Kappa Opioid Receptor Antagonism for the Tx of AUD and Comorbid 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 veterans and service members with comorbid AUD
and PTSD

Subject Completion Target: A total of 135 male and female, treatment-seeking veterans and
service members 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 (buprenorphine 8 mg SL with naltrexone 380mg IM) or
treatment C (SL placebo and IM placebo) in a double-blind fashion. The treatment allocation
ratio for the treatment vs. placebo regimens is 1:1:1.

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, either active duty or with a history of US
military service, 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; symptoms must be present according to
the DSM-5 criteria, i.e. minimum number in each cluster: at least 1 B symptom, 1 C
symptoms, 2 D symptoms and 2 E symptoms.

5. Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total score ≥26 for the past one
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,
baclofen, and gabapentin).

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.)

- Full listing, with generic and brand names, of allowed and disallowed
medications are provided in the study manual of operations (MOP).

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 MINI-5.

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 moderate or severe non-alcohol substance use disorder (except for
caffeine and nicotine) during the preceding 1 month, based on participant screening
interview. Participants must agree to abstain from illicit drugs during the study.
Patients who utilize cannabis but do not meet substance abuse criteria are permitted.

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 >450 msec (male) or >470 msec (female) 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.