Abuse Potential of Oral Gabapentin in Healthy, Non-Drug-Dependent Individuals With Recreational Sedative Drug Use Experience

A Phase 4, Randomized, Double-Blind, Placebo and Active-Controlled, Single-Dose, Four-Way Crossover Study Evaluating the Abuse Potential of Two Doses of Gabapentin Taken Orally in Healthy, Non-Drug-Dependent Participants With Sedative Drug Use Experience

The purpose of the present study is to assess prospectively the abuse potential of gabapentin compared to placebo and alprazolam in healthy non-drug-dependent recreational sedative drug users under fasted condition.

The study includes Screening, a Qualification Phase consisting of a Naloxone Challenge and Drug Discrimination crossover study, a Treatment Phase and Follow-up. Following successful completion of the Qualification Phase the participants will be enrolled in the Treatment phase. The Treatment Phase is a randomized, double-blind, placebo- and active-controlled, 4 period crossover, single-dose, Williams square design study in healthy male and female adult, non-dependent, recreational sedative users. On Day 1 of each of the Treatment Phase 4 periods, which will be separated by a washout of at least 6 days, participants will receive an oral dose of either gabapentin 1800 mg or 1200 mg or 2 mg alprazolam, or placebo. Study treatments will be administered under fasted conditions (overnight fast and no food until 4 hours after dosing). Water will be allowed without restriction except from 1 hour prior to dosing until 1 hour after dosing.

Inclusion Criteria:

1. Male and female participants must be 18 to 55 years of age, inclusive, at the time of screening. At least 20% of participants randomized into the Treatment Phase should be female.

2. Male participants must agree to the following requirements during the intervention period and for at least 93 days after the last dose of study intervention, which corresponds to the time needed to eliminate study intervention(s) plus an additional 90 days (a spermatogenesis cycle):

   • Refrain from donating sperm.

   PLUS either:

   • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; OR

   • Must agree to use contraception/barrier as detailed below:

   • Agree to use a male condom and spermicide when engaging in any activity that allows for passage of ejaculate to another person.

   • Male participants should be advised of the benefit for a female partner to use a highly effective method of contraception, as a condom may break or leak when having sexual intercourse with a woman of child-bearing potential (WOCBP) who is not currently pregnant.

     - A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:

   • Is not a WOCBP; OR

   • Is a WOCBP and using a contraceptive method

   • A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for 30 days after the last dose of investigational product. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

3. Participants who are overtly healthy. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, complete physical examination, vital signs, 12-lead electrocardiogram (ECG), and/or clinical laboratory tests.

4. Participants must be recreational sedative drug users, defined as those reporting using a sedative agent (e.g., barbiturates, benzodiazepines) for its intoxicating effects on at least 10 lifetime occasions and at least once in the 12 weeks before the Screening Visit, but who have no signs of dependence and are not seeking treatment for their sedative use.

5. Participants must satisfactorily complete the Drug Discrimination phase.

6. Body mass index (BMI) of 17.5 to 34 kg/m2, inclusive; and a total body weight ≥50 kg (110 lb).

Exclusion Criteria:

1. Participants with current or past diagnosis of any type of drug dependence within the past year. Diagnosis of substance and/or alcohol dependence (excluding caffeine and nicotine) will be assessed by the Investigator using the Diagnostic and Statistical Manual of Mental Disorders-5-Text Revision (DSM-5-TR) criteria performed at Screening. Current drug use will be allowed if the candidate can produce a negative urine sample (excluding THC) prior to first dose and are free of any signs/symptoms of withdrawal. The candidate will be informed if they have a positive breathalyzer or urine ethanol test.

2. Participants who are heavy smokers (>20 cigarettes equivalents per day)

3. Participants who are unable to abstain from smoking for at least 2 hours before and at least 8 hours after study drug administration.

4. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).

5. Participants with any history of sleep apnea, myasthenia, or glaucoma.

6. Any condition possibly affecting drug absorption (e.g., gastrectomy) excluding cholecystectomy within 1 year prior to study.

7. Participants with a positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCVAb).

8. Participants with active suicidal ideation or suicidal behavior within 5 years prior to Screening as determined through the use of the Columbia Suicide Severity Rating Scale (C-SSRS) or active ideation identified at Screening or on Day -1.

9. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or clinically significant laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.

10. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of investigational product. (Refer to Section 6.8 for additional details).

11. Herbal supplements and herbal medications must be discontinued at least 14 days prior to the first dose of study medication.

12. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives (whichever is longer) prior to screening.

13. Positive urine drug screen (UDS) for substances of abuse at admission to the Qualification Phase, excluding tetrahydrocannabinol (THC). If a participant presents with a positive UDS (excluding THC) at admission or any visit, the investigator, at his/her discretion, may reschedule a repeat UDS until the UDS is negative (excluding THC) before the participant is permitted to be dosed in any phase of the study.

14. Participants who are unable to abstain from using THC during the inpatient stays in the Qualification and Treatment Phases of the study.

15. Has participated in, is currently participating in, or is seeking treatment for substance and/or alcohol related disorders (excluding nicotine and caffeine). If participation in a rehabilitation program was court-mandated as part of a plea agreement, entry may be permissible at the Investigator's discretion.

16. Has a positive urine ethanol test upon admission to the study center. Positive results may be repeated and/or participants rescheduled at the Investigator's discretion.

17. Screening sitting BP 145 mm Hg (systolic) or 95 mm Hg (diastolic), following at least 5 minutes of rest. If BP is 145 mm Hg (systolic) or 95 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility. Repeated BP tests should be spaced at least 5 minutes apart.

18. Baseline (screening) 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (e.g., baseline corrected QT (QTc) interval as determined by the Fridericia method (QTcF) >450 msec (males) or >470 msec (females), complete left bundle branch block [LBBB], signs of an acute or indeterminate-age myocardial infarction, ST T interval changes suggestive of myocardial ischemia, second- or third-degree atrioventricular [AV] block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 msec (males) or 470 msec (females), or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by an Investigator experienced in reading ECGs before excluding participants.

19. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat test, if deemed to be clinically significant in the opinion of the investigator:

    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 1.5 × upper limit of normal (ULN);
    • Total bilirubin level 1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ULN.

20. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 56 days prior to dosing.

21. History of sensitivity to heparin or heparin-induced thrombocytopenia.

22. Unwilling or unable to comply with the criteria in the Lifestyle considerations section of the protocol.

23. History of hypersensitivity to gabapentin or alprazolam or any of the components in the formulation of the study products.

24. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Sponsor employees, including their family members, directly involved in the conduct of the study.