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

Study Overview
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Brief Summary
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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)

Detailed Description
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Hypothesis: The treatment of (sublingual buprenorphine) SL-BUP + (extended release naltrexone) XR-NTX will significantly reduce both (alcohol use disorder) AUD and (post-traumatic stress disorder) PTSD symptoms. Primary Inclusion Criteria: Treatment-seeking individuals with comorbid AUD and PTSD Subject Completion Target: A total of 90 male and female, treatment-seeking individuals with comorbid AUD and PTSD screened, enrolled, and randomized to treatment group Study Protocol: Screening: Potential participants are pre-screened by phone to ensure they meet basic study criteria. During informed consent and screening processes, participants receive thorough pre-enrollment education and the commitment to and feasibility for follow-up are confirmed. Screening visit is separate (at least 2-day interval) from Baseline visit. A participant who is otherwise meeting eligibility criteria except for taking an excluded medication can undergo a medically supervised discontinuation and 5-day washout of medication(s). At any point in the screening process and based on the inclusion and exclusion criteria listed above, the participant may be deemed eligible and proceed to baseline visit or investigator may exclude a participant and refer him/her for appropriate treatment. At baseline, participants are randomized to receive either treatment A (buprenorphine 2mg SL with naltrexone 380mg IM) or treatment B (SL placebo and IM placebo) in a double-blind fashion. The treatment allocation ratio for the treatment vs. placebo regimens is 1:1. At Screening, Baseline and Follow-up, an independent rater at each site performs the Timeline Follow Back (TLFB), Clinician Administered PTSD Scale for DSM-5 (CAPS-5), and Columbia Suicide Severity Rating (CSSR) assessments. Safety endpoints, adverse events (AEs), vital signs, and laboratory measures are tracked for each subject to assess study drug safety.

Official Title
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Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder (AUD) and Comorbid Post-Traumatic Stress Disorder (PTSD)

Conditions
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Post Traumatic Stress Disorder, Alcohol Abuse

Intervention / Treatment
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* Drug: 2mg Buprenex and 380mg Vivitrol
* Drug: Placebo (SL pill qd, IM injection q4weeks)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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.) Exclusion Criteria: 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. Unable or unwilling to refrain from medications thought to influence alcohol consumption (see inclusion criteria above.) Unable or unwilling to refrain from psychotropic medications (see inclusion criteria above); with the exception of stable doses of antidepressants, prazosin, and non-benzodiazepine hypnotics and non-benzodiazepine anxiolytics to treat PTSD or insomnia. Persons who are imprisoned, of minor age, diagnosed with dementia, diagnosed with a terminal illness, or otherwise require a surrogate to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: proof-of-concept study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2mg Buprenex and 380mg Vivitrol<br>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<br>* 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<br>* Other names: 2mg BUP/NLTRX;|
| Placebo Comparator: Placebo<br>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)<br>* 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<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol Abuse, Alcohol Use Disorder (AUD), Alcoholism, Post Traumatic Stress Disorder (PTSD)