Futility analysis

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)

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.

Inclusion Criteria:

1. 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).

2. Current moderate to severe AUD as determined by MINI International Neuropsychiatric Interview for DSM-5 (MINI-5).

3. 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.

4. PTSD diagnosis defined by MINI-5 at screening.

5. Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total score ≥26 for the past week at baseline.

6. 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.

7. Must have a CIWA-Ar score of < 8 prior to randomization.

8. Willing and able to refrain from medications thought to influence alcohol consumption (other formulations of naltrexone, disulfiram, acamprosate, topiramate, ondansetron, and baclofen).

9. 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:

1. Current diagnosis of DSM-5 bipolar I, schizophrenia, schizoaffective, and/or major depressive disorder with psychotic features (defined by MINI-5 at screening).
2. 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).
3. 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.
4. Current diagnosis of severe non-alcohol substance use disorder (except for caffeine and nicotine) during the preceding 1 month, based on participant screening interview.
5. Use of opioids within 2 weeks of baseline or opioid use disorder in the previous 90 days.
6. History of severe traumatic brain injury (TBI) per Ohio State University TBI Identification Method. Note: history of mild or moderate TBI is allowed.
7. 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.
8. 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.
9. History of allergic reaction, bronchospasm or hypersensitivity to a naltrexone or buprenorphine.
10. Unable or unwilling to refrain from medications thought to influence alcohol consumption (see inclusion criteria above.)
11. 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.
12. Persons who are imprisoned, of minor age, diagnosed with dementia, diagnosed with a terminal illness, or otherwise require a surrogate to provide informed consent.

CDMRP has a policy to share and make available to the public the results and accomplishments of the activities that it funds. The PASA consortium plans to share de-identified data after final publication in a government-supported data repository.

From baseline visit (after first treatment allocation) through the Week 14 study visit.

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

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.