Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD

February 15, 2024 updated by: Melanie E Bennett, University of Maryland, Baltimore
The primary study objective is to determine the efficacy of pregabalin administered orally for a period of 12 weeks in reducing risky drinking and symptoms of posttraumatic stress disorder who have selected genotypes at the gamma-amino butyric acid transporter and receptor genes. The secondary objective is to assess the safety and tolerability of pregabalin in participants with alcohol use disorder and co-occurring posttraumatic stress disorder who have selected genotypes at the gamma-amino butyric acid transporter and receptor genes. The investigators will utilize a sample of African-Americans that includes both genders and individuals with different types of trauma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Nearly 60% of individuals with posttraumatic stress disorder (PTSD) have a comorbid alcohol use disorder (AUD). This comorbidity is associated with more severe PTSD symptoms, higher rates of psychosocial and medical problems, higher relapse rates, and poorer treatment outcome. Pre-clinical studies have indicated that PTSD and AUD share common molecular underpinnings. Particularly, the adaptations in the brain neurotransmitter systems to chronic excessive drinking that are evident during alcohol withdrawal share similarities with PTSD cluster B and E symptoms (characterized by symptoms of re-experiencing and hyper-arousal), which initiate a cycle of relapse into excessive drinking and worsening of PTSD symptoms. Excessive glutamate and reduced gamma-amino butyric acid (GABA) neurotransmitter concentrations were found in various brain regions in individuals with co-morbid PTSD/AUD. The anticonvulsant pregabalin (with high affinity for the alpha-2-delta auxiliary site of voltage gated calcium channels) that modulates the effects of the GABA transporter (GAT-1) and increases its density of GABA, has shown preliminary efficacy in reducing drinking in AUD with comorbid generalized anxiety disorder, and improves outcomes from PTSD. Large scale studies with ample statistical power in VA settings and community populations, with diverse combat and non-combat related trauma, are now warranted to evaluate the promising preliminary evidence that pregabalin can improve outcomes for those with AUD and PTSD. An important personalized medicine approach to optimize pregabalin efficacy would be to select individuals with AUD and PTSD with genetic variation at the GAT-1 transporter so as to match its potential therapeutic effects with specific types of individual. In African-Americans, variants at the SLC6A1 gene promoter region insertion (i.e., non-insertion/insertion or insertion/insertion (NI/I or I/I) compared with those of Non-insertion/Non-insertion (NI/NI) type have significantly higher levels of GAT-1promoter activity. The investigators will, therefore, segregate our target sample by genetic variation at the GAT-1 transporter. Because of the low allelic frequency of individuals with the double copy insertion, the investigators will combine these into one group with those with the single copy (i.e., NI/I/II).

This study will test the efficacy of pregabalin in reducing both alcohol consumption and PTSD symptoms in 2 treatment groups of medication (pregabalin 450 mg/day and placebo) x 2 genetic variants (NI/I/II vs. NI/NI) in a double- blind, placebo-controlled 14-week clinical trial (screening, 12 weeks of study medication, follow-up call). After a one-week screening period, pregabalin dose (and placebo) will be titrated to the target dose from baseline to week 3 using a double-dummy procedure to ensure equivalence of capsules received. The investigators will utilize a sample of African-American participants with co-occurring AUD and PTSD that includes both genders and individuals with different types of trauma. Participants will receive standardized discussions to enhance compliance with study medication at all visits. The specific aims are:

Specific Aim 1: Independent of race, to test the hypothesis that AUD/PTSD participants treated with pregabalin will demonstrate a greater reduction in heavy drinking than placebo treated participants.

Specific Aim 2: Independent of race, to test the hypothesis that AUD/PTSD participants treated with pregabalin will demonstrate a greater reduction in PTSD cluster B or E symptoms (or both) than placebo-treated participants.

Specific Aim 3: To test the hypothesis that race will moderate the effects of pregabalin examined in Aims 1 and 2.

Specific Aim 4: To test the hypothesis that the treatment responses to pregabalin specified in Aims 1 and 2 are modulated by genetic variations within SLC6A1 gene in AUD/PTSD in both African American and European American populations.

Study Type

Interventional

Enrollment (Actual)

57

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21228
        • University of Maryland School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Males and females of self-reported European or African American ancestry who have given written informed consent
  2. Age 18 to 65 years and weighing within 30% of their ideal body weight (Metropolitan Life Tables). Also, subjects must weigh at least 40 kg and no more than 155 kg.
  3. Good physical health as determined by a complete physical examination, an EKG within normal limits, and laboratory screening tests within acceptable parameters (see exclusion criteria)
  4. Current Diagnostic and Statistical Manual of Mental Disorders Version 5 (DSM-5) diagnosis of posttraumatic stress disorder (PTSD)
  5. Current DSM-5 diagnosis of alcohol use disorder (AUD) of moderate or greater severity (i.e., 4 or more AUD criteria endorsed) in the last 3 months
  6. Currently drinking ≥21 alcohol units/week for women and ≥28 alcohol units/week for men in the last 30 days and have met these criteria 7 days prior to randomization.
  7. Provide evidence of stable residence in the last month prior to enrollment in the study, and have no plans to move in the next 9 months
  8. The pregnancy test for females at intake must be negative. Additionally, women of childbearing potential must be using an acceptable form of contraception. These include: oral contraceptives, hormonal (levonorgestrel) or surgical implants, or barrier plus spermicide.
  9. Literate in English and able to read, understand, and complete the rating scales and questionnaires accurately, follow instructions, and make use of the behavioral treatments
  10. Express a wish to stop drinking
  11. Willing to participate in behavioral treatments for PTSD and AUD

Exclusion Criteria:

  1. Any current DSM 5 psychiatric disorder other than PTSD, AUD, or Tobacco Use Disorder that warrants treatment or would preclude safe participation in the protocol
  2. Elevation of liver enzymes (SGOT), serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), or lactate dehydrogenase (LDH) greater than four times the upper limit of the normal range, or elevated bilirubin
  3. Severe alcohol withdrawal symptoms that, in the physician's opinion, require inpatient treatment
  4. Serious medical comorbidity requiring medical intervention or close supervision, or any condition that can interfere with the receipt of topiramate
  5. Severe or life-threatening adverse reactions to medications in the past or during this clinical trial
  6. Female subjects who are pregnant, lactating, or not adhering to an acceptable form of contraception at any time during the study
  7. Received inpatient or outpatient treatment for alcohol dependence within the last 30 days
  8. Compelled to participate in an alcohol treatment program to maintain their liberty
  9. Members of the same household
  10. Active tuberculosis
  11. Concurrent treatment with any medications having a potential effect on alcohol consumption and related behaviors, or mood. These include: opioid antagonists (e.g., naltrexone), glutamate antagonists (e.g., topiramate or acamprosate), serotonin reuptake inhibitors (e.g., fluoxetine), serotonin antagonists (e.g., ritanserin or buspirone), other antidepressants (e.g., tricyclic antidepressants or monoamine oxidase inhibitors), dopamine antagonists (e.g., haloperidol), calcium channel antagonists (e.g., isradipine), or compounds with actions similar to disulfiram (Antabuse®) or nicotine.
  12. Before double-blind randomization, urine positive for opiates, cocaine, amphetamines, barbiturates, benzodiazepines, or prescription or non-prescription drugs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pregabalin + BBCET - NI/I/II type
This group will be comprised of subjects with the NI/I/II type who receive study medication (Pregabalin) and Brief Behavioral Compliance Enhancement Treatment (BBCET).
Drug: Pregabalin plus BBCET
Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment
Other Names:
  • Lyrica
Experimental: Pregabalin + BBCET - NI/NI type
This group will be comprised of subjects with the NI/NI type who receive study medication (Pregabalin) and Brief Behavioral Compliance Enhancement Treatment (BBCET).
Drug: Pregabalin plus BBCET
Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment
Other Names:
  • Lyrica
Placebo Comparator: Placebo + BBCET - NI/I/II type
This group will be comprised of subjects with the NI/I/II type who receive placebo and Brief Behavioral Compliance Enhancement Treatment (BBCET).
Other: Placebo plus BBCET
Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment
Placebo Comparator: Placebo + BBCET - NI/NI type
This group will be comprised of subjects with the NI/NI type who receive placebo and Brief Behavioral Compliance Enhancement Treatment (BBCET).
Other: Placebo plus BBCET
Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB)
Time Frame: 12 weeks
Heavy drinking days will be derived from the data collected by the TLFB interview for the last 7 days.
12 weeks
PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL)
Time Frame: 12 weeks
PTSD Cluster B symptoms assessed during treatment will be derived from the data collected with the PCL.
12 weeks
PTSD Cluster E Symptoms as Measured by the PCL
Time Frame: 12 weeks
PTSD Cluster E symptoms assessed during treatment will be derived from the data collected with the PCL.
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Maryland, Baltimore

Collaborators

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 7, 2017

Primary Completion (Actual)

January 19, 2022

Study Completion (Actual)

January 19, 2022

Study Registration Dates

First Submitted

August 26, 2016

First Submitted That Met QC Criteria

August 26, 2016

First Posted (Estimated)

August 31, 2016

Study Record Updates

Last Update Posted (Actual)

March 13, 2024

Last Update Submitted That Met QC Criteria

February 15, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 00069465
  • 5R01AA024760 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Following the NIH policy, and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources, the investigators will provide all of our research resources available for research purposes to qualified individuals within the scientific community after publication of our results.

Sharing of all of the research resources generated by this funded project will be in accordance with the federal rules or regulations imposed upon by the University of Maryland, Baltimore. The investigators will make the results available in accordance with the NIH Data Sharing policy. The investigators will analyze data and submit for peer reviewed publications in scientific journals. The investigators will also present the data in scientific meetings, symposia, or other scientific communications consistent with academic standards.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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