Clinical Trial to Evaluate the Safety of PT150 (Formerly ORG34517) When it is Taken Concurrently With Alcohol

PT150 (Formerly ORG34517) as a Potential Treatment for Alcohol Dependence-Alcohol Interaction Study

The purpose of the clinical study is to compare pharmacodynamic and safety endpoints following an alcohol challenge prior to and concurrent with PT150 (study drug) treatment.

This study can be classified as a phase 1, single center, and drug study. This within-subjects experimental procedure will assess the effects of PT150 (900 mg qd) on the subjective effects of alcohol in non-treatment-seeking alcohol-experienced volunteers (to include military service members, veterans and/or civilians). Study duration will be six days; in-house; Day 0 (admission) until day six (final study day and day of discharge). Participants will undergo two alcohol challenges on day 1 separated by 4 hours (one with alcohol, 0.8g/kg; 16% ethanol by volume, and one with placebo beverage, 1% ethanol by volume, randomly ordered) and receive active study drug (PT150) from days 1-5 (after alcohol challenge for day 1). On day 5, the study drug dosing will be followed by two more alcohol challenges (alcohol and placebo beverage randomly ordered). Physiologic (e.g., vital signs, electrocardiogram), subjective and psychometric effects (e.g., mood, urge, craving, stimulant and sedative effects), and breath alcohol levels (BAL) will be obtained after the alcohol challenges. On day six, an electrocardiogram (ECG) will be performed, adverse events (AEs) and symptom checklist will be collected, including symptoms of adrenal insufficiency (AI), and a blood draw for electrolyte levels and cortisol will be collected in the morning followed by breakfast and discharge if laboratory tests are within normal ranges. All serious adverse events will be followed clinically until resolved or clinically stable. Pharmacodynamic and safety endpoints will be assessed during the alcohol challenge prior to, and after 5 days of PT150 treatment, when PT150 has reached steady state. For females, a follow-up visit will be scheduled to occur at least 14 days after the final dose of PT150 is administered to ensure pregnancy does not occur. The objectives of the study are to compare pharmacodynamics and safety endpoints following an alcohol challenge prior to and concurrent with PT150. Given available pre-clinical and clinical evidence for the salutatory effect of glucocorticoid receptor (GR) antagonists on alcohol withdrawal, it was hypothesized that PT150 will not significantly alter pharmacodynamic measures and will be safe and well-tolerated under conditions of alcohol consumption.

Inclusion Criteria: - Provide signed and dated informed consent;

• male and female, ages 21 to 64;
• must score <10 on the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) assessed in the context of a blood alcohol level (BAL) ≤ 0.02% to demonstrate that they do not need medical detoxification; must have blood laboratory test results within acceptable limits (normal range as noted per protocol);
• have normal vitals (heart rate 60-100 beats per minute (bpm), systolic blood pressure 90-140 millimeter of mercury (mmHg) and diastolic blood pressure 60-90 mmHg); a baseline electrocardiogram (ECG) that demonstrates clinically normal sinus rhythm, clinically normal conduction, normal QTc, and no clinically significant arrhythmias;
• have a self-reported medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgement of the admitting physician;
• must be willing to comply with all study procedures and be available for the duration of the study;
• women must either be unable to conceive (i.e., surgically sterilized, sterile, or post-menopausal) or using non-hormonal, medically acceptable contraception during the study and for at least 2 weeks after study completion, with or without additional hormonal contraception Women can be receiving hormone replacement treatment (HRT) as long as the HRT dose has been stable for a period of at least 3 months;
• women must provide negative urine pregnancy tests before study entry (urine), and before alcohol administrations on day 0 or 1 (serum) and on day 5 (urine);
• able to provide proof of age and identity (includes providing full name and date of birth), forms of proof as defined per protocol.

Exclusion Criteria:

• Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for substance use disorders other than alcohol or nicotine or test positive for prescription or illegal substances. With regard to marijuana/tetrahydrocannabinols (THC), an individual must test negative at the baseline. If an individual tests positive they will be given a grace period where they will have the opportunity to return and test negative prior to being enrolled;
• pregnant or nursing;
• receiving HRT where their dose has not been stable for a minimum of 3 months;
• use of concomitant medications (except birth control pills) or other the counter (OTC) supplements for at least 14 days or 5 half-lives (whichever is longer) before the start of the study and for the entire duration of the study. Concomitant medication use includes any prescription, OTC medications, or herbal supplements;
• receiving any non-pharmacotherapy treatments or procedures for which there are precautions for taking concomitantly with PT150 and/or those that interfere with the study;
• have neurological or psychiatric disorders other than Alcohol Use Disorder (AUD);
• history of suicide attempts and/or current suicidal ideation/plan;
• have evidence of untreated or unstable medical illness including: cardiovascular, neuroendocrine, autoimmune, renal, hepatic, or active Human Immucodeficiency Virus (HIV) +, Acquired Immune Deficiency Syndrome (AIDS) infection;
• have a history of medically adverse reactions to alcohol (e.g., loss of consciousness, chest pain, or epileptic seizure) or major alcohol-related medical complications requiring hospitalization (i.e., hepatitis or pancreatitis);
• have contraindication(s) to take the study medications such as renal or hepatic impairment, congenital metabolic disorders, or hypersensitivity to study medication class (i.e., glucosteroid abntagonist);
• have past brain injury/head trauma with current symptoms (e.g., not photophobic, dizziness etc.) or past report of loss of consciousness (LOC) for >30 minutes and/or have been blast-exposed or had LOC >1 minute and current post-concussive symptoms;
• self report more than thirty days' abstinence from alcohol during the three months prior to enrollment/consent;
• current signs or violence or aggression, assessed as part of the consent process;
• a history of adrenal insufficiency or a plasma cortisol level of ≤ 5 microgram per deciliter (mcg/dl) at screening or intake;
• participation in a pharmaceutical trial or exposure to investigational drugs within 1 month of the screening visit;
• currently seeking treatment for AUD
• have any other illness, condition, or use medication (psychotropic or antiretroviral), which in the opinion of the principal investigator (PI) and/or the admitting physician would preclude safe and/or successful completion of the study.
• Have cortisol levels > 5 mcg/dl but < 18 mcg/dL at baseline and an ACTH stimulation test that does not rule out adrenal insufficiency. Those with cortisol levels > 5 mcg/dl but < 18 mcg/dL at baseline and cortisol levels ≥ 18 after stimulation testing can be enrolled.
• Have been treated with any form of corticosteroid in the past 30 days.
• Have a history of endometrial hyperplasia, endometrial cancer, uterine polyps, or unexplained vaginal bleeding.
• Have uncontrolled hypertension (systolic blood pressure >140 mmHg and diastolic blood pressure >90 mmHg).
• Have potassium levels below the normal reference range. Low serum potassium must be corrected prior to dosing in patients with abnormal baseline potassium levels.
• Men taking testosterone replacement therapy.
• Men or women currently interested in fertility.
• Have underlying inflammatory or auto-immune disorders.
• Have elevated thyroid stimulating hormone (TSH) levels.
• Have diabetes.