Kappa Opioid Receptor Antagonism for the Tx of AUD and Comorbid PTSD

NCT03852628 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: AS140026-A5
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 2

Brief Summary

Objective: Evaluate the efficacy and physiological effects of sublingual buprenorphine (SL-BUP; Subutex) combined with extended-release injectable naltrexone (XR-NTX; Vivitrol) in the treatment alcohol use disorder of comorbid (AUD) and post-traumatic stress disorder (PTSD)

Conditions

Post Traumatic Stress Disorder; Alcohol Abuse

Keywords

Alcohol Use Disorder (AUD); Alcoholism; Alcohol Abuse; Post Traumatic Stress Disorder (PTSD)

Outcome Measures

Primary Outcomes (3)

• Number of Participants With a Reduction in Alcohol Use Disorder (AUD), With TLFB Tool

  Timeline Follow Back (TLFB) is a calendar-based method of assessing drinking patterns used to document the frequency and amount of daily alcohol consumption and to categorize the World Health Organization Risk Levels of Alcohol Use. An AUD reduction is defined as a WHO risk reduction of at least one category from baseline to week 8. The are 4 different WHO Risk Levels based on the grams of alcohol consumed per day: Very High Risk, High Risk, Medium Risk, and Low Risk (including abstinence).

  Baseline and 8 weeks

• Number of Participants With a Reduction in CAPS-5 Total Symptom Severity Score (TSSS) of 10 or More Points

  The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a 30-item structured interview to assess PTSD diagnosis and symptom severity. The CAPS-5 produces a PTSD Total Symptom Severity Score (TSSS) that ranges from 0 to 80, with a higher score indication worse PTSD symptoms. For this study, a reduction in PTSD symptoms is defined as a 10 or more point decrease in the CAPS-5 Total Symptom Severity Score (TSSS) from baseline to week 8.

  Baseline and 8 weeks

• Composite Outcome Measure for a Reduction in Both Alcohol Use Disorder (AUD) and Post-Traumatic Stress Disorder (PTSD) Symptoms

  AUD is measured by the Timeline Follow Back (TLFB). This instrument documents the amount of daily alcohol consumption (in grams) and categorizes the World Health Organization Risk Levels of Alcohol Use. The are 4 different WHO Risk Levels: Very High Risk, High Risk, Medium Risk, and Low Risk (including abstinence). An AUD reduction is defined as a WHO risk reduction of at least one category from baseline to week 8. PTSD symptom is measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). This 30-item interview assesses PTSD diagnosis and symptom severity. The CAPS-5 Total Symptom Severity Score (TSSS) ranges from 0 to 80, with higher scores indicating worse symptoms. A reduction in PTSD symptom is defined as a 10+ point decrease in the TSSS from baseline to week 8. A positive response for the composite primary outcome measure is defined as at least a 1-category risk reduction on the WHO s and at least a 10-point decrease in TSSS from baseline to Week 8.

  Baseline and 8 Weeks

Study Arms (2)

2mg Buprenex and 380mg Vivitrol

ACTIVE COMPARATOR

2mg Buprenex and 380mg Vivitrol Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks)

Drug: 2mg Buprenex and 380mg Vivitrol

Placebo

PLACEBO COMPARATOR

Placebo (SL pill qd, IM injection q4weeks) Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8)

Drug: Placebo (SL pill qd, IM injection q4weeks)

Interventions

2mg Buprenex and 380mg Vivitrol DRUG

Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX

Also known as: 2mg Buprenex (SL, qd) and 380mg Vivitrol (IM, q4weeks), 2mg BUP/NLTRX

2mg Buprenex and 380mg Vivitrol

Placebo (SL pill qd, IM injection q4weeks) DRUG

Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, 18 to 70 years of age, capable of reading and understanding English, and able to provide written informed consent (i.e. no surrogate).
• Current moderate to severe AUD as determined by MINI International Neuropsychiatric Interview for DSM-5 (MINI-5).
• At least two recent episodes of heavy drinking (\>5 standard drinks/sessions for men and \>4 standard drinks/sessions for women) over the past 30 days, and heavy drinking pattern defined as 14 drinks per week for women and 21 drinks per week for men for at least 2 of a 4-week interval within the 90 days prior to baseline; i.e. at least Moderate Risk level on WHO category.
• PTSD diagnosis defined by MINI-5 at screening.
• Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total score ≥26 for the past week at baseline.
• Females of child-bearing potential must be using medically acceptable birth control (e.g. oral, implantable, injectable, or transdermal contraceptives; intrauterine device; double-barrier method) AND not be pregnant OR have plans for pregnancy or breastfeeding during the study.
• Must have a CIWA-Ar score of \< 8 prior to randomization.
• Willing and able to refrain from medications thought to influence alcohol consumption (other formulations of naltrexone, disulfiram, acamprosate, topiramate, ondansetron, and baclofen).
• Willing and able to refrain from psychotropic medications: stimulants/ADHD treatment, Alzheimer's medications, antipsychotics, benzodiazepines, antianxiety medications, mood stabilizers, and other sedatives.
• Notes:
• Participants may continue stable dose of antidepressants, prazosin, and non-benzodiazepine hypnotics and non-benzodiazepine anxiolytics to treat PTSD or insomnia.
• Stable dose is defined as taken for ≥2 months prior to randomization and current does has been stable for ≥3 weeks prior to randomization and held constant during 12 weeks of study medication.)

You may not qualify if:

• Current diagnosis of DSM-5 bipolar I, schizophrenia, schizoaffective, and/or major depressive disorder with psychotic features (defined by MINI-5 at screening).
• Increased risk of suicide that necessitates inpatient treatment or warrants therapy excluded by the protocol, and/or current suicidal plan, per investigator clinical judgement, based on interview and defined on the Columbia Suicidality Severity Rating Scale (C-SSRS).
• Treatment with trauma-focused therapy for PTSD (e.g. Cognitive Processing Therapy, Prolonged Exposure, or EMDR) within two weeks of baseline study visit. Note: Supportive psychotherapy in process for PTSD at time of Screening may be continued.
• Current diagnosis of severe non-alcohol substance use disorder (except for caffeine and nicotine) during the preceding 1 month, based on participant screening interview.
• Use of opioids within 2 weeks of baseline or opioid use disorder in the previous 90 days.
• History of severe traumatic brain injury (TBI) per Ohio State University TBI Identification Method. Note: history of mild or moderate TBI is allowed.
• Any clinically significant, uncontrolled, or medical/surgical condition that would contraindicate use of SL-BUP + XR-NTX, or limit ability to complete study assessments, including seizures (other than childhood febrile seizures), severe renal insufficiency, significant arrhythmia or heart block, heart failure, or myocardial infarction within the past 2 years, severe thrombocytopenia or hemophilia, severe hepatic failure, complete hearing loss, and/or need for surgery that might interfere with ability to participate.
• Clinically significant laboratory abnormalities, including a thyroid stimulating hormone (TSH) \>1.5 times upper limit of normal, hyperthyroidism, and aspartate aminotransferase and/or alanine aminotransferase \> 3 times upper limit of normal; cardiovascular findings QTcF \>500 msec on electrocardiogram (ECG) or blood pressure \>190/110.
• History of allergic reaction, bronchospasm or hypersensitivity to a naltrexone or buprenorphine.
• Persons who are imprisoned, of minor age, diagnosed with dementia, diagnosed with a terminal illness, or otherwise require a surrogate to provide informed consent.

Sponsors & Collaborators

• Pharmacotherapies for Alcohol and Substance Use Disorders Alliance: lead
• United States Department of Defense: collaborator
• RTI International: collaborator

Study Sites (2)

Tuscaloosa VA Medical Center

Tuscaloosa, Alabama, 35404, United States

Location

VA Connecticut Healthcare System

West Haven, Connecticut, 06516, United States

Location

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Alcoholism

Interventions

Buprenorphine; vivitrol

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

There are no secondary outcome results to report as this study was closed for futility before enough data was collected to report secondary outcomes. .

Results Point of Contact

• Title: PASA Core Leadership
• Organization: RTI International

shirsch@rti.org

919-541-6002

Study Officials

• Lori Davis

  Associate Chief of Staff, Research & Development Service VA Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: To minimize bias, a placebo drug is employed as the comparison group to active study drug and the study is conducted in a double-masked fashion in that both the participants and the Independent Assessors who are assessing study outcomes are masked to treatment assignment. The only individuals at the site with access to treatment assignment information are the research pharmacists.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: proof-of-concept study

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: February 25, 2019
• Study Start: May 20, 2019
• Primary Completion: May 2, 2022
• Study Completion: January 30, 2023
• Last Updated: September 14, 2023
• Results First Posted: June 7, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

US (2)