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Trial registered on ANZCTR


Registration number
ACTRN12619001723178
Ethics application status
Approved
Date submitted
23/11/2019
Date registered
6/12/2019
Date last updated
22/12/2020
Date data sharing statement initially provided
6/12/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Study to Assess the Safety and Pharmacokinetics of CHI-541 among Healthy Participants
Scientific title
This is a randomized, double-blinded, placebo-controlled, multiple-dose study is to evaluate the safety, tolerability, and PK of CHI-541 among healthy participants.
Secondary ID [1] 299856 0
APA710-3004
Universal Trial Number (UTN)
U1111-1243-9339
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain 315258 0
Nausea 315261 0
Muscle Spasticity 315262 0
Epilepsy 315263 0
Condition category
Condition code
Alternative and Complementary Medicine 313561 313561 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
his is a Phase 1a, randomized, double-blind, placebo-controlled, multiple-dose study to assess the safety, tolerability, and PK of CHI-541 versus placebo in healthy male and female participants ages 18–55 years. The study will enroll 40 participants (8 participants per group; 4 active treatment groups and 1 placebo group).

During the Treatment Period, participants will be randomized in a 1:1:1:1:1 ratio to 1 of 5 treatment groups:
• Treatment A: 5 mg total THC and 0.2 mg total CBD daily (1 CHI-541 softgel and 5 placebo tablets, twice daily)
• Treatment B: 10 mg total THC and 0.4 mg total CBD daily (2 CHI-541 softgels and 4 placebo tablets, twice daily)
• Treatment C: 15 mg total THC and 0.6 mg total CBD daily (3 CHI-541 softgels and 3 placebo tablets, twice daily)
• Treatment D: 20 mg total THC and 0.8 mg total CBD daily (4 CHI-541 softgels and 2 placebo tablets, twice daily)
• Treatment E: Placebo (4 placebo capsules and 2 placebo tablets, twice daily).

Treatment will be administered every 12 hours. CHI-541 is a standardized cannabis extract in an oil softgel preparation that contains an approximate 26:1 ratio of THC to CBD (2.5 mg THC and < 0.25 mg CBD). The intervention (i.e. treatment with IMP) will be 7 days and will monitored and documented during inpatient stay.
Intervention code [1] 316133 0
Treatment: Drugs
Comparator / control treatment
Treatment E: Placebo (4 placebo capsules and 2 placebo tablets, twice daily)

The placebo tablet is composed of Microcrystalline Cellulose, Colloidal Silicon Dioxide, Sodium Starch Glycolate, and Sodium Strearyl Fumarate. The placebo capsule is composed of MCT (Medium-chain triglyceride) oil, Alfalfa Extract, Beta-Carotene, Gelatin, Glycerin and Light mineral oil. The change was made prior to enrolment commencement.
Control group
Placebo

Outcomes
Primary outcome [1] 322032 0
To evaluate the safety and tolerability of CHI-541 administered twice daily for a total daily dose of 5 mg THC and 0.2 mg CBD, 10 mg THC and 0.4 mg CBD, 15 mg THC and 0.6 mg CBD, or 20 mg THC and 0.8 mg CBD.

This outcome is assessed be evaluating:
• AEs (Adverse Events) and Serious AEs (SAEs)
• Vital signs
• 12-lead ECG
• Clinical laboratory parameters
• Use of concomitant medications
• Changes to responses on the C-SSRS

Known/Possible Adverse Events such as Dizziness, Drowsiness, Fatigue, Sleepiness, and Nausea would be assessed in multiple ways such as participant self-reporting, examination by the investigator, or comparing the differences in answers in the study-specific questionnaires.
Timepoint [1] 322032 0
For 7 consecutive days relative to placebo
Secondary outcome [1] 377081 0
To characterize and compare the PK of CBD assessed in blood plasma of 4 different daily doses of CHI-541.

PK parameters for CBD, and metabolites will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [1] 377081 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.
Secondary outcome [2] 377082 0
To characterize and compare the PK of THC assessed in blood plasma of 4 different daily doses of CHI-541.

PK parameters for THC, and metabolites will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [2] 377082 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.
Secondary outcome [3] 377083 0
To characterize and compare the PK of 6a-OH-CBD assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for 6a-OH-CBD will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [3] 377083 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [4] 377084 0
To characterize and compare the PK of 6ß-OH-CBD assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for 6ß-OH-CBD will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [4] 377084 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [5] 377085 0
To characterize and compare the PK of 7-OH-CBD assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for 7-OH-CBD will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [5] 377085 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [6] 377086 0
To characterize and compare the PK of 7-CBD-COOH assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for 7-CBD-COOH will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [6] 377086 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [7] 377087 0
To characterize and compare the PK of CBD-Gluc assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for CBD-Gluc will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [7] 377087 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [8] 377088 0
To characterize and compare the PK of 11-OH-THC assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for 11-OH-THC will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [8] 377088 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [9] 377089 0
To characterize and compare the PK of THC-COOH assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for THC-COOH will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [9] 377089 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [10] 377090 0
To characterize and compare the PK of THC-COOH-Gluc assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for THC-COOH-Gluc will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [10] 377090 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [11] 377091 0
To characterize and compare the PK of CBN assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for CBN will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [11] 377091 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [12] 377092 0
To characterize and compare the PK of CBG assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for CBG will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [12] 377092 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [13] 377093 0
To characterize and compare the PK of CBDV assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for CBDV will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [13] 377093 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [14] 377094 0
To characterize and compare the PK of CBC assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for CBC will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [14] 377094 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [15] 377095 0
To characterize and compare the PK of THCV assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for THCV will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [15] 377095 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [16] 377096 0
To characterize and compare the PK of THCV-COOH assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for THCV-COOH will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [16] 377096 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [17] 377097 0
To characterize and compare the PK of THC-Gluc assessed in blood plasma and urine of 4 different daily doses of CHI-541. This is a composite secondary outcome.

PK parameters for THC-Gluc will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [17] 377097 0
Blood samples (4 mL per sample) for plasma PK measurements will be collected at the following time points:
Day 1: Pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose
Days 2–6: Pre-morning dose
Day 7: Pre-morning dose and at 1, 2, 4, 6, 8, 12, and 16 hours after the morning dose
Day 8: 24 and 32 hours after the Day 7 morning dose
Day 9: 48 hours after the Day 7 morning dose
Day 10: 72 hours after the Day 7 morning dose
Day 11: 96 hours after the Day 7 morning dose
Day 13: 144 hours after the Day 7 morning dose.

Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [18] 377098 0
To explore the subjective effects of CHI-541 in healthy participants via the completion of a Drug Effects Questionnaire (DEQ).
Timepoint [18] 377098 0
The DEQ will be administered pre-morning dose and at 1, 2, 4, 6, 8, and 12 hours after the morning dose on Days 1, 3, and 7.
Secondary outcome [19] 377557 0
To characterize and compare the PK of CBD assessed in urine of 4 different daily doses of CHI-541.

PK parameters for CBD, and metabolites will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [19] 377557 0
Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.
Secondary outcome [20] 377558 0
To characterize and compare the PK of THC assessed in blood plasma and urine of 4 different daily doses of CHI-541.

PK parameters for THC, and metabolites will be calculated/derived from the data using a non-compartmental analysis with WinNonlin. Actual sampling times will be used to estimate plasma PK parameters. Descriptive statistics (arithmetic mean, SD, median, minimum, maximum, coefficient of variation, and geometric mean) for the individual PK parameters and plasma concentration over time will be presented by treatment group and period. Differences in dose-dependent PK parameters (Cmax, Cmin, Cav, and AUC) between Treatments A, B, C, and D will be compared using an ANOVA model or an appropriate non-parametric approach. The pre-dose Ctrough plasma levels across all the days of dosing will be compared statistically for assessment of the steady state at each dose regimen using a mixed effect ANOVA model. Attainment of the steady state will be concluded if the 90% CI for the geometric mean ratio of Days 5/6, 5/7, and 6/7 are completely within the acceptance range of 0.80–1.25.
Timepoint [20] 377558 0
Urine samples for urine PK measurements will be collected at the following time points:
Days 1–6: Pre-morning dose
Day 7: Output (all samples provided) for the 00:00–12:00 and 12:00–24:00 intervals.

Eligibility
Key inclusion criteria
1. Is a healthy male or female adult aged 18–55 years at the time of screening.
2. Has a minimum of 2 lifetime exposures to THC-containing cannabis products.
3. Has a body mass index between 18 and 30 kg/m2.
4. Is judged by the Investigator to be in generally good health at screening based on the results of a medical history, physical examination, 12-lead ECG, and clinical laboratory test results. Laboratory results outside of the reference range deemed to be acceptable will be documented as not clinically significant at the discretion of the Investigator.
5. For women of childbearing potential, has a negative serum pregnancy test (ß-human chorionic gonadotropin [hCG]) at the Screening Visit and a negative urine pregnancy test at intake to the inpatient research facility.
6. Agrees to abide by all study restrictions and comply with all study procedures.
7. Must be adequately informed of the nature and risks of the study and give written informed consent prior to screening.
8. Is, in the Investigator’s opinion, reliable, able, and willing to comply with all protocol requirements and procedures (including scheduled visits and confinement periods).
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Women who are pregnant, lactating, breastfeeding, or planning a pregnancy.
2. Women of childbearing potential, or men who are sexually active with a woman of childbearing potential, who are unwilling or unable to use an acceptable method of contraception (abstinence or the use of a highly effective method of contraception, including hormonal contraception, diaphragm, cervical cap, vaginal sponge, condom, vasectomy, or intrauterine device) from at least 21 days prior to the first dose of study medication until 28 days after the last dose of study medication. Participants with same sex partners do not require contraception.
3. Has a history of epilepsy.
4. Has used tobacco/nicotine-containing products on more than 5 occasions within 1 month of the Screening Visit or during the study.
5. Has used any prescription drugs or herbal supplements (except hormonal contraception) within four weeks prior to the Screening Visit, unless approved by the Investigator and stable for at least 4 weeks prior to Screening through the final study visit.
6. Use of any over-the-counter drugs, vitamins, or supplements within 72 hours prior to the first dose of study medication.
7. Has or has previously had a positive result for the presence of Hepatitis B surface antigen (HBsAg), Hepatitis C virus antibodies (HCVAb), or human immunodeficiency virus (HIV) antibodies.
8. Has a positive breath test for ethanol or a positive urine screen for cocaine, THC, barbiturates, amphetamines, methamphetamines, benzodiazepines, methylenedioxymethamphetamine, phencyclidine, methadone, or opiates at the Screening Visit or prior to study treatment.
9. Has a history of psychosis or schizophrenia, including among first-degree relatives.
10. Any clinically significant condition or abnormal finding at the Screening Visit that would, in the opinion of the Investigator, preclude study participation or interfere with evaluation of the study treatment.
11. Has a history of a known significant allergic condition, significant drug-related hypersensitivity, or allergic reaction to any compound or chemical class related to cannabis, including phytocannabinoids and cannabinoid analogues, or excipients utilized within the IMP.
12. Has taken grapefruit products and/or Seville oranges within the 7 days prior to dosing with study medication or during the study.
13. Is taking a prohibited medication including warfarin, clobazam, valproic acid, phenobarbital, mTOR inhibitors, oral tacrolimus, and St. John’s Wort within 30 days of the Screening Visit or during the study.
14. Has used cannabis, synthetic cannabinoid or cannabinoid analogues (e.g., dronabinol, nabilone), hemp products, synthetic cannabinoid receptor agonists (e.g., spice, K2), or any CBD- or THC-containing product (e.g., Sativex, Epidiolex) within 8 weeks of the Screening Visit or during the study.
15. Has a history of treatment for or exhibits evidence of alcohol or drug abuse within the past year or regular alcohol consumption exceeding an average of 2 units of alcohol per day.
16. Has a history or current diagnosis of a significant psychiatric disorder that would, in the opinion of the Investigator, affect the subject’s ability to comply with the study requirements.
17. Has a history of suicidal behavior or any active suicidal ideation as indexed by endorsement of questions #4 or #5 on the C-SSRS.
18. Has suspected or confirmed cardiovascular disease.
19. Has participated in any investigational product or device study within 30 days prior to the Screening Visit, or is scheduled to participate in another investigational product or device study during the course of this study.
20. Demonstrates behavior indicating unreliability or inability to comply with the requirements of the protocol.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A randomisation list will be generated by the unblinded statistician and be transferred electronically to the pharmacist on site
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software; via SAS programming
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Descriptive statistics will be provided for all measured outcomes. The number of observations, mean, SD, median, minimum, and maximum will be provided for continuous variables. The number and percentage of participants in each category will be calculated for categorical variables.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/02/2020
Actual
2/12/2019
Date of last participant enrolment
Anticipated
24/02/2020
Actual
12/12/2019
Date of last data collection
Anticipated
8/03/2020
Actual
2/04/2020
Sample size
Target
40
Accrual to date
Final
41
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 15275 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 28585 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304313 0
Commercial sector/Industry
Name [1] 304313 0
10607410 CANADA INC. DBA Spectrum Therapeutics
Country [1] 304313 0
Canada
Primary sponsor type
Commercial sector/Industry
Name
10607410 CANADA INC. DBA Spectrum Therapeutics
Address
55 St. Clair Avenue West, Suite 202
Toronto, Ontario, Canada, M4V 1N5
Country
Canada
Secondary sponsor category [1] 304560 0
Commercial sector/Industry
Name [1] 304560 0
10607410 CANADA INC. DBA Spectrum Therapeutics
Address [1] 304560 0
Level 2, 381 MacArthur Ave, Hamilton, QLD, 4007, Australia
Country [1] 304560 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304767 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 304767 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 304767 0
Australia
Date submitted for ethics approval [1] 304767 0
20/11/2019
Approval date [1] 304767 0
16/12/2019
Ethics approval number [1] 304767 0

Summary
Brief summary
CHI-541 is a standardized cannabis oil softgel preparation that contains an approximate 26:1 ratio of THC to CBD (2.5 mg THC and <0.25 mg CBD). At present, regulatory approval, physician acceptance, and the utilization of CHI-541 in Phase 2/3 clinical trials for specific indications are hampered by the absence of critical Phase 1 data regarding its safety, tolerability, and PK profile. Therefore, the aim of this randomized, double-blinded, placebo-controlled, multiple-dose study is to rigorously evaluate the safety, tolerability, and PK of CHI-541 in healthy participants.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98134 0
Dr Ingrid Hopper
Address 98134 0
Centre for Clinical Studies
Level 5, Burnet Tower
89 Commercial Road
Melbourne 3004 VIC
Country 98134 0
Australia
Phone 98134 0
+61 800 243 733
Fax 98134 0
Email 98134 0
[email protected]
Contact person for public queries
Name 98135 0
Ingrid Hopper
Address 98135 0
Centre for Clinical Studies
Level 5, Burnet Tower
89 Commercial Road
Melbourne 3004 VIC
Country 98135 0
Australia
Phone 98135 0
+61 800 243 733
Fax 98135 0
Email 98135 0
[email protected]
Contact person for scientific queries
Name 98136 0
Ingrid Hopper
Address 98136 0
Centre for Clinical Studies
Level 5, Burnet Tower
89 Commercial Road
Melbourne 3004 VIC
Country 98136 0
Australia
Phone 98136 0
+61 800 243 733
Fax 98136 0
Email 98136 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The data sharing statement was marked "NO" due to the reason that it’s a healthy volunteer study and the individual participant results are not useful to the participants or to others outside of the sponsor.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.