Trial Investigating the Efficacy and Safety of SCH 900435 (Org 25935) in Relapse Prevention in Participants With Alcohol Dependence (P05718)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the effects of SCH 900435 (Org 25935, MK-8435) on heavy drinking, safety and tolerability of SCH 900435 in participants with alcohol dependence.

Official Title
-----------------
A Prospective, Double-Blind, Placebo-Controlled Trial Investigating the Efficacy and Safety of SCH 900435 (Org 25935) in Relapse Prevention in Subjects With Alcohol Dependence.

Conditions
-----------------
Alcoholism

Intervention / Treatment
-----------------
* Drug: SCH 900435
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provide written informed consent after the scope and nature of the investigation, have been explained to the participant before screening; Diagnosis of alcohol dependence - meeting at least 5 out of 7 criteria according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) specifier; one of which should be criterion 1 (tolerance) or 2 (withdrawal); Primary complaints according to Mini-International Neuropsychiatric Interview (MINI) should be alcohol problems; Participants must have gone through a detoxification program, have a clearly stated desire to stay abstinent and present at baseline with the following: be alcohol abstinent for at least 3 days, benzodiazepine free for at least 3 days, and a Clinical Institute Withdrawal Assessment (CIWA) score <10; Age 18-65 years at screening; Males, or females who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or who are non-pregnant, non-lactating and using a medically accepted method of contraception; these include condoms with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), and hormonal contraceptives; Body Mass Index (BMI) >16 kg/m^2; Breath alcohol concentration < 0.02% (at screening and baseline) Exclusion Criteria: Participants requiring pharmacological treatment for a primary diagnosis of major depressive disorder, anxiety, panic disorder or social phobia; Participants with psychotic disorders (according to MINI); Participants with a medium or high suicidality risk (as assessed by MINI) Active substance abuse (resulting in either physical or mental damage as defined by International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD10] or dependence other than alcohol (excluding nicotine) within 12 months prior to screening, e.g. cannabis, benzodiazepine, amphetamines, chlo(r)methiazole, opiates, cocaine, hallucinogens or other substances; Use of one of the following drugs during the last 14 days prior to screening: cannabis, amphetamines, opiates, cocaine, hallucinogens; Use of any medication that can have an effect on alcohol consumption within 30 days of study initiation, including naltrexone, acamprosate, disulfiram, ondansetron, topiramate, selective serotonin reuptake inhibitors (SSRIs), mirtazapine, varencicline, gabapentin, levetiracetam; A clinically relevant visual disturbance, such as cataract, color blindness, macular degeneration, glaucoma or retinal disease; Untreated or uncompensated clinically significant renal, endocrine, hepatic, respiratory, cardiovascular, hematological, immunological or cerebrovascular disease, malignancy, or other chronic and/or degenerative process at screening; Any clinically meaningful abnormal laboratory, vital sign, physical examination or electrocardiogram (ECG) finding which, in the opinion of the investigator, may interfere with the interpretation of safety or efficacy evaluations; QTc interval (Fridericia corrected) at screening >450 ms (male), >470 ms (female); Serious neuropsychiatric condition that can impair judgment or cognitive function (including dementia or amnestic disorder) to an extent that providing informed consent or complying with treatment is precluded; History or present evidence of epileptic disorders or withdrawal seizures; History of substance withdrawal delirium; Breast-feeding woman, or a positive result of urine pregnancy test (at screening), or plan to become pregnant during the course of the trial (females only); Pending legal charges with the potential for incarceration, probation, or parole; Homelessness (less than 2 months stable residence); Participation in a clinical trial during the 3 months prior to screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCH 900435<br>Participants received SCH 900435 12 mg (as three SCH 900435 4 mg tablets) by mouth twice daily for 12 weeks. | Drug: SCH 900435<br>* tablets<br>* Other names: MK-8435;|
| Placebo Comparator: Placebo<br>Participants received matching placebo tablets by mouth twice daily for 12 weeks. | Drug: Placebo<br>* tablets<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Heavy Drinking Days | Percentage of heavy drinking days was defined as days with ≥5 standard drinks for men and ≥4 standard drinks for women assessed by Alcohol Timeline Follow Back (TLFB) method. The Alcohol TLFB is a drinking assessment method that obtains estimates of daily drinking by means of an interview between investigator and participant. The TLFB assesses recent drinking behavior. On the TLFB, clients retrospectively estimate their daily alcohol consumption in standard drinks over a time period prior to the interview, and thus the measure provides quantitative estimates of alcohol use. A drink is standardized to an equivalent to 25-30 cL of beer or wine coolers (5% alcohol), 12-15 cL of table wine (11-14% alcohol) and 4-6 cL of hard liquor/spirits (35-40% alcohol). Percentage was calculated based on number of heavy drinking days divided by total number of days in the given 2-week interval. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Drinks Per Drinking Day | The amount of drinking was defined as drinks per drinking day (TLFB). Drinking day is a day on which an alcoholic drink is consumed, with 'day' being defined as the period between waking up and going to sleep; the end of a day may have crossed the time point of midnight. | 12 weeks | 
| Number of Relapses Into Heavy Drinking | An alcohol relapse was defined as either a daily alcohol intake of 5 or more drinks for males and 4 or more drinks for females or an overall consumption of 14 drinks or more per week during at least 4 weeks (TLFB). | 12 weeks | 
| Number of Lapses Into Any Drinking | An alcohol lapse was defined as any episode of alcohol consumption not classified as a relapse (TLFB). | 12 weeks | 
| Time to First Relapse Into Drinking | Time to relapse was defined as the time to first relapse into heavy drinking (TLFB). A Hazard Ratio (SCH 900435/Placebo) of <1 means that SCH 900435 has a lower risk of relapsing as compared to Placebo. | 12 weeks | 
| Percentage of Abstinent Days | Percentage of abstinent days is the percentage of study days in which participants remained abstinent during the treatment period. | 12 weeks | 
| Percentage of Participants With Complete Abstinence | Percentage of total abstinence is the percentage of participants who remained abstinent during the entire treatment period. | 12 weeks | 
| Global Functioning: Clinical Global Impression (CGI) - Severity of Illness | The CGI scale is a standardized tool used by investigators to rate the severity of illness, taking into account the participant's clinical condition and the severity of side effects. The CGI scores could range from 1 to 7, with a lower score reflecting a better outcome. | Day 84 | 
| Global Functioning: CGI - Therapeutic Effect | The CGI scale is a standardized tool used by investigators to rate the efficacy of study drug (therapeutic effect), taking into account the participant's clinical condition and the severity of side effects. The CGI scores could range from 1 to 7, with a lower score reflecting a better outcome. | Day 84 | 
| Change From Baseline in Craving Visual Analog Scale (VAS) Score | Rating of craving is included to assess a potential relationship between treatment and craving severity. Participants were asked to answer the question: Over the past week, what has your desire or craving for an alcoholic beverage been at the time of day that you usually drink? The 100 mm line of the VAS was anchored on the left by No desire at all and on the right by Extreme desire. Participants marked a spot on the line where they felt their craving severity fit best. Craving VAS scores could range from 0 to 100, with a lower VAS score reflecting a better outcome. | Baseline and Day 84 | 
| Change From Baseline in Motivation VAS Score | Participants were asked to answer the question: Over the past week, how motivated were you to stay alcohol abstinent? The 100 mm line of the VAS was anchored on the left by No motivation at all and on the right by Extremely motivated. Motivation VAS scores could range from 0 to 100, with a higher score reflecting a better outcome. | Baseline and Day 84 | 
| Change From Baseline in Mood VAS Score | Participants were asked to answer the question: Over the past week, how did you feel? The 100 mm line of the VAS was anchored on the left by Extremely bad and on the right by Extremely good. Mood VAS scores could range from 0 to 100, with a higher VAS score reflecting a better outcome. | Baseline and Day 84 | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. | Up to 16 weeks | 
| Number of Participants Who Discontinued Study Drug Due to an AE | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. | Up to 12 weeks |