Efficacy of PP-01 in Mitigating Cannabis Withdrawal Symptoms in Adults With Cannabis Use Disorder

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo and Active-Controlled Clinical Trial of Titrating Doses of PP-01 for the Mitigation of Cannabis Withdrawal Symptoms in Adults With Cannabis Use Disorder: Core Study With Safety Extension Phase

This study is a randomized, double-blind, placebo and active-controlled, multicenter trial conducted to evaluate whether PP-01 mitigates the withdrawal symptoms associated with discontinuing cannabis in participants with moderate to severe cannabis use disorder (CUD). Study participants will receive PP-01, nabilone, or placebo every day for 34 days. The total study duration will be approximately 78 days, including screening and a one-week inpatient stay. Following the initial inpatient portion of the study, participants will return to the clinic for six clinic visits and complete two telemedicine appointments. Participants will complete daily symptom diaries and other study-related questionnaires.

Participants who complete the core study may be eligible to participate in a repeat dosing extension study if they meet required criteria.

Inclusion Criteria:

1. Generally healthy adults between the ages of 18 and 55, inclusive.

2. Meet DSM-5 diagnostic criteria for current moderate to severe CUD as confirmed by a licensed physician or psychologist or addiction medicine specialist. An individual with documented experience in the diagnosis of CUD may be qualified upon Sponsor approval.

3. BMI within 18.0 to 38.0 kg/m2, inclusive.

4. Female participants must not be pregnant or lactating. Nonpregnancy will be confirmed for all females by a urine pregnancy test conducted at Screening and at the Randomization Visit prior to enrollment into the study.

   • If of childbearing potential - the participant agrees to use one of the accepted contraceptive regimens from Screening 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 one of the following:

     • Hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
     • Intrauterine device (with or without hormones)
     • OR agrees to use a double barrier method (e.g., condom and spermicide) during the study and for at least 30 days after the last dose of the study medication
     • The Investigator can use their judgement and familiarity with the participant's preferred and usual lifestyle to understand which form of birth control would be the best and also to determine if abstinence is an option what would achieve 100% effectiveness

   • Females of non-childbearing potential - should be surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or be postmenopausal (at least 1 year without menses)

5. Male participants who are fertile and engage in sexual activity must agree to use a double barrier method (e.g., condom and spermicide) and agree to not donate sperm during the study and for at least 90 days after the last dose of the study medication.

6. Be seeking and motivated to discontinue cannabis and to minimize withdrawal symptoms related to cannabis discontinuation.

7. Agree to not use cannabis or any product containing CBD, hemp derivatives, terpenes or any THC containing product including delta-8, delta-10, THC-A or any other cannabinoid-like product following Randomization and throughout the study duration.

8. Have experienced cravings for cannabis and at least three withdrawal symptoms as defined by DSM-5 Cannabis Withdrawal Syndrome diagnostic criteria within the past year when previously trying to discontinue or reduce use of cannabis

9. Meet Criterion C on the DSM-5 Cannabis Withdrawal Diagnostic Criteria

10. Participants should be self-reported heavy cannabis users ("medical marijuana" users are allowed) who report use of cannabis multiple times per day at least 6 days per week for at least 6 months:

    1. Self-reported use of an approximate average of at least 1.5 grams or greater each day of dry leaf flower, or the equivalent (as defined by the participant) of other forms of cannabis
    2. Must use cannabis during the Screening period for an average of 6 out of 7 days per week and must use the day prior to Randomization

11. Have a urine drug screen positive for THC-COOH and have a negative result for all other illicit/excluded drugs at Screening and Randomization and a negative urine for alcohol at Randomization.

12. Capable of giving informed consent and stated willingness to comply with all study procedures including inpatient and weekly outpatient visits, daily evening video calls, restrictions, and availability for the duration of the study.

13. Willing to be admitted to an inpatient clinic with overnight stays on Days 1 through 6 and return for all outpatient visits.

14. Ability to take study drug capsules, agree to daily monitoring of study drug intake during the outpatient period, and have a regular schedule such that daily monitoring and study drug capsule intake can be done at approximately the same time each day.

15. Have regular access to the internet and access to video/virtual capabilities for video calls by any means.

16. Agree to not use any alcohol during the study.

17. Nicotine users must agree to continue their current nicotine use.

18. Ability to read, understand, and complete daily diaries.

Exclusion Criteria:

Participants with history or significant presence of any of the following criteria should be excluded from enrollment into the study:

1. Lifetime history of DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder.

2. Current DSM-5 criteria for a psychiatric disorder that in the Investigator's judgment is unstable, would be disrupted by the study medication, or is likely to require new pharmacotherapy or psychotherapy during the study period. Individuals who are currently stable on psychotropic medication for at least 3 months may be included at the discretion of the Investigator's judgement.

3. Participants who meet DSM-5 criteria for any history of or current drug use disorder within the previous 2 years, other than cannabis, nicotine, or caffeine use disorders.

4. Participants who consume alcohol on a regular or frequent basis and who do not agree or are deemed by the Investigator to be unable to discontinue alcohol for the duration of the study.

5. Participants using cannabis for a physician directed medical condition requiring use such as epilepsy.

6. Unstable medical conditions, such as AIDS, cancer, uncontrolled hypertension, Type 1 diabetes or uncontrolled or multi-dose insulin treated Type 2 diabetes, pulmonary hypertension, or heart disease.

7. Positive test results for HIV-1/HIV-2 Ag/Ab, HBsAg, or HCVAb unless previously treated and successfully cleared of Hepatitis C virus.

8. Current or recent history of significant violent or suicidal behavior, risk for suicide or homicide:

   - Participants with any suicidal behavior or answering "yes" to Question 4 or 5 on suicidal ideation within the past 1 year based on the Screening version of the C-SSRS

9. History of clinically significant hepatic, renal, cardiovascular, pulmonary, hematologic, neurological, psychiatric, gastrointestinal, endocrine, oncologic, immunologic, dermatologic disease of any etiology (including infections), or any other condition that, in the opinion of the Principal Investigator, would jeopardize the safety of the participant or impact the validity of the study results.

10. Presence or history of clinically significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability, with the exception that cholecystectomy is permitted at the discretion of the Investigator.

11. Any clinically important abnormalities on Screening PE, assessments, ECG, or laboratory tests, including but not limited to:

    1. Hemoglobin < 10.0 g/dL

    2. Serum creatinine:

       • Central lab: Serum creatinine > 1.30 mg/dL for females or > 1.52 mg/dL for males
       • Non-central lab: Serum creatinine > 30% above the ULN for the laboratory used

    3. Serum bilirubin > 1.5 times ULN, unless documented Gilbert's Disease; AST or ALT > 1.5 times ULN

    4. Clinically significant abnormal fasting glucose For criteria a, b, c, and d the test can be repeated one time during the Screening period at the discretion of the Investigator. If this option is used the last obtained reading will be used for determination of eligibility. Averages will not be used.

    5. Hypertension at Screening or Randomization; participants with elevated sitting BP, defined as greater than 145 mmHg systolic or greater than 95 mmHg diastolic

       - Use of more than 3 antihypertensive medications for the treatment of hypertension (where an antihypertensive combination of 2 or more products would be considered as separate products) may be permitted at the discretion of the Medical Monitor

    6. Hypotension at Screening or Randomization; participants with sitting BP lower than 85 mmHg systolic or lower than 55 mmHg diastolic

    7. Clinically significant abnormal HR or RR based on Investigator judgment For criteria e, f and/or g two repeat measurements within 10 minutes of the first BP are permitted at the discretion of the Investigator. If this option is used the last obtained reading will be used for determination of eligibility. Averages will not be used.

    8. A clinically significant abnormal 12-lead ECG, such as myocardial infarction, other findings suggestive of ischemia, or prolonged QT/QTc interval, defined as:

       • Corrected QT interval using Fridericia's formula > 450 msec for males and > 470 msec for females at Randomization, mean values are allowed to be assessed

12. Known history of allergy, intolerance, or hypersensitivity to nabilone, gabapentin or pregabalin.

13. Prohibited medications at Screening:

    • Current use of narcotics, opioid agonists and antagonists, kratom, illicit drugs, ketamine, or products intended to induce a feeling of being high except for cannabis
    • Psychedelics
    • Medications, including OTC products, to help with sleep or anxiety within 2 months of Screening
    • Current use of nabilone, dronabinol, Sativex, Epidiolex, synthetic cannabinoids
    • Gabapentin or pregabalin or use within 30 days of Screening
    • Medications listed in Section 9.3 of the study protocol (cannabis and "medical marijuana" are allowed during Screening)

14. Heavy users of alcohol (> 2 drinks/day for men and > 1 drink/day for women) over the past year.

15. Binge drinkers of alcohol (≥ 5 drinks for men and ≥ 4 drinks for women on the same occasion) within 30 days of Screening.

16. A positive urine drug/alcohol test at Screening or Randomization for narcotics and/or illicit drugs other than cannabis. If the test is positive for benzodiazepines or alcohol at Screening, and if it is reported that they are only occasional users, a repeat urine drug screen can be performed at the discretion of the Medical Monitor and must be negative at the time of Randomization.

17. Use of an investigational drug or biologic within 30 days or 5 times the half-life (whichever is longer) prior to the Screening Visit.

18. Suspected active influenza or COVID-19 infection.

19. Vaccinations including COVID-19:

    • Participants planning to have a COVID-19 vaccine during study participation
    • History of COVID-19 vaccine within 5 days of Screening. Participant can be rescreened after a 5-day post vaccine period

20. Prior participation in any PleoPharma clinical study.