Spironolactone in Alcohol Use Disorder (SAUD)

Study Overview
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Brief Summary
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Background: Alcohol use disorder (AUD) affects about 29.5 million people in the United States. Only 3 medicines have been approved by Food and Drug Administration to treat AUD. Researchers want to find better treatments for AUD. Animal studies found that a medicine called spironolactone, may decrease the amount of alcohol the animals drank. Spironolactone is approved to treat high blood pressure, or heart failure in people. It is not approved to treat AUD. Objective: To test a medicine (spironolactone) in people who sometimes drink excessive alcohol in order to understand how the body breaks down spironolactone and if there are any side effects in people who drink alcohol while taking this medicine. Eligibility: People aged 21 and older with AUD. Design: Participants will have 4 separate 7-day stays at a clinic in Baltimore over 2 months. Spironolactone is a capsule you swallow. Participants will take a capsule twice a day for 5 days during each clinic stay. During 1 of their 4 stays, they will take a placebo instead of the medicine. The placebo capsule looks just like the spironolactone capsule but contains no medicine. Participants will not know when they are taking the medicine or the placebo. Participants will not drink alcohol until day 6 of each clinic stay. Then they will be asked to drink alcohol in a bar-like area in the clinic. Their breath and blood alcohol levels and their well-being will be measured. Participants will undergo other tests in the clinic: A DEXA (dual energy X-ray absorptiometry) scan uses X-rays to measure bone density and muscle mass. Participants will lie on an open-top, padded table, then a small arm will scan the full length of their body. The radiation participants will get in this study is about the same as from one regular x-ray. Blood tests. Participants may feel some discomfort at the site of needle entry. Electrocardiogram. This test records the heart activity. Sensors are attached to the skin with stickers and removed after a few minutes. Urine tests. All urine will be collected over a 3-day period during each stay. We will measure the amount of urine, and different hormones and salts in the urine. Questionnaires and tasks. Participants will answer questions about their alcohol use. They will perform tasks to test mood, craving, mental and physical coordination, and how much they feel an effect from alcohol after drinking.

Detailed Description
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Study Description: This study will examine pharmacokinetic (PK) and pharmacodynamic (PD) parameters of spironolactone and alcohol, during concomitant oral administration (0, 100, 200, 400 mg/day spironolactone PO), and test the safety and tolerability of spironolactone, co-administered with alcohol, in individuals with alcohol use disorder (AUD). Objectives: Our objective is to assess PK and PD parameters during spironolactone-alcohol co-administration, in individuals with AUD. We will also test the safety, tolerability, and potential drug-alcohol interaction. Endpoints: Primary endpoint: Spironolactone and alcohol PK during concomitant administration (0, 100, 200, and 400 mg/day spironolactone). Secondary endpoints: Assessment of subjective and cognitive effects of acute alcohol administration during concomitant spironolactone treatment (0, 100, 200, and 400 mg/day). Number and severity of adverse events (AEs) experienced, compared between placebo (0 mg/day) and all three spironolactone doses (100, 200, 400 mg/day). PK characteristic of spironolactone active metabolites, canrenone, 7-alpha-thiomethylspirolactone (TMS) and 6beta- hydroxy-7alpha-thiomethylspirolactone (HTMS), before and after administration of alcohol.

Official Title
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Spironolactone in Alcohol Use Disorder (SAUD): A Double-Blind, Placebo-Controlled, Ascending Dose, Phase 1b Study

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: Spironolactone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: In order to be eligible to enroll in this study, an individual must meet all of the following criteria: At least 21 years old Alcohol Use Disorder (minimum 2 symptoms on a validated diagnostic tool, e.g., the Mini- International Neuropsychiatric Interview (MINI) or the Structured Clinical Interview for DSM Disorders (SCID)) Self-reported drinking, according to alcohol TimeLine Follow Back (TLFB) at least five days with >= 4 drinks for females or >= 5 drinks for males AND on average more than 1 drink per day for females or more than 2 drinks per day for males during the 28-day period prior to screening Most recent Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) score is < 10 Able to speak, read, write, and understand English as demonstrated by their ability to understand and sign the consent for the NIDA screening protocol. Female participants must be postmenopausal for at least one year, surgically sterile, or practicing an effective method of birth control before entry and throughout the study and must have a negative urine pregnancy test at each visit. Examples of birth control methods include (but are not limited to) oral contraceptives or Norplant , barrier methods such as diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms, intrauterine devices, a partner with a vasectomy, or abstinence from intercourse. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: Most recent blood tests: potassium > 5.2 mmol/L; creatinine >= 2 mg/dL; eGFR < 60 mL/min/1.73 m^2, hemoglobin A1c (HbA1c) > 6.5 % Clinically significant and/or symptomatic hyponatremia, hypomagnesemia, hypocalcemia, and hyperuricemia based on Medical Advisory Investigators (MAI) or designee judgment. Known history of clinically significant orthostatic hypotension Known history of hypoaldosteronism, hyperaldosteronism, Addison s disease Diagnosis of NYHA class III-IV heart failure, or unstable cardiovascular conditions (e.g., arrhythmias, clinically significant ECG abnormalities) Current use of any diuretic, angiotensin receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), potassium supplementation, potassium containing salt substitute, heparin and low molecular weight heparin (LMWH), trimethoprim, lithium, digoxin, cholestyramine Current use of MR antagonists Current use of FDA-approved pharmacotherapy for AUD, or seeking treatment for AUD Known history of prior hypersensitivity reaction to spironolactone or other MR antagonists, or any of the product components Known history of alcohol withdrawal seizure and delirium tremens. Physical and/or mental health conditions that are clinically unstable, as determined by the study clinicians, including (but not limited to) major depressive disorder or generalized anxiety disorder unstable during the past three months or other psychiatric conditions (e.g., schizophrenia, bipolar disorder) unstable during the past twelve months prior to screening. Pregnancy, intention to become pregnant, or breastfeeding. Any other reason or clinical condition that the Investigators judge would interfere with study participation and/or be unsafe for a participant

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo 1st visit<br>Visit 1: PlaceboVisit 2: 100 mg/day spironolactoneVisit 3: 200 mg/day spironolactoneVisit 4: 400 mg/day spironolactone | Drug: Spironolactone<br>* Spironolactone and its matched placebo will be encapsulated into hard gelatin capsules, in same color, size and taste, to allow blinding. Participants will receive 2x50 mg/day, 2x100 mg, and 2x200 mg/day in three sessions (Visits); these Visits always occur in ascending order of dosage. In the remaining session, participants receive the placebo. Spironolactone is approved by the FDA, commercially available, and used in clinical practice for the treatment of hypertension, NYHA Class III-IV heart failure, edema in cirrhotic patients, and primary hyperaldosteronism. Comprehensive information about spironolactone, including its pharmacological properties, are provided in the Prescribing Information.<br>Other: Placebo<br>* Placebo<br>|
| Experimental: Placebo 2nd visit<br>Visit 1: 100 mg/day spironolactoneVisit 2: PlaceboVisit 3: 200 mg/day spironolactoneVisit 4: 400 mg/day spironolactone | Drug: Spironolactone<br>* Spironolactone and its matched placebo will be encapsulated into hard gelatin capsules, in same color, size and taste, to allow blinding. Participants will receive 2x50 mg/day, 2x100 mg, and 2x200 mg/day in three sessions (Visits); these Visits always occur in ascending order of dosage. In the remaining session, participants receive the placebo. Spironolactone is approved by the FDA, commercially available, and used in clinical practice for the treatment of hypertension, NYHA Class III-IV heart failure, edema in cirrhotic patients, and primary hyperaldosteronism. Comprehensive information about spironolactone, including its pharmacological properties, are provided in the Prescribing Information.<br>Other: Placebo<br>* Placebo<br>|
| Experimental: Placebo 3rd visit<br>Visit 1: 100 mg/day spironolactoneVisit 2: 200 mg/day spironolactoneVisit 3: PlaceboVisit 4: 400 mg/day spironolactone | Drug: Spironolactone<br>* Spironolactone and its matched placebo will be encapsulated into hard gelatin capsules, in same color, size and taste, to allow blinding. Participants will receive 2x50 mg/day, 2x100 mg, and 2x200 mg/day in three sessions (Visits); these Visits always occur in ascending order of dosage. In the remaining session, participants receive the placebo. Spironolactone is approved by the FDA, commercially available, and used in clinical practice for the treatment of hypertension, NYHA Class III-IV heart failure, edema in cirrhotic patients, and primary hyperaldosteronism. Comprehensive information about spironolactone, including its pharmacological properties, are provided in the Prescribing Information.<br>Other: Placebo<br>* Placebo<br>|
| Experimental: Placebo 4th visit<br>Visit 1: 100 mg/day spironolactoneVisit 2: 200 mg/day spironolactoneVisit 3: 400 mg/day spironolactoneVisit 4: Placebo | Drug: Spironolactone<br>* Spironolactone and its matched placebo will be encapsulated into hard gelatin capsules, in same color, size and taste, to allow blinding. Participants will receive 2x50 mg/day, 2x100 mg, and 2x200 mg/day in three sessions (Visits); these Visits always occur in ascending order of dosage. In the remaining session, participants receive the placebo. Spironolactone is approved by the FDA, commercially available, and used in clinical practice for the treatment of hypertension, NYHA Class III-IV heart failure, edema in cirrhotic patients, and primary hyperaldosteronism. Comprehensive information about spironolactone, including its pharmacological properties, are provided in the Prescribing Information.<br>Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Describe steady-state PK of spironolactone in individuals with AUD, before and after oral alcohol administration. | PK characteristics of spironolactone (e.g., total concentration, peak concentration, elimination half-life) before (day 5) and after (day 6) oral alcohol administration. | Before and after oral alcohol administration. | 
| Describe alcohol PK during concomitant spironolactone use | PK characteristics of alcohol (e.g., blood alcohol concentrations, time for elimination) during concomitant spironolactone treatment (0, 100, 200, and 400 mg/day) | 12 hours after oral alcohol administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine whether spironolactone alters subjective and cognitive effects of acute alcohol administration | Subjective response to alcohol (e.g., sedation, stimulation, mood) and cognitive performance (e.g., psychomotor function, attention) under alcohol administration, during concomitant spironolactone treatment (0, 100, 200, and 400 mg/day) | 12 hours after oral alcohol administration | 
| Determine safety, tolerability, and potential drug-alcohol interaction by administering spironolactone, combined with alcohol, in individuals with AUD | Number and intensity of adverse events (AEs) experienced under different spironolactone doses (0, 100, 200, 400 mg/day) | 12 hours after oral alcohol administration | 
| Describe steady-state PK of spironolactone metabolites in individuals with AUD, before and after alcohol administration | PK characteristics (e.g., total concentration, peak concentration, elimination half-life) of spironolactone metabolites; canrenone, TMS, HTMS, before (day 5) and after (day 6) alcohol administration. | Before and after oral administration of alcohol. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol Consumption, Alcohol Problems, Alcohol Use Disorder, SPIRONOLACTONE, Mineralocorticoid Receptor