EXTEND: Managing Alcoholism in People Who Do Not Respond to Naltrexone

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT00115037
• Collaborator: (none)
• Enrollment: 302
• Location: 1
• Arms: 6
• Duration (Months): 58
• Patients Per Site Per Month: 5.2

Study Details

Study Description

Brief Summary

This is a study involving treatment for alcohol dependence (alcoholism). The study will combine motivational enhancement therapy and cognitive behavioral therapy (combined behavioral intervention, or CBI) and tests the benefits of continued/discontinued treatment with naltrexone in a randomized placebo-controlled trial. CBI may have advantages in motivating patients to greater medication adherence and may address psychosocial factors that may limit the effects of naltrexone.

Condition or Disease	Intervention/Treatment	Phase
Alcoholism	Drug: Naltrexone; Drug: placebo; Behavioral: Medication Management (MM); Behavioral: Combined Behavioral Intervention (CBI); Behavioral: Telephone Counseling	Phase 4

Detailed Description

Naltrexone has been established as an efficacious medication to treat alcohol dependence but studies thus far have focused mostly on the acute phase of treatment rather than long-term management and have not offered alternative treatment strategies when patients do not respond to an initial course of naltrexone. For these initial non-responders to naltrexone, it is unclear what adjustments to treatment should be made to increase the likelihood of treatment success. We are unaware of previous research focused specifically on naltrexone non-response. Pilot data from ongoing trials at our center, however, suggest that up to a third of patients fail to respond to naltrexone. Moreover, these non-responsive patients go on to have the worst outcomes during the next 6 months of treatment if maintained on the same combination of naltrexone and medication management (MM). We propose to augment medication management with a combination of motivational enhancement therapy and cognitive behavioral therapy (combined behavioral intervention - CBI) and to test the benefits of continued/discontinued treatment with naltrexone in a randomized placebo-controlled trial. Clinical strategies for second line treatments often favor switching treatments rather than augmentation. However, there may be synergies between naltrexone and CBI that were not apparent with medication management. Specifically, CBI may have advantages in motivating patients to greater medication adherence (a leading cause of naltrexone treatment failure) and CBI may address psychosocial factors that limited or attenuated the effects of naltrexone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Non-Response to Naltrexone (NTX): Next Steps in Managing Alcoholism
• Study Start Date: Sep 1, 2003
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 Liberal Response From the start of baseline subjects were randomly assigned to this arm which defined relapse/non-responder as having 5 or heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder.	Drug: Naltrexone; 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.; Other Names: ReVia
Experimental: Phase 1 Stringent Response From the start of baseline subjects were randomly assigned to this arm which defined relapse/non-responder as having 2 or heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder.	Drug: Naltrexone; 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.; Other Names: ReVia
Experimental: Phase 2 nalt and tele for responders Phase 2: Naltrexone and telephone counseling for responders.	Drug: Naltrexone; 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.; Other Names: ReVia ; Behavioral: Telephone Counseling; Bi-weekly telephone calls lasting 15-20 minutes focused on the same content as MM.
Experimental: Phase 2 nalt, MM and CBI for NR Phase 2: naltrexone, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR).	Drug: Naltrexone; 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.; Other Names: ReVia ; Behavioral: Medication Management (MM); Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2.; Other Names: MM ; Behavioral: Combined Behavioral Intervention (CBI); 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.; Other Names: CBI
Placebo Comparator: Phase 2 placebo, MM and CBI for NR Phase 2: placebo, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR)	Drug: placebo; placebo comparer for 16 weeks in phase 2.; Other Names: placebo pill ; Behavioral: Medication Management (MM); Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2.; Other Names: MM ; Behavioral: Combined Behavioral Intervention (CBI); 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.; Other Names: CBI
Experimental: Phase 2 naltrexone for responders Phase 2: Naltrexone and TAU for phase 1 responders.	Drug: Naltrexone; 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.; Other Names: ReVia

Outcome Measures

Primary Outcome Measures

1. Count of Responders and Non-responders in Phase 1 [8 weeks]

   This is the number of patients who responded to phase 1 treatment based on the definition that subjects were randomly assigned to.

2. Percentage of Heavy Drinking Days [16 weeks]

   Percentage of days with heavy drinking, where heavy drinking is 4 (5) or more drinks for females (males) in a 24 hour period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 18 years of age or older

• Current DSM-IV diagnosis of alcohol dependence using the MINI.

• Meets the following drinking criteria as measured by the Timeline Followback (TLFB): * drank within 30 days of randomization; * reports a minimum of 48 standard alcoholic drinks (avg. 12 drinks/wk.) in a consecutive 30-day period over the 90-day period prior to intake; and * has 2 or more days of heavy drinking (defined as over 5 drinks per day in males and over 4 drinks per day in females) in this same pre-treatment period, prior to intake.

• Prior to starting NTX, scores below 8 on the Clinical Inventory of Withdrawal from Alcohol (CIWA), and at least 3 consecutive days of abstinence (2 days abstinence will be permitted with approval by the principal investigator) directly prior to randomization, as determined by Subject report and breathalyzer measures

• Speaks, understands and prints in English.

Exclusion Criteria:

• Has abused or been dependent on opiates in the past 12 months, or evidence of opiate use in month prior to treatment, as assessed by subject report and intake urine drug screen. Use of prescription opioids prior to treatment entry is allowed at the discretion of the investigator. However, subjects must be free from use at the time of randomization.

• Meets DSM IV criteria for current dependence, abuse, or dependence in partial remission on any substance other than alcohol (except nicotine and marijuana). Subjects who test positive on the urine drug screen (with the exception of THC) at the initial visit (a repeat UDSis permitted in cases that are not clear. The repeat UDS should be at least 5 days after the initial test)

• Has a lifetime DSM-IV diagnosis of schizophrenia or any psychotic disorder. Has a current DSM-IV diagnosis of post-traumatic stress disorder (PTST) or bipolar disorder, or any disorder that may interfere with study participation, at the discretion of the investigator.

• Hepatocellular disease indicated by elevations of SGPT (ALT) and SGOT (AST) of at least 5 times normal, or elevated bilirubin (of 1.3 or higher), as evidenced by the most recent lab results prior to randomization. (documentation of Gilberts syndrome will not constitute an exclusion despite elevated bilirubin).

• Has evidence of significant hematological, pulmonary, endocrine, cardiovascular, renal or gastrointestinal disease that the principal investigator considers a risk to participation.

• Has taken any psychotropic medications (or disulfiram) regularly within the last seven days prior to randomization or needs immediate treatment with a psychotropic medication (with the exception of detoxification medications or benadryl used sparingly for sleep). The required washout period for fluoxetine (Prozac®) is 14 days prior to randomization, and the required washout period for other psychotropic medications is 7 days prior to randomization.

• Has taken any detoxification medication on the day of randomization.

• Tests positive on a pregnancy test, is contemplating pregnancy in the next 12 months, is nursing, or is not using an effective contraceptive method if the subject is of child-bearing potential.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania Treatment Research Center, Chestnut Street	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: David W. Oslin, M.D., University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Oslin, Professor, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT00115037
• Other Study ID Numbers: NIAAAOSL014851, 708534
• First Posted: Jun 21, 2005
• Last Update Posted: Sep 18, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by David Oslin, Professor, University of Pennsylvania: Alcoholism; alcohol abuse; therapy; drug resistance; naltrexone; patient care management; human subject
• Additional relevant MeSH terms: Alcoholism; Naltrexone

Study Results

Participant Flow

Recruitment Details	Study participants were recruited through advertisements in the local media, referrals from physicians, or self referrals.
Pre-assignment Detail	All participants were offered medically monitored outpatient detox as needed.

Arm/Group Title	Phase1: Liberal	Phase1: Stringent	Phase2: Responder - Naltx (Usual Care)	Phase2: Responder - Naltx+Phone (TDM)	Phase2: Non-responder - Naltx, MM and CBI	Phase2: Non-responder - Placebo, MM and CBI
Arm/Group Description	Relapse/non-responder defined as having 5 or more heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.	Relapse/non-responder defined as having 2 or more heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.	Phase 2: Naltrexone and TAU for phase 1 responders. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.	Phase 2: Naltrexone and telephone counseling for responders. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2. Telephone Counseling: Bi-weekly telephone calls lasting 15-20 minutes focused on the same content as MM.	Phase 2: naltrexone, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR). Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2. Medication Management (MM): Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2. Combined Behavioral Intervention (CBI): 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.	Phase 2: placebo, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR) placebo: placebo comparer for 16 weeks in phase 2. Medication Management (MM): Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2. Combined Behavioral Intervention (CBI): 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.
Period Title: Phase1
STARTED	152	150	0	0	0	0
COMPLETED	127	123	0	0	0	0
NOT COMPLETED	25	27	0	0	0	0
Period Title: Phase1
STARTED	0	0	91	92	34	33
COMPLETED	0	0	76	77	28	21
NOT COMPLETED	0	0	15	15	6	12

Baseline Characteristics

Arm/Group Title	Phase1: Liberal	Phase1: Stringent	Total
Arm/Group Description	Definition B of heavy drinker: 5+ days of binge drinking	Definition A of heavy drinker: 2+ days of binge drinking	Total of all reporting groups
Overall Participants	152	150	302
Age (years) [Mean (Standard Deviation) ]
Age	48.70 (10.40)	48.49 (10.36)	48.6 (10.4)
Sex: Female, Male (Count of Participants)
Female	22 14.5%	20 13.3%	42 13.9%
Male	130 85.5%	130 86.7%	260 86.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 3.9%	4 2.7%	10 3.3%
Not Hispanic or Latino	146 96.1%	146 97.3%	292 96.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.7%	1 0.3%
Asian	1 0.7%	1 0.7%	2 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	40 26.3%	45 30%	85 28.1%
White	111 73%	103 68.7%	214 70.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Count of Responders and Non-responders in Phase 1
Description	This is the number of patients who responded to phase 1 treatment based on the definition that subjects were randomly assigned to.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Liberal Response	Phase 1 Stringent Response
Arm/Group Description	From the start of baseline subjects were randomly assigned to this arm which defined relapse/non-responder as having 5 or more heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.	From the start of baseline subjects were randomly assigned to this arm which defined relapse/non-responder as having 2 or more heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.
Measure Participants	127	123
Count of Participants [Participants]	103 67.8%	80 53.3%

2. Primary Outcome

Title	Percentage of Heavy Drinking Days
Description	Percentage of days with heavy drinking, where heavy drinking is 4 (5) or more drinks for females (males) in a 24 hour period.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 Naltrexone for Responders	Phase 2 Nalt and Tele for Responders	Phase 2 Nalt, MM and CBI for NR	Phase 2 Placebo, MM and CBI for NR
Arm/Group Description	Phase 2: Naltrexone and TAU for phase 1 responders. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.	Phase 2: Naltrexone and telephone counseling for responders. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2. Telephone Counseling: Bi-weekly telephone calls lasting 15-20 minutes focused on the same content as MM.	Phase 2: naltrexone, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR). Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2. Medication Management (MM): Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2. Combined Behavioral Intervention (CBI): 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.	Phase 2: placebo, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR) placebo: placebo comparer for 16 weeks in phase 2. Medication Management (MM): Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2. Combined Behavioral Intervention (CBI): 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.
Measure Participants	83	84	30	27
Median (Inter-Quartile Range) [percentage days of heavy drinking]	0	0	27.7	17.8

Adverse Events

Arm/Group Title	Phase1: Liberal		Phase1: Stringent		Phase2: Responder - Naltx (Usual Care)		Phase2: Responder - Naltx+Phone (TDM)		Phase2: Non-responder - Naltx, MM and CBI		Phase2: Non-responder - Placebo, MM and CBI
Arm/Group Description	Relapse/non-responder defined as having 5 or more heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.		Relapse/non-responder defined as having 2 or more heavy drinking days in the first 8 weeks of treatment otherwise the subject was considered a responder. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.		Phase 2: Naltrexone and TAU for phase 1 responders. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2.		Phase 2: Naltrexone and telephone counseling for responders. Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2. Telephone Counseling: Bi-weekly telephone calls lasting 15-20 minutes focused on the same content as MM.		Phase 2: naltrexone, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR). Naltrexone: 100mg/day, up to 8 weeks during Phase 1, 16 weeks in phase 2. Medication Management (MM): Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2. Combined Behavioral Intervention (CBI): 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 weeks.		Phase 2: placebo, Medication Management (MM) and Combined Behavioral Intervention (CBI) for non-responders (NR) placebo: placebo comparer for 16 weeks in phase 2. Medication Management (MM): Brief manual-based therapy for up to 8 weeks during phase 1, 16 during phase 2. Combined Behavioral Intervention (CBI): 45-60 minute sessions with a certified therapist focused on resolving ambivalence and skill building. Number of sessions guided by achievement of goals identified within treatment plan; minimum 9, maximum 20 sessions over 16 wee
All Cause Mortality
	Phase1: Liberal		Phase1: Stringent		Phase2: Responder - Naltx (Usual Care)		Phase2: Responder - Naltx+Phone (TDM)		Phase2: Non-responder - Naltx, MM and CBI		Phase2: Non-responder - Placebo, MM and CBI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/150 (0%)		1/91 (1.1%)		0/92 (0%)		0/34 (0%)		1/33 (3%)
Serious Adverse Events
	Phase1: Liberal		Phase1: Stringent		Phase2: Responder - Naltx (Usual Care)		Phase2: Responder - Naltx+Phone (TDM)		Phase2: Non-responder - Naltx, MM and CBI		Phase2: Non-responder - Placebo, MM and CBI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/150 (0%)		0/91 (0%)		0/92 (0%)		0/34 (0%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Phase1: Liberal		Phase1: Stringent		Phase2: Responder - Naltx (Usual Care)		Phase2: Responder - Naltx+Phone (TDM)		Phase2: Non-responder - Naltx, MM and CBI		Phase2: Non-responder - Placebo, MM and CBI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/150 (0%)		0/91 (0%)		0/92 (0%)		0/34 (0%)		0/33 (0%)

Limitations/Caveats

Overall the sample size was limited for detecting results in the second phase.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.