Assessment of Abuse Potential of Rapastinel in Humans

Study Overview
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Brief Summary
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Based on the pharmacological class of rapastinel, this study will be conducted to evaluate the abuse potential of single doses of rapastinel as compared with ketamine, a NMDAR antagonist that is a Schedule III dissociative anesthetic, and placebo in recreational polydrug users.

Official Title
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A Two-part, Single-dose, Randomized, Double-blind, Placebo and Active-Controlled Crossover Study to Evaluate the Abuse Potential of Rapastinel in Healthy, Non-dependent, Adult Recreational Polydrug Users

Conditions
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Human Abuse Potential

Intervention / Treatment
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* Drug: Rapastinel
* Drug: Ketamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be a current recreational polydrug user Have a supine systolic blood pressure (BP) ≥ 95 mm Hg and ≤ 145 mg Hg, or supine diastolic BP ≥ 50 mm Hg and ≤ 90 mm Hg at the Screening Visit. Have negative test results for benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, oxycodone and other opioids, and phencyclidine at any admission Able, as assessed by the investigator, and willing to follow study instructions and likely to complete all required study visits Exclusion Criteria: Evidence of drug or alcohol dependence (excluding nicotine and caffeine) within the past 2 years Suicidal risk based on the opinion of the principal investigator (or appropriately trained designee) History of violent or psychotic behavior when taking psychedelic drugs, or unwilling to take a drug that might alter perception in a controlled setting Have taken or require concomitant treatment with any CNS depressants, or cannot safely discontinue these medications within 14 days (or 5 half-lives, whichever is longer) before study treatment administration Previously participated in an investigational study of rapastinel. Participation in any other clinical investigation using an experimental drug within 30 days, 5 half-lives or twice the duration of the biological effect of the study treatment (whichever is longer), prior to study treatment administration or is concurrently enrolled in any clinical trial, judged not to be scientifically or medically compatible with this study Consumption of alcohol within 72 hours before administration of study treatment Breastfeeding Unable to refrain from consuming caffeine or xanthine-containing compounds such as tea, coffee, soft drinks, energy sports drinks or chocolate (more than 48 oz/day) from 48 hours before administration of study treatment. Have consumed dietary supplements or other foods or beverages that may affect various drug metabolizing enzymes and transporters (eg, grapefruit, grapefruit juice, grapefruit-containing beverages), vegetables from the mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard), and charbroiled meats within 14 days prior to dosing or unable to refrain from consumption during the study. The ability to tolerate IV ketamine as judged by the Investigator, based on available safety data, as well as pharmacodynamic data.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Cohort 1: Ketamine Low Dose<br>Some participants will be administered a single IV dose of ketamine on Day 1. | Drug: Ketamine<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Placebo Comparator: Part 1, Cohort 1: Placebo<br>Some participants will be administered a single IV dose of placebo on Day 1. | Drug: Placebo<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Experimental: Part 1, Cohort 2: Ketamine Medium Dose<br>Some participants will be administered a single IV dose of ketamine on Day 1. | Drug: Ketamine<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Placebo Comparator: Part 1, Cohort 2: Placebo<br>Some participants will be administered a single IV dose of placebo on Day 1. | Drug: Placebo<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Experimental: Part 1, Cohort 3 (Optional): Ketamine High Dose<br>Optional: some participants will be administered a single IV dose of ketamine on Day 1. | Drug: Ketamine<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Placebo Comparator: Part 1, Cohort 3 (Optional): Placebo<br>Optional: some participants will be administered a single IV dose of placebo on Day 1. | Drug: Placebo<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Experimental: Part 2, Qualification Phase: Ketamine<br>Participants will receive IV ketamine on Day 1 and placebo on Day 2 in a randomized crossover manner. | Drug: Ketamine<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Placebo Comparator: Part 2, Qualification Phase: Placebo<br>Participants will receive IV ketamine on Day 2 and placebo on Day 1 in a randomized crossover manner. | Drug: Placebo<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Experimental: Part 2, Treatment Phase: Rapastinel Low Dose<br>Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner. | Drug: Rapastinel<br>* During the Treatment Phase in Part 2, participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Experimental: Part 2, Treatment Phase: Rapastinel Medium Dose<br>Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner. | Drug: Rapastinel<br>* During the Treatment Phase in Part 2, participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Experimental: Part 2, Treatment Phase: Rapastinel High Dose<br>Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner. | Drug: Rapastinel<br>* During the Treatment Phase in Part 2, participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Active Comparator: Part 2, Treatment Phase: Ketamine<br>Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner. | Drug: Ketamine<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|
| Placebo Comparator: Part 2, Treatment Phase: Placebo<br>Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner. | Drug: Placebo<br>* Part 1 Part 2, Qualification Phase: Participants will be administered single IV doses of ketamine and placebo in a randomized crossover manner Part 2, Treatment Phase: Participants will be administered single IV doses of rapastinel, ketamine, and placebo in a randomized crossover manner.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum effect (Emax) for At this Moment Drug Liking visual analog scale (VAS). | The drug liking VAS measures the participant's liking for the drug and is scored from 0 to 100, with 0 reflecting Strong disliking and 100 reflecting Strong liking. | Treatment Phase: Pre-dose and up to 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum effect (Emax) |  | Treatment Phase: Pre-dose and up to 24 hours post-dose | 
| Minimum effect (Emin) |  | Treatment Phase: Pre-dose and up to 24 hours post-dose | 
| Time to Emax (TEmax) |  | Treatment Phase: Pre-dose and up to 24 hours post-dose | 
| Time to Emin (TEmin) |  | Treatment Phase: Pre-dose and up to 24 hours post-dose | 
| Time averaged area under the effect curve (TA_AUE) |  | Treatment Phase: Hour 0 and up to 24 Hours post-dose | 
| Maximum plasma drug concentration (Cmax) |  | Treatment Phase: Pre-dose and up to 24 hours post-dose | 
| Area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration (AUClast) |  | Treatment Phase: Pre-dose and up to 24 hours post-dose | 
| Adverse events |  | Part 1: 6 weeks, Part 2: 9 weeks | 
| Proportion of abnormal electrocardiograms |  | Part 1: 6 weeks, Part 2: 9 weeks | 
| Columbia-Suicide Severity Rating Scale | The C-SSRS is a clinician-rated instrument that reports the severity of both suicidal ideation and behavior. Suicidal ideation is classified on a 5-item scale: 1 (least severe) to 5 (most severe). | Part 1: 6 weeks, Part 2: 9 weeks |