Alcohol Use Disorder, PTSD
Conditions
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 sample of African-Americans that includes both genders and individuals with different types of trauma.
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.
Interventions
DRUGPregabalin plus BBCET
Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment
OTHERPlacebo plus BBCET
Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB) | 12 weeks | Heavy drinking days will be derived from the data collected by the TLFB interview for the last 7 days. |
| PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL) | 12 weeks | PTSD Cluster B symptoms assessed during treatment will be derived from the data collected with the PCL. |
| PTSD Cluster E Symptoms as Measured by the PCL | 12 weeks | PTSD Cluster E symptoms assessed during treatment will be derived from the data collected with the PCL. |
Countries
United States
Participant flow
Recruitment details
The trial took place at University of Maryland School of Medicine. Participants were from Baltimore and surrounding counties. The study ran 7/17-6/19 when the research center closed. Recruitment resumed 7/19-3/20 when it stopped due to the pandemic. Recruitment resumed 10/20-12/21 with a 1-month stoppage in 1/21 due to the pandemic.
Pre-assignment details
N=152 signed consent. Of these, 57 were randomized: 32 to pregabalin, 25 to placebo. 94 were not randomized: 1) did not meet alcohol use disorder criteria; 2) did not meet criteria for PTSD or other trauma disorder; 3) did not meet other eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin + BBCET 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).
Pregabalin plus BBCET: Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment | 32 |
| Placebo + BBCET This group will be comprised of subjects with the NI/I/II type who receive placebo and Brief Behavioral Compliance Enhancement Treatment (BBCET).
Placebo plus BBCET: Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment | 25 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 13 | 18 |
Baseline characteristics
| Characteristic | Pregabalin + BBCET | Placebo + BBCET | Total |
|---|---|---|---|
| Age, Continuous | 44.1 years STANDARD_DEVIATION 11 | 42.5 years STANDARD_DEVIATION 13 | 43.4 years STANDARD_DEVIATION 11.8 |
| Diagnostic and Statistical Manual 5 (DSM5) Alcohol Use Disorder (AUD) severity | 7.8 Number of AUD symptoms STANDARD_DEVIATION 2.3 | 8.3 Number of AUD symptoms STANDARD_DEVIATION 1.7 | 8.0 Number of AUD symptoms STANDARD_DEVIATION 2.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 24 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heavy drinking days in the last 30 days | 10.3 days STANDARD_DEVIATION 13.2 | 9.9 days STANDARD_DEVIATION 11.4 | 10.2 days STANDARD_DEVIATION 12.4 |
| PTSD Cluster B Symptoms (last week) | 9.5 Number of symptoms STANDARD_DEVIATION 4.7 | 9.8 Number of symptoms STANDARD_DEVIATION 4.2 | 9.7 Number of symptoms STANDARD_DEVIATION 4.5 |
| PTSD Cluster E Symptoms (last week) | 11.5 Number of symptoms STANDARD_DEVIATION 5.6 | 13.1 Number of symptoms STANDARD_DEVIATION 4.3 | 12.2 Number of symptoms STANDARD_DEVIATION 5.1 |
| 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 | 30 Participants | 24 Participants | 54 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 | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 14 Participants | 12 Participants | 26 Participants |
| Sex: Female, Male Male | 18 Participants | 13 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 18 |
| other Total, other adverse events | 26 / 26 | 18 / 18 |
| serious Total, serious adverse events | 1 / 26 | 1 / 18 |
Outcome results
Primary
Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB)
Heavy drinking days will be derived from the data collected by the TLFB interview for the last 7 days.
Time frame: 12 weeks
Population: 44 took at least 1 dose of study medication: 26 in the experimental condition and 18 in the placebo condition. This is the analysis population. For some outcomes, there was missing data at the 12-week assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin + BBCET | Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB) | Baseline | 10.5 days | Standard Deviation 13.1 |
| Pregabalin + BBCET | Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB) | 12-week assessment | 1.1 days | Standard Deviation 2 |
| Placebo + BBCET | Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB) | Baseline | 10.2 days | Standard Deviation 11.2 |
| Placebo + BBCET | Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB) | 12-week assessment | 1.0 days | Standard Deviation 1.8 |
p-value: 0.8Mixed Models Analysis
Primary
PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL)
PTSD Cluster B symptoms assessed during treatment will be derived from the data collected with the PCL.
Time frame: 12 weeks
Population: 4 took at least 1 dose of study medication: 26 in the experimental condition and 18 in the placebo condition. This is the analysis population. For some outcomes, there was missing data at the 12-week assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin + BBCET | PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL) | Baseline | 9.7 number of symptoms | Standard Deviation 4.7 |
| Pregabalin + BBCET | PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL) | 12-week assessment | 3.6 number of symptoms | Standard Deviation 4.6 |
| Placebo + BBCET | PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL) | Baseline | 9.8 number of symptoms | Standard Deviation 4.1 |
| Placebo + BBCET | PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL) | 12-week assessment | 1.6 number of symptoms | Standard Deviation 2.2 |
p-value: 0.9Mixed Models Analysis
Primary
PTSD Cluster E Symptoms as Measured by the PCL
PTSD Cluster E symptoms assessed during treatment will be derived from the data collected with the PCL.
Time frame: 12 weeks
Population: 44 took at least 1 dose of study medication: 26 in the experimental condition and 18 in the placebo condition. This is the analysis population. For some outcomes, there was missing data at the 12-week assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin + BBCET | PTSD Cluster E Symptoms as Measured by the PCL | Baseline | 12.2 number of symptoms | Standard Deviation 5.4 |
| Pregabalin + BBCET | PTSD Cluster E Symptoms as Measured by the PCL | 12-week assessment | 6.4 number of symptoms | Standard Deviation 5 |
| Placebo + BBCET | PTSD Cluster E Symptoms as Measured by the PCL | Baseline | 13.3 number of symptoms | Standard Deviation 4.8 |
| Placebo + BBCET | PTSD Cluster E Symptoms as Measured by the PCL | 12-week assessment | 4.4 number of symptoms | Standard Deviation 3.9 |
p-value: 0.38Mixed Models Analysis