Alcoholism, Alcohol Use Disorder (AUD)
Conditions
Keywords
Topiramate, Pharmacogenetics, Personalized Medicine
Brief summary
The purpose of this study is to advance the effort to develop personalized pharmacotherapy for alcohol use disorders (AUDs). The investigators propose to conduct a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy of TOP in reducing heavy drinking (HD) in 200 individuals of European descent with DSM-5 AUD. The investigators will stratify the randomization on genotype and oversample rs2832407\*C homozygotes, the most TOP-responsive genotype, to ensure comparable numbers of patients in the four medication x genotype groups. The investigators will use daily data collection to examine changes in relevant process variables (e.g., alcohol expectancies) and their interaction with genotype and medication group as predictors of HD. The proposed study is innovative in that it will be the first prospective test of a pharmacogenetic hypothesis involving TOP; it will use daily reports to examine expectancies and how they interact with medication and genotype to predict HD; and it will enroll DSM-5 AUD patients whose goal is either to reduce or stop drinking, which will increase the study's external validity.
Detailed description
This is a 12-week, prospective, randomized clinical trial of the moderating effect of rs2832407 on the efficacy of topiramate in reducing HD in 200 individuals of European descent with DSM-5 AUD. The investigators will stratify the randomization on genotype and oversample rs2832407\*C homozygotes, the most topiramate-responsive genotype, to ensure comparable numbers of subjects in the four medication x genotype groups. The investigators will compare the efficacy of topiramate to placebo in reducing the frequency of HDDs in subjects with AUD using a two-arm, parallel-groups design. Subjects will either have a goal of reducing their drinking to safe levels or abstinence. The investigators will use daily data collection to examine changes in relevant process variables and their interaction with genotype and medication group as predictors of HD. At each visit, all subjects will receive Medication Management (Pettinati, Weiss et al. 2004), which was developed for the COMBINE Trial and which the investigators modified to be relevant for both reducing heavy drinking and promoting abstinence. Random assignment to treatment group and double-blind conditions will be maintained throughout the study. Raters will be trained in the reliable use of all assessments. The investigators will use serum GGTP and percent disialotransferrin (%dCDT), an improved assay for carbohydrate deficient transferrin, to validate subject reports. Following a one-week pre-treatment assessment period, subjects will receive 12 weeks of treatment, after which there will be a 6-day taper period, during which subjects will reduce their dosage of topiramate gradually and then discontinue it completely. Daily reports during the treatment period will be obtained using interactive voice response (IVR) to identify subjective correlates of medication effects and to monitor medication use. Following the 12-week treatment period, subjects will be asked to return to the clinic for 3-month and 6-month post-treatment follow-up visits to evaluate the durability of treatment effects. Two hundred men and women of European descent will be randomized to study medication. Subjects will be recruited using referrals from treatment programs throughout Philadelphia; IRB-approved advertisements on mass transit, on local radio and television stations and in newspapers, social media, and broadcast email messages at institutions that offer such a service and by posting/distributing recruitment materials in community and college settings. Respondents will initially be evaluated by telephone prior to an in-person visit to the Treatment Research Center of the University of Pennsylvania Perelman School of Medicine. The investigators will select subjects based on their genotype to ensure comparable numbers of individuals who are rs2832407\*C-allele homozygotes and A-allele carriers. The investigators will block randomize subjects to balance the groups on treatment goal (i.e., reduced drinking or abstinence).
Interventions
DRUGTopiramate
Max therapeutic dose of 200mg/day
BEHAVIORALMedical Management
Medical Management (MM; Pettinati, 2004) will support subjects' efforts to reduce or stop their drinking. The study nurse makes direct recommendations for reducing drinking to sensible levels. The first session will use the brochure A Guide to Sensible Drinking (WHO 1996). The subject is provided with information about pharmacotherapy and the importance of adherence to topiramate/placebo. Subsequent treatment sessions (15-25 minutes) will be conducted at each study visit, during which the nurse will perform an assessment of the subject's drinking, monitor his/her medication adherence, and make recommendations to follow until the next visit. Men will be advised to consume no more than 3 drinks 4 times per week; women will be advised to consume no more than 2 drinks 4 times per week.
DRUGInactive Placebo
In capsules indistinguishable from topiramate capsules and gradually increased to a maximum equivalent of 200 mg of topiramate/day
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institutes of Health (NIH)
Department of Health and Human Services
Corporal Michael J. Crescenz VA Medical Center
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Determined to be physically healthy, based on medical history and physical examination and approval of the study physician 2. Age 18 to 70 years, inclusive 3. Self-identified European ancestry 4. Meets DSM-5 criteria for AUD 5. Average weekly ethanol consumption of \>24 standard drinks for men and \>18 standard drinks for women, with a weekly average of \> 2 HDDs during the month before screening 6. Stated goal to reduce drinking to safe levels or to stop drinking 7. Able to read English at an 8th grade or higher level and no gross cognitive impairment 8. Willingness to nominate an individual who will know the subject's whereabouts to facilitate follow up during the study 9. Women of child-bearing potential (i.e., who have not had a hysterectomy, bilateral oophorectomy, tubal ligation or is less than two years postmenopausal): must be non-lactating and practicing a reliable method of birth control, and have a negative urine pregnancy test prior to the initiation of treatment. Examples of medically acceptable methods for this protocol include: the birth control pill, intrauterine device, injection of Depo-Provera, Norplant, contraceptive patch, contraceptive ring, double-barrier methods (such as condoms and diaphragm/spermicide), male partner sterilization, abstinence (and agreement to continue abstinence or to use an acceptable method of contraception, as listed above, should sexual activity commence), and tubal ligation. 10. Willingness to provide signed, informed consent and commit to completing the procedures in the study
Exclusion criteria
1. A current, clinically significant physical disease or abnormality on the basis of medical history, physical examination, or routine laboratory evaluation, including direct bilirubin elevations of \>110% or a transaminase elevation \>300% of normal 2. A history of nephrolithiasis 3. A history of glaucoma 4. Current treatment with carbonic anhydrase inhibitors, due to the added risk of metabolic acidosis. 5. Current, serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or psychotic major depression, panic disorder, borderline or antisocial personality disorder, organic mood or mental disorders, eating disorder, or imminent suicide or violence risk) 6. Current DSM-IV diagnosis of dependence on a drug other than alcohol or nicotine 7. A history of hypersensitivity to topiramate 8. Current regular treatment with a psychotropic medication (e.g., benzodiazepines, antidepressants), which affect neurotransmitter systems, or a medication to treat alcohol dependence 9. Currently taking any tricyclic antidepressant (e.g., Adapin (doxepin), Anafranil (clomipramine), Elavil (amitryptyline), Pamelor (nortryptyline), Tofranil (imipramine), Sinequan (doxepin) 10. Urine drug screen positive for recent use of opioids, cocaine, or amphetamines (may be repeated once and if the result is negative on repeat it is not exclusionary) 11. Because co-administration of topiramate with dolutegravir reduced plasma concentrations of the antiretroviral through induction of CYP3A, the use of dolutegravir is exclusionary. 12. Judged by the principal investigator or his designee to be an unsuitable candidate for receipt of an investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Heavy Drinking Days by Medication Group (Timeline Follow Back Calendar). | 12 weeks | The number of Heavy Drinking Days during 12 weeks of treatment in the topiramate and placebo groups. |
| Frequency of Heavy Drinking Days Per Day by Medication and Genotype Group (Timeline Follow Back Calendar). | 12 weeks | Number of Heavy Drinking Days in the last week of the 12 week treatment phase by medication group and rs2832407 genotype group. |
| Numbers of Drinking Days Over 12 Weeks Treatment by Medication Group. | 12 weeks | Numbers of drinking days over 12 week treatment phase by medication group. Data was collected using timeline follow back calendar. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adverse Effects in Study Participants (Questionnaire) | 12 weeks | Cumulative number of adverse events as assessed at each study visit to determine the safety of topiramate. |
Countries
United States
Participant flow
Recruitment details
The study was conducted from December 18, 2014 through August 1, 2019 at the University of Pennsylvania Treatment Research Center (Penn; n=164) and the Corporal Michael J. Crescenz Veterans Affairs Medical Center (CMCVAMC; n=6).
Pre-assignment details
Participants completed an in-person visit, where they gave informed consent, underwent a medical history, physical examination, routine clinical laboratory testing, a urine drug screen, and, if appropriate, pregnancy testing. We excluded 150 participants based on the first in-person visit based on the inclusion/exclusion criteria from the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Topiramate + Medical Management Topiramate 200 mg/day orally in two divided doses. Dose will be titrated upward over a six-week period, maintained for 6 weeks, then tapered over 6 days + Medical Management sessions for 15-25 minutes per study visit
Medical Management: Medical Management (MM; Pettinati, 2004) will support subjects' efforts to reduce or stop their drinking. | 85 |
| Placebo Pill + Medical Management Inactive placebo with dosing schedule matched to intervention group + Medical Management sessions for 15-25 minutes per study visit
Medical Management: Medical Management (MM; Pettinati, 2004) will support subjects' efforts to reduce or stop their drinking. | 85 |
| Total | 170 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse medication effect | 11 | 2 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 6 | 5 |
| Overall Study | Personal time constraints | 2 | 4 |
| Overall Study | Relapse | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Pill + Medical Management | Topiramate + Medical Management | Total |
|---|---|---|---|
| Age, Customized | 50 years STANDARD_DEVIATION 12.8 | 52.3 years STANDARD_DEVIATION 10.5 | 51.2 years STANDARD_DEVIATION 11.6 |
| Drinking Days 90days prior to screening | 86.3 Drinking days STANDARD_DEVIATION 16.8 | 87.2 Drinking days STANDARD_DEVIATION 16.5 | 86.5 Drinking days STANDARD_DEVIATION 17.01 |
| Genotype AC/AA genotype | 54 Participants | 55 Participants | 109 Participants |
| Genotype CC genotype | 31 Participants | 30 Participants | 61 Participants |
| Heavy drink days 90 days prior to screening | 68.7 Heavy drinking days STANDARD_DEVIATION 25.6 | 73.8 Heavy drinking days STANDARD_DEVIATION 23.5 | 68.9 Heavy drinking days STANDARD_DEVIATION 26.58 |
| Lifetime Anxiety Disorder AC/AA genotype | 19 Participants | 6 Participants | 25 Participants |
| Lifetime Anxiety Disorder CC genotype | 4 Participants | 5 Participants | 9 Participants |
| Lifetime Major Depression AC/AA genotype | 8 Participants | 11 Participants | 19 Participants |
| Lifetime Major Depression CC genotype | 11 Participants | 7 Participants | 18 Participants |
| Married or cohabiting | 51 Participants | 47 Participants | 98 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 85 Participants | 85 Participants | 170 Participants |
| Region of Enrollment United States | 85 participants | 85 participants | 170 participants |
| Sex: Female, Male Female | 25 Participants | 24 Participants | 49 Participants |
| Sex: Female, Male Male | 60 Participants | 61 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 85 | 1 / 85 |
| other Total, other adverse events | 80 / 85 | 76 / 85 |
| serious Total, serious adverse events | 1 / 85 | 1 / 85 |
Outcome results
Primary
Frequency of Heavy Drinking Days by Medication Group (Timeline Follow Back Calendar).
The number of Heavy Drinking Days during 12 weeks of treatment in the topiramate and placebo groups.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate + Medical Management | Frequency of Heavy Drinking Days by Medication Group (Timeline Follow Back Calendar). | 29.00 Heavy drinking days | Standard Deviation 23.82 |
| Placebo Pill + Medical Management | Frequency of Heavy Drinking Days by Medication Group (Timeline Follow Back Calendar). | 41.25 Heavy drinking days | Standard Deviation 26.38 |
Primary
Frequency of Heavy Drinking Days Per Day by Medication and Genotype Group (Timeline Follow Back Calendar).
Number of Heavy Drinking Days in the last week of the 12 week treatment phase by medication group and rs2832407 genotype group.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate + Medical Management | Frequency of Heavy Drinking Days Per Day by Medication and Genotype Group (Timeline Follow Back Calendar). | 1.86 Heavy drinking days during week 12 | Standard Deviation 2.27 |
| Placebo Pill + Medical Management | Frequency of Heavy Drinking Days Per Day by Medication and Genotype Group (Timeline Follow Back Calendar). | 3.17 Heavy drinking days during week 12 | Standard Deviation 2.69 |
| Genotype AA/AC Topiramate + Medical Management | Frequency of Heavy Drinking Days Per Day by Medication and Genotype Group (Timeline Follow Back Calendar). | 2.24 Heavy drinking days during week 12 | Standard Deviation 2.46 |
| Genotype AA/AC Placebo Pill + Medical Management | Frequency of Heavy Drinking Days Per Day by Medication and Genotype Group (Timeline Follow Back Calendar). | 3.14 Heavy drinking days during week 12 | Standard Deviation 2.68 |
Primary
Numbers of Drinking Days Over 12 Weeks Treatment by Medication Group.
Numbers of drinking days over 12 week treatment phase by medication group. Data was collected using timeline follow back calendar.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate + Medical Management | Numbers of Drinking Days Over 12 Weeks Treatment by Medication Group. | 58.58 Drinking days | Standard Deviation 25.35 |
| Placebo Pill + Medical Management | Numbers of Drinking Days Over 12 Weeks Treatment by Medication Group. | 65.14 Drinking days | Standard Deviation 22.31 |
Other Pre-specified
Adverse Effects in Study Participants (Questionnaire)
Cumulative number of adverse events as assessed at each study visit to determine the safety of topiramate.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate + Medical Management | Adverse Effects in Study Participants (Questionnaire) | 3.5 Number of adverse events | Standard Deviation 1.7 |
| Placebo Pill + Medical Management | Adverse Effects in Study Participants (Questionnaire) | 2.6 Number of adverse events | Standard Deviation 1.3 |