ALK21-013: Efficacy and Safety of Medisorb® Naltrexone (VIVITROL®) in Adults With Opioid Dependence

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00678418
• Collaborator: (none)
• Enrollment: 250
• Location: 1
• Arms: 2
• Duration (Months): 29
• Patients Per Site Per Month: 8.6

Study Details

Study Description

Brief Summary

This is a Phase 3 multi-center trial designed to evaluate the clinical efficacy and safety of VIVITROL® (Medisorb® naltrexone 380 mg) versus placebo when administered to adults upon discharge from inpatient treatment for opioid dependence.

The study was conducted in 2 parts, Part A and Part B. The clinical portion of both parts has completed. Results for Part B are not yet available.

Condition or Disease	Intervention/Treatment	Phase
Opiate Dependence	Drug: VIVITROL® 380 mg; Drug: Placebo	Phase 3

Detailed Description

Part A was a double-blind, randomized, placebo-controlled assessment of the efficacy and safety of 24 weeks of monthly treatment with VIVITROL compared to placebo in opioid-dependent adults.

Subjects who completed Part A could choose to continue to Part B, which was an open-label extension to assess longer-term safety, durability of effect, health economics, and quality of life (QOL) in the continuing study population for up to 1 year.

At the conclusion of both parts, each completing subject will have received a total of up to 19 injections of study drug over approximately 1.5 years.

Dosing was performed by the principal investigator or designated study staff member.

All subjects received standardized, manual-based psychosocial support at each scheduled visit. Opioid use was tracked through urine drug testing and subjects' self reports. Other evaluations for efficacy and safety, health economics, and quality of life were routinely conducted throughout the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of VIVITROL® (Naltrexone for Extended-release Injectable Suspension) in Adults With Opioid Dependence
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VIVITROL® 380 mg	Drug: VIVITROL® 380 mg; Administered via intramuscular (IM) injection once every 4 weeks for 24 weeks during Part A, followed by once every 4 weeks for 52 weeks in Part B.; Other Names: Naltrexone for extended-release injectable suspension Medisorb® naltrexone
Placebo Comparator: Placebo	Drug: Placebo; Administered via IM injection once every 4 weeks for 24 weeks during Part A, followed by VIVITROL® 380 mg via IM injection once every 4 weeks for 52 weeks in Part B.

Outcome Measures

Primary Outcome Measures

1. Percentage (%) of Opioid-free Weeks Per Subject in Double-blind Period (Part A) [20 weeks]

   Included are data from the last 20 weeks of the 24-week double-blind treatment period (Part A). Response profiles for each Arm are based on subjects' individual rates of weekly opioid-free data, including negative urine test results, attendance at study visits, and self-reports of opioid use/non-use.

Secondary Outcome Measures

1. Days to Discontinuation During Part A [168 days (24 weeks)]

   Defined as the duration of study participation and calculated as the number of days from Dose 1 to the day of study discontinuation.

2. Craving Score: Change From Baseline [Baseline to 6 months (24 weeks)]

   Measured using subjects' response on a validated Visual Analog Scale at prespecified weekly visits throughout Part A, with comparison of baseline to end of Part A. The scale ranged from 0 ("No craving") to 100 ("highest possible craving").

3. Incidence of Subjects Who Relapsed to Physiologic Opioid Dependence During the 24-week Treatment Period (Part A) [24 Weeks]

   Assessment of relapse to physiologic opioid dependence was based on individual subjects' results on the naloxone challenge test. A positive naloxone challenge test result was considered as a relapse to physiologic opioid dependence.

4. Change in Percentage of Self-reported Opioid-free Days From Baseline to Week 24 [24 Weeks]

   Opioid use was measured using subjects' entries on a validated Timeline FollowBack (TLFB) calendar in which they recorded their use/non-use of opioids each day.

Eligibility Criteria

Criteria

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

Primary Inclusion Criteria:

• Written, informed consent

• 18 years of age or older

• Current diagnosis of opioid dependence, based on Diagnostic and Statistical Manual of Mental Health Disorders, 4th Ed. (DSM-IV-TR) criteria

• Voluntarily seeking treatment for opioid dependence

• Completing or recently completed up to 30 days of inpatient treatment for opioid detoxification, and off all opioids (including buprenorphine and methadone) for at least 7 days

• Noncustodial, stable residence and phone, plus 1 contact with verifiable address and phone

• Significant other (eg, spouse, relative) willing to supervise compliance with the study visit schedule and procedures

• Agree to use contraception for study duration if of childbearing potential

Primary Exclusion Criteria:

• Pregnancy or lactation

• Clinically significant medical condition or observed abnormalities (eg: physical exam, electrocardiogram (ECG), lab and/or urinalysis findings)

• Positive naloxone challenge test at randomization (Day 0)

• Evidence of hepatic failure including: ascites, bilirubin >10% above upper limit of normal (ULN) and/or esophageal variceal disease

• Past or present history of an acquired immunodeficiency syndrome (AIDS)-indicator disease in HIV-infected subjects

• Active hepatitis and/or aspartate aminotransferase (AST), alanine aminotransferase(ALT) >3xULN

• Current major depression with suicidal ideation, psychosis, bipolar disorder, or any psychiatric disorder that would compromise ability to complete the study

• Recent history (within 6 months prior to screening) of suicidal ideation or attempt

• Dependence within prior year based on DSM-IV-TR, to any drugs other than prescription opioids or heroin, caffeine, marijuana, or nicotine

• Active alcohol dependence within prior 6 months

• Current alcohol use disorder that would, in the Investigator's opinion, preclude successful completion of the study

• Positive urine drug test for cocaine, benzodiazepines, or amphetamines at screening

• Use of oral naltrexone for 7 consecutive days within 60 days prior to screening

• Known intolerance and/or hypersensitivity to naltrexone, carboxymethylcellulose, or polylactide-co-glycolide (PLG)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ethics Committee within the Federal Authority for Healthcare and Social Development Regulation	Moscow		Russian Federation	109074

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

• Principal Investigator: Evgeny Krupitsky, Prof., Leningrad Regional Addiction Center
• Principal Investigator: Ruslan Ilyuk, Dr., Bekhterev Psychoneurological Research Institute
• Principal Investigator: Edvin Zvartau, Prof., Saint-Petersburg State Medical University n.a. Pavlov
• Principal Investigator: Alexander Sofronov, Prof., Saint-Petersburg Addiction Hospital
• Principal Investigator: Alexey Egorov, Prof., Saint-Petersburg Addiction Hospital
• Principal Investigator: Alexander Okhapkin, Prof., Addiction Treatment Center, Clinical Facility of Smolensk State Medical Academy
• Principal Investigator: Nikolay Bokhan, Prof., Tomsk Mental Health Research Institute
• Principal Investigator: Vladimir Mendelevich, Prof., Kazan State Medical University
• Principal Investigator: Yuri Sivolap, Prof., Moscow Medical Academy n.a. I.M. Sechenov
• Principal Investigator: Oleg Eryshev, Prof., Bekhterev Psychoneurological Research Institute
• Principal Investigator: Nikolay Ivanets, Prof., National Addiction Scientific Center
• Principal Investigator: Vitaliy Sinitskiy, Prof., Northern State Medical University
• Principal Investigator: Andrey Anipchenko, Dr., Saint-Petersburg Addiction Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Trials Central clinical trials listing
• Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial

Publications

None provided.

• Responsible Party: Alkermes, Inc.
• ClinicalTrials.gov Identifier: NCT00678418
• Other Study ID Numbers: ALK21-013
• First Posted: May 15, 2008
• Last Update Posted: Feb 10, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Alkermes, Inc.: Addiction; Opiate dependence; Inpatient detoxification; opioid dependence; heroin dependence
• Additional relevant MeSH terms: Opioid-Related Disorders; Naltrexone

Study Results

Participant Flow

Arm/Group Title	VIVITROL® 380 mg	Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks
Period Title: Part A (Double Blind)
STARTED	126	124
COMPLETED	67	47
NOT COMPLETED	59	77
Period Title: Part A (Double Blind)
STARTED	114	0
COMPLETED	71	0
NOT COMPLETED	43	0

Baseline Characteristics

Arm/Group Title	VIVITROL® 380 mg	Placebo	Total
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks	Total of all reporting groups
Overall Participants	126	124	250
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	126 100%	124 100%	250 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.4 (4.8)	29.7 (3.6)	29.6 (4.2)
Gender (Count of Participants)
Female	13 10.3%	17 13.7%	30 12%
Male	113 89.7%	107 86.3%	220 88%
Region of Enrollment (participants) [Number]
Russian Federation	126 100%	124 100%	250 100%

Outcome Measures

1. Primary Outcome

Title	Percentage (%) of Opioid-free Weeks Per Subject in Double-blind Period (Part A)
Description	Included are data from the last 20 weeks of the 24-week double-blind treatment period (Part A). Response profiles for each Arm are based on subjects' individual rates of weekly opioid-free data, including negative urine test results, attendance at study visits, and self-reports of opioid use/non-use.
Time Frame	20 weeks

Outcome Measure Data

Analysis Population Description

Analyses include all randomized subjects who received at least 1 dose of study drug (Intent-to-treat [ITT] population).

Arm/Group Title	VIVITROL® 380 mg	Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks
Measure Participants	126	124
Median (Inter-Quartile Range) [Percentage of opioid-free weeks]	90.0 (40.1)	35.0 (43.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIVITROL® 380 mg, Placebo
	Comments	Null hypothesis = the distribution function of opioid-free weeks is the same for both treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Van der Waerden
	Comments

2. Secondary Outcome

Title	Days to Discontinuation During Part A
Description	Defined as the duration of study participation and calculated as the number of days from Dose 1 to the day of study discontinuation.
Time Frame	168 days (24 weeks)

Outcome Measure Data

Analysis Population Description

Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population).

Arm/Group Title	VIVITROL® 380 mg	Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks
Measure Participants	126	124
Median (95% Confidence Interval) [Days to study discontinuation]	NA	96.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIVITROL® 380 mg, Placebo
	Comments	P-value was calculated using the log-rank test for the null hypothesis: the distribution of days to discontinuation does not differ by treatment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0042
	Comments	A total of 114 subjects continued on-study beyond the 168-day endpoint for Part A; these subjects were censored as of the first dosing day in Part B.
	Method	Kaplan Meier
	Comments

3. Secondary Outcome

Title	Craving Score: Change From Baseline
Description	Measured using subjects' response on a validated Visual Analog Scale at prespecified weekly visits throughout Part A, with comparison of baseline to end of Part A. The scale ranged from 0 ("No craving") to 100 ("highest possible craving").
Time Frame	Baseline to 6 months (24 weeks)

Outcome Measure Data

Analysis Population Description

Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population).

Arm/Group Title	VIVITROL® 380 mg	Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks
Measure Participants	126	124
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-10.087	0.654

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIVITROL® 380 mg, Placebo
	Comments	P-value was calculated using the Chi-square test for the null hypothesis: mean treatment difference = 0. Calculations were based on the Generalized Estimating Equation (GEE) model (normal distribution, identity link and AR(1) correlation structure) for repeated data on change from baseline with treatment and visit as main effects, and baseline as a covariate. Missing data were imputed using the Last Observation Carried Forward (LOCF) method.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Incidence of Subjects Who Relapsed to Physiologic Opioid Dependence During the 24-week Treatment Period (Part A)
Description	Assessment of relapse to physiologic opioid dependence was based on individual subjects' results on the naloxone challenge test. A positive naloxone challenge test result was considered as a relapse to physiologic opioid dependence.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population).

Arm/Group Title	VIVITROL® 380 mg	Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks
Measure Participants	126	124
Number [Percentage of participants who relapsed]	46.8 37.1%	62.1 50.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIVITROL® 380 mg, Placebo
	Comments	Chi-square test was used to calculate the p-value for treatment. Null hypothesis = no association between relapse to dependence and study treatment. Subjects who discontinued prematurely from the study were imputed as having a positive naloxone challenge test result.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0154
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.75
	Confidence Interval	() 95%; 0.60 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Percentage of Self-reported Opioid-free Days From Baseline to Week 24
Description	Opioid use was measured using subjects' entries on a validated Timeline FollowBack (TLFB) calendar in which they recorded their use/non-use of opioids each day.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

Analyses include all randomized subjects who received at least 1 dose of study drug (ITT population). Change from baseline was calculated per subject as the percent of subjects' self-reported opioid-free days in Part A minus the percent of opioid-free days prior to the subjects' hospitalization for pre-study detoxification.

Arm/Group Title	VIVITROL® 380 mg	Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks	Single intramuscular (IM) injection administered every 4 weeks
Measure Participants	126	124
Median (Inter-Quartile Range) [Percentage of opioid-free days]	75.83	46.43

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIVITROL® 380 mg, Placebo
	Comments	Null hypothesis: Treatment difference=0. Missing data from subjects due to early discontinuation during Part A were imputed using the baseline rate; thus data for subjects who discontinued early were imputed as having no change from baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	van der Waerden
	Comments

Adverse Events

Time Frame	6 Months (Part A)
Adverse Event Reporting Description	All participants who received at least 1 dose of randomized, double-blinded study drug (VIVITROL or placebo) are included in the safety population for Part A. Adverse events were tallied by number of participants affected as opposed to number of incidences reported for a given preferred term.
Arm/Group Title	VIVITROL® 380 mg		Placebo
Arm/Group Description	Single intramuscular (IM) injection administered every 4 weeks		Single intramuscular (IM) injection administered every 4 weeks
All Cause Mortality
	VIVITROL® 380 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	VIVITROL® 380 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/126 (2.4%)		4/124 (3.2%)
Gastrointestinal disorders
Peptic ulcer	0/126 (0%)		1/124 (0.8%)
Infections and infestations
Acquired immunodeficiency syndrome	1/126 (0.8%)		0/124 (0%)
Acute sinusitis	0/126 (0%)		1/124 (0.8%)
Adnexitis	1/126 (0.8%)		0/124 (0%)
HIV infection WHO clinical stage III	1/126 (0.8%)		0/124 (0%)
Herpes virus infection	1/126 (0.8%)		0/124 (0%)
Lobar pneumonia	0/126 (0%)		1/124 (0.8%)
Psychiatric disorders
Drug dependence	0/126 (0%)		1/124 (0.8%)
Psychotic disorder	0/126 (0%)		1/124 (0.8%)
Other (Not Including Serious) Adverse Events
	VIVITROL® 380 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/126 (50%)		40/124 (32.3%)
Gastrointestinal disorders
Toothache	5/126 (4%)		2/124 (1.6%)
Hypertension	6/126 (4.8%)		4/124 (3.2%)
Nausea	1/126 (0.8%)		2/124 (1.6%)
General disorders
Injection site pain	6/126 (4.8%)		1/124 (0.8%)
Pyrexia	1/126 (0.8%)		2/124 (1.6%)
Infections and infestations
Nasopharyngitis	9/126 (7.1%)		3/124 (2.4%)
Influenza	6/126 (4.8%)		5/124 (4%)
Bronchitis	0/126 (0%)		2/124 (1.6%)
Investigations
Alanine aminotransferase increased	16/126 (12.7%)		7/124 (5.6%)
Aspartate aminotransferase increased	13/126 (10.3%)		3/124 (2.4%)
Gamma-glutamyl transferase increased	9/126 (7.1%)		4/124 (3.2%)
Transaminases increased	3/126 (2.4%)		0/124 (0%)
Hepatic enzyme increased	0/126 (0%)		2/124 (1.6%)
Blood creatine phosphokinase increased	3/126 (2.4%)		1/124 (0.8%)
Protein total increased	2/126 (1.6%)		0/124 (0%)
Nervous system disorders
Headache	4/126 (3.2%)		3/124 (2.4%)
Psychiatric disorders
Insomnia	8/126 (6.3%)		1/124 (0.8%)
Drug dependence	1/126 (0.8%)		2/124 (1.6%)
Respiratory, thoracic and mediastinal disorders
Respiratory tract infection	2/126 (1.6%)		2/124 (1.6%)
Pharyngolarnygeal pain	2/126 (1.6%)		0/124 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

No individual investigator may publish results until after the publication of the overall study without receiving Alkermes' written approval. After that time, a PI/Institution may publish results for noncommercial purposes. Should an investigator wish to do so, the Sponsor will have 30 days to review the proposed publication. The PI/Institution will delete any Sponsor Confidential Information other than study results and will revise a publication based on regulatory requirements of the Sponsor.