Alcohol Dependence, Alcohol Use Disorder, Heavy Drinking
Conditions
Keywords
alcohol, heavy drinking, naltrexone, hospital, alcohol use disorder, alcohol dependence, comparative effectiveness
Brief summary
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.
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.
Interventions
DRUGOral naltrexone (PO-NTX)
oral naltrexone
DRUGExtended-release injectable naltrexone (XR-NTX)
injectable naltrexone
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Boston University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 \[\*criteria not changed since study start; change reflects correction of typo\]
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Care Hospital Utilization | 3 months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Medication Adherence | 1, 2 and 3 months | 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. |
| Alcohol Consequences Via Questionnaire | 3 months | 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. |
| Alcohol Use Disorder-related Treatment Utilization Via Questionnaire and Health Records | 3 months | 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. |
| Cost Via Utilization Questionnaire, Health Records and Estimates From Local and National Sources | 3 and 12 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Extended-release injectable naltrexone (XR-NTX): injectable naltrexone | 123 |
| 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.
Oral naltrexone (PO-NTX): oral naltrexone | 125 |
| Total | 248 |
Baseline characteristics
| Characteristic | Extended-release Injectable Naltrexone (XR-NTX) | Oral Naltrexone (PO-NTX) | Total |
|---|---|---|---|
| Age, Continuous | 49.4 Years STANDARD_DEVIATION 10.3 | 49.4 Years STANDARD_DEVIATION 10.5 | 49.4 Years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 19 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 103 Participants | 106 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Percent heavy drinking days over the past 30 days assessed at baseline by Timeline Followback | 70.7 Percent heavy drinking days of past 30 STANDARD_DEVIATION 31.5 | 66.7 Percent heavy drinking days of past 30 STANDARD_DEVIATION 31.5 | 68.7 Percent heavy drinking days of past 30 STANDARD_DEVIATION 31.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 10 Participants | 3 Participants | 13 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 64 Participants | 125 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 54 Participants | 101 Participants |
| Sex: Female, Male Female | 24 Participants | 25 Participants | 49 Participants |
| Sex: Female, Male Male | 99 Participants | 100 Participants | 199 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 123 | 3 / 125 |
| other Total, other adverse events | 59 / 123 | 39 / 125 |
| serious Total, serious adverse events | 43 / 123 | 43 / 125 |
Outcome results
Primary
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.
Time frame: Baseline, 3 months
Population: Analysis population includes those who completed the 3 month follow-up assessment. Population does not match baseline sample due to attrition / loss to follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Extended-release Injectable Naltrexone (XR-NTX) | 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 | -46.4 change in percent heavy drinking days | Standard Deviation 38.5 |
| Oral Naltrexone (PO-NTX) | 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 | -38.4 change in percent heavy drinking days | Standard Deviation 43.3 |
Secondary
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.
Time frame: 3 months
Population: Analysis population includes those who completed the 3 month follow-up assessment. Population does not match baseline sample due to attrition / loss to follow-up.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Extended-release Injectable Naltrexone (XR-NTX) | Acute Care Hospital Utilization | No acute care hospital utilization (emergency department visit or inpatient stay) | 42 Participants |
| Extended-release Injectable Naltrexone (XR-NTX) | Acute Care Hospital Utilization | Any acute care hospital utilization (emergency department visit or inpatient stay) | 66 Participants |
| Oral Naltrexone (PO-NTX) | Acute Care Hospital Utilization | Any acute care hospital utilization (emergency department visit or inpatient stay) | 59 Participants |
| Oral Naltrexone (PO-NTX) | Acute Care Hospital Utilization | No acute care hospital utilization (emergency department visit or inpatient stay) | 50 Participants |
Other Pre-specified
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.
Time frame: 3 months
Other Pre-specified
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.
Time frame: 3 months
Other Pre-specified
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.
Time frame: 3 and 12 months
Other Pre-specified
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.
Time frame: 1, 2 and 3 months