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

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ClinicalTrials.gov Identifier: NCT03667846
Recruitment Status : Not yet recruiting
First Posted : September 12, 2018
Last Update Posted : February 8, 2019
Sponsor:
Information provided by (Responsible Party):
New York University School of Medicine

Brief Summary:
This is a double-blind, 2-group randomized controlled trial evaluating the effects of topiramate versus placebo in patients with comorbin 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 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
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Topiramate

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




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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • DSM-5 80 diagnosis of moderate or severe AUD;
  • endorse desire to cut down or stop drinking;
  • At least 10 heavy drinking days in the month prior to screening, as assessed by the Time Line Follow Back (TLFB) 81,82;
  • DSM-5 diagnosis of PTSD;
  • Clinician Administered PTSD Scale for DSM-5 (CAPS-5) current symptom score > 25;
  • If female of childbearing potential, are willing to use approved form of contraception for the duration of the trial (Acceptable methods of contraception include oral contraceptives, barrier with spermicide, IUD, levonorgestrel implant (Norplant ®), medroxyprogesterone acetate (Depo Provera ®), surgical sterilization, contraceptive patch, vaginal contraceptive ring, and complete abstinence (not having sex));
  • able to provide at least 2 locators;
  • able to provide voluntary informed consent.

Exclusion Criteria:

  • Current alcohol withdrawal (AW), evidenced by CIWA-Ar scale > 7
  • Severe psychiatric conditions, including past or current DSM-5 diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or current suicidality;
  • DSM-5 diagnosis of current moderate or severe substance use disorder for a substance other than alcohol or nicotine;
  • Traumatic brain injury involving current concussive symptoms or a Post-Concussion Syndrome score greater than or equal to 12
  • Exposure to trauma in the last 30 days, including police duty or military service; significantly impaired liver function, defined as a) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN); b) ALT or AST > 3 × ULN with concomitant total bilirubin > 2.0 × ULN; or c) ALT or AST ≥ 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia;
  • other medical conditions which would preclude safe participation in the study;
  • significant laboratory abnormalities, including significantly impaired hepatic function, abnormalities in complete blood count or metabolic panel;
  • serious ECG abnormalities (e.g., evidence of ischemia, myocardial infarction);
  • current use of exclusionary medications, including antidepressants, antipsychotics, anticonvulsants, psychostimulants, and pharmacologic treatments for addictions including alcohol use disorder
  • pregnancy or lactation,
  • current treatment for substance use disorder or PTSD;
  • allergy or hypersensitivity to topiramate; and
  • active legal problems likely to result in incarceration within 12 weeks of treatment initiation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03667846


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 Not yet 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
New York University School of Medicine
Investigators
Principal Investigator: Charles Marmar, MD New York University School of Medicine

Responsible Party: New York University School of Medicine
ClinicalTrials.gov Identifier: NCT03667846     History of Changes
Other Study ID Numbers: 18-A0-00-008287
First Posted: September 12, 2018    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: February 2019
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
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Alcohol Drinking
Pathologic Processes
Trauma and Stressor Related Disorders
Mental Disorders
Drinking Behavior
Topiramate
Anticonvulsants
Neuroprotective Agents
Protective Agents
Physiological Effects of Drugs
Anti-Obesity Agents