A118G SNP and OPRM1 Gene Opioid-Mediated Effects in Humans

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02360371
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 100
• Location: 1
• Arms: 4
• Actual Duration (Months): 73
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Within-subject, double-blind, placebo-controlled examination of opioid abuse potential in healthy individuals as a function of A118G SNP on the OPRM1 gene.

Condition or Disease	Intervention/Treatment	Phase
Opioid Sensitivity; Individual Difference; Abuse Opioids	Drug: Within-subject test of blinded study medication	Phase 2

Detailed Description

Participants completed a 5-day, within-subject, double-blind, placebo-controlled, randomized, human laboratory abuse potential trial. Healthy individuals were admitted to a residential research unit for 5 consecutive days. Blood samples were drawn for genome wide analyses using the Global Screening Array on day 1. Participants were administered an oral dose of the opioid hydromorphone (4mg) on day 2 of the study. Persons who did not evidence strong agonist effects then proceeded into the randomized period wherein they received 0mg, 2mg, and 8mg of oral hydromorphone on the remaining three study days. The order of dosing was randomized, with only 1 dose administered per day and all participants receiving 1 exposure to each dose. Outcomes were standard human abuse potential metrics, including self-reported drug effects and feeling high. Data were analyzed as a function of the A118SNP on the OPRM1 gene that codes for the mu opioid receptor. The overall aim was to determine whether signal for abuse potential among persons with no history of opioid misuse was associated with genotype.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Within-subject, double-blind, randomized, placebo-controlled, human laboratory design wherein each participant completed each of the study conditions (outlined below as four arms). Participants were genotyped for rs-1799971and data were analyzed using between-group designs based upon rs-1799971 status.Within-subject, double-blind, randomized, placebo-controlled, human laboratory design wherein each participant completed each of the study conditions (outlined below as four arms). Participants were genotyped for rs-1799971and data were analyzed using between-group designs based upon rs-1799971 status.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Neither participants nor staff were informed of the class of drugs under investigation. Strict blinding was maintained.
• Primary Purpose: Basic Science
• Official Title: A118G SNP and OPRM1 Gene Opioid-Mediated Effects in Humans
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: May 1, 2020
• Actual Study Completion Date: May 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo (oral) Within-subject double-blind, administration of placebo oral capsule. Order of dose randomized session days 3-5.	Drug: Within-subject test of blinded study medication; Within-subject double-blind, randomized, placebo-controlled, residential human abuse potential study. All participants received 4mg oral hydromorphone on study day 2 and a subset continued into the randomized portion for study days 3-5 wherein they received placebo, 2mg hydromorphone, and 8mg hydromorphone in randomized order. Only one dose was administered per day and following randomized all participants received each dose in random order. Outcomes were collected during 8-hour residential-based sessions and included metrics of FDA human abuse potential testing as well as secondary outcomes of laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition. Participants were genotyped for rs-1799971 status and results were analyzed as between-group comparisons based upon genotype.
Experimental: Hydromorphone (oral) 2mg Within-subject double-blind, administration of hydromorphone via oral capsule. Order of dose randomized session days 3-5.	Drug: Within-subject test of blinded study medication; Within-subject double-blind, randomized, placebo-controlled, residential human abuse potential study. All participants received 4mg oral hydromorphone on study day 2 and a subset continued into the randomized portion for study days 3-5 wherein they received placebo, 2mg hydromorphone, and 8mg hydromorphone in randomized order. Only one dose was administered per day and following randomized all participants received each dose in random order. Outcomes were collected during 8-hour residential-based sessions and included metrics of FDA human abuse potential testing as well as secondary outcomes of laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition. Participants were genotyped for rs-1799971 status and results were analyzed as between-group comparisons based upon genotype.
Experimental: Hydromorphone (oral) 4mg Hydromorphone oral capsule administered in double-blind manner on Day 2 as first study drug administration. Hydromorphone 4mg dosing day was set for safety purposes and non-randomized.	Drug: Within-subject test of blinded study medication; Within-subject double-blind, randomized, placebo-controlled, residential human abuse potential study. All participants received 4mg oral hydromorphone on study day 2 and a subset continued into the randomized portion for study days 3-5 wherein they received placebo, 2mg hydromorphone, and 8mg hydromorphone in randomized order. Only one dose was administered per day and following randomized all participants received each dose in random order. Outcomes were collected during 8-hour residential-based sessions and included metrics of FDA human abuse potential testing as well as secondary outcomes of laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition. Participants were genotyped for rs-1799971 status and results were analyzed as between-group comparisons based upon genotype.
Experimental: Hydromorphone (oral) 8mg Within-subject double-blind, administration of hydromorphone via oral capsule. Order of dose randomized session days 3-5.	Drug: Within-subject test of blinded study medication; Within-subject double-blind, randomized, placebo-controlled, residential human abuse potential study. All participants received 4mg oral hydromorphone on study day 2 and a subset continued into the randomized portion for study days 3-5 wherein they received placebo, 2mg hydromorphone, and 8mg hydromorphone in randomized order. Only one dose was administered per day and following randomized all participants received each dose in random order. Outcomes were collected during 8-hour residential-based sessions and included metrics of FDA human abuse potential testing as well as secondary outcomes of laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition. Participants were genotyped for rs-1799971 status and results were analyzed as between-group comparisons based upon genotype.

Outcome Measures

Primary Outcome Measures

1. Self-report Visual Analog Ratings of HIGH [30 minutes after study drug administration]

   Peak visual analog rating scale values of HIGH (rated on 0-100 scale with higher scores indicating higher feeling of being HIGH) collected at 30 minute intervals post-drug administration for 6 hours.

2. Self-report Visual Analog Ratings of DRUG EFFECT [30 minutes after study drug administration]

   Peak visual analog rating scale values of DRUG EFFECT (rated on 0-100 scale with higher scores indicating higher drug effect) collected at 30 minute intervals post-drug administration for 6 hours.

Eligibility Criteria

Criteria

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

Inclusion Criterion:

1. Provide a urine sample that tests negative for opioids, methadone, buprenorphine, oxycodone, amphetamine, cocaine, and benzodiazepines

2. Negative ethanol breath test (0.000)

3. Aged 21-50

4. Deemed medically eligible to take hydromorphone

Exclusion Criterion:

1. Answer "yes" to question 1 of the Brief Pain Inventory (89) to assess the presence of chronic pain.

2. Current use of opioids or other medications for pain

3. Meet DSM-5 criteria for current or lifetime alcohol or drug use disorder (excluding nicotine)

4. Self-report any illicit drug use in the past 7 days

5. Self-report opioid use >5 days in the past 30

6. Evidence of opioid physical dependence at screening or following 1st residential overnight (following confirmed opioid abstinence)

7. Allergy to hydromorphone or other opioid agonists

8. Experience an adverse event that warrants opioid antagonist treatment following 1st hydromorphone dose.

9. If female, not be pregnant or breastfeeding

10. Presence of any clinically significant medical (e.g., chronic renal insufficiency, history of myocardial infarction, seizure disorder) and/or psychiatric illness (e.g., schizophrenia, bipolar disorder) that may interfere with study participation.

11. BMI >30 (obese category)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University Bayview Medical Campus	Baltimore	Maryland	United States	21224

Sponsors and Collaborators

• Johns Hopkins University
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Kelly E Dunn, Ph.D., MBA, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 16, 2019
• Informed Consent Form - Oct 29, 2019

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02360371
• Other Study ID Numbers: IRB00047423; R01DA035246-01A1
• First Posted: Feb 10, 2015
• Last Update Posted: Oct 5, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Johns Hopkins University: opioid; abuse; genetic; A118G; OPRM1
• Additional relevant MeSH terms: Hypersensitivity

Study Results

Participant Flow

Recruitment Details	100 participants were recruited from the community for participation. Analyses were based upon OPRM1 rs-1799971 allele status (A, G), which was available for 97 participants. All participants completed the same 4 study arms.

Arm/Group Title	A118G (rs1799971-G)	A118A (rs1799971-A)
Arm/Group Description	This is a within-subject study wherein the same participants moved from one treatment arm to the next and results were analyzed posthoc as a function of genotype.	This is a within-subject study wherein the same participants moved from one treatment arm to the next and results were analyzed posthoc as a function of genotype.
Period Title: Overall Study
STARTED	13	84
Placebo (Oral)	13	69
Hydromorphone (Oral) 2mg	13	69
Hydromorphone (Oral) 4mg	13	69
Hydromorphone (Oral) 8mg	13	69
COMPLETED	13	69
NOT COMPLETED	0	15

Baseline Characteristics

Arm/Group Title	A118G (rs1799971-G)	A118A (rs1799971-A)	Total
Arm/Group Description	This is a within-subject study wherein the same 100 participants moved from one treatment arm to the next.	This is a within-subject study wherein the same 100 participants moved from one treatment arm to the next.	Total of all reporting groups
Overall Participants	13	84	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.6 (10.0)	33.3 (8.9)	33.9 (9.1)
Sex: Female, Male (Count of Participants)
Female	4 30.8%	45 53.6%	49 50.5%
Male	9 69.2%	39 46.4%	48 49.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 23.1%	5 6%	8 8.2%
Not Hispanic or Latino	10 76.9%	79 94%	89 91.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 7.7%	0 0%	1 1%
Asian	1 7.7%	4 4.8%	5 5.2%
Native Hawaiian or Other Pacific Islander	0 0%	2 2.4%	2 2.1%
Black or African American	2 15.4%	43 51.2%	45 46.4%
White	9 69.2%	28 33.3%	37 38.1%
More than one race	0 0%	5 6%	5 5.2%
Unknown or Not Reported	0 0%	2 2.4%	2 2.1%
Region of Enrollment (participants) [Number]
United States	13 100%	84 100%	97 100%

Outcome Measures

1. Primary Outcome

Title	Self-report Visual Analog Ratings of HIGH
Description	Peak visual analog rating scale values of HIGH (rated on 0-100 scale with higher scores indicating higher feeling of being HIGH) collected at 30 minute intervals post-drug administration for 6 hours.
Time Frame	30 minutes after study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A118G (rs1799971-G)	A118A (rs1799971-A)
Arm/Group Description	This is a within-subject study wherein the same 100 participants moved from one treatment arm to the next.	This is a within-subject study wherein the same 100 participants moved from one treatment arm to the next.
Measure Participants	13	84
Placebo (oral)	7.2 (13.2)	6.6 (16.3)
Hydromorphone (oral) 2mg	4.5 (5.9)	5.6 (15.4)
Hydromorphone (oral) 4mg	12.5 (19.8)	18.4 (26.4)
Hydromorphone (oral) 8mg	25.5 (29.7)	22.5 (27.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A118G (rs1799971-G), A118A (rs1799971-A)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.567
	Comments
	Method	Mixed methods
	Comments

2. Primary Outcome

Title	Self-report Visual Analog Ratings of DRUG EFFECT
Description	Peak visual analog rating scale values of DRUG EFFECT (rated on 0-100 scale with higher scores indicating higher drug effect) collected at 30 minute intervals post-drug administration for 6 hours.
Time Frame	30 minutes after study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A118G (rs1799971-G)	A118A (rs1799971-A)
Arm/Group Description	This is a within-subject study wherein the same participants moved from one treatment arm to the next and results were analyzed posthoc as a function of genotype.	This is a within-subject study wherein the same participants moved from one treatment arm to the next and results were analyzed posthoc as a function of genotype.
Measure Participants	13	84
Placebo (oral)	13.3 (21.3)	11.1 (20.0)
Hydromorphone (oral) 2mg	10.8 (16.5)	11.0 (20.7)
Hydromorphone (oral) 4mg	23.6 (27.0)	31.9 (29.9)
Hydromorphone (oral) 8mg	39.2 (37.3)	39.5 (32.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A118G (rs1799971-G), A118A (rs1799971-A)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.805
	Comments
	Method	Mixed Model
	Comments

Adverse Events

Time Frame	Adverse events collected for 6 hours post each drug administration session. Only adverse events (AEs) judged to be possibly, probably, or definitely related to study participation are reported.
Adverse Event Reporting Description	AEs were documented the end of each session or in response to spontaneous reporting from participants, as a function of dose but not allele status, during the session. AEs were queried by asking "are you experiencing any side effects of the study medication?" The 4mg hydromorphone dose was the safety test dose and all individuals who had strong agonist responses (e.g., vomiting) in response to that dose were discontinued; therefore more individuals received 4mg than did other doses.
Arm/Group Title	Placebo (Oral)		Hydromorphone (Oral) 2mg		Hydromorphone (Oral) 4mg		Hydromorphone (Oral) 8mg
Arm/Group Description	Within-subject double-blind, administration of placebo oral capsule. Order of dose randomized session days 3-5.		Within-subject double-blind, administration of hydromorphone via oral capsule. Order of dose randomized session days 3-5.		Hydromorphone oral capsule administered in double-blind manner on Day 2 as first study drug administration. Hydromorphone 4mg dosing day was set for safety purposes and non-randomized.		Within-subject double-blind, administration of hydromorphone via oral capsule. Order of dose randomized session days 3-5.
All Cause Mortality
	Placebo (Oral)		Hydromorphone (Oral) 2mg		Hydromorphone (Oral) 4mg		Hydromorphone (Oral) 8mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/82 (0%)		0/82 (0%)		0/97 (0%)		0/82 (0%)
Serious Adverse Events
	Placebo (Oral)		Hydromorphone (Oral) 2mg		Hydromorphone (Oral) 4mg		Hydromorphone (Oral) 8mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/82 (0%)		0/82 (0%)		0/97 (0%)		0/82 (0%)
Other (Not Including Serious) Adverse Events
	Placebo (Oral)		Hydromorphone (Oral) 2mg		Hydromorphone (Oral) 4mg		Hydromorphone (Oral) 8mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/82 (23.2%)		21/82 (25.6%)		65/97 (67%)		49/82 (59.8%)
Gastrointestinal disorders
Vomiting	0/82 (0%)	0	0/82 (0%)	0	14/97 (14.4%)	16	7/82 (8.5%)	8
Nausea	3/82 (3.7%)	3	5/82 (6.1%)	5	29/97 (29.9%)	39	18/82 (22%)	29
General disorders
Headache	5/82 (6.1%)	5	8/82 (9.8%)	8	6/97 (6.2%)	6	6/82 (7.3%)	7
Dry Mouth (Xerostomia)	1/82 (1.2%)	1	0/82 (0%)	0	5/97 (5.2%)	6	6/82 (7.3%)	6
Nervous system disorders
Dizziness	0/82 (0%)	0	0/82 (0%)	0	8/97 (8.2%)	11	9/82 (11%)	10
Drowsiness	10/82 (12.2%)	17	10/82 (12.2%)	13	31/97 (32%)	48	20/82 (24.4%)	35
Euphoria/High	0/82 (0%)	0	0/82 (0%)	0	2/97 (2.1%)	2	3/82 (3.7%)	3
Fatigue	0/82 (0%)	0	0/82 (0%)	0	0/97 (0%)	0	3/82 (3.7%)	6
Impaired, Groggy	0/82 (0%)	0	0/82 (0%)	0	4/97 (4.1%)	4	4/82 (4.9%)	4
Lethargy	2/82 (2.4%)	4	1/82 (1.2%)	1	9/97 (9.3%)	10	1/82 (1.2%)	2
Light Headedness	1/82 (1.2%)	1	1/82 (1.2%)	1	10/97 (10.3%)	12	7/82 (8.5%)	7
Shaky	0/82 (0%)	0	0/82 (0%)	0	3/97 (3.1%)	4	2/82 (2.4%)	3
Sleepiness	1/82 (1.2%)	1	2/82 (2.4%)	2	8/97 (8.2%)	9	4/82 (4.9%)	4
Sluggish	0/82 (0%)	0	0/82 (0%)	0	1/97 (1%)	1	5/82 (6.1%)	5
Pruritus (Itching)	0/82 (0%)	0	2/82 (2.4%)	2	4/97 (4.1%)	5	8/82 (9.8%)	10
Hot Flashes	0/82 (0%)	0	0/82 (0%)	0	3/97 (3.1%)	3	6/82 (7.3%)	7

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.