Validation of the Drug Impaired Driving Scenario (DIDS) on the CRCDS-miniSim

Validation of the Drug Impaired Driving Scenario (DIDS) on the CRCDS-miniSim: Evaluating Sensitivity to the Effects of Cannabis and Alprazolam

Subjects will participate in a 4-visit study protocol at the National Advanced Driving Simulator, part of the University of Iowa, in which they will be asked to complete assorted questionnaires, computerized cognitive tasks, and a simulator drive. Subjects will be administered 0.75 mg alprazolam (Xanax) or placebo and 500 mg vaporized cannabis (6.18% THC / <0.025% CBD) or placebo (0% THC / 0% CBD).

The primary objective of this study is to validate the Drug Impaired Driving Scenario (DIDS) using the CRCDS-2 driving simulator by assessing the acute effects of cannabis relative to placebo on simulated driving performance. Assay sensitivity will be demonstrated by the significant effect of 0.75 mg alprazolam (active comparator) on driving and cognitive endpoints.

At the University of Iowa's National Advanced Driving Simulator (NADS), normal healthy subjects who currently use cannabis recreationally (at least once a month) will be recruited. The study involves four visits, the first of which is a screening visit of approximately 3 hours. At the screening visit, consent is obtained, questionnaires are given, and a physical and psychological exam is administered. Subjects will also train on study procedures, such as the cognitive testing, the simulator drive, and the cannabis inhalation procedure. Subjects will then be scheduled for their three treatment visits, which will be one week apart..

The treatment visits will have a clean (double placebo) and two treatment visits (active alprazolam and placebo cannabis, placebo alprazolam and active cannabis). The alprazolam dose is 0.75 mg and the cannabis dose is 500 mg. All cannabis will be inhaled via a Volcano® Digit vaporizer using the Foltin Puff Procedure. Each of the treatment visits will last approximately twenty-three hours and will include intake with eligibility and baseline testing, transport to a local hotel, an overnight stay at the hotel, transport to NADS, being dosed with study drugs or placebos, cognitive assessments, a simulator drive, and assorted questionnaires. There will also be 8 mL blood sampling before dosing, before driving, and after driving. Each randomized subject will complete a treatment visit of each type one week apart in a counterbalanced sequence.

Meals will be provided at the treatment visits (dinner, snack, breakfast, lunch). Subjects will be monitored until the drug effects have subsided sufficiently to ensure it is safe to transport them home. Subjects will need to arrange their own transportation; they will not be permitted to drive themselves home after the treatment visits.

Inclusion Criteria:

• Understands and provides written informed consent prior to the initiation of any protocol-specific procedures.
• Able to comprehend and willing to comply with the requirements of the protocol.
• Healthy male or female adult, 19 to 45 years of age, inclusive, at Screening.
• Regular sleep pattern (usual bedtime between 21:00 and 00:00).
• Score <10 on Epworth Sleepiness Scale at Screening.
• Able to reliably perform study assessments at Screening (On practice scenario, SDLP no higher than 1 standard deviation greater than the mean for normal healthy adults completing the practice scenario and subject has 7 or more correct hits on the Divided Attention task; CogScreen SDC Correct no less than 1 standard deviation below the mean for healthy adults); demonstrates the ability to understand task instructions at Screening; and is physically (e.g., adequate manual dexterity, vision, and hearing) and cognitively capable of performing study tasks at Screening.
• Possesses (and is willing to provide) a valid driver's license and is an active driver.
• Determined to be (by self-report) an active cannabis user with use of at least once per month over the preceding 90 days.
• Willing to abstain from cannabis use (other than study drug) beginning at the end of Screening until discharge from NADS on Day 2 of Treatment Period 3.
• Female subjects must meet one of the following criteria: 1) If of childbearing potential, female subjects agree to use two contraceptive regimens or remain abstinent during the study; or 2) if of non-childbearing potential, female subjects should be surgically sterile or in a menopausal state.

Exclusion Criteria:

• A significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, neurological, psychiatric, gastrointestinal, hematological, immunologic, ophthalmologic, metabolic, or oncological disease, or any other medical issue that would, in the opinion of the Investigator, present undue risk for the subject in the study.
• A history of suicidal behavior within 24 months of Screening, has answered YES to questions 3, 4, or 5 on the C-SSRS at Screening or at any clinic admission, or is currently at risk of suicide in the opinion of an Investigator.
• A recent history (within 6 months prior to Screening) of substance use disorder (including alcohol) (as judged by the Investigator) or regularly consumes >2 alcoholic drinks/day during the last 3 months prior to Screening (1 alcoholic drink is approximately equivalent to: beer [284 mL], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]). Subjects who consume 3 drinks per day but less than 14 drinks per week may be enrolled at the discretion of the Investigator.
• Demonstrates simulator sickness questionnaire scores which are indicative of simulator sickness as defined in the driving simulation operations manual.
• Regularly consumes excessive amounts of caffeine, defined as greater than 6 servings of coffee, tea, cola, or other caffeinated beverages per day.
• Smokes more than 10 cigarettes or e-cigarettes, or 3 cigars or pipes per day, or is unable to refrain from smoking during study visits.
• Has been exposed to an investigational drug or device within the 30 days, or 5 half lives (if known), whichever is longer, prior to Screening.
• Has used a prescription or over-the-counter medication known to cause sedation within 7 days prior to Admission for Period 1 and is unwilling or unable to refrain from sedating medication use during study participation.
• Has used any benzodiazepine, barbiturate, or GABAA modulator (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Admission for Period 1 or is unwilling or unable to refrain from medication use during study participation.
• Has a history of hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus (HIV) antibodies 1 or 2.
• Is pregnant or breastfeeding at Screening or any clinic admission or will attempt to become pregnant at any time during study participation.
• Has a clinically significant abnormal finding on 6-lead electrocardiogram (ECG) at Screening or at any clinic admission. The ECG may be repeated once for confirmatory purposes if initial values obtained exceed the limits specified.
• Has a positive urine test for drugs of abuse (other than tetrahydrocannabinol (THC)) or Breath Alcohol Concentration (BrAC) > 0.0 at Screening or any admission.
• Has any clinically significant abnormal physical examination finding at Screening or any clinic admission.
• Participates in night shift work.
• Has traveled across ≥1 time zone in the 2 weeks prior to Admission for Period 1 or is expected to travel across ≥1 time zone during the study.
• Is investigative site personnel or their immediate families (spouse, parent, child, or sibling whether biological or legally adopted).