ALK21-004: Single-dose Opiate Challenge of Medisorb® Naltrexone (VIVITROL®) in Adults Who Use Opioids

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01218984
• Collaborator: (none)
• Enrollment: 27
• Arms: 3
• Duration (Months): 14

Study Details

Study Description

Brief Summary

This was a Phase 2, multicenter, randomized, double-blind pilot study in opioid-using adults to assess the presence, duration, and degree of opiate blockade as well as the safety and tolerability of Medisorb® naltrexone (VIVITROL®). Subjects were randomized in a 1:1:1 ratio to receive a single gluteal intramuscular (IM) injection of Medisorb naltrexone 75, 150, or 300 mg.

Condition or Disease	Intervention/Treatment	Phase
Opiate Dependence	Drug: Medisorb naltrexone 75 mg; Drug: Medisorb naltrexone 150 mg; Drug: Medisorb naltrexone 300 mg; Drug: Hydromorphone (10 mg/mL); Drug: Naloxone Challenge and Oral Naltrexone Tolerability Testing	Phase 2

Detailed Description

Potential subjects were screened within 21 days prior to dosing of study drug (Medisorb naltrexone or placebo) on Day 0. Screening evaluations included a baseline hydromorphone challenge session in which increasing doses of hydromorphone (0 mg [placebo], 3 mg, 4.5 mg, and 6 mg) were administered at hourly intervals to produce a cumulative dose-response curve. Throughout the 4-hour challenge period, subject-rated measures (Visual Analog Scale [VAS] questions) and physiological measures (ie, pupil size) were recorded.

As a safety measure, at least 7 days after the baseline hydromorphone challenge, a naloxone challenge was performed followed by a 1-day oral naltrexone tolerability assessment. On Day 0, eligible subjects were administered a single dose of study drug. To assess the level of opiate blockade and surmountability attributable to Medisorb naltrexone, experimental hydromorphone challenge sessions were conducted postdose at Days 7, 14, 21, 28, 42, and 56, with a single placebo hydromorphone challenge administered at a randomly selected visit. Pupil size was measured 15 minutes prior to the first hydromorphone dose and at 15, 30, 45, and minutes after each ascending hydromorphone/placebo for hydromorphone dose. Blood samples for measurement of naltrexone and 6B-naltrexol were obtained at screening and before hydromorphone/placebo administration on Days 7, 14, 21, 28, 42, and 56.

Subjects were monitored for safety through Day 56.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Single-Dose Opiate Challenge Study of Medisorb® Naltrexone in Opioid-Using Adults
• Study Start Date: Mar 1, 2002
• Actual Primary Completion Date: May 1, 2003
• Actual Study Completion Date: May 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Medisorb naltrexone 75 mg	Drug: Medisorb naltrexone 75 mg; Single administration via intramuscular (IM) injection.; Other Names: Naltrexone for extended-release injectable suspension ; Drug: Hydromorphone (10 mg/mL); Increasing doses of 0, 3, 4.5, and 6 mg were administered at baseline (pre-study drug administration). After study drug administration, additional hydromorphone challenge sessions consisting of administering 0, 3, 4.5, and 6 mg were administered at 1-hr intervals at each of the postdose evaluation visits. In addition, at a randomly selected evaluation visit, subjects received four 0 mg (placebo) doses at 1-hour intervals.; Other Names: Dilaudid-HP® opioid agonist ; Drug: Naloxone Challenge and Oral Naltrexone Tolerability Testing; Administered according to the instructions provided by the respective manufacturer. Testing occurred at least 7 days after the baseline hydromorphone challenge and prior to study drug administration.; Other Names: Narcan® (naloxone) ReVia® (oral naltrexone)
Experimental: Medisorb naltrexone 150 mg	Drug: Medisorb naltrexone 150 mg; Single administration via IM injection.; Other Names: Naltrexone for extended-release injectable suspension ; Drug: Hydromorphone (10 mg/mL); Increasing doses of 0, 3, 4.5, and 6 mg were administered at baseline (pre-study drug administration). After study drug administration, additional hydromorphone challenge sessions consisting of administering 0, 3, 4.5, and 6 mg were administered at 1-hr intervals at each of the postdose evaluation visits. In addition, at a randomly selected evaluation visit, subjects received four 0 mg (placebo) doses at 1-hour intervals.; Other Names: Dilaudid-HP® opioid agonist ; Drug: Naloxone Challenge and Oral Naltrexone Tolerability Testing; Administered according to the instructions provided by the respective manufacturer. Testing occurred at least 7 days after the baseline hydromorphone challenge and prior to study drug administration.; Other Names: Narcan® (naloxone) ReVia® (oral naltrexone)
Experimental: Medisorb naltrexone 300 mg	Drug: Medisorb naltrexone 300 mg; Single administration via IM injection.; Other Names: Naltrexone for extended-release injectable suspension ; Drug: Hydromorphone (10 mg/mL); Increasing doses of 0, 3, 4.5, and 6 mg were administered at baseline (pre-study drug administration). After study drug administration, additional hydromorphone challenge sessions consisting of administering 0, 3, 4.5, and 6 mg were administered at 1-hr intervals at each of the postdose evaluation visits. In addition, at a randomly selected evaluation visit, subjects received four 0 mg (placebo) doses at 1-hour intervals.; Other Names: Dilaudid-HP® opioid agonist ; Drug: Naloxone Challenge and Oral Naltrexone Tolerability Testing; Administered according to the instructions provided by the respective manufacturer. Testing occurred at least 7 days after the baseline hydromorphone challenge and prior to study drug administration.; Other Names: Narcan® (naloxone) ReVia® (oral naltrexone)

Outcome Measures

Primary Outcome Measures

1. Slope Change From Baseline for Pupil Size [4 weeks (Baseline to Day 28)]

   Photographs of subjects' pupils were measured horizontally and vertically, 15 minutes before the first hydromorphone dose and every 15 minutes after each hydromorphone/placebo for hydromorphone dose, for up to 1 hour. Size was the product of vertical and horizontal measures. The slope, determined by linear regression, was used as a summary measure of the dose-response relationship between the hydromorphone dose and pupil size. The steeper the slope, the greater the hydromorphone effect. A slope of zero indicated no evidence of a hydromorphone effect.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Primary Inclusion Criteria:

• Adults who had used opioids: non-medically for at least 1 year; at least once per week for at least some period during their use history; and fewer than 3 times per week on average for the 30 days prior to screening.

• Provided written informed consent

• Demonstrated a positive response to hydromorphone challenge during screening

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

Primary Exclusion Criteria:

• Any clinically significant medical condition or laboratory abnormality at screening

• Participated in a clinical trial within prior 30 days

• Dependent on opioids

• Seeking treatment for opioid abuse

• Psychosis or any major mood or anxiety disorder

• Pregnancy or lactation

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

• Study Director: Bernard L. Silverman, MD, Alkermes, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01218984
• Other Study ID Numbers: ALK21-004
• First Posted: Oct 13, 2010
• Last Update Posted: Jan 11, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by , ,: Opiate Dependence
• Additional relevant MeSH terms: Opioid-Related Disorders; Naltrexone; Hydromorphone; Naloxone

Study Results

Participant Flow

Arm/Group Title	Medisorb Naltrexone 75 mg	Medisorb Naltrexone 150 mg	Medisorb Naltrexone 300 mg
Arm/Group Description	Administered as a single gluteal intramuscular (IM) injection	Administered as a single gluteal IM injection	Administered as a single gluteal IM injection
Period Title: Overall Study
STARTED	9	8	10
COMPLETED	8	6	7
NOT COMPLETED	1	2	3

Baseline Characteristics

Arm/Group Title	Medisorb Naltrexone 75 mg	Medisorb Naltrexone 150 mg	Medisorb Naltrexone 300 mg	Total
Arm/Group Description	Administered as a single gluteal intramuscular (IM) injection	Administered as a single gluteal IM injection	Administered as a single gluteal IM injection	Total of all reporting groups
Overall Participants	9	8	10	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	9 100%	8 100%	10 100%	27 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.22 (9.28)	42.88 (4.70)	32.5 (8.02)	36.48 (8.60)
Gender (Count of Participants)
Female	1 11.1%	0 0%	2 20%	3 11.1%
Male	8 88.9%	8 100%	8 80%	24 88.9%
Region of Enrollment (participants) [Number]
United States	9 100%	8 100%	10 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Slope Change From Baseline for Pupil Size
Description	Photographs of subjects' pupils were measured horizontally and vertically, 15 minutes before the first hydromorphone dose and every 15 minutes after each hydromorphone/placebo for hydromorphone dose, for up to 1 hour. Size was the product of vertical and horizontal measures. The slope, determined by linear regression, was used as a summary measure of the dose-response relationship between the hydromorphone dose and pupil size. The steeper the slope, the greater the hydromorphone effect. A slope of zero indicated no evidence of a hydromorphone effect.
Time Frame	4 weeks (Baseline to Day 28)

Outcome Measure Data

Analysis Population Description

Placebo hydromorphone challenge sessions were excluded from the analysis. Results for subjects who discontinued prior to Day 28 were not imputed.

Arm/Group Title	Medisorb Naltrexone 75 mg	Medisorb Naltrexone 150 mg	Medisorb Naltrexone 300 mg
Arm/Group Description	Administered as a single gluteal intramuscular (IM) injection	Administered as a single gluteal IM injection	Administered as a single gluteal IM injection
Measure Participants	6	4	6
Mean (Standard Deviation) [cm(2)/hr]	-0.5540 (0.3473)	-0.3607 (0.3998)	-0.1410 (0.1745)

Adverse Events

Time Frame	56 Days
Arm/Group Title	Medisorb Naltrexone 75 mg		Medisorb Naltrexone 150 mg		Medisorb Naltrexone 300 mg
Arm/Group Description	Administered as a single gluteal intramuscular (IM) injection		Administered as a single gluteal IM injection		Administered as a single gluteal IM injection
All Cause Mortality
	Medisorb Naltrexone 75 mg		Medisorb Naltrexone 150 mg		Medisorb Naltrexone 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Medisorb Naltrexone 75 mg		Medisorb Naltrexone 150 mg		Medisorb Naltrexone 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/8 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Medisorb Naltrexone 75 mg		Medisorb Naltrexone 150 mg		Medisorb Naltrexone 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/9 (66.7%)		5/8 (62.5%)		7/10 (70%)
Gastrointestinal disorders
Abdominal pain upper	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Anal fissure	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Dyspepsia	0/9 (0%)		0/8 (0%)		1/10 (10%)
Nausea	0/9 (0%)		0/8 (0%)		1/10 (10%)
Toothache	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
General disorders
Application site rash	0/9 (0%)		1/8 (12.5%)		0/10 (0%)
Fatigue	0/9 (0%)		1/8 (12.5%)		1/10 (10%)
Infusion site pain	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Pain NOS	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Pyrexia	0/9 (0%)		0/8 (0%)		1/10 (10%)
Infections and infestations
Hepatitis C	0/9 (0%)		0/8 (0%)		1/10 (10%)
Influenza	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Nasopharyngitis	1/9 (11.1%)		0/8 (0%)		1/10 (10%)
Injury, poisoning and procedural complications
Chemical burns of eye	0/9 (0%)		0/8 (0%)		1/10 (10%)
Injury NOS	1/9 (11.1%)		1/8 (12.5%)		0/10 (0%)
Joint sprain	0/9 (0%)		1/8 (12.5%)		0/10 (0%)
Limb injury NOS	0/9 (0%)		1/8 (12.5%)		0/10 (0%)
Mouth injury	0/9 (0%)		0/8 (0%)		1/10 (10%)
Tendon injury	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Investigations
Blood in stool	0/9 (0%)		0/8 (0%)		1/10 (10%)
Heart rate increased	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Liver function tests NOS abnormal	0/9 (0%)		0/8 (0%)		1/10 (10%)
Musculoskeletal and connective tissue disorders
Back pain	0/9 (0%)		0/8 (0%)		1/10 (10%)
Muscle tightness	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Myalgia	0/9 (0%)		1/8 (12.5%)		0/10 (0%)
Nervous system disorders
Dizziness	0/9 (0%)		0/8 (0%)		1/10 (10%)
Headache NOS	1/9 (11.1%)		1/8 (12.5%)		1/10 (10%)
Somnolence	0/9 (0%)		0/8 (0%)		1/10 (10%)
Tremor	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Psychiatric disorders
Factitious disorder NOS	0/9 (0%)		0/8 (0%)		1/10 (10%)
Insomnia	1/9 (11.1%)		0/8 (0%)		1/10 (10%)
Libido decreased	0/9 (0%)		1/8 (12.5%)		0/10 (0%)
Reproductive system and breast disorders
Dysmennorhoea	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Chest wall pain	0/9 (0%)		0/8 (0%)		1/10 (10%)
Pharyngolaryngeal pain	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Contusion	0/9 (0%)		1/8 (12.5%)		0/10 (0%)
Dermatitis contact	0/9 (0%)		0/8 (0%)		1/10 (10%)
Pruritis NOS	0/9 (0%)		0/8 (0%)		1/10 (10%)
Rash pruritic	1/9 (11.1%)		0/8 (0%)		0/10 (0%)
Sweating increased	1/9 (11.1%)		0/8 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Should a PI wish to disclose results, the Sponsor will review the results communications prior to public release and can embargo results communications for a period of at least 30 days prior to the submission, for review and approval. Revisions will be negotiated in good faith by the Investigator and Sponsor and may be submitted for publication or disclosed by the Investigator only following receipt of written approval from the Sponsor.