Leveraging Biomarkers for Personalized Treatment of Alcohol Use Disorder Comorbid With PTSD

• ClinicalTrials.gov Identifier: NCT03667846
• Recruitment Status: Recruiting
• First Posted: September 12, 2018
• Last Update Posted: February 5, 2021
• Sponsor: NYU Langone Health
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

This is a double-blind, 2-group randomized controlled trial evaluating the effects of topiramate versus placebo in patients with comorbid PTSD and moderate-to-severe AUD. This trial will provide one of the first rigorous tests of whether the effects of topiramate in AUD generalize to patients with co-occurring PTSD, and one of the first rigorous tests of whether topiramate has beneficial effects on PTSD symptoms in this population. It will be the first study to test whether the rs2832407 genotype predicts clinical response to topiramate for AUD and PTSD in patients with both disorders. Further, it will contribute to the understanding of topiramate's mechanisms of action in the co-morbid AUD/PTSD population, and to the discovery of predictors of treatment response.

Condition or disease	Intervention/treatment	Phase
Post Traumatic Stress Disorder; Alcohol Use Disorder	Drug: Topiramate; Other: Placebo	Phase 2

Detailed Description:

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, and present a clinical challenge for which existing treatments have limited efficacy. Existing clinical evidence suggests treatments that simultaneously address symptoms of both PTSD and AUD should be more efficacious than treating either disorder in isolation. The overlap in the neurobiological basis of PTSD and AUD (involving alterations in incentive salience, stress/negative affect, and executive control network functioning) suggests that there could be treatments that would effectively treat both disorders. However, there is no pharmacotherapy or psychotherapy treatment that is clearly effective for both disorders.

Topiramate, an FDA-approved anticonvulsant with effects on GABAergic and glutamatergic signaling, has demonstrated efficacy in the treatment of AUD in several randomized clinical trials (RCTs), and has also been tested in several open-label and small RCTs for treatment of PTSD with some evidence of effectiveness. Positive results in one open-label trial and one small RCT in patients with co-occurring PTSD and AUD suggest that topiramate may have beneficial effects on symptoms of both PTSD and AUD in this population. Preclinical work also supports the efficacy of topiramate in ameliorating anxiety-like behavior and altered stress response in animal models of stress and chronic alcohol exposure. A recent clinical study demonstrated that the effects of topiramate on alcohol use were moderated by a polymorphism of the GRIK1 gene (coding for the kainate receptor GluK1 subunit), such that significant benefit was found only among rs2832407 C-allele homozygotes.

This trial is designed to contrast acute and persisting effects of topiramate to those of placebo treatment in a sample of 150 participants with comorbid PTSD and moderate to severe AUD, and to evaluate the moderating effect of rs2832407 genotype on medication effects. Drug will be titrated over 8 weeks to a maximum dose of 200 mg and continued for 4 more weeks for a total of 12 weeks of treatment, followed by a 2-week taper. Alcohol and PTSD-related outcomes will be assessed at multiple time points throughout the study. Plasma biomarkers and neuropsychological assessments will be obtained at baseline and at week 12. In support of the overall aims of the center focusing on personalized medicine, the trial will serve as a platform for studies of topiramate's effects on brain chemistry and function as measured by fMRI, and EEG . Data from this clinical trial will also contribute to Overall Center Aims investigating the relationship of plasma biomarkers to neuroimaging markers.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Leveraging Biomarkers for Personalized Treatment of Alcohol Use Disorder Comorbid With Post Traumatic Stress Disorder
• Actual Study Start Date: October 16, 2019
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo	Other: Placebo; Placebo tablets will be encapsulated in identical capsules.
Experimental: Topiramate; Week 0-1: 25 mg qhs Week 1-2: 25 mg qAM, 25 mg qhs Week 2-3: 25 mg qAM, 50 mg qhs Week 3-4: 50 mg qAM, 50 mg qhs Week 4-5: 50 mg qAM, 75 mg qhs Week 5-6: 75 mg qAM, 75 mg qhs Week 6-7: 75 mg qAM, 100 mg qhs Week 7-8: 100 mg qAM, 100 mg qhs Week 8-10: 100 mg qAM, 100 mg qhs Week 10-12: 100 mg qAM, 100 mg qhs Week 12-14: 2-week taper	Drug: Topiramate; Generic topiramate, FDA-approve for clinical use, will be purchased in 25mg, 50mg, and 100mg strengths, and encapsulated.; Other Name: Topamax

Outcome Measures

Primary Outcome Measures :

1. Measure of Time-line Follow-back (TLFB) [ Time Frame: Day 1 ]
   Retrospective estimate of daily alcohol consumption over a time period ranging from 7 days to 24 months prior to initial interview
2. Percent Day Abstinent from Alcohol [ Time Frame: Week 9 to Week 12 ]
   Percentage of day abstinent from alcohol between week 9 and week 12
3. PCL-5 score [ Time Frame: Week 9 to Week 12 ]
   20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. The symptom severity score (range - 0-80) can be obtained by summing the scores for each of the 20 items. Each question is measured on a 5-point Likert (0 = "Not at all" to 4 = "Extremely"). A total symptom severity score (range - 0-80; 80 being more severe) can be obtained by summing the scores for each of the 20 items.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Males and females aged 18-70 years old
2. DSM-5 diagnosis of moderate or severe AUD (using SCID5)
3. Endorse a desire to cut down or stop drinking
4. At least 6 heavy drinking days (4 or more drinks per day for a woman, 5 or more drinks per day for a man) in the 30 days prior to screen
5. DSM-5 current diagnosis of PTSD with the Clinician Administered PTSD Scale OR subPTSD diagnosis (meeting criterion A, F, G, H and at least 6 symptoms across any criteria B-E) with Clinician Administered PTSD Scale (CAPS-5)
6. If of childbearing potential (male or female), are willing to use contraception for duration of the trial
7. Able to provide at least 2 locators
8. Able to provide voluntary informed consent
9. Confirms they are reliably domiciled

Exclusion Criteria:

1. Current alcohol withdrawal (CIWA-Ar score >7)
2. DSM-5 diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, current significant suicidality (assessed using the C-SSRS), any significant suicidal behavior in the past 12 months, or any history of serious suicide attempts requiring hospitalization, or active homicidality
3. DSM-5 diagnosis of current moderate or severe substance use disorder for a substance other than alcohol or nicotine
4. Any history of severe traumatic brain injury (assessed using the OSU TBI-ID modified). If current (past 12 months) mild/moderate TBI and CSI score ≥12 (for either lifetime month or current month), the PI will determine eligibility.
5. Exposure to trauma in the last 30 days, including police duty or military service
6. Significantly impaired liver function defined as a) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN); b) ALT or AST > 3 x ULN with concomitant total bilirubin > 2.0 x ULN; or c) ALT or AST ≥ 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia
7. Other medical conditions which would preclude safe participation in the study
8. Significant laboratory abnormalities, including significantly impaired hepatic function, abnormalities in complete blood count or metabolic panel
9. Current use of medications with the potential for adverse drug-drug interactions including but not limited to CNS depressants specified anticonvulsants (such as: Phenytoin, Carbamazepine and Depakote), metformin, and pharmacologic treatments for addictions including alcohol use disorder ,and other Carbonic Anhydrase inhibitors (i.e. zonisamide, acetazolamide, dichlorphenamide). Oral contraceptives are permitted as long as participants who are on an estrogen and/or estrogen-progesterone form use a double barrier contraceptive. Antidepressant medications are permitted if participants have been on a stable dose for at least 4 weeks prior to screening and the dose may not be changed during treatment phase (weeks 0-14) of the study.
10. Pregnancy or lactation
11. Current treatment for AUD (with the exception of AA/12-step treatment and/or psychosocial treatment initiated more than 3 months prior to the screening visit)
12. Psychotherapy for PTSD or other psychiatric condition, if initiated within 3 months of screening
13. Allergy or hypersensitivity to topiramate
14. Active legal problems likely to result in incarceration within 12 weeks of treatment initiation
15. Significantly impaired renal function defined as) creatinine clearance rate <70 mL/min/1.73 m2.
16. High risk of adverse emotional or behavioral reaction, and/or an inability to understand study procedures or the informed consent process, based on investigator's clinical evaluation (e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful social support)
17. Inpatient psychiatric treatment in the last 12 months, with the exception of detox and extended Emergency Department stays

Contacts and Locations

Contacts

Contact: Duna Abu-Amara, MPH; (646) 754-4793; Duna.Abu-Amara@nyulangone.org

Contact: Michael Bogenschutz, MD; (646) 501-4026; Michael.Bogenschutz@nyulangone.org

Locations

United States, New York

New York University School of Medicine; Recruiting

New York, New York, United States, 10016

Contact: Duna Abu Amara 646-754-4793 Duna.Abu-Amara@nyulangone.org

Principal Investigator: Charles Marmar, MD

Sponsors and Collaborators

NYU Langone Health

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Investigators

• Principal Investigator: Charles Marmar, MD; NYU Langone Health

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT03667846
• Other Study ID Numbers: 18-A0-00-008287; P01AA027057 ( U.S. NIH Grant/Contract )
• First Posted: September 12, 2018
• Last Update Posted: February 5, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All of the individual participant data collected during the trial, after deidentification.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Data will be made available within twelve months of database lock or following publication of primary manuscript, whichever occurs first. Data will be available indefinitely.
• Access Criteria: Anyone who wishes to access the data.

• 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.: Yes

Additional relevant MeSH terms:

Disease; Alcoholism; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Alcohol Drinking; Pathologic Processes; Trauma and Stressor Related Disorders; Mental Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Topiramate; Anticonvulsants; Hypoglycemic Agents; Physiological Effects of Drugs