Clinical trial NCT04570436: Evaluating the Abuse Potential of NEURONTIN® When Taken Orally in Healthy Non-drug Dependent Participants With Sedative Drug Abuse Experience
Official title: A Phase 4, Randomized, Double-blind, Double-dummy, Placebo and Active-controlled, Single-dose, Five-way Crossover Study Evaluating the Abuse Potential of Three Doses of NEURONTIN® Taken Orally in Healthy, Non-drug Dependent Participants With Sedative Drug Abuse Experience
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Abuse Potential
Keywords: Neurontin
Diazepam
Abuse Liability
Gabapentin
Lead sponsor: Viatris Inc.
Sponsor class: INDUSTRY
First posted: 2020-09-30
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: This will be a randomized, double-blind, double-dummy, placebo- and active controlled, 5 treatment, 10 sequence, 5 period crossover single dose, Williams square design study in healthy adult, non drug dependent male and female participants with drug abuse experience with sedative drugs.

Detailed description: 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, double dummy, placebo- and active controlled, 5 treatment, 10-sequence, 5 period crossover, single-dose, Williams square design study in healthy male and/or female adult, non drug-dependent recreational users. On Day 1 of each of the Treatment Phase 5 periods, which will be separated by a washout of at least 14 days, participants will receive an oral dose of either NEURONTIN® 1800 mg, 1200 mg or 600 mg or 20 mg diazepam, 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 until 1 hour prior to dosing and 1 hour after dosing.

Eligibility criteria: Inclusion Criteria:

1. Male and female participants must be 18 to 65 years of age, inclusive, at the time of screening.
2. Participants must meet reproductive criteria as outlined in the protocol.
3. Male and female 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 users, defined as those reporting using a sedative agent (eg, barbiturates, benzodiazepines) for its intoxicating effects on at least 10 lifetime occasions and at least once in the 12 weeks before the Screening Visit (Visit 1), but who have no signs of dependence and are not seeking treatment for their sedative use.
5. Participants must satisfactorily complete both the Naloxone Challenge and the Drug Discrimination phases.
6. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
7. Body mass index (BMI) of 17.5 to 34 kg/m2, inclusive; and a total body weight \>50 kg (110 lb).
8. Capable of giving signed informed consent as described in the protocol, which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol.

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 IV (DSM-IV) criteria performed at Screening. Current drug use will be allowed if the candidate can produce a negative urine sample and are free of any signs/symptoms of withdrawal. The candidate will be informed if they have a positive breathalyzer test.
2. Participants are heavy smokers or users of other types of nicotine products (\>20 cigarettes equivalents per day)
3. Participants 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 (eg, gastrectomy) excluding cholecystectomy within 1 year prior to study.
7. Clinical or laboratory evidence of active hepatitis A infection or a history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C, and/or positive testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (HCVAb).
8. Participants with active suicidal ideation or suicidal behavior within 5 year 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 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 6.5 for additional details).
11. Herbal supplements and herbal medications must be discontinued at least 28 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) preceding the first dose of investigational product used in this study.
13. Positive urine drug screen (UDS) for substances of abuse at each admission in Qualification and Treatment Phase, excluding tetrahydrocannabinol (THC). If a participant presents with a positive UDS excluding THC at any 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 participate in any phase of the study.
14. Participants unable to abstain from using THC during 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).
16. Has a positive alcohol breathalyzer test at Screening or upon admission to the study center at Visits 2-6. Positive results may be repeated and/or participants re-scheduled at the Investigator's discretions.
17. Screening sitting BP \>=140 mm Hg (systolic) or \>=90 mm Hg (diastolic), following at least 5 minutes of rest. If BP is \>=140 mm Hg (systolic) or \>=90 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 electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, baseline corrected QT (QTc) interval \>450 msec, 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 the baseline uncorrected QT interval is \>450 msec, this interval should be rate-corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or QRS values should be used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician 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 60 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 this protocol.
23. History of hypersensitivity to gabapentin or diazepam 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.

Primary outcomes:
measure: Bipolar Visual Analog Scale (VAS) for "Drug Liking" Maximum Effect (Emax).
timeFrame: up to 72 hours after treatments
Secondary outcomes:
measure: Bipolar VAS for "Drug Liking" (Time for Maximum Effect, Emax [TEmax])
timeFrame: up to 72 hours after treatments
measure: Bipolar VAS for "Drug Liking" (Area Under the Effect-time Profile From Time 0 to the Time of the Last Quantifiable Concentration [AUEClast])
timeFrame: Up to 72 hours after treatments (Assessments were made at the following timepoints after each treatment: 0, 0.25, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, and 72 hours)
measure: Unipolar VAS for "High" (Maximum Effect, Emax)
timeFrame: up to 72 hours after treatments
measure: Unipolar VAS for "High" (Time for Maximum Effect, Emax [TEmax])
timeFrame: up to 72 hours after treatments
measure: Unipolar VAS for "High" (Area Under the Effect-time Profile From Time 0 to the Time of the Last Quantifiable Concentration [AUEClast])
timeFrame: Up to 72 hours after treatments (Assessments were made at the following timepoints after each treatment: 0, 0.25, 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, and 72 hours)
measure: Bipolar VAS for "Take Drug Again" at 24 Hour Post Dose
timeFrame: At 24 hours after treatment
measure: Bipolar VAS for "Take Drug Again" at 36 Hour Post Dose
timeFrame: At 36 hours after treatment
measure: Bipolar VAS for "Take Drug Again" at 48 Hour Post Dose
timeFrame: At 48 hours after treatment
measure: Bipolar VAS for "Take Drug Again" at 72 Hour Post Dose
timeFrame: At 72 hours after treatment
measure: Bipolar VAS for "Overall Drug Liking" at 24 Hour Post Dose
timeFrame: At 24 hours after treatment
measure: Bipolar VAS for "Overall Drug Liking" at 36 Hour Post Dose
timeFrame: At 36 hours after treatment
measure: Bipolar VAS for "Overall Drug Liking" at 48 Hour Post Dose
timeFrame: At 48 hours after treatment
measure: Bipolar VAS for "Overall Drug Liking" at 72 Hour Post Dose
timeFrame: At 72 hours after treatment
measure: Cmax of Gabapentin
timeFrame: Up to 72 hours after treatments (concentrations were measured at the following timepoints after each treatment for this outcome measure: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, and 72 hours)
measure: Tmax of Gabapentin
timeFrame: Up to 72 hours after treatments (concentrations were measured at the following timepoints after each treatment for thisoutcome measure: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48 and 72 hours)
measure: AUClast of Gabapentin
timeFrame: up to 72 hours after treatment (concentrations were measured at the following timepoints after each treatment for thisoutcome measure: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48 and 72 hours)
measure: Terminal Half-life of Gabapentin
timeFrame: up to 72 hours after treatment (concentrations were measured at the following timepoints after each treatment for thisoutcome measure: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48 and 72 hours)
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: Pharmaceutical Research Associates, Inc.
state: Utah
Study officials:
References: