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

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ClinicalTrials.gov Identifier: NCT02884908
Recruitment Status : Recruiting
First Posted : August 31, 2016
Last Update Posted : April 28, 2021
Sponsor:
Collaborator:
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information provided by (Responsible Party):
Melanie Bennett, University of Maryland, Baltimore

Tracking Information
First Submitted Date  ICMJE August 26, 2016
First Posted Date  ICMJE August 31, 2016
Last Update Posted Date April 28, 2021
Study Start Date  ICMJE September 2016
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 26, 2016)
  • Drinking variables as measured by the Time Line Follow Back (TLFB) [ Time Frame: 90 days ]
    Drinking variables pre- and post-target quit date (TQD) will be derived from the data collected by the TLFB interview.
  • PTSD Cluster B symptoms as measured by the Clinician Administered PTSD Scale (CAPS-5) [ Time Frame: 90 days ]
    PTSD Cluster B symptoms pre- and post-TQD will be derived from the data collected with the CAPS-5.
  • PTSD Cluster E symptoms as measured by the CAPS-5 [ Time Frame: 90 days ]
    PTSD Cluster E symptoms pre- and post-TQD will be derived from the data collected with the CAPS-5.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD
Official Title  ICMJE Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD
Brief Summary 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 large and diverse sample of African-Americans that includes both genders and individuals with different types of trauma. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment (BBCET).
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 neuro- transmitter 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 pregabalin efficacy in reducing both AUD and PTSD Clusters B or E in 2 treatment groups of medication (pregabalin, placebo) x 2 genetic variants (NI/I/II vs. NI/NI) in a double- blind, placebo-controlled 12-week clinical trial with a set target quit-date (TQD) for drinking. The investigators will utilize a large and diverse sample of African-Americans that includes both genders and individuals with different types of trauma. Pregabalin dose and placebo will be titrated to the maximum dose from baseline to week 6 using a double-dummy procedure to ensure equivalence of capsules received. The TQD will be set at week 6. The split design (post-TQD vs. pre-TQD) will allow the study to separately examine both whether pregabalin's therapeutic effects reduce drinking and prevent relapse post cessation and whether the cessation of drinking results in improved PTSD cluster B or E symptoms in carriers of specific GAT-1 transporter genotypes. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment (BBCET) and follow-up post treatment and 3 month assessments. The specific aims are as follows:

Specific Aim 1: To test the hypothesis that AUD patients treated with pregabalin and having the non-insertion/insertion or insertion/insertion (NI/I or I/I) variant of the SLC6A1 gene for GABA transporter (GAT-1) will be more predictive of the ability not drink heavily than pregabalin-treated patients with the NI/NI genetic variant and placebo-treated patients.

Specific Aim 2: To test the hypothesis that AUD patients treated with pregabalin and having the non-insertion/insertion or insertion/insertion (NI/I or I/I) variant of the SLC6A1 gene for GABA transporter (GAT-1) will be more efficacious in reducing PTSD cluster B or E symptoms (or both) than pregabalin-treated patients with the NI/NI genetic variant and placebo-treated patients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • PTSD
  • Alcohol Use Disorder
Intervention  ICMJE
  • Drug: Pregabalin plus BBCET
    Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment
    Other Name: Lyrica
  • Other: Placebo plus BBCET
    Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Pregabalin plus BBCET
  • 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).
    Intervention: Drug: Pregabalin plus BBCET
  • 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).
    Intervention: Other: Placebo plus BBCET
  • 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).
    Intervention: Other: Placebo plus BBCET
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 26, 2016)
252
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2022
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Melanie Bennett, PhD 410-706-0892 mbennett@som.umaryland.edu
Contact: Brian Brandler, MS 410-402-6425 bbrandler@som.umaryland.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02884908
Other Study ID Numbers  ICMJE 00069465
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.

Responsible Party Melanie Bennett, University of Maryland, Baltimore
Study Sponsor  ICMJE University of Maryland, Baltimore
Collaborators  ICMJE National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators  ICMJE Not Provided
PRS Account University of Maryland, Baltimore
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP