Alcohol Disorder hOsPital Treatment Trial (ADOPT)

Oral v. Injection Naltrexone in Hospital: Comparative Effectiveness for Alcoholism

The specific aims of this pragmatic randomized controlled trial are to compare initiating injectable extended release naltrexone (XR-NTX) or oral naltrexone (PO-NTX) at the time of discharge from a medical hospitalization for patients with alcohol use disorder (AUD) on: 1) alcohol consumption and consequences, and 2) acute healthcare utilization (including hospital readmission and emergency visits) and cost-effectiveness. In exploratory analyses, the investigators will assess moderators of medication effects including demographic, behavioral, and genetic factors.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence; Alcohol Use Disorder; Heavy Drinking
• Intervention / Treatment: Drug: Extended-release injectable naltrexone (XR-NTX); Drug: Oral naltrexone (PO-NTX)

Detailed Description

Hospitalization for medical illness is a unique and missed opportunity for intervention for alcohol use disorders (AUDs). Referrals can help link patients from hospitals to alcohol treatment. But most patients return to heavy drinking after hospital discharge and do not follow-up with alcohol treatment, risking hospital readmission. Pharmacotherapy has efficacy for AUD, but adherence to these medications is poor. Furthermore, these medications are rarely prescribed in general medical settings, during or after hospitalization. Beginning treatment for AUD during a hospitalization for medical illness could broaden the reach of effective treatment and is likely to be more effective than delaying treatment until a specialist visit or treatment program entry. Hospital discharge is a time of both risk (i.e., for drinking and non-adherence to medical care) and opportunity (i.e., to begin alcohol treatment and complete medical treatments). Interventions that work quickly and improve adherence could improve medical and alcohol-related outcomes.

Oral naltrexone (PO-NTX), and the more-costly-per-dose long-acting injectable extended release naltrexone (XR-NTX) are Food and Drug Administration (FDA)-approved efficacious treatments for AUD. The XR-NTX half-life is 5-10 days and is dosed monthly, whereas the PO-NTX half-life is 13 hours and is dosed daily. The longer half-life of XR-NTX translates into patients receiving effective pharmacotherapy for a longer time without having to adhere to a daily dose. Thus, although more costly per dose, greater effectiveness could mean overall reduced costs of care (including alcohol-related health consequences and healthcare utilization). Despite potential differences in costs and patient preferences, PO-NTX and XR-NTX have not been directly compared in a randomized controlled trial (RCT), they have not been studied as treatments at medical hospital discharge, and their effectiveness in real world practice settings compared with standard care is unknown.

This trial is significant because it will address the clinically relevant comparative effectiveness question and lead to greater adoption of the most effective and cost-effective approach for treating AUD with pharmacotherapy in general hospitals.

• Study Type: Interventional
• Enrollment (Actual): 248
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 alcohol use disorder (AUD) (assessed using Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS))
• ≥1 heavy drinking episodes (≥5 standard drinks [4 for women] in a day) in 30 days prior to hospitalization*
• Inpatient on a hospital general medical service
• Adult (age 18 years or greater)
• Ability to speak English (fluency)
• ≥2 contact persons*

Exclusion Criteria:

• Pregnancy (urine testing if childbearing potential)
• Currently breast-feeding
• Urine expanded panel drug test (dipstick) positive for opiates, semi-synthetic or synthetic opioids
• Opioid use (self-report and verification in medical record) in past 7 days for long-acting opioids
• Opioid use in past 24 hours for short-acting opioids
• Discharge prescription for opioids
• Future need for opioids for an anticipated painful event or surgery
• Known hypersensitivity to NTX
• Acute severe psychiatric illness (currently suicidal or psychotic)
• Cognitive dysfunction that precludes informed consent or research assistant (RA) assessment that subject cannot understand interview questions
• Alanine aminotransferase or aspartate aminotransferase >5 times the upper limit of normal
• Acute hepatitis
• Liver failure
• Known severe thrombocytopenia (<50,000)
• Coagulopathy
• Coagulation disorder
• Body habitus that precludes intramuscular injection
• Plans to leave the Boston area in less than one year
• Enrollment in a research study which involves taking a pharmaceutical agent that is expected to interact with naltrexone

[*criteria not changed since study start; change reflects correction of typo]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Extended-release injectable naltrexone (XR-NTX); Monthly XR-NTX (380 mg) Subjects randomized to XR-NTX will receive one intramuscular gluteal injection (in accordance with the FDA approved label/package insert) of 380 mg of NTX for extended-release injectable suspension at study entry (in the hospital) and 1, and 2 months later (outpatient in the primary care clinic), alternating buttocks.	Drug: Extended-release injectable naltrexone (XR-NTX); injectable naltrexone; Other Names: Vivitrol
ACTIVE_COMPARATOR: Oral naltrexone (PO-NTX); Daily PO-NTX (50 mg, up to 100 mg if heavy drinking continues) Subjects randomized to PO-NTX will receive a study prescription (first one in the hospital)(fillable only at the medical center research pharmacy and prepared by the research pharmacist) for a 1-month supply of oral NTX to be taken once daily- 25 mg a day for 3 days, then 50 mg a day. If the subject has a prior history of taking PO-NTX and tolerating it well, the participant may be started at 50 mg. The dose may be increased to 100 mg daily for any participant who continues to have heavy drinking.	Drug: Oral naltrexone (PO-NTX); oral naltrexone; Other Names: Revia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percent Heavy Drinking Days (%HDDs) Over the Past 30 Days From Baseline to 3 Month Follow-up, Assessed Using the Timeline Follow-Back	The primary alcohol use outcome will be change in percent heavy drinking days (%HDDs) from baseline to 3 month follow-up. %HDDs out of the past 30 days is assessed using the Timeline Follow-Back. %HDDs is the most likely (and most sensitive) to be affected by NTX and is clinically important (any reduction means less risk of harm). We chose self-report because biological testing is not sufficiently valid for detecting drinking levels and changes of clinical importance. The self-report tool is valid, particularly so when staff are well trained, and when the context for the subject is: they are informed they are being tested for consumption (breath alcohol and carbohydrate deficient transferrin (CDT), there are no consequences related to consumption levels, and that results are being recorded confidentially.	Baseline, 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Care Hospital Utilization	Any acute hospital utilization (emergency department visit or inpatient stay) over the past 90 days assessed at 3-month follow-up by the Form 90. Self-report for short-term high impact, memorable health utilization such as emergency and hospital stays is valid and can measure utilization at any site. Using the clinical data warehouse at one site (Boston Medical Center (BMC)) and statewide data, we will compare self-report to the utilization databases. But, self-report data will remain primary, with databases used to provide a descriptive frame of reference.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Medication Adherence	High adherence to XR-NTX will be defined as administration of XR-NTX by the study nurse 3 times. Medium adherence will be defined as 1 or 2 injections. For PO-NTX, high adherence will be defined as participant self-report of taking PO-NTX for 90 out of the past 90 days at the 3 month study visit, and medium adherence as participant self-report of taking PO-NTX for 30-89 out of the past 90 days at the 3 month study visit (Form 90). We will also assess the presence of detectable beta-naltrexol to confirm reports of recent pill taking.	1, 2 and 3 months
Alcohol Consequences Via Questionnaire	Alcohol consequences over the past 3 months will be measured by collecting participant self-report data via the Short Inventory of Problems (SIP-2R) at 3-month follow-up. The SIP-2R is a validated 15-item measure for assessing recent adverse consequences associated with alcohol use.	3 months
Alcohol Use Disorder-related Treatment Utilization Via Questionnaire and Health Records	Alcohol use disorder-related treatment utilization over the past 90 days assessed at 3-month follow-up by the Form 90. Using the clinical data warehouse at one site (Boston Medical Center (BMC)) and statewide data, we will compare self-report to the utilization databases. But, self-report data will remain primary, with databases used to provide a descriptive frame of reference.	3 months
Cost Via Utilization Questionnaire, Health Records and Estimates From Local and National Sources	Healthcare utilization cost data will be collected via the Form 90 for self-reported outpatient and emergency visits, hospitalizations, and specialty addiction treatment. Utilization episodes will be converted to costs by use of Medicare relative value units (RVUs) for acute inpatient care, Resource Based Relative Value System (RBRVS) units for Medicare reimbursement of outpatient visits, and the average daily rate for long-term care.	3 and 12 months

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2016
• Primary Completion (ACTUAL): July 1, 2020
• Study Completion (ACTUAL): October 1, 2020

Study Registration Dates

• First Submitted: June 11, 2015
• First Submitted That Met QC Criteria: June 22, 2015
• First Posted (ESTIMATE): June 23, 2015

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2021
• Last Update Submitted That Met QC Criteria: June 9, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: alcohol dependence; alcohol; comparative effectiveness; naltrexone; hospital; alcohol use disorder; heavy drinking
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: H-32911; R01AA021335 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The ADOPT study dataset will include data from 260 subjects, including self-reported demographic and alcohol/drug use information as well as study-specific assessments and information obtained from urine and blood samples. All IPD and sample repository data will be made available to interested and qualified researchers wishing to conduct secondary analyses of the data. The final datasets will be stripped of identifiers prior to release for sharing.
• IPD Sharing Time Frame: IPD will first be available to ADOPT study investigators and Boston Medical Center and Boston University affiliated trainees. After establishing the specific areas to be addressed in the papers reporting the main findings of the study, all IPD and sample repository data will be made available for sharing starting 12 months after publication of these main study findings.
• IPD Sharing Access Criteria: The ADOPT study PI (Saitz), with co-investigator consultation as necessary, will review and approve proposals submitted by interested and qualified researchers wishing to conduct secondary analysis of the data and use of biological samples beyond the main planned reports of study findings. If proposals are approved, the investigators will make the de-identified IPD and samples available for analysis, provided IRB approval is obtained. These investigators will be provided with study forms and documents (e.g., data dictionary, procedure manuals, study questionnaires as appropriate) that allow accurate understanding of the datasets. Costs associated with data sharing will be the responsibility of investigators seeking the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes