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Effect of AEF0117 on Subjective Effects of Cannabis in CUD Subjects

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ClinicalTrials.gov Identifier: NCT03717272
Recruitment Status : Recruiting
First Posted : October 24, 2018
Last Update Posted : May 13, 2019
Sponsor:
Collaborators:
National Institute on Drug Abuse (NIDA)
Columbia University
New York State Psychiatric Institute
ClinStar, LLC
Information provided by (Responsible Party):
Aelis Farma

Brief Summary:

Cannabis use is increasing and will only further escalate with legalization of recreational and medical cannabis use in western countries , with a prevalence greater than 30 % in the US and most European countries for individuals between 16 and 24 years of age. Approximately 9 % of those who use cannabis will become addicted. The number goes up to about 1 in 6 among those who start using cannabis as teenagers and to 25 to 50 % among those who smoke cannabis daily. The consequences of cannabis abuse in the most prone population (14-25 years of age) are extremely serious, and may include addiction, altered brain development, poorer educational outcomes, cognitive impairment, lower income, greater welfare dependence, unemployment and lower relationship and life satisfaction. There are no available pharmacological treatments of cannabis use disorder (CUD). Thus, the development of safe and effective medications for the treatment of CUD is an urgent public health priority.

The preclinical efficacy and available ADMET (Administration, Distribution, Metabolism, Elimination and Toxicology) in animal and human data suggest that AEF0117, an investigational new study drug, could constitute a very efficacious and safe treatment for cannabis abuse disorders. The purpose of this research is to study how AEF0117 influences the subjective effects of cannabis in subjects with CUD. AEF0117 acts in the same parts of the brain as THC (tetrahydrocannabinol), the active ingredient of marijuana, and may temporarily alter some of cannabis's effects.

This will be a single center study in healthy male and non-pregnant female, non-treatment seeking, cannabis smoking subjects with cannabis use disorder (CUD). The study design will be a randomized, double-blind, placebo-controlled, cross-over design, multiple dose escalation study with AEF0117. This study is designed to test the effects of two to four doses of AEF0117 compared to placebo on primarily peak subjective effects of cannabis as primary objectives. The secondary objectives are to test the effects of AEF0117 compared to placebo on cannabis self-administration, on cannabis-induced analgesia and on cognitive performance in cannabis smoking subjects. The study hypothesis is that AEF0117 will decrease ratings of cannabis' positive subject effects (e.g., 'good drug effect', high) and decrease cannabis self-administration compared to placebo and also decrease the other unconditioned effects of cannabis studied here. Each subject will have a screening visit, then be included for two 6-day inpatient periods separated by a minimum 14-day outpatient washout. Subjects will be advised that they will receive both active and placebo study medication but will remain blinded to whether they will receive AEF0117 or placebo on Period A and Period B. Each period is composed of 5 consecutive days of treatment (active or placebo), one administration per day. Research staff that interacts with study subjects will also remain blinded to whether subjects are receiving AEF0117 or placebo. The study duration for the first 3 doses of AEF0117 is estimated to be approximately up to 10 months from the start of subject recruitment to the last subject last visit.


Condition or disease Intervention/treatment Phase
Marijuana Abuse Drug: AEF0117 Drug: Placebo oral capsule Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Single Center, Double-Blind, Placebo-Controlled, Randomized, Dose-Ranging Cross Over Study to Evaluate the Effects of Multiple Oral Doses of AEF0117 on the Subjective Effects of Cannabis and Cannabis Self-Administration in Subjects With CUD
Actual Study Start Date : October 23, 2018
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Marijuana

Arm Intervention/treatment
Experimental: AEF0117
AEF0117 capsules ; dose range 0.02 to 1.2mg by mouth, once a day for 5 consecutive days.
Drug: AEF0117
AEF0117 capsules

Drug: Placebo oral capsule
Corn oil capsule manufactured to mimic AEF0117 capsule

Placebo Comparator: Placebo oral capsule
corn oil capsules once a day for 5 consecutive days.
Drug: AEF0117
AEF0117 capsules

Drug: Placebo oral capsule
Corn oil capsule manufactured to mimic AEF0117 capsule




Primary Outcome Measures :
  1. Subjective Effects of Cannabis [ Time Frame: On Days 1, 2, 3, 4 and 5 of each Period: Mean VAS will be assessed predose and postdose ]
    Mean Visual Analog Scale (VAS) rating assessing positive subjective drug effect, (Good Drug Effect). This scale uses a 0-100mm rating, where higher numbers indicate a better drug effect.


Secondary Outcome Measures :
  1. Changes in cannabis self-administration [ Time Frame: On Days 2, 3, 4 and 5 of each Period: at 5.5 hours, 7.5 hours , 9.5 hours and 11.5 hours post dose ]
    Number of purchased puffs of cannabis cigarette per day (possibility of 0-24 puffs per day). Higher numbers indicate more cannabis self-administration.

  2. Percent Change in Subjective Ratings of Cannabis. [ Time Frame: On Days 1, 2, 3, 4 and 5 of each Period: CRF will be completed at 3.84 hours, 4.17 hours , 4.5 hours, 5.0 hours and 5.25 hours postdose ]
    Five-item Cannabis Rating Form Visual Analog Scale (CRF-VAS) where subjects report, on a 0-100mm scale, ratings of 'cannabis strength', 'liking', 'desire to take again', 'good cannabis effect', and 'bad cannabis effect'. Higher reported ratings indicate more agreement with each term.

  3. Changes in pain threshold and pain tolerance [ Time Frame: Baseline at 1430 hours; experimenter-administered cannabis at 1445 hours; CPT at 1515 hours, 1545 hours, 1615 hours, 1645 hours and 1745 hours ]
    Changes in pain response (threshold and tolerance) as a function of cannabis and medication condition will be assessed using the Cold pressor test. Pain threshold is determined by latency (in seconds) to first self-report of subjective feelings of pain while the hand is immersed in cold water (4 degrees celsius), and pain tolerance is determined by latency (in seconds) to hand withdrawal from cold water.

  4. Cognitive Performance (Sustained Attention) [ Time Frame: On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose ]
    Sustained Attention to Response Task (SART). Participants are presented with a single digit 1-9 in the middle of the screen in varying font sizes. The digit disappears after a short while and is replaced with a mask (circle with an X). Participants are asked to press the spacebar if any digit other than 3 is presented and to withhold the response if digit 3 presented. The outcome is the total number of correct suppressions. More correct suppressions indicate better cognitive performance.

  5. Cognitive Performance (Processing speed) [ Time Frame: On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose ]
    Digit Symbol Substitution Task (DSST). Participants are presented with an 18 (columns) x 16 (rows) matrix. Odd rows contain symbols, even rows contain empty answer boxes (18x8 = 144). The task is to translate the symbols into digits with the help of a provided key within a 2 min time frame. The outcome is the total number of correct responses. More correct responses indicate better cognitive performance.

  6. Cognitive Performance (Recognition Memory) [ Time Frame: On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose ]
    Behavioral Pattern Separation Task. The first part of the experiment presents 128 pictures (default) of everyday items and participants have to decide whether the item is an OUTDOOR or an INDOOR item. The second part of the experiment presents 64 of the previously seen pictures (targets), 64 of very similar items (lures), and 64 new items (foils). Participants are asked to categorize the items as old, new, or similar within 2.5s (default) The outcome is percent correct. Higher percentage correct indicates better cognitive performance.

  7. Cognitive Performance (Reaction time) [ Time Frame: On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose ]
    Color Stroop Task. Participants are given names of color words written in varying color ink, and are asked to indicate the printed color of the word (not its meaning) by pressing a key as fast as they can without making too many errors. The outcome is mean reaction time of correctly answered trials. More correctly answered trials indicates better cognitive performance.

  8. AUC (area under curve) of AEF0117 Plasma exposure [ Time Frame: Pharmacokinetic measures (e.g., 0, 3 hours, 9.5 hours and 24hours post first dose and 24 hours after the last dose administered on Day5 ]
    Plasmatic exposure to AEF0117

  9. AUC of Plasma concentrations of THC [ Time Frame: Pharmacokinetic measures (e.g., 0, 3 hours, 9.5 hours and 24 hours post first dose and 24 hours after the last dose administered on Day5 ]
    Plasmatic exposure to THC

  10. AUC of Plasma concentrations of 11-OH-THC [ Time Frame: Pharmacokinetic measures (e.g., 0, 3 hours, 9.5 hours and 24hours post first dose and 24 hours after the last dose administered on Day5 ]
    Plasmatic exposure to 11-OH-THC

  11. AUC of Plasma concentrations of 11-COOH-THC [ Time Frame: Pharmacokinetic measures (e.g., 0, 3 hours, 9.5 hours and 24 hours post first dose and 24 hours after the last dose administered on Day5 ]
    Plasmatic exposure to 11-COOH-THC

  12. Food intake [ Time Frame: Daily from Day 1 to Day 5 of each period ]
    Daily caloric intake will be calculated by recording and summing the calorie counts for all food items each participant consumes on each day. Consumption of food items will be self-reported by each participant, and verified by checking each participant's trash every day during the inpatient phase.

  13. Sleep Quality [ Time Frame: Each day during inpatient phase at -0.75h prior to medication dosing. ]
    Self-reported 7-item Visual Analog Scale (VAS) of sleep quality. Participants rate, on a 0-100mm scale, the following: 'I slept well last night', 'I woke up early this morning', 'I fell asleep easily last night', 'I feel clear-headed this morning', 'I woke up often last night', 'I am satisfied with my sleep last night', and 'I had a lot of dreams last night'. Higher ratings indicate more agreement with each statement.

  14. Sleep Quantity [ Time Frame: Daily from Day 1 to Day 5 of each period ]
    Number of hours slept as measured by an Actiwatch worn by the participant each night. Higher numbers indicate more hours slept.

  15. Incidence of Treatment-Emergent Adverse Events [safety and tolerability] [ Time Frame: Screening, Predose on Day 1 and on Day 6 ]
    Collection of AE, weight, hematology, serum chemistry and urinalysis



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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be a healthy male, at least 21 years old and no more than 60 years old, inclusively. As the effect of the study drug on sperm is still unknown, male subjects will be instructed to refrain from donating sperm or planning a pregnancy during the study and for 90 days after study completion. They will be instructed to tell the study doctor if their partner becomes pregnant during the study or during 90 days after study completion. Male subjects will have to use double-barrier contraceptive methods: male condoms and spermicide.
  • Be a healthy, non-pregnant female, at least 21 years old and no more than 60 years old, inclusively, and meet one of the following criteria with regard to child-bearing status:

    1. Be a woman of non-child-bearing potential, defined as surgically sterile (e.g., hysterectomy, tubal ligation) or post-menopausal [amenorrhea >1 year and FSH (follicle stimulating hormone) > 30 microU/ml] with a negative pregnancy test; OR
    2. Be a woman of child-bearing potential and practicing a highly effective method of contraception (i.e., >99% effective when used consistently and correctly, or, in other words, <1% failure rate per year) including the following methods: Intrauterine Copper Contraceptive (as for example, Paragard T 380A), sexual abstinence, or vasectomized male partner with a negative pregnancy test.
  • Have a body mass index (BMI) within the range of >18.5 and <32 kg/m2 unless approved by the sponsor and investigator.
  • Be a current cannabis smoker of ≥ 1 grams of cannabis per day, at least 6 days per week.
  • Meet the diagnostic criteria for Cannabis Use Disorder (CUD) based on DSM-5 criteria
  • Have no significant diseases in their medical history or clinically significant findings on physical examination or clinical laboratory evaluations.
  • Be informed of the nature of the study and provide signed informed consent.
  • Be legally competent and able to communicate effectively with study personnel.

Exclusion Criteria:

  • Any disease or condition that might compromise the cardiovascular, hematological, renal, hepatic, pulmonary (including chronic asthma), endocrine (e.g., diabetes), central nervous, or gastrointestinal (including an ulcer) systems.
  • The presence of clinically significant laboratory values. Subjects with AST (aspartate aminotransferase), ALT (alanine transaminase) or GGT (gamma-glutamyltransferase) values >2x the upper limit of normal, alkaline phosphatase, bilirubin, BUN (blood urea nitrogen), creatinine >15% above the upper limit of normal, or hemoglobin or hematocrit level >15% below the lower limit of normal may only be enrolled upon joint agreement of the sponsor and investigator.
  • Have abnormal baseline values for the steroid hormones: cortisol, testosterone, estradiol and progesterone in accordance to their reproductive status (for example but not limited to surgical or post-menopausal).
  • A history of alcoholism or drug addiction other than cannabis use disorder within the past 2 years, or positive results from a urine screen for substances of abuse other than THC.
  • A history of smoking greater than 20 cigarettes per day on average, in the month prior to Screening, or having an inability to abstain from smoking (or use of any nicotine-containing substance) for at least 8 hours.
  • A history of major Axis I psychopathology, e.g., mood disorder with functional impairment, schizophrenia).
  • Inadequate venous access.
  • A known history of Hepatitis B or C or HIV infection.
  • Ingestion of an investigational drug or product, or participation in a drug study within a period of 30 days prior to screening (for investigational drugs with an elimination half-life greater than 10 days, this will be extended to 60 days).
  • Use of any prescription or over-the-counter (OTC) drug therapy, including herbal, homeopathic, vitamins, minerals and nutritional supplements, unapproved by the sponsor, within 2 weeks prior to receiving the study medication (for drugs with an elimination half-life greater than 10 days, this will be extended to 60 days). The use of any food supplement or body cream containing pregnenolone or any other steroid including phytosteroids.
  • Use of a drug therapy known to induce or inhibit hepatic drug metabolism within 30 days prior to screening or during the study.
  • Unable to follow the restrictions outlined in the protocol.
  • Previous participation in a cohort for any dose level of AEF0117.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03717272


Locations
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United States, New York
Substance Use Research Center Recruiting
New York, New York, United States, 10032
Contact: Margareth Haney, PhD    646-774-7777    mh235@columbia.edu   
Principal Investigator: Margareth Haney, PhD         
Sponsors and Collaborators
Aelis Farma
National Institute on Drug Abuse (NIDA)
Columbia University
New York State Psychiatric Institute
ClinStar, LLC
Investigators
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Principal Investigator: Margareth Haney, PhD Substance Use Research Center

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Responsible Party: Aelis Farma
ClinicalTrials.gov Identifier: NCT03717272     History of Changes
Other Study ID Numbers: AEF0117-201
5R01DA038875-02 ( U.S. NIH Grant/Contract )
First Posted: October 24, 2018    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Aelis Farma:
AEF0117
Cannabis-related Use Disorder
Cannabis subjective effects
Cannabis self-administration
cannabis-induced analgesia
cannabis-related cognitive disorder

Additional relevant MeSH terms:
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Marijuana Abuse
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders