Alcoholism
Conditions
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.
Interventions
DRUGSCH 900435
tablets
DRUGPlacebo
tablets
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Heavy Drinking Days | 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Relapses Into Heavy Drinking | 12 weeks | 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). |
| Number of Lapses Into Any Drinking | 12 weeks | An alcohol lapse was defined as any episode of alcohol consumption not classified as a relapse (TLFB). |
| Time to First Relapse Into Drinking | 12 weeks | 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. |
| Percentage of Abstinent Days | 12 weeks | Percentage of abstinent days is the percentage of study days in which participants remained abstinent during the treatment period. |
| Percentage of Participants With Complete Abstinence | 12 weeks | Percentage of total abstinence is the percentage of participants who remained abstinent during the entire treatment period. |
| Global Functioning: Clinical Global Impression (CGI) - Severity of Illness | Day 84 | 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. |
| Number of Drinks Per Drinking Day | 12 weeks | 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. |
| Change From Baseline in Craving Visual Analog Scale (VAS) Score | Baseline and Day 84 | 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. |
| Change From Baseline in Motivation VAS Score | Baseline and Day 84 | 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. |
| Change From Baseline in Mood VAS Score | Baseline and Day 84 | 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. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 16 weeks | 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. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to 12 weeks | 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. |
| Global Functioning: CGI - Therapeutic Effect | Day 84 | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SCH 900435 12 mg Participants received SCH 900435 12 mg (as three SCH 900435 4 mg tablets) by mouth twice daily for 12 weeks. | 75 |
| Placebo Participants received matching placebo tablets by mouth twice daily for 12 weeks. | 66 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Did Not Meet Protocol Eligibility | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Noncompliance With Protocol | 5 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 3 |
Baseline characteristics
| Characteristic | SCH 900435 12 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 48.5 Years STANDARD_DEVIATION 10.3 | 50.3 Years STANDARD_DEVIATION 9.3 | 49.3 Years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 37 Participants |
| Sex: Female, Male Male | 55 Participants | 49 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 53 / 75 | 43 / 66 |
| serious Total, serious adverse events | 10 / 75 | 11 / 66 |
Outcome results
Primary
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.
Time frame: 12 weeks
Population: The modified Intent-to-Treat (mITT) population consisted of all participants from the All-Participants-Treated (APT) population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SCH 900435 12 mg | Percentage of Heavy Drinking Days | 18.7 Percentage of Days |
| Placebo | Percentage of Heavy Drinking Days | 16.3 Percentage of Days |
p-value: 0.4195% CI: [-3.4, 8.2]Repeated Measures Model
Secondary
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.
Time frame: Baseline and Day 84
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SCH 900435 12 mg | Change From Baseline in Craving Visual Analog Scale (VAS) Score | -3.56 Score on a Scale |
| Placebo | Change From Baseline in Craving Visual Analog Scale (VAS) Score | -6.44 Score on a Scale |
p-value: 0.5495% CI: [-6.3, 12.06]Contrained Longitudinal Data Analysis
Secondary
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.
Time frame: Baseline and Day 84
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SCH 900435 12 mg | Change From Baseline in Mood VAS Score | -5.29 Score on a Scale |
| Placebo | Change From Baseline in Mood VAS Score | 3.88 Score on a Scale |
p-value: 0.0595% CI: [-18.27, -0.07]cLDA Model
Secondary
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.
Time frame: Baseline and Day 84
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SCH 900435 12 mg | Change From Baseline in Motivation VAS Score | -8.09 Score on a Scale |
| Placebo | Change From Baseline in Motivation VAS Score | -4.99 Score on a Scale |
p-value: 0.5195% CI: [-12.35, 6.15]cLDA Model
Secondary
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.
Time frame: Day 84
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 900435 12 mg | Global Functioning: CGI - Therapeutic Effect | 2.1 Score on a Scale | Standard Deviation 1.2 |
| Placebo | Global Functioning: CGI - Therapeutic Effect | 2.0 Score on a Scale | Standard Deviation 1 |
Secondary
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.
Time frame: Day 84
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 900435 12 mg | Global Functioning: Clinical Global Impression (CGI) - Severity of Illness | 2.7 Score on a Scale | Standard Deviation 1.3 |
| Placebo | Global Functioning: Clinical Global Impression (CGI) - Severity of Illness | 2.7 Score on a Scale | Standard Deviation 1.4 |
Secondary
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.
Time frame: 12 weeks
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SCH 900435 12 mg | Number of Drinks Per Drinking Day | 10.9 Drinks |
| Placebo | Number of Drinks Per Drinking Day | 12.8 Drinks |
p-value: 0.395% CI: [-5.5, 1.7]Repeated Measures Model
Secondary
Number of Lapses Into Any Drinking
An alcohol lapse was defined as any episode of alcohol consumption not classified as a relapse (TLFB).
Time frame: 12 weeks
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 900435 12 mg | Number of Lapses Into Any Drinking | 5.59 Lapses | Standard Deviation 6.33 |
| Placebo | Number of Lapses Into Any Drinking | 6.37 Lapses | Standard Deviation 6.49 |
p-value: 0.8195% CI: [0.71, 1.31]Chi-squared
Secondary
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.
Time frame: Up to 12 weeks
Population: The APT population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SCH 900435 12 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 6 Participants |
| Placebo | Number of Participants Who Discontinued Study Drug Due to an AE | 3 Participants |
Secondary
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.
Time frame: Up to 16 weeks
Population: The All-Participants-Treated (APT) population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SCH 900435 12 mg | Number of Participants Who Experienced an Adverse Event (AE) | 65 Participants |
| Placebo | Number of Participants Who Experienced an Adverse Event (AE) | 53 Participants |
Secondary
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).
Time frame: 12 weeks
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 900435 12 mg | Number of Relapses Into Heavy Drinking | 4.65 Relapses | Standard Deviation 6.24 |
| Placebo | Number of Relapses Into Heavy Drinking | 4.52 Relapses | Standard Deviation 5.27 |
p-value: 0.5295% CI: [0.57, 1.33]Chi-squared
Secondary
Percentage of Abstinent Days
Percentage of abstinent days is the percentage of study days in which participants remained abstinent during the treatment period.
Time frame: 12 weeks
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SCH 900435 12 mg | Percentage of Abstinent Days | 70.5 Percentage of Days |
| Placebo | Percentage of Abstinent Days | 72.6 Percentage of Days |
p-value: 0.5995% CI: [-9.9, 5.7]Repeated Measures Model
Secondary
Percentage of Participants With Complete Abstinence
Percentage of total abstinence is the percentage of participants who remained abstinent during the entire treatment period.
Time frame: 12 weeks
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SCH 900435 12 mg | Percentage of Participants With Complete Abstinence | 33.8 Percentage of Participants |
| Placebo | Percentage of Participants With Complete Abstinence | 27.7 Percentage of Participants |
p-value: 0.3495% CI: [0.65, 3.43]Regression, Logistic
Secondary
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.
Time frame: 12 weeks
Population: The mITT population consisted of all participants from the APT population who had at least post randomization efficacy data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 900435 12 mg | Time to First Relapse Into Drinking | 37.1 Days | Standard Deviation 35.5 |
| Placebo | Time to First Relapse Into Drinking | 41.6 Days | Standard Deviation 36.3 |
p-value: 0.2695% CI: [0.81, 2.12]Kaplan-Meier