Phase 1, Single-dose, Double-blind, Rand., Placebo- and Active-controlled, 4-period, 4-sequence Crossover, Proof-of-Concept Study to Evaluate Effect of Naltrexone on Abuse Potential of Methylphenidate in Healthy Recreational Stimulant Users
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Avekshan LLC
- Enrollment
- 94
- Locations
- 1
- Primary Endpoint
- Maximum Effect of Naltrexone
Overview
Brief Summary
The current abuse liability study aims to assess the potential for co-administration of naltrexone (NTX) to reduce the abuse potential of methylphenidate (MPH).
Detailed Description
The abuse of MPH, as a Schedule II substance, is a well-documented problem. Studies in animal models, including primates, show that high-dose MPH can produce reinforcement or reward. A number of studies suggest that the rapid elevation of MPH levels in the blood and brain that occurs following intranasal or oral administration of supra-therapeutic doses is a key requirement for development of MPH-associated euphoria, reinforcement, and addiction. The concerns about MPH abuse potential and addiction often play a role in the decision of patients, parents, or physicians who opt against treatment with MPH, despite its effectiveness. This provides an imperative for development of MPH formulations that are therapeutically potent but with lower abuse potential. Methylphenidate acts mainly through the dopaminergic system. At sufficiently high doses, MPH can also activate the mu opioid receptors (MOPR) in the brain. Recent data indicate that blockade of MOPRs by naltrexone (NTX) blocks the rewarding effects of MPH in mice. Clinical studies on the modulatory effect of NTX on dopamine release following chronic amphetamine use also support the involvement of opioid-dopamine interactions in the reinforcing and rewarding effects of amphetamine. These data support the hypothesis that NTX will block the reinforcing effect of MPH in humans.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Masking Description
Double-blind, randomized
Eligibility Criteria
- Ages
- 18 Years to 45 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Recreational stimulant users, defined as ≥10 lifetime non-therapeutic experiences (i.e., for psychoactive effects) with CNS stimulants (e.g., amphetamines, cocaine, MPH) and ≥1 non-therapeutic use of a CNS stimulant within the 12 weeks prior to Screening.
- •A body mass index of ≥18 to ≤34 kg/m2 at Screening.
- •In good health, as determined by medical history, PE, vital signs assessments, 12-lead ECG, and clinical laboratory evaluations.
- •A female study subject must meet one of the following criteria:
- •If of childbearing potential - is abstinent from heterosexual intercourse or uses 2 of the accepted contraceptive regimens from at least 30 days prior to the first administration of the study medication, during the study, and for at least 30 days after the last dose of the study medication. An acceptable method of contraception includes the following:
- •Progestogen-containing hormonal contraceptives (birth control pills, injectable/implantable/insertable hormonal birth control products, transdermal patch) and use of condom with spermicide
- •Intrauterine device (without hormones)
- •Spermicide
- •If of non-childbearing potential - should be surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses), as confirmed by follicle-stimulating hormone (FSH) levels (postmenopausal must be confirmed by the subject having a serum FSH greater than 40 mIU/mL at Screening). Females of non-childbearing potential must present a proof of postmenopausal status and/or partial or total hysterectomy; if such proof is not available, the female will be considered to be of childbearing potential.
- •A male study subject must agree to use one of the accepted contraceptive regimens during the study and for at least 90 days after the last dose of the study medication:
Exclusion Criteria
- •Evidence of moderate or severe substance use disorder (excluding nicotine and/or caffeine) within the past 2 years, as defined by the DSM-V, or has a lifetime history of participation in a drug rehabilitation program (excluding past participation in tobacco smoking cessation program or previous court-mandated treatment).
- •History of opioid dependence.
- •Subject has a positive urine drug or alcohol screen upon admission into the clinic at the start of the Qualification or Treatment Phase (Day -1 of Parts 1 and 2), except for cannabinoids (delta-9-tetrahydrocannabinol \[THC\]), which may be seen because of the long half-life of THC and slow release from adipose tissue. If THC is positive, inclusion will be at the discretion of the Investigator. Tests with positive results may be repeated and/or subjects may be rescheduled at the Investigator's discretion.
- •Abnormal pulse rate, blood pressure, oral body temperature, or respiration rate at Screening and prior to administration of any study drug that, in the opinion of the Investigator, increases the risk to the subject of participation in the study. For these parameters, out-of-range values that are not clinically significant (as determined by the Investigator) may be repeated twice and the subject may be enrolled if at least 1 repeated value is within acceptable range.
- •Abnormal 12-lead ECG at Screening and prior to first dose of any study drug that, in the opinion of the Investigator, increases the risk to the subject of participation in the study.
- •Any clinically significant medical history that, in the opinion of the Investigator, increases the risk to the subject of participation in the study.
- •A history of a major surgical procedure within 30 days prior to the start of study drug administration (Day 1 of Part 1), or any planned surgery during the study.
- •A history of any clinically significant illness within 30 days of the start of study drug administration (Day 1 of Part 1), as determined by the Investigator.
- •History of liver disease.
- •History of narrow-angle glaucoma, based on medical history and/or subject self-reporting.
Arms & Interventions
Qualification Phase (Part A)
Placebo/Methylphenidate (60 mg) on days 1 and 3
Intervention: Placebo (Drug)
Qualification Phase (Part A)
Placebo/Methylphenidate (60 mg) on days 1 and 3
Intervention: Methylphenidate 60 mg (Drug)
Qualification Phase (Part B)
Methylphenidate (60 mg)/Placebo on days 1 and 3
Intervention: Placebo (Drug)
Qualification Phase (Part B)
Methylphenidate (60 mg)/Placebo on days 1 and 3
Intervention: Methylphenidate 60 mg (Drug)
Treatment Phase Sequence 4213
Methylphenidate 60 mg/Naltrexone 100 mg Methylphenidate 60 mg/Placebo Placebo/Placebo Methylphenidate 60 mg/Naltrexone 50 mg
Intervention: Treatment Phase Sequence 4213 (Drug)
Treatment Phase Sequence 2134
Methylphenidate 60 mg/Placebo Placebo/Placebo Methylphenidate 60 mg/Naltrexone 50 mg Methylphenidate 60 mg/Naltrexone 100 mg
Intervention: Treatment Phase Sequence 2134 (Drug)
Treatment Phase Sequence 1342
Placebo/Placebo Methylphenidate 60 mg/Naltrexone 50 mg Methylphenidate 60 mg/Naltrexone 100 mg Methylphenidate 60 mg/Placebo
Intervention: Treatment Phase Sequence 1342 (Drug)
Treatment Phase Sequence 3421
Methylphenidate 60 mg/Naltrexone 50 mg Methylphenidate 60 mg/Naltrexone 100 mg Methylphenidate 60 mg/Placebo Placebo/Placebo
Intervention: Treatment Phase Sequence 3421 (Drug)
Outcomes
Primary Outcomes
Maximum Effect of Naltrexone
Time Frame: 70 days
To evaluate the maximum effect of 2 doses (50 and 100 mg) of Naltrexone on the abuse potential of a single dose (60 mg) of Methylphenidate in healthy recreational stimulant users using the bipolar Visual Analogue Scale for Drug Liking. Visual Analogue Scale (bipolar) is an administered test where the patient assess the following.: • Drug Liking, Overall Drug Liking, Alertness/Drowsiness, Overall Take the Drug Again; The response anchors are 0 (strong disliking), 50 (neither like nor dislike), and 100 (strong liking). Visual Analogue Scale for Drug Liking will be determined periodically over the 8 hour period following each dose administration to assess for response to test question, "At this moment, my liking for this drug is...".
Secondary Outcomes
- Time to Maximum Effect of Naltrexone(70 days)
- Time-Average Area Under the Effect Curve(70 days)
- Effect of Naltrexone(70 days)
- Adverse Events(70 days)
- Clinical Laboratory Abnormalities(70 days)
- Heart Rate Assessment via Electrocardiogram(70 days)
- Heart Rate Assessment via Cardiac Telemetry(70 days)
- Time to Minimum Effect(70 days)
- Supine Pulse Rate Assessment(70 days)
- Supine Blood Pressure Assessment(70 days)
- Respiratory Rate Assessment(70 days)
- Oral Body Temperature Assessment(70 days)
- Physical Examinations (PEs)(70 days)
- Maximum Observed Plasma Concentration(70 days)
- Time of the Maximum Observed Plasma Concentration(70 days)
- Area Under the Plasma Concentration-time Curve(24 hours)