes: V117957 1 mg 100.88 +/- 45.098; V117957 2 mg 99.70 +/- 36.496; Placebo 103.51 +/- 32.456
• Change From Baseline in Mean Sleep Efficiency (SE) (Secondary), Mean, Percent: V117957 1 mg 64.54 +/- 11.502; V117957 2 mg 67.18 +/- 9.919; Placebo 63.17 +/- 12.825
• Change From Baseline in Mean Latency to Persistent Sleep (LPS) (Secondary), Mean, Minutes: V117957 1 mg 76.63 +/- 34.305; V117957 2 mg 66.30 +/- 25.653; Placebo 81.58 +/- 48.928
• Change From Baseline in Mean Total Sleep Time (TST) (Secondary), Mean, Minutes: V117957 1 mg 309.87 +/- 55.265; V117957 2 mg 323.11 +/- 48.065; Placebo 303.24 +/- 61.559
• Change From Baseline in Mean Number of Awakenings (NAW) (Secondary), Mean, Number of Awakenings: V117957 1 mg 10.70 +/- 5.733; V117957 2 mg 14.05 +/- 5.101; Placebo 10.32 +/- 5.609
• Change From Baseline in Subjective Sleep Quality (sSleep) (Secondary), Mean, score on a scale: V117957 1 mg 1.80 +/- 0.686; V117957 2 mg 1.82 +/- 0.683; Placebo 1.99 +/- 0.727
• Change From Baseline in Subjective Total Sleep Time (sTST) (Secondary), Mean, Minutes: V117957 1 mg 296.42 +/- 45.586; V117957 2 mg 304.60 +/- 50.458; Placebo 315.05 +/- 56.092
• Change From Baseline in Subjective Wakefulness After Sleep Onset (sWASO) (Secondary), Mean, Minutes: V117957 1 mg 92.51 +/- 42.137; V117957 2 mg 85.93 +/- 42.222; Placebo 83.49 +/- 63.929
• Change From Baseline in Subjective Sleep Onset Latency (sSOL) (Secondary), Mean, Minutes: V117957 1 mg 74.54 +/- 30.022; V117957 2 mg 75.84 +/- 31.274; Placebo 63.45 +/- 19.795
• Change From Baseline in Subjective Sleep Efficiency (sSE) (Secondary), Mean, Percent: V117957 1 mg 61.51 +/- 8.768; V117957 2 mg 63.14 +/- 8.898; Placebo 63.50 +/- 10.924
• Change From Baseline in Subjective Number of Awakenings (sNAW) (Secondary), Mean, Number of Awakenings: V117957 1 mg 2.49 +/- 1.100; V117957 2 mg 2.24 +/- 1.013; Placebo 2.37 +/- 0.984
• Change From Baseline in Subjective Morning Sleepiness on Awakening (Secondary), Mean, score on a scale: V117957 1 mg 1.54 +/- 0.655; V117957 2 mg 1.60 +/- 0.613; Placebo 1.72 +/- 0.611
• Proportion of Responders to V117957 1 mg and 2 mg Compared to Placebo (Secondary), Count of participants, Participants: V117957 1 mg 29; V117957 2 mg 33; Placebo 30
• Occurrence of Rebound Insomnia During the Washout/Follow-up Period (Secondary), Mean, Minutes: V117957 1 mg 100.88 +/- 45.098; V117957 2 mg 99.70 +/- 36.496; Placebo 103.51 +/- 32.456
• Next Day Residual Effects as Determined by Digit Symbol Substitution Test (DSST). (Secondary), Mean, Correct Responses: V117957 1 mg 49.0 +/- 17.82; V117957 2 mg 46.4 +/- 15.85; Placebo 46.2 +/- 18.95
• Next Day Residual Effects as Determined by Karolinska Sleepiness Scale (KSS) (Secondary), Mean, score on a scale: V117957 1 mg 4.3 +/- 2.30; V117957 2 mg 4.4 +/- 2.23; Placebo 4.4 +/- 2.09
• Next Day Residual Effects as Determined by Profile of Mood States (POMS) - Brief (Secondary), Mean, score on a scale: V117957 1 mg 13.54 +/- 23.612; V117957 2 mg 12.03 +/- 15.658; Placebo 11.80 +/- 16.863

Adverse events

Time frame: Adverse events (AEs) were reported from the start of study participation up to 3 weeks. All-cause mortality and serious adverse events were reported from the start of study participation up to 30 days after last study drug dose (approximately 7 weeks).

Other adverse events by term

• Results publication: Whiteside GT, Kyle DJ, Kapil RP, Cipriano A, He E, Zhou M, Shet MS, Hummel M, Knappenberger T, Fukumura K, Matsuo Y, Uehira M, Hiroyama S, Takai N, Willsie SK, Harris SC. The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia. J Clin Invest. 2024 Jan 2;134(1):e171172. doi: 10.1172/JCI171172. PMID 37883189

• Study Protocol and Statistical Analysis Plan (PDF, 2019-09-27)