Cannabidiol, Drug Induced Liver Injury, Drug Interaction
Conditions
Keywords
Cannabidiol, CBD, Liver enzyme elevation, Drug interactions
Brief summary
Cannabidiol (CBD) is available as a prescription drug product for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. At labeled doses up to 25 mg/kg/day, an increased risk of liver enzyme elevation and drug-induced liver injury has been observed. However, only limited evaluations of the risk of liver enzyme elevation of daily, lower dose CBD use are available. The potential for liver enzyme elevations with lower CBD doses with unapproved consumer products highlights a need for further research. In addition, CBD has the capacity to inhibit cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, leading to potential drug-drug interactions with multiple common medications. The clinical significance of many of these interactions is also unclear. Furthermore, nonclinical studies have suggested the potential for CBD to cause reproductive and endocrine effects. As such, additional high-quality clinical pharmacology studies are needed to further characterize CBD's safety profile. The objective of this study is to characterize the effects of daily CBD use at a dose within the range of what consumers are taking as unapproved CBD products on liver enzyme elevations, drug interactions, and endocrine measures.
Detailed description
The cannabis plant contains bioactive compounds known as cannabinoids; delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent cannabinoids in most varieties of cannabis. The Agricultural Improvement Act (Farm Bill) of 2018 removed hemp, defined as cannabis and derivatives of cannabis with extremely low concentrations of THC, from the definition of marijuana in the Controlled Substances Act. Following this, many CBD products have been made available to consumers. However, hemp products remain subject to regulation under the Federal Food Drug & Cosmetic Act, when applicable (e.g., as drugs, foods, dietary supplements, cosmetics, veterinary products) and the growing CBD products market raises various safety concerns, especially with long-term use. CBD is available as a prescription drug product for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. At labeled doses up to 25 mg/kg/day, an increased risk of liver enzyme elevation and drug-induced liver injury has been observed. However, only limited evaluations of the risk of liver enzyme elevation of daily, lower dose CBD use are available. The potential for liver enzyme elevations with CBD doses in unapproved consumer products highlights a need for further research to quantify risks at these doses. In addition, CBD has the capacity to inhibit cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, leading to potential drug-drug interactions with multiple common medications. The clinical significance of many of these interactions is also unclear. Furthermore, nonclinical studies have suggested the potential for CBD to cause reproductive and endocrine effects. As such, additional high-quality clinical pharmacology studies are needed to further characterize CBD's safety profile. This study will be divided into two parts. In Part 1, 200 healthy subjects will be randomized to 5 mg/kg/day of CBD (150 subjects) or placebo (50 subjects) for 4 weeks with weekly laboratory assessments to characterize the percentage of participants with liver enzyme elevation (primary endpoint) or meeting withdrawal criteria for potential drug-induced liver injury (secondary endpoint). Additional secondary endpoints include the change from baseline after 4 weeks of daily CBD dosing for male reproductive (testosterone and inhibin B) and thyroid hormones (thyroid stimulating hormone \[TSH\], triiodothyronine \[T3\] and thyroxine \[T4\]) as secondary endpoints. Exploratory endpoints include additional characterization of liver findings and other blood biomarkers. In Part 2, 40 healthy subjects will receive either oral citalopram (20 subjects) or morphine (20 subjects) at baseline and then again after receiving CBD 5 mg/kg/day to characterize the effect of daily cannabidiol use on the plasma concentration of citalopram and morphine. Citalopram was selected because it is a common prescription medication for depression and anxiety that is metabolized by CYP2C19 and CYP3A4, which CBD inhibits. Morphine was selected because it is a common opioid analgesic that is metabolized by UGT2B7, which CBD inhibits.
Interventions
DRUGCannabidiol
Cannabidiol (Epidiolex) will be administered orally 2.5 mg/kg twice daily (5 mg/kg/day) for 28 days in Part 1 and for 9 days (morphine cohort) or 12 days (citalopram cohort) in Part 2.
DRUGPlacebo
Placebo will be administered orally twice daily for 28 days in Part 1
DRUGCitalopram
Citalopram (Celexa) will be administered once at 20 mg on days 1 and 13.
DRUGMorphine
Morphine will be administered once at 15 mg on days 1, 4, and 11.
Sponsors
Spaulding Clinical Research LLC
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Part 1 of the study will be double-blind, and the blind will be maintained through a randomization schedule held by the dispensing pharmacist. The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing. Part 2 is an open label study.
Intervention model description
This is a two-part study. Part 1 is a randomized, double-blind, placebo-controlled, parallel study in 200 subjects (150 subjects receiving cannabidiol and 50 subjects receiving placebo). Part 2 is an open-label, sequential study in 40 subjects (two separate cohorts of 20 subjects).
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject signs an institutional review board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed. 2. Subject is a healthy, non-smoking man or woman, 18 to 55 years of age, inclusive, who weighs at least 50 kg (110 lbs) and has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening and check-in (Day -1). 3. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12-lead ECG results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee). 4. Subject must have a negative test result for alcohol and illicit drugs at screening and check-in (Day -1). 5. Participants must agree to refrain from using any of the following for the duration of the study: alcohol, nicotine containing products, marijuana or marijuana-derived products, hemp or hemp-derived products, including CBD (except for provided study drug), and illicit drugs of any kind. 6. Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in for all study periods. If a subject's test comes back as invalid, the test can be repeated. 7. Female subjects must be of non-childbearing potential (non-childbearing potential includes post-menopausal females defined as spontaneous amenorrhea for at least 12 months with FSH in the post-menopausal range and females who have undergone a hysterectomy) or, if they are of childbearing potential, they must: 1) have negative serum HCG at screening and check-in 2) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1 month after the last application of study drug; OR 3) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from Screening until at least 1 month after the end of the study. 8. Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) beginning at check-in (Day -1) until at least 3 months after the last dose of study drug. Male subjects may not donate sperm for 90 days after the end of the study. 9. Subject agrees to and is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.
Exclusion criteria
1. Abnormal liver labs at screening on check-in (Day -1), defined as any of the following (tests may be repeated once for confirmation at screening and check-in): 1. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 1.5 × ULN. (The ULN for ALT will be 33 U/L for males and 25 U/L for females.) 2. Total bilirubin (TBL) \> ULN. 3. International normalized ratio (INR) \> 1.3 2. Use or intend to use any medications/products in the 14 days prior to check-in (Day -1), unless deemed acceptable by the investigator 3. Subject is currently participating in another clinical study of an investigational drug or has been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of dosing for this study. 4. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must refrain from using these throughout the study. 5. Subject has consumed alcohol, xanthine-containing products (e.g., tea, coffee, chocolate, cola), caffeine, kava melatonin, St Johns Wart, grapefruit, or grapefruit juice within 24 hours of check-in. Subjects must refrain from ingesting these throughout the study. 6. Subject is unable to tolerate a controlled, quiet study conduct environment, including avoidance of music, television, movies, games, and activities that may cause excitement, emotional tension, or arousal during the prespecified time points (e.g., before and during CBD dosing). 7. Subject has a history of consuming more than 14 units of alcoholic beverages per week within 6 months before Screening, has a history of alcoholism or drug/chemical/substance abuse within 2 years before Screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits/hard liquor) 8. Subject has a positive test result for alcohol or drugs of misuse (amphetamines, barbiturates, benzodiazepines, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and methadone) at Screening or Check-in (Day -1 \[both Parts\]; Day 10 \[Part 2, morphine DDI\]; Day 12 \[Part 2, citalopram DDI\]). 9. Subject has a positive test result for cannabinoids (THC) at screening or Day -1. 10. Subject has a history of opioid or narcotic misuse. 11. Subject has a history of suicidal ideation or previous suicide attempts 12. Subject has a history or evidence of a clinically significant disorder, condition, or disease (e.g., cancer, human immunodeficiency virus \[HIV\], hepatic or renal impairment) that, in the opinion of the investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. 13. Subject has any signs or symptoms that are consistent with Coronavirus Disease 2019 (COVID-19) per Center for Disease Control (CDC) recommendations at screening or check-in (Day -1). These include subjects with fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea may have COVID-19. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator. 14. Subject has known or suspected allergies or sensitivities to the study drug or placebo components (e.g., sucralose, sesame). 15. Subjects with a documented hypersensitivity reaction to cannabidiol 16. Subjects with a documented medical history of clinical disorders related to mood, anxiety or panic, including diagnosed depression, generalized anxiety disorder or panic attacks. 17. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome). Uncomplicated cholecystectomies and appendectomies may be included at the investigator's discretion. 18. Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) at Screening or Check-In that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. Tests may be repeated once for confirmation at both Screening and Check-In. 19. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen. 20. Subject has a mean systolic blood pressure \<85 or \>145 mmHg or a mean diastolic blood pressure \<45 or \>95 mmHg at either Screening or Check-in. Blood pressure will be measured in triplicate after the subject has been resting in a supine position for a minimum of 5 minutes. 21. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or is unlikely to complete the study due to poor venous access. 22. Female subject is currently pregnant or lactating or was within 3 months of the study. 23. Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days, or donated plasma within 7 days before Check-in. 24. Subject has any other condition that precludes his or her participation in the study (as determined by the investigator).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 - Percentage of Participants With an Alanine Transaminase (ALT) or Aspartate Aminotransferase (AST) Liver Enzyme Elevation Greater Than Three Times the Upper Limit of Normal (> 3 × ULN). | Days 1 through 35 | The upper limit of normal (ULN), based on consensus criteria, for the liver transaminase ALT (Alanine transaminase) is defined as 33 U/L for males and 25 U/L for females. An ALT evaluation three times the ULN for males would be 99 U/L and 75 U/L for females. |
| Part 2 - Area Under the Plasma Concentration-time Curve (AUC) of Citalopram When Administered Alone Versus When Co-administered With Cannabidiol After 7 Days of CBD Dosing. | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after each citalopram dose (Days 1 and 13) | AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis. 13 PK samples will be obtained with each citalopram dose for a total number of 26 PK samples per citalopram cohort participant. The outcome measure reported will be the geometric mean ratio for citalopram alone compared to citalopram after 7 days of CBD dosing. |
| Part 2 - Maximum Concentration (Cmax) of Citalopram When Administered Alone Versus When Co-administered With CBD After 7 Days of Cannabidiol Dosing. | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after each citalopram dose (Days 1 and 13) | Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis. 13 PK samples will be obtained with each citalopram dose for a total number of 26 PK samples per citalopram cohort participant. The outcome measure reported will be the geometric mean ratio for citalopram alone compared to citalopram after 7 days of CBD dosing. |
| Part 2 - Morphine AUC When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of CBD Dosing. | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11) | AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine alone compared to morphine after 7 days of CBD dosing. |
| Part 2 - Morphine Cmax When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of Cannabidiol Dosing. | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11) | Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine alone compared to morphine after 7 days of CBD dosing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 - Change From Baseline in Free T4 After Cannabidiol Administration Compared to Placebo. | Days 1 and 29 | Endocrine assessments for free T4 will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group. |
| Part 2 - Morphine-3-glucuronide (M3G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11) | AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-3-glucuronide (M3G) alone compared to morphine-3-glucuronide (M3G) after 7 days of CBD dosing. |
| Part 1 - Change From Baseline in Inhibin B in Male Participants After Cannabidiol Administration Compared to Placebo. | Days 1 and 29 | Endocrine assessments for inhibin B will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group. |
| Part 2 - Morphine-6-glucuronide (M6G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11) | AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-6-glucuronide (M6G) alone compared to morphine-6-glucuronide (M6G) after 7 days of CBD dosing. |
| Part 2 - M6G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11) | Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-6-glucuronide (M6G) alone compared to morphine-6-glucuronide (M6G) after 7 days of CBD dosing. |
| Part 2 - M3G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11) | Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-3-glucuronide (M3G) alone compared to morphine-3-glucuronide (M3G) after 7 days of CBD dosing. |
| Part 1 - Percentage of Participants Meeting Withdrawal Criteria for Potential Drug-induced Liver Injury (DILI). | Days 1 through 35 | Withdrawal criteria for potential drug-induced liver-injury: laboratory results meeting any of the following criteria. * ALT or AST \> 3 x ULN (ULN for ALT is 33 U/L for males and 25 U/L for females) with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (\> 5%) OR * ALT elevation ≥ 5 × ULN (ULN for ALT is 33 U/L for males and 25 U/L for females) OR * Alkaline phosphatase (ALP) elevation ≥ 2 × ULN (with accompanying elevations of gamma-glutamyl transpeptidase (GGT) in the absence of known bone pathology driving the rise in ALP level) OR * ALT elevation ≥ 3 × ULN and bilirubin concentration \> 2 × ULN |
| Part 1 - Change From Baseline in Total Testosterone in Male Participants After Cannabidiol Administration Compared to Placebo. | Days 1 and 29 | Endocrine assessments for total testosterone will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group. |
| Part 1 - Change From Baseline in Thyroid Stimulating Hormone (TSH) After Cannabidiol Administration Compared to Placebo. | Days 1 and 29 | Endocrine assessments for TSH will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group. |
| Part 1 - Change From Baseline in Total T3 After Cannabidiol Administration Compared to Placebo. | Days 1 and 29 | Endocrine assessments for total T3 will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cannabidiol (Part 1) Subjects in this arm will receive oral solution cannabidiol at a dosage of 2.5 mg/kg twice a day, for a total of 5 mg/kg cannabidiol daily for 28 days.
Cannabidiol: Cannabidiol (Epidiolex) will be administered orally 2.5 mg/kg twice daily (5 mg/kg/day) for 28 days in Part 1 and for 9 days (morphine cohort) or 12 days (citalopram cohort) in Part 2. | 151 |
| Placebo (Part 1) Subjects in this arm will receive oral solution placebo twice a day for 28 days.
Placebo: Placebo will be administered orally twice daily for 28 days in Part 1 | 50 |
| Citalopram and Cannabidiol (Part 2) Subjects in this arm will receive citalopram (20 mg) on Day 1 and Day 13 and oral solution cannabidiol at a dosage of 2.5 mg/kg twice a day (5 mg/kg cannabidiol daily) for 12 days (Day 6-17).
Cannabidiol: Cannabidiol (Epidiolex) will be administered orally 2.5 mg/kg twice daily (5 mg/kg/day) for 28 days in Part 1 and for 9 days (morphine cohort) or 12 days (citalopram cohort) in Part 2.
Citalopram: Citalopram (Celexa) will be administered once at 20 mg on days 1 and 13. | 20 |
| Morphine and Cannabidiol (Part 2) Subjects in this arm will receive morphine (15 mg) on Day 1 (baseline), Day 4, and Day 11 (with CBD). Oral solution cannabidiol at a dosage of 2.5 mg/kg twice a day (5 mg/kg cannabidiol daily) for 9 days (Day 4-12).
Cannabidiol: Cannabidiol (Epidiolex) will be administered orally 2.5 mg/kg twice daily (5 mg/kg/day) for 28 days in Part 1 and for 9 days (morphine cohort) or 12 days (citalopram cohort) in Part 2.
Morphine: Morphine sulfate tablet will be administered once at 15 mg on days 1, 4 and 11. | 20 |
| Total | 241 |
Baseline characteristics
| Characteristic | Total | Morphine and Cannabidiol (Part 2) | Citalopram and Cannabidiol (Part 2) | Cannabidiol (Part 1) | Placebo (Part 1) |
|---|---|---|---|---|---|
| Age, Continuous | 36 years | 38 years | 37 years | 36 years | 32 years |
| Median Body Mass Index | 26.7 kg/m2 | 26.7 kg/m2 | 26.6 kg/m2 | 27.1 kg/m2 | 26 kg/m2 |
| Median Body Weight | 80.1 kg | 82.7 kg | 79.5 kg | 80.2 kg | 75.9 kg |
| Median Height | 1.72 m | 1.76 m | 1.74 m | 1.71 m | 1.72 m |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 1 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 104 Participants | 8 Participants | 9 Participants | 64 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 0 Participants | 2 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 117 Participants | 10 Participants | 8 Participants | 77 Participants | 22 Participants |
| Sex: Female, Male Female | 104 Participants | 8 Participants | 7 Participants | 68 Participants | 21 Participants |
| Sex: Female, Male Male | 137 Participants | 12 Participants | 13 Participants | 83 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 151 | 0 / 50 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 43 / 151 | 9 / 50 | 7 / 20 | 5 / 20 |
| serious Total, serious adverse events | 0 / 151 | 0 / 50 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Part 1 - Percentage of Participants With an Alanine Transaminase (ALT) or Aspartate Aminotransferase (AST) Liver Enzyme Elevation Greater Than Three Times the Upper Limit of Normal (> 3 × ULN).
The upper limit of normal (ULN), based on consensus criteria, for the liver transaminase ALT (Alanine transaminase) is defined as 33 U/L for males and 25 U/L for females. An ALT evaluation three times the ULN for males would be 99 U/L and 75 U/L for females.
Time frame: Days 1 through 35
Population: The liver safety analysis population will include all subjects who receive at least 1 dose of the study drug and have at least one on-treatment liver and hematology lab assessment. Subjects in the liver safety analysis population will be used for the planned primary, secondary, and exploratory analyses related to liver enzyme elevations and liver events. Results will be reported as percentages with a 95% confidence interval (CI) based on a Kaplan-Meier analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Percentage of Participants With an Alanine Transaminase (ALT) or Aspartate Aminotransferase (AST) Liver Enzyme Elevation Greater Than Three Times the Upper Limit of Normal (> 3 × ULN). | 5.6 percentage of participants |
| Placebo (Part 1) | Part 1 - Percentage of Participants With an Alanine Transaminase (ALT) or Aspartate Aminotransferase (AST) Liver Enzyme Elevation Greater Than Three Times the Upper Limit of Normal (> 3 × ULN). | 0 percentage of participants |
Primary
Part 2 - Area Under the Plasma Concentration-time Curve (AUC) of Citalopram When Administered Alone Versus When Co-administered With Cannabidiol After 7 Days of CBD Dosing.
AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis. 13 PK samples will be obtained with each citalopram dose for a total number of 26 PK samples per citalopram cohort participant. The outcome measure reported will be the geometric mean ratio for citalopram alone compared to citalopram after 7 days of CBD dosing.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after each citalopram dose (Days 1 and 13)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. One subject was removed from the analysis due to a protocol violation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - Area Under the Plasma Concentration-time Curve (AUC) of Citalopram When Administered Alone Versus When Co-administered With Cannabidiol After 7 Days of CBD Dosing. | 1033 ng*hr/mL | Geometric Coefficient of Variation 26 |
| Placebo (Part 1) | Part 2 - Area Under the Plasma Concentration-time Curve (AUC) of Citalopram When Administered Alone Versus When Co-administered With Cannabidiol After 7 Days of CBD Dosing. | 1475 ng*hr/mL | Geometric Coefficient of Variation 24 |
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: <0.0190% CI: [1.34, 1.52]Mixed Models Analysis
Primary
Part 2 - Maximum Concentration (Cmax) of Citalopram When Administered Alone Versus When Co-administered With CBD After 7 Days of Cannabidiol Dosing.
Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis. 13 PK samples will be obtained with each citalopram dose for a total number of 26 PK samples per citalopram cohort participant. The outcome measure reported will be the geometric mean ratio for citalopram alone compared to citalopram after 7 days of CBD dosing.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after each citalopram dose (Days 1 and 13)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. One subject was removed from the analysis due to a protocol violation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - Maximum Concentration (Cmax) of Citalopram When Administered Alone Versus When Co-administered With CBD After 7 Days of Cannabidiol Dosing. | 23 ng/mL | Geometric Coefficient of Variation 21 |
| Placebo (Part 1) | Part 2 - Maximum Concentration (Cmax) of Citalopram When Administered Alone Versus When Co-administered With CBD After 7 Days of Cannabidiol Dosing. | 26 ng/mL | Geometric Coefficient of Variation 24 |
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: <0.0190% CI: [1.06, 1.17]Mixed Models Analysis
Primary
Part 2 - Morphine AUC When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of CBD Dosing.
AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine alone compared to morphine after 7 days of CBD dosing.
Time frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. For morphine and its metabolites, number of subjects is 20 for morphine alone and morphine with a single dose of CBD. For morphine with multiple doses of CBD, the sample size is 18 as two subjects discontinued from the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - Morphine AUC When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of CBD Dosing. | 44 ng*hr/mL | Geometric Coefficient of Variation 45 |
| Placebo (Part 1) | Part 2 - Morphine AUC When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of CBD Dosing. | 47 ng*hr/mL | Geometric Coefficient of Variation 51 |
| Part 2: Morphine and Multiple Doses of Cannabidiol | Part 2 - Morphine AUC When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of CBD Dosing. | 51 ng*hr/mL | Geometric Coefficient of Variation 60 |
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.3490% CI: [0.96, 1.16]Mixed Models Analysis
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effect.p-value: 0.190% CI: [1, 1.26]Mixed Models Analysis
Primary
Part 2 - Morphine Cmax When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of Cannabidiol Dosing.
Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine alone compared to morphine after 7 days of CBD dosing.
Time frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. For morphine and its metabolites, number of subjects is 20 for morphine alone and morphine with a single dose of CBD. For morphine with multiple doses of CBD, the sample size is 18 as two subjects discontinued from the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - Morphine Cmax When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of Cannabidiol Dosing. | 8.3 ng/mL | Geometric Coefficient of Variation 40 |
| Placebo (Part 1) | Part 2 - Morphine Cmax When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of Cannabidiol Dosing. | 9.9 ng/mL | Geometric Coefficient of Variation 45 |
| Part 2: Morphine and Multiple Doses of Cannabidiol | Part 2 - Morphine Cmax When Administered Alone Versus When Co-administered With the First Dose of Cannabidiol and After 7 Days of Cannabidiol Dosing. | 9.3 ng/mL | Geometric Coefficient of Variation 31 |
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.0290% CI: [1.05, 1.35]Mixed Models Analysis
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.2990% CI: [0.94, 1.3]Mixed Models Analysis
Secondary
Part 1 - Change From Baseline in Free T4 After Cannabidiol Administration Compared to Placebo.
Endocrine assessments for free T4 will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group.
Time frame: Days 1 and 29
Population: Analyses include all participants with time-matched samples at day 1 and 29. Participants without day 29 samples (e.g., discontinued treatment prior to day 29) were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Change From Baseline in Free T4 After Cannabidiol Administration Compared to Placebo. | -0.014 ng/mL |
| Placebo (Part 1) | Part 1 - Change From Baseline in Free T4 After Cannabidiol Administration Compared to Placebo. | -0.012 ng/mL |
Secondary
Part 1 - Change From Baseline in Inhibin B in Male Participants After Cannabidiol Administration Compared to Placebo.
Endocrine assessments for inhibin B will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group.
Time frame: Days 1 and 29
Population: Analyses include male participants with time-matched samples at day 1 and 29
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Change From Baseline in Inhibin B in Male Participants After Cannabidiol Administration Compared to Placebo. | 5.8 pg/mL |
| Placebo (Part 1) | Part 1 - Change From Baseline in Inhibin B in Male Participants After Cannabidiol Administration Compared to Placebo. | 8.2 pg/mL |
Secondary
Part 1 - Change From Baseline in Thyroid Stimulating Hormone (TSH) After Cannabidiol Administration Compared to Placebo.
Endocrine assessments for TSH will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group.
Time frame: Days 1 and 29
Population: Analyses include all participants with time-matched samples at day 1 and 29. Participants without day 29 samples (e.g., discontinued treatment prior to day 29) were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Change From Baseline in Thyroid Stimulating Hormone (TSH) After Cannabidiol Administration Compared to Placebo. | 0.073 mU/mL |
| Placebo (Part 1) | Part 1 - Change From Baseline in Thyroid Stimulating Hormone (TSH) After Cannabidiol Administration Compared to Placebo. | 0.005 mU/mL |
Secondary
Part 1 - Change From Baseline in Total T3 After Cannabidiol Administration Compared to Placebo.
Endocrine assessments for total T3 will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group.
Time frame: Days 1 and 29
Population: Analyses include all participants with time-matched samples at day 1 and 29. Participants without day 29 samples (e.g., discontinued treatment prior to day 29) were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Change From Baseline in Total T3 After Cannabidiol Administration Compared to Placebo. | -0.006 ng/mL |
| Placebo (Part 1) | Part 1 - Change From Baseline in Total T3 After Cannabidiol Administration Compared to Placebo. | 0.014 ng/mL |
Secondary
Part 1 - Change From Baseline in Total Testosterone in Male Participants After Cannabidiol Administration Compared to Placebo.
Endocrine assessments for total testosterone will be obtained through blood samples. A linear mixed effect model will be utilized to obtain least squares means for each treatment group.
Time frame: Days 1 and 29
Population: Analyses include male participants with time-matched samples at day 1 and 29
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Change From Baseline in Total Testosterone in Male Participants After Cannabidiol Administration Compared to Placebo. | 5.0 ng/dL |
| Placebo (Part 1) | Part 1 - Change From Baseline in Total Testosterone in Male Participants After Cannabidiol Administration Compared to Placebo. | -13.6 ng/dL |
Secondary
Part 1 - Percentage of Participants Meeting Withdrawal Criteria for Potential Drug-induced Liver Injury (DILI).
Withdrawal criteria for potential drug-induced liver-injury: laboratory results meeting any of the following criteria. * ALT or AST \> 3 x ULN (ULN for ALT is 33 U/L for males and 25 U/L for females) with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (\> 5%) OR * ALT elevation ≥ 5 × ULN (ULN for ALT is 33 U/L for males and 25 U/L for females) OR * Alkaline phosphatase (ALP) elevation ≥ 2 × ULN (with accompanying elevations of gamma-glutamyl transpeptidase (GGT) in the absence of known bone pathology driving the rise in ALP level) OR * ALT elevation ≥ 3 × ULN and bilirubin concentration \> 2 × ULN
Time frame: Days 1 through 35
Population: The liver safety analysis population will include all subjects who receive at least 1 dose of the study drug and have at least one on-treatment liver and hematology lab assessment. Subjects in the liver safety analysis population will be used for the planned primary, secondary, and exploratory analyses related to liver enzyme elevations and liver events. Results will be reported as percentages with a 95% confidence interval (CI) based on a Kaplan-Meier analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cannabidiol (Part 1) | Part 1 - Percentage of Participants Meeting Withdrawal Criteria for Potential Drug-induced Liver Injury (DILI). | 4.9 percentage of participants |
| Placebo (Part 1) | Part 1 - Percentage of Participants Meeting Withdrawal Criteria for Potential Drug-induced Liver Injury (DILI). | 0 percentage of participants |
Secondary
Part 2 - M3G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol.
Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-3-glucuronide (M3G) alone compared to morphine-3-glucuronide (M3G) after 7 days of CBD dosing.
Time frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. For morphine and its metabolites, number of subjects is 20 for morphine alone and morphine with a single dose of CBD. For morphine with multiple doses of CBD, the sample size is 18 as two subjects discontinued from the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - M3G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 265 ng/mL | Geometric Coefficient of Variation 21 |
| Placebo (Part 1) | Part 2 - M3G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 296 ng/mL | Geometric Coefficient of Variation 29 |
| Part 2: Morphine and Multiple Doses of Cannabidiol | Part 2 - M3G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 256 ng/mL | Geometric Coefficient of Variation 25 |
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.0390% CI: [1.03, 1.21]Mixed Models Analysis
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.6690% CI: [0.91, 1.06]Mixed Models Analysis
Secondary
Part 2 - M6G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol.
Cmax will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-6-glucuronide (M6G) alone compared to morphine-6-glucuronide (M6G) after 7 days of CBD dosing.
Time frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. For morphine and its metabolites, number of subjects is 20 for morphine alone and morphine with a single dose of CBD. For morphine with multiple doses of CBD, the sample size is 18 as two subjects discontinued from the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - M6G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 47 ng/mL | Geometric Coefficient of Variation 24 |
| Placebo (Part 1) | Part 2 - M6G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 51 ng/mL | Geometric Coefficient of Variation 28 |
| Part 2: Morphine and Multiple Doses of Cannabidiol | Part 2 - M6G Cmax When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 52 ng/mL | Geometric Coefficient of Variation 28 |
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.1290% CI: [1, 1.17]Mixed Models Analysis
Comparison: Maximum concentration was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.0790% CI: [1.01, 1.21]Mixed Models Analysis
Secondary
Part 2 - Morphine-3-glucuronide (M3G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol.
AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-3-glucuronide (M3G) alone compared to morphine-3-glucuronide (M3G) after 7 days of CBD dosing.
Time frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. For morphine and its metabolites, number of subjects is 20 for morphine alone and morphine with a single dose of CBD. For morphine with multiple doses of CBD, the sample size is 18 as two subjects discontinued from the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - Morphine-3-glucuronide (M3G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 2416 ng*hr/mL | Geometric Coefficient of Variation 18 |
| Placebo (Part 1) | Part 2 - Morphine-3-glucuronide (M3G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 2450 ng*hr/mL | Geometric Coefficient of Variation 17 |
| Part 2: Morphine and Multiple Doses of Cannabidiol | Part 2 - Morphine-3-glucuronide (M3G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 2382 ng*hr/mL | Geometric Coefficient of Variation 14 |
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.4790% CI: [0.98, 1.05]Mixed Models Analysis
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: 0.7390% CI: [0.96, 1.03]Mixed Models Analysis
Secondary
Part 2 - Morphine-6-glucuronide (M6G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol.
AUC will be determined by collecting pharmacokinetic (PK) blood samples and calculated using noncompartmental analysis.13 PK samples will be obtained with each morphine dose for a total number of 39 PK samples per morphine cohort participant. The outcome measure reported will be the geometric mean ratio for morphine-6-glucuronide (M6G) alone compared to morphine-6-glucuronide (M6G) after 7 days of CBD dosing.
Time frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after each morphine dose (Days 1, 4, and 11)
Population: All subjects who receive at least one dose of study drug and have at least one on-treatment PK sample collected. For morphine and its metabolites, number of subjects is 20 for morphine alone and morphine with a single dose of CBD. For morphine with multiple doses of CBD, the sample size is 18 as two subjects discontinued from the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cannabidiol (Part 1) | Part 2 - Morphine-6-glucuronide (M6G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 327 ng*hr/mL | Geometric Coefficient of Variation 30 |
| Placebo (Part 1) | Part 2 - Morphine-6-glucuronide (M6G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 355 ng*hr/mL | Geometric Coefficient of Variation 28 |
| Part 2: Morphine and Multiple Doses of Cannabidiol | Part 2 - Morphine-6-glucuronide (M6G) AUC When Morphine is Administered Alone Versus When Co-administered With Cannabidiol. | 416 ng*hr/mL | Geometric Coefficient of Variation 27 |
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effect.p-value: 0.1390% CI: [0.99, 1.18]Mixed Models Analysis
Comparison: Area under the curve was log-transformed and the values between groups were compared using a linear mixed effects model with group as a categorical variable and subject as a random effectp-value: <0.0190% CI: [1.17, 1.36]Mixed Models Analysis