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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Aelis Farma
- 入组人数
- 29
- 试验地点
- 1
- 主要终点
- Subjective Effects of Cannabis
研究概览
简要总结
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.
详细描述
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 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, 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. It is hypothesized that AEF0117 will antagonize cannabis effects on the basis of data: (a) in mice showing that AEF0117 antagonized all unconditioned effects of THC tested; (b) in rats showing that AEF0117 decreased THC- induced dopamine release, and (c) in nonhuman primates showing that AEF0117 antagonized THC self-administration and THC-induced reinstatement of THC seeking. The study is also designed to evaluate the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of escalating multiple oral doses of AEF0117 in adult male and non-pregnant female, nontreatment seeking, cannabis smoking subjects with cannabis use disorder (CUD). In this study, subjects will be closely monitored through adverse event monitoring and vital signs measurements. This study will be conducted in adherence to the study protocol, Good Clinical Practices (GCP). Data from this study will be used to aid the design of future clinical studies in patients.
This protocol represents the first clinical study of AEF0117 in subjects with cannabis use disorder and the third clinical study of AEF0117 in humans, therefore, the risks and benefits in this patient population are not well known. The study hypothesis is that AEF0117 will not precipitate withdrawal in cannabis abusers at any of the doses tested because (a): its signaling-specific effects only partially modify the activity of the CB1 (cannabinoid receptor type 1) receptor, and (b) AEF0117 did not precipitate withdrawal in THC-dependent mice at doses 30 times higher than the ED50 (median effective dose ) antagonizing most of the behavioral effects of THC.
This will be a single-center study conducted in the USA. Approximately 48 cannabis-smoking subjects with cannabis use disorder will be randomized into the study for the first 3 doses of AEF0117. 16 additional cannabis-smoking subjects with CUD could be randomized into the study for completion of Cohort 4. The study duration for the first 3 doses of AEF0117 is estimated to be up to 10 months from the start of subject recruitment to the last subject last visit. Each subject will have a screening visit, then be included for two 6-day inpatient periods separated by a minimum 14-day outpatient washout period. Subjects will provide signed informed consent upon enrollment into the study. 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 in Period A and Period B. Each period is composed of 5 consecutive days of treatment (active or placebo), one administration per day. Research staff who interact with study subjects will also remain blinded as to whether subjects are receiving AEF0117 or placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 21 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
AEF0117
AEF0117 capsules ; dose range 0.02 to 1.2mg by mouth, once a day for 5 consecutive days.
干预措施: AEF0117 (Drug)
AEF0117
AEF0117 capsules ; dose range 0.02 to 1.2mg by mouth, once a day for 5 consecutive days.
干预措施: Placebo oral capsule (Drug)
Placebo oral capsule
corn oil capsules once a day for 5 consecutive days.
干预措施: AEF0117 (Drug)
Placebo oral capsule
corn oil capsules once a day for 5 consecutive days.
干预措施: Placebo oral capsule (Drug)
结局指标
主要结局
Subjective Effects of Cannabis
时间窗: 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.
次要结局
- Cognitive Performance (Processing speed)(On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose)
- Food intake(Daily from Day 1 to Day 5 of each period)
- Changes in cannabis self-administration(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)
- Percent Change in Subjective Ratings of Cannabis.(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)
- Changes in pain threshold and pain tolerance(Baseline at 1430 hours; experimenter-administered cannabis at 1445 hours; CPT at 1515 hours, 1545 hours, 1615 hours, 1645 hours and 1745 hours)
- AUC (area under curve) of AEF0117 Plasma exposure(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)
- AUC of Plasma concentrations of THC(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)
- Cognitive Performance (Sustained Attention)(On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose)
- Cognitive Performance (Recognition Memory)(On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose)
- Cognitive Performance (Reaction time)(On Days 1, 2, 3, 4 and 5 of each Period, at 0.5 hours and 4.5 hours post dose)
- Sleep Quality(Each day during inpatient phase at -0.75h prior to medication dosing.)
- AUC of Plasma concentrations of 11-OH-THC(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)
- Incidence of Treatment-Emergent Adverse Events [safety and tolerability](Screening, Predose on Day 1 and on Day 6)
- AUC of Plasma concentrations of 11-COOH-THC(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)
- Sleep Quantity(Daily from Day 1 to Day 5 of each period)