A Study to Investigate the Safety and Efficacy of TMP-301 Compared to Placebo in Adult Patients With Alcohol Use Disorder

Exclusion Criteria

• •1. History of hypersensitivity to TMP-301 or other mGluR5 antagonists.
• •2. Evidence of suicidal risk as assessed by the Columbia-Suicide Severity Rating Scale at screening or baseline as follows:
• •* Suicidal Ideation Section: "Yes" on item 4 or 5 if within 6 months of screening or between screening and baseline.
• •* Suicidal Behavior Section: "Yes" on any item (except non-suicidal self-injurious behavior) if within 2 years of screening or between screening and baseline.
• •3. Significant risk of acute alcohol withdrawal syndrome (either of the following):
• •* Any history of Delirium Tremens or seizures from alcohol withdrawal.
• •* Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score \>7 at screening or baseline.
• •4. Any history of seizures, except febrile seizures as a child.
• •5. Other (non-alcohol) substance use disorders (by DSM-5) as follows:
• •* Any cocaine or stimulant use disorder
• •* Moderate or severe use disorder of all other substances (mild allowed).
• •6. Use of the following within the last 90 days or ≥ 5 times the half-life prior to randomization:
• •* Pharmacotherapy for any substance use disorder (e.g.: disulfiram, acamprosate, modafinil, topiramate, or baclofen).
• •* Use of prescribed methylphenidate or other stimulant.
• •* Use of any Glucagon-like peptide 1 (GLP-1) agonist for any indication.
• •7. Past or current history of any mental, behavioral, or neurodevelopmental disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or significant risk of developing a psychosis (assessed by PRIME screen) or a personal history of psychotic symptoms (hallucinations or delusions) with or without a formal psychiatric diagnosis.
• •* Individuals with AUD or mild other substance use disorder (except for cocaine or stimulants) may participate.
• •* Individuals who meet criteria for a current major depressive episode are excluded.
• •8. Requires treatment with any psychoactive medications, including any anti-seizure medications (except medications used for short-term treatment of insomnia).
• •\- Antidepressant medications are allowed if the patients have been on an adequate and stable dose for at least 3 months prior to study treatment dosing with the exception of CYP1A2 substrates or CYP3A4 inhibitors as detailed in Exclusion 19.
• •9. Having had initiation of, or change in intensity of, psychotherapy or other non-drug therapies within 6 weeks prior to enrollment or unwillingness to maintain current psychotherapeutic and non-drug therapy levels from screening through the or at any time during the acute treatment phase of the study.
• •10. Use of other investigational drugs or devices at the time of screening, or within 5 half-lives of randomization, or within 30 days, whichever is longer or has been part of any clinical study within 30 days of randomization.
• •11. Pregnant or nursing (lactating) females.
• •12. Recent history or active clinically significant manifestations of metabolic, hepatic, renal (including porphyria), hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, ophthalmic, or ears, nose, and throat (ENT) disorders, or any other acute or chronic condition or medication use that, in the Investigator's opinion, would limit the subject's ability to complete or participate in this clinical study.
• •13. Concomitant use of agents known to prolong the QT interval unless these can be permanently discontinued for the duration of study.
• •14. History or current diagnosis of ECG abnormalities at screening indicating significant risk of safety for subjects participating in the study such as:
• •* Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second- or third-degree Atrioventricular (AV) block without a pacemaker.
• •* History of familial long QT syndrome or known family history of Torsades de Pointes.
• •* QTcF \> 450 msec (males); QTcF \> 460 msec (females).
• •* Note: sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are not exclusionary.
• •15. Patients with history of chronic hypertension, unless well controlled by taking antihypertensive treatment at a stable dose for ≥3 months
• •16. History or presence of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there was evidence of local recurrence or metastases.
• •17. Detectable hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus (HIV) antibody at screening.
• •\- Participants in remission for HCV or HIV, as demonstrated by a sustained virological response (undetectable viral load) may be enrolled in the study.
• •18. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study.
• •19. Need/plan to take or substrates of cytochrome P450 (CYP)1A2 or inhibitors of CYP3A4. (Note: CYP1A2 inhibitors are permitted, as they are not expected to increase TMP-301 exposures above what was shown to be safe and generally well-tolerated in study TMP-301- HNV-101.).
• •* CYP1A2 Substrates: (Exposure could increase when taken with TMP-301):
• •* alosetron, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine, pimozide, agomelatine, tacrine, clozapine, pirfenidone, theophylline, tacrine, ropivacaine
• •* CYP3A4 Inhibitors: Could increase TMP-301 exposure at steady- state
• •* grapefruit juice, Seville orange-containing food (e.g. bitter orange marmalade) or drink (e.g. bitter orange liqueurs including Curaçao and Grand Marnier)
• •* ketoconazole, diltiazem, verapamil, clarithromycin, itraconazole, erythromycin, fluconazole, ceritinib, cobicistat, idelalisib, indinavir. ritonavir, nefazodone, lopinavir, aprepitant, ciprofloxacin, conivaptan, crizotinib, dronedarone, imatinib
• •20. Patient cannot:
• •* Anticipate any significant problems with transportation arrangements or available time to travel to the study site and have any plans to move within the next months to a location which would make continued participation in the study' impractical.
• •* Be involved in any unresolved legal problems that could jeopardize continuation or completion of the study.
• •* Have any pending charges for violent crime (not including Driving Under the Influence (DUI) offenses).
• •* Have any court case with a pending decision that could prohibit participation or compliance in the study.
• •21. Living situation precludes an ability to adhere to study visits in the opinion of the investigator.
• •22. Has been previously treated in this study or randomized or treated in any other study employing TMP-301 (i.e., subject may not have received study drug and then reenrolled).
• •23. Any condition not identified in the protocol that in the opinion of the investigator would confound the evaluation and interpretation of the study data or may put the subject at risk.