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Spironolactone in Alcohol Use Disorder (SAUD)

Primary Purpose

Alcohol Use Disorder

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Spironolactone
Placebo
Sponsored by
National Institute on Drug Abuse (NIDA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Alcohol Use Disorder focused on measuring Alcohol Consumption, Alcohol Problems, Alcohol Use Disorder, SPIRONOLACTONE, Mineralocorticoid Receptor

Eligibility Criteria

21 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • National Institute on Drug AbuseRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Placebo 1st visit

Placebo 2nd visit

Placebo 3rd visit

Placebo 4th visit

Arm Description

Visit 1: PlaceboVisit 2: 100 mg/day spironolactoneVisit 3: 200 mg/day spironolactoneVisit 4: 400 mg/day spironolactone

Visit 1: 100 mg/day spironolactoneVisit 2: PlaceboVisit 3: 200 mg/day spironolactoneVisit 4: 400 mg/day spironolactone

Visit 1: 100 mg/day spironolactoneVisit 2: 200 mg/day spironolactoneVisit 3: PlaceboVisit 4: 400 mg/day spironolactone

Visit 1: 100 mg/day spironolactoneVisit 2: 200 mg/day spironolactoneVisit 3: 400 mg/day spironolactoneVisit 4: Placebo

Outcomes

Primary Outcome Measures

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.
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)

Secondary Outcome Measures

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)
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)
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.

Full Information

First Posted
April 10, 2023
Last Updated
September 2, 2023
Sponsor
National Institute on Drug Abuse (NIDA)
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1. Study Identification

Unique Protocol Identification Number
NCT05807139
Brief Title
Spironolactone in Alcohol Use Disorder (SAUD)
Official Title
Spironolactone in Alcohol Use Disorder (SAUD): A Double-Blind, Placebo-Controlled, Ascending Dose, Phase 1b Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 31, 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 6, 2023 (Anticipated)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
September 7, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute on Drug Abuse (NIDA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcohol Use Disorder
Keywords
Alcohol Consumption, Alcohol Problems, Alcohol Use Disorder, SPIRONOLACTONE, Mineralocorticoid Receptor

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo 1st visit
Arm Type
Experimental
Arm Description
Visit 1: PlaceboVisit 2: 100 mg/day spironolactoneVisit 3: 200 mg/day spironolactoneVisit 4: 400 mg/day spironolactone
Arm Title
Placebo 2nd visit
Arm Type
Experimental
Arm Description
Visit 1: 100 mg/day spironolactoneVisit 2: PlaceboVisit 3: 200 mg/day spironolactoneVisit 4: 400 mg/day spironolactone
Arm Title
Placebo 3rd visit
Arm Type
Experimental
Arm Description
Visit 1: 100 mg/day spironolactoneVisit 2: 200 mg/day spironolactoneVisit 3: PlaceboVisit 4: 400 mg/day spironolactone
Arm Title
Placebo 4th visit
Arm Type
Experimental
Arm Description
Visit 1: 100 mg/day spironolactoneVisit 2: 200 mg/day spironolactoneVisit 3: 400 mg/day spironolactoneVisit 4: Placebo
Intervention Type
Drug
Intervention Name(s)
Spironolactone
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Describe steady-state PK of spironolactone in individuals with AUD, before and after oral alcohol administration.
Description
PK characteristics of spironolactone (e.g., total concentration, peak concentration, elimination half-life) before (day 5) and after (day 6) oral alcohol administration.
Time Frame
Before and after oral alcohol administration.
Title
Describe alcohol PK during concomitant spironolactone use
Description
PK characteristics of alcohol (e.g., blood alcohol concentrations, time for elimination) during concomitant spironolactone treatment (0, 100, 200, and 400 mg/day)
Time Frame
12 hours after oral alcohol administration
Secondary Outcome Measure Information:
Title
Determine whether spironolactone alters subjective and cognitive effects of acute alcohol administration
Description
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)
Time Frame
12 hours after oral alcohol administration
Title
Determine safety, tolerability, and potential drug-alcohol interaction by administering spironolactone, combined with alcohol, in individuals with AUD
Description
Number and intensity of adverse events (AEs) experienced under different spironolactone doses (0, 100, 200, 400 mg/day)
Time Frame
12 hours after oral alcohol administration
Title
Describe steady-state PK of spironolactone metabolites in individuals with AUD, before and after alcohol administration
Description
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.
Time Frame
Before and after oral administration of alcohol.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
NIDA IRP Screening Team
Phone
(800) 535-8254
Email
researchstudies@nida.nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Lorenzo Leggio, M.D.
Phone
(240) 478-1503
Email
lorenzo.leggio@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lorenzo Leggio, M.D.
Organizational Affiliation
National Institute on Drug Abuse (NIDA)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institute on Drug Abuse
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21224
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lorenzo Leggio, M.D.
Phone
240-478-1503
Email
lorenzo.leggio@nih.gov

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
.Data sharing with other protocols. Data obtained under this protocol and the NIDA screening protocol may be shared and combined for analysis. This will also allow us to avoid repeating assessments that are scheduled in both protocols during the same period of time, therefore avoiding duplication and minimizing participant fatigue. Participants may also consent for other NIH protocols and data collected under those protocols may be combined with data from this protocol for exploratory purposes.
IPD Sharing Time Frame
12 months after publication
IPD Sharing Access Criteria
To be determined
Citations:
PubMed Identifier
35748762
Citation
Leko AH, McGinn MA, Farokhnia M. The Mineralocorticoid Receptor: An Emerging Pharmacotherapeutic Target for Alcohol Use Disorder? ACS Chem Neurosci. 2022 Jul 6;13(13):1832-1834. doi: 10.1021/acschemneuro.2c00326. Epub 2022 Jun 24.
Results Reference
background
PubMed Identifier
36123420
Citation
Farokhnia M, Rentsch CT, Chuong V, McGinn MA, Elvig SK, Douglass EA, Gonzalez LA, Sanfilippo JE, Marchette RCN, Tunstall BJ, Fiellin DA, Koob GF, Justice AC, Leggio L, Vendruscolo LF. Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies. Mol Psychiatry. 2022 Nov;27(11):4642-4652. doi: 10.1038/s41380-022-01736-y. Epub 2022 Sep 20.
Results Reference
background
PubMed Identifier
34341493
Citation
Palzes VA, Farokhnia M, Kline-Simon AH, Elson J, Sterling S, Leggio L, Weisner C, Chi FW. Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study. Neuropsychopharmacology. 2021 Nov;46(12):2140-2147. doi: 10.1038/s41386-021-01117-z. Epub 2021 Aug 2.
Results Reference
background
PubMed Identifier
28461696
Citation
Aoun EG, Jimenez VA, Vendruscolo LF, Walter NAR, Barbier E, Ferrulli A, Haass-Koffler CL, Darakjian P, Lee MR, Addolorato G, Heilig M, Hitzemann R, Koob GF, Grant KA, Leggio L. A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans. Mol Psychiatry. 2018 Jun;23(6):1466-1473. doi: 10.1038/mp.2017.97. Epub 2017 May 2.
Results Reference
background
PubMed Identifier
18486430
Citation
Leggio L, Ferrulli A, Cardone S, Miceli A, Kenna GA, Gasbarrini G, Swift RM, Addolorato G. Renin and aldosterone but not the natriuretic peptide correlate with obsessive craving in medium-term abstinent alcohol-dependent patients: a longitudinal study. Alcohol. 2008 Aug;42(5):375-81. doi: 10.1016/j.alcohol.2008.03.128. Epub 2008 May 16.
Results Reference
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Spironolactone in Alcohol Use Disorder (SAUD)

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