A Randomized, Double-blind Placebo-Controlled Pharmacogenetic Study of Topiramate in European-American Heavy Drinkers

NCT02371889 | Completed Phase 2 Results DMC

• 2 other identifiers: 821035R01AA023192
• Study Type: interventional
• Target: 320
• Locations: 1 country
• Sites: 2

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.

Conditions

Alcoholism; Alcohol Use Disorder (AUD)

Keywords

Topiramate; Pharmacogenetics; Personalized Medicine

Outcome Measures

Primary Outcomes (3)

• 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.

  12 weeks

• 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.

  12 weeks

• 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.

  12 weeks

Other Outcomes (1)

• Adverse Effects in Study Participants (Questionnaire)

  12 weeks

Study Arms (2)

Topiramate + Medical Management

EXPERIMENTAL

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

Drug: Topiramate; Behavioral: Medical Management

Placebo Pill + Medical Management

PLACEBO COMPARATOR

Inactive placebo with dosing schedule matched to intervention group + Medical Management sessions for 15-25 minutes per study visit

Behavioral: Medical Management; Drug: Inactive Placebo

Interventions

Topiramate DRUG

Max therapeutic dose of 200mg/day

Also known as: Topamax

Topiramate + Medical Management

Medical Management BEHAVIORAL

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.

Also known as: MM

Placebo Pill + Medical Management; Topiramate + Medical Management

Inactive Placebo DRUG

In capsules indistinguishable from topiramate capsules and gradually increased to a maximum equivalent of 200 mg of topiramate/day

Placebo Pill + Medical Management

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Determined to be physically healthy, based on medical history and physical examination and approval of the study physician
• Age 18 to 70 years, inclusive
• Self-identified European ancestry
• Meets DSM-5 criteria for AUD
• 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
• Stated goal to reduce drinking to safe levels or to stop drinking
• Able to read English at an 8th grade or higher level and no gross cognitive impairment
• Willingness to nominate an individual who will know the subject's whereabouts to facilitate follow up during the study
• 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.
• Willingness to provide signed, informed consent and commit to completing the procedures in the study

You may not qualify if:

• 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
• A history of nephrolithiasis
• A history of glaucoma
• Current treatment with carbonic anhydrase inhibitors, due to the added risk of metabolic acidosis.
• 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)
• Current DSM-IV diagnosis of dependence on a drug other than alcohol or nicotine
• A history of hypersensitivity to topiramate
• Current regular treatment with a psychotropic medication (e.g., benzodiazepines, antidepressants), which affect neurotransmitter systems, or a medication to treat alcohol dependence
• Currently taking any tricyclic antidepressant (e.g., Adapin (doxepin), Anafranil (clomipramine), Elavil (amitryptyline), Pamelor (nortryptyline), Tofranil (imipramine), Sinequan (doxepin)
• Judged by the principal investigator or his designee to be an unsuitable candidate for receipt of an investigational drug

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator
• National Institutes of Health (NIH): collaborator
• Department of Health and Human Services: collaborator
• Corporal Michael J. Crescenz VA Medical Center: collaborator

Study Sites (2)

Corporal Michael J. Crescenz VA Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pennsylvania Treatment Research Center

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (2)

• Kranzler HR, Feinn R, Pond T, Hartwell E, Gelernter J, Crist RC, Witkiewitz K. Post-treatment effects of topiramate on alcohol-related outcomes: A combined analysis of two placebo-controlled trials. Addict Biol. 2022 Mar;27(2):e13130. doi: 10.1111/adb.13130.

  PMID: 35229945 DERIVED

• Kranzler HR, Hartwell EE, Feinn R, Pond T, Witkiewitz K, Gelernter J, Crist RC. Combined analysis of the moderating effect of a GRIK1 polymorphism on the effects of topiramate for treating alcohol use disorder. Drug Alcohol Depend. 2021 Aug 1;225:108762. doi: 10.1016/j.drugalcdep.2021.108762. Epub 2021 May 21.

  PMID: 34049101 DERIVED

MeSH Terms

Conditions

Alcoholism

Interventions

Topiramate; Practice Management, Medical

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses; Practice Management; Professional Practice; Organization and Administration; Health Services Administration

Results Point of Contact

• Title: Henry R. Kranzler, M.D.
• Organization: University of Pennsylvania Perelman School of Medicine

kranzler@pennmedicine.upenn.edu

215-746-1943

Study Officials

• Henry R Kranzler, M.D.

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2015
• First Posted: February 26, 2015
• Study Start: December 18, 2014
• Primary Completion: February 1, 2020
• Study Completion: February 1, 2020
• Last Updated: January 20, 2022
• Results First Posted: February 21, 2021

Record last verified: 2022-01

Locations

US (2)