Pilot Study of Entacapone for Methamphetamine Abuse

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02058966
• Collaborator: Portland VA Medical Center (U.S. Fed)
• Enrollment: 29
• Location: 1
• Arms: 4
• Duration (Months): 24
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Addiction to methamphetamine is a serious health problem. There are no medications that a doctor can give someone to help them stop using methamphetamine. Entacapone (Comtan©) is a medication that could help people addicted to methamphetamine.

This study will see how entacapone works in healthy people who are given methamphetamine. We think that the study drug will be well tolerated, and that it will prevent some of the effects of methamphetamine that make it so addictive. We also want to see how differences in people's genes may cause differences in the ways the study drug and methamphetamine work for them.

The study has six total visits. The first visit is for screening. Tests and procedures will make sure it is safe for subjects to participate.

The second visit is a familiarization day. Subjects will receive methamphetamine, but no entacapone. This is done to make sure they can tolerate the drug and recognize its effects before being given a second drug on the same day. Subjects will take surveys and computer tests to see how the medications change mood, thinking, and liking the drug.

The final four visits are the actual study days. Subjects will be randomly assigned (like the flip of a coin) to the different ways to get either 1) study medication or placebo (placebo contains no active study medication) and then 2) methamphetamine or placebo. Subjects will be in all four groups during the study, which means that each day a subject will get a different group.

Condition or Disease	Intervention/Treatment	Phase
Methamphetamine Dependence	Drug: Entacapone; Drug: Methamphetamine; Drug: Placebo	Early Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Health Services Research
• Official Title: Pilot Study of the Dose Response of Entacapone on Methamphetamine Induced Interest, Mood Elevation, and Reward
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo followed by Placebo Subjects will receive placebo, then one hour later, placebo	Drug: Placebo; capsules compounded to be of similar appearance to the active drugs
Experimental: Placebo followed by Methamphetamine Subjects will receive placebo, then one hour later, methamphetamine	Drug: Methamphetamine; Methamphetamine 20 mg oral dose; Other Names: Desoxyn ; Drug: Placebo; capsules compounded to be of similar appearance to the active drugs
Experimental: Entacapone followed by Placebo Subjects will receive entacapone, then one hour later, placebo	Drug: Entacapone; Entacapone 200 mg oral dose; Other Names: Comtam ; Drug: Placebo; capsules compounded to be of similar appearance to the active drugs
Experimental: Entacapone followed by Methamphetamine Subjects will receive entacapone, then one hour later, methamphetamine	Drug: Entacapone; Entacapone 200 mg oral dose; Other Names: Comtam ; Drug: Methamphetamine; Methamphetamine 20 mg oral dose; Other Names: Desoxyn

Outcome Measures

Primary Outcome Measures

1. Effect of Entacapone on Methamphetamine-induced Mood [Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.]

   Profile of Mood States is a 65 item questionnaire using a Likert rating scale to assess transient, distinct moods. The questionnaire contains 65 words/statements that describe feelings people have. The test requires you to indicate for each word or statement how you have been feeling in the past week including today. A Total Mood Disturbance score is calculated by adding scores for Tension, Depression, Anger, Fatigue and Confusion and then subtracting the Vigour score. The Total Mood Disturbance scale ranges from -32 to 200 with lower scores indicative of people with more stable mood profiles.

2. Effect of Entacapone on Subjective Effects of Methamphetamine [Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.]

   The subjective effects of the study drug were evaluated with the Addiction Research Center Inventory (ARCI-49), a 49 item questionnaire consisting of true/false items. True items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when answer is opposite to scoring direction. There are 5 subscales: Morphine Benzedrine group scale to measure euphoria (range: 0-16 with higher numbers indicating more euphoria), A Lysergic Acid Diethylamide group scale to estimate dysphoria and agitation (range: 0-14 with higher scores indicating more dysphoria), a Pentobarbital Chlorpromazine Alcohol group scale to measure sedation (range: 0-15 with higher scores indicating more sedation), and a Benzedrine group scale and an Amphetamine Scale to assess stimulant effects (range: 0-13 and 0-11, respectively, with higher scores indicating higher stimulant effects) .

3. Effect of Entacapone on Methamphetamine-induced Stimulation [Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.]

   The Global Rating of Stimulation is a 1-item question "I feel light-headed, restless, or speeded-up" in which the participant is asked to circle one answer on a scale from 0-4, 0 is 'normal', 1 is 'slightly', 2 is 'moderately', 3 is 'very much', and 4 is 'extremely'. Whichever number they circled is their reported score. A higher score is indicative of a greater stimulating effect.

Secondary Outcome Measures

1. Cognitive Function [Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.]

   Two computer tests were administered to measure how each medication intervention effects cognitive functioning. The tests administered included the Rapid Visual Information Processing Task (RVIPT), a 6 minute test of sustained attention in which participants are requested to detect target sequences of digits and the Digit Symbol Substitution Task (DSST), a 2 minute test of psychomotor speed and sustained attention consisting of digit-symbol pairs followed by a list of digits where the subject identifies the symbol that corresponds to each digit as fast as possible. The number of correct responses within the allowed time is measured. Higher scores on both tasks indicate better performance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• No history of pre-existing physical (including cardiovascular) illness

• No history of drug abuse or dependence

• Ability to read and write English

• Have had at least one exposure to a stimulant (e.g. cocaine, methamphetamine, ecstasy, methylphenidate or any medication in the stimulant class) in their lifetime

Exclusion Criteria:

• Pregnant

• Taking any psychotropic medication

• Meeting DSM-IV criteria for active substance abuse or dependence

• On any stimulant medication

• History or current hypertension (BP > 140/90 mm Hg) or systolic hypotension (SBP < 90 mm Hg)

• Subjects with resting pulse rate > 90/min

• Any active medical illness

• Family history of abnormal heart rhythms, or sudden cardiac death

• Subjects who anticipate they may require the emergent use of epinephrine (such as an Epi-Pen®) for the treatment of severe allergic reactions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Oregon Health and Science University
• Portland VA Medical Center

Investigators

• Principal Investigator: Jonathan C Fellers, MD, Oregon Health and Science University
• Principal Investigator: William F Hoffman, MD, PhD, VA Portland Healthcare System

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: William Hoffman, Principal Investigator, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT02058966
• Other Study ID Numbers: 8874; 1004805; 3986
• First Posted: Feb 11, 2014
• Last Update Posted: Sep 12, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by William Hoffman, Principal Investigator, Oregon Health and Science University: Entacapone; COMT val158met; Methamphetamine
• Additional relevant MeSH terms: Entacapone; Methamphetamine

Study Results

Participant Flow

Recruitment Details	Study staff screened 80 subjects over the phone between June 2014 to June 2016 at a clinical hospital in Portland, OR.
Pre-assignment Detail	51 subjects failed the pre-screen primarily due to history of substance use disorder, time commitment conflicts, or unwilling to take methamphetamine. 14 of 29 subjects completed first randomization. Of the 29, 6 declined to participate, 4 did not meet inclusion criteria, 1 was excluded due to an adverse event, and 6 dropped out.

Arm/Group Title	All Subjects
Arm/Group Description	Subjects will get either entacapone or placebo, then one hour later, either methamphetamine or placebo. Placebo: capsules compounded to be of similar appearance to the active drugs Entacapone: Entacapone 200 mg oral dose Methamphetamine: Methamphetamine 20 mg oral dose The research pharmacy will assign randomization; they have no contact with the subjects or clinical staff involved in direct subject care so this medication combination could occur at any of the 4 randomization visits.
Period Title: Open-Label Methamphetamine
STARTED	19
Received Methamphetamine	18
COMPLETED	18
NOT COMPLETED	1
Period Title: Open-Label Methamphetamine
STARTED	15
Received Placebo-Placebo	3
Received Placebo-Meth	4
Received Entacapone-Placebo	2
Received Entacapone-Meth	5
COMPLETED	14
NOT COMPLETED	1
Period Title: Open-Label Methamphetamine
STARTED	13
Received Placebo-Placebo	2
Received Placebo-Meth	2
Received Entacapone-Placebo	6
Received Entacapone-Meth	3
COMPLETED	13
NOT COMPLETED	0
Period Title: Open-Label Methamphetamine
STARTED	12
Received Placebo-Placebo	4
Received Placebo-Meth	4
Received Entacapone-Placebo	1
Received Entacapone-Meth	3
COMPLETED	12
NOT COMPLETED	0
Period Title: Open-Label Methamphetamine
STARTED	12
Received Placebo-Placebo	4
Received Placebo-Meth	3
Received Entacapone-Placebo	3
Received Entacapone-Meth	2
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Participants who completed all four study arms including: Placebo followed by Placebo Placebo followed by Methamphetamine (20 mg) Entacapone (200 mg) followed by Placebo Entacapone (200 mg) followed by Methamphetamine (20 mg)
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.1 (5.12)
Sex: Female, Male (Count of Participants)
Female	9 75%
Male	3 25%
Region of Enrollment (Count of Participants)
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Effect of Entacapone on Methamphetamine-induced Mood
Description	Profile of Mood States is a 65 item questionnaire using a Likert rating scale to assess transient, distinct moods. The questionnaire contains 65 words/statements that describe feelings people have. The test requires you to indicate for each word or statement how you have been feeling in the past week including today. A Total Mood Disturbance score is calculated by adding scores for Tension, Depression, Anger, Fatigue and Confusion and then subtracting the Vigour score. The Total Mood Disturbance scale ranges from -32 to 200 with lower scores indicative of people with more stable mood profiles.
Time Frame	Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.

Outcome Measure Data

Analysis Population Description

The analysis population includes only the 12 subjects that completed each intervention of the study.

Arm/Group Title	Baseline	Placebo Followed by Placebo	Placebo Followed by Methamphetamine	Entacapone Followed by Placebo	Entacapone Followed by Methamphetamine
Arm/Group Description	Baseline measurements were taking for each subject before drug intervention during each of the 4 visits then averaged over the 4 visits. Baseline measurements reported here are averaged across all subjects.	Subjects will receive placebo, then one hour later, placebo Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive placebo, then one hour later, methamphetamine Methamphetamine: Methamphetamine 20 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, placebo Entacapone: Entacapone 200 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, methamphetamine Entacapone: Entacapone 200 mg oral dose Methamphetamine: Methamphetamine 20 mg oral dose
Measure Participants	12	12	12	12	12
Mean (Standard Deviation) [units on a scale]	12.500 (8.187)	13.750 (9.037)	7.500 (4.166)	9.833 (4.783)	8.750 (4.309)

2. Primary Outcome

Title	Effect of Entacapone on Subjective Effects of Methamphetamine
Description	The subjective effects of the study drug were evaluated with the Addiction Research Center Inventory (ARCI-49), a 49 item questionnaire consisting of true/false items. True items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when answer is opposite to scoring direction. There are 5 subscales: Morphine Benzedrine group scale to measure euphoria (range: 0-16 with higher numbers indicating more euphoria), A Lysergic Acid Diethylamide group scale to estimate dysphoria and agitation (range: 0-14 with higher scores indicating more dysphoria), a Pentobarbital Chlorpromazine Alcohol group scale to measure sedation (range: 0-15 with higher scores indicating more sedation), and a Benzedrine group scale and an Amphetamine Scale to assess stimulant effects (range: 0-13 and 0-11, respectively, with higher scores indicating higher stimulant effects) .
Time Frame	Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.

Outcome Measure Data

Analysis Population Description

The analysis population includes only the 12 subjects that completed each arm, or intervention, of the study.

Arm/Group Title	Baseline	Placebo Followed by Placebo	Placebo Followed by Methamphetamine	Entacapone Followed by Placebo	Entacapone Followed by Methamphetamine
Arm/Group Description	Baseline measurements were taking for each subject before drug intervention during each of the 4 visits then averaged over the 4 visits. Baseline measurements reported here are averaged across all subjects.	Subjects will receive placebo, then one hour later, placebo Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive placebo, then one hour later, methamphetamine Methamphetamine: Methamphetamine 20 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, placebo Entacapone: Entacapone 200 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, methamphetamine Entacapone: Entacapone 200 mg oral dose Methamphetamine: Methamphetamine 20 mg oral dose
Measure Participants	12	12	12	12	12
Morphine Benzedrine	1.9375 (2.6610)	1.8333 (2.8868)	7.9167 (5.9308)	2.5833 (4.1000)	6.9167 (6.2879)
Lysergic Acid Diethylamide	3.0625 (1.1923)	3.25 (1.1382)	4.75 (2.0944)	3.25 (1.1382)	3.8333 (1.3371)
Pentobarbital Chlorpromazine Alcohol	4.8125 (2.5066)	5.0000 (2.9233)	1.5833 (1.8320)	4.0833 (2.8110)	2.0000 (2.1320)
Benzedrine	4.9583 (1.4869)	5.1667 (2.0817)	8.6667 (3.6013)	5.3333 (2.1462)	7.8333 (3.7376)
Amphetamine	2.0000 (1.8451)	2.1667 (2.4802)	5.9167 (3.4499)	2.5833 (2.6097)	5.5833 (4.0104)

3. Primary Outcome

Title	Effect of Entacapone on Methamphetamine-induced Stimulation
Description	The Global Rating of Stimulation is a 1-item question "I feel light-headed, restless, or speeded-up" in which the participant is asked to circle one answer on a scale from 0-4, 0 is 'normal', 1 is 'slightly', 2 is 'moderately', 3 is 'very much', and 4 is 'extremely'. Whichever number they circled is their reported score. A higher score is indicative of a greater stimulating effect.
Time Frame	Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.

Outcome Measure Data

Analysis Population Description

The analysis population includes only the 12 subjects that completed each arm, or intervention, of the study.

Arm/Group Title	Baseline	Placebo Followed by Placebo	Placebo Followed by Methamphetamine	Entacapone Followed by Placebo	Entacapone Followed by Methamphetamine
Arm/Group Description	Baseline measurements were taking for each subject before drug intervention during each of the 4 visits then averaged over the 4 visits. Baseline measurements reported here are averaged across all subjects.	Subjects will receive placebo, then one hour later, placebo Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive placebo, then one hour later, methamphetamine Methamphetamine: Methamphetamine 20 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, placebo Entacapone: Entacapone 200 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, methamphetamine Entacapone: Entacapone 200 mg oral dose Methamphetamine: Methamphetamine 20 mg oral dose
Measure Participants	12	12	12	12	12
Mean (Standard Deviation) [units on a scale]	0.1667 (0.5586)	0.1667 (0.5774)	1.4167 (1.1645)	0.4167 (0.9003)	1.3333 (1.1547)

4. Secondary Outcome

Title	Cognitive Function
Description	Two computer tests were administered to measure how each medication intervention effects cognitive functioning. The tests administered included the Rapid Visual Information Processing Task (RVIPT), a 6 minute test of sustained attention in which participants are requested to detect target sequences of digits and the Digit Symbol Substitution Task (DSST), a 2 minute test of psychomotor speed and sustained attention consisting of digit-symbol pairs followed by a list of digits where the subject identifies the symbol that corresponds to each digit as fast as possible. The number of correct responses within the allowed time is measured. Higher scores on both tasks indicate better performance.
Time Frame	Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.

Outcome Measure Data

Analysis Population Description

The analysis population includes only the 12 subjects that completed each arm, or intervention, of the study.

Arm/Group Title	Baseline	Placebo Followed by Placebo	Placebo Followed by Methamphetamine	Entacapone Followed by Placebo	Entacapone Followed by Methamphetamine
Arm/Group Description	Baseline measurements were taking for each subject before drug intervention during each of the 4 visits then averaged over the 4 visits. Baseline measurements reported here are averaged across all subjects.	Subjects will receive placebo, then one hour later, placebo Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive placebo, then one hour later, methamphetamine Methamphetamine: Methamphetamine 20 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, placebo Entacapone: Entacapone 200 mg oral dose Placebo: capsules compounded to be of similar appearance to the active drugs	Subjects will receive entacapone, then one hour later, methamphetamine Entacapone: Entacapone 200 mg oral dose Methamphetamine: Methamphetamine 20 mg oral dose
Measure Participants	12	12	12	12	12
Rapid Visual Information Processing Task	38.813 (11.230)	40.500 (13.215)	41.333 (11.073)	42.583 (10.423)	40.083 (10.396)
Digital Symbol Substitution Task	73.167 (17.765)	72.000 (20.662)	71.167 (27.788)	72.750 (14.973)	72.750 (15.004)

Adverse Events

Arm/Group Title	Open-label Methamphetamine		Placebo-Placebo		Placebo-Meth		Entacapone-Placebo		Entacapone-Meth
Arm/Group Description	Subject will receive one dose of open-label methamphetamine 20 mg oral dose on their second visit, the familiarization visit.		Subjects will receive placebo, then one hour later, placebo Placebo: capsules compounded to be of similar appearance to the active drugs		Subjects will receive placebo, then one hour later, methamphetamine Placebo: capsules compounded to be of similar appearance to the active drugs Methamphetamine: Methamphetamine 20 mg oral dose		Subjects will receive entacapone, then one hour later, placebo Placebo: capsules compounded to be of similar appearance to the active drugs Entacapone: Entacapone 200 mg oral dose		Subjects will receive entacapone, then one hour later, methamphetamine Methamphetamine: Methamphetamine 20 mg oral dose Entacapone: Entacapone 200 mg oral dose
All Cause Mortality
	Open-label Methamphetamine		Placebo-Placebo		Placebo-Meth		Entacapone-Placebo		Entacapone-Meth
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/13 (0%)		0/13 (0%)		0/12 (0%)		0/13 (0%)
Serious Adverse Events
	Open-label Methamphetamine		Placebo-Placebo		Placebo-Meth		Entacapone-Placebo		Entacapone-Meth
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/13 (0%)		0/13 (0%)		0/12 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Open-label Methamphetamine		Placebo-Placebo		Placebo-Meth		Entacapone-Placebo		Entacapone-Meth
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/13 (0%)		0/13 (0%)		0/12 (0%)		0/13 (0%)
Cardiac disorders
Tachycardia	1/19 (5.3%)	1	0/13 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/13 (0%)	0

Limitations/Caveats

[Not Specified]

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.