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Cannabidiol Oral Solution in Pediatric Participants With Treatment-resistant Seizure Disorders

Phase 1
Completed
Conditions
Seizures
Interventions
Drug: Cannabidiol Oral Solution
Registration Number
NCT02324673
Lead Sponsor
INSYS Therapeutics Inc
Brief Summary

This is a Phase 1/2, open-label trial designed to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of 3 multiple ascending doses of Cannabidiol Oral Solution in a sequential fashion.

Participants will be pediatric (aged 1-17, inclusive), experiencing treatment-resistant seizures, and satisfy all inclusion/exclusion criteria.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
61
Inclusion Criteria
  • Meets protocol-specified criteria for qualification and contraception, including treatment-resistant seizure disorder
  • Is able to speak and understand the language in which the study is being conducted, is able to understand the procedures and study requirements and has voluntarily signed and dated an informed consent form approved by the Institutional Review Board before the conduct of any study procedure
  • In the opinion of the Investigator, the participants and parent(s)/caregiver(s) are willing and able to comply with the study procedures and visit schedules, including venipuncture, inpatient stay at the study center, dosing at the study center twice a day as needed while an outpatient), and the Follow-up Visits (if applicable)
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Exclusion Criteria

  • Participant or parent(s)/caregiver(s) have daily commitments during the study duration that would interfere with attending all study visits

  • History or current use of dietary supplements, drugs or over-the counter medications outside protocol-specified parameters

  • Signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise:

    1. the safety or well-being of the participant or study staff
    2. the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding)
    3. the analysis of results
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Low Dose Cannabidiol Oral Solution [10 mg/kg/day]Cannabidiol Oral SolutionLow Dose \[10 milligrams/kilogram/day (mg/kg/day)\] oral solution containing pharmaceutical grade cannabidiol (nonplant-based). Starting dose of 5 mg/kg in the morning on Day 1 followed by total dose of 10 mg/kg/day (5 mg/kg in the morning and 5 mg/kg in the evening) on Days 4 to 10.
Mid Dose Cannabidiol Oral Solution [20 mg/kg/day]Cannabidiol Oral SolutionMid Dose \[20 mg/kg/day\] oral solution containing pharmaceutical grade cannabidiol (nonplant-based). Starting dose of 10 mg/kg in the morning on Day 1 followed by total dose of 20 mg/kg/day (10 mg/kg in the morning and 10 mg/kg in the evening) on Days 4 to 10.
High Dose Cannabidiol Oral Solution [40 mg/kg/day]Cannabidiol Oral SolutionHigh Dose \[40 mg/kg/day\] oral solution containing pharmaceutical grade cannabidiol (nonplant-based). Starting dose of 20 mg/kg in the morning on Day 1 followed by total dose of 40 mg/kg/day (20 mg/kg in the morning and 20 mg/kg in the evening) on Days 4 to 10.
Primary Outcome Measures
NameTimeMethod
Half Life (t1/2) for Cannabidiol and Metabolite 7-OH Cannabidiol for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Elimination Rate (Lambda-z [λz]) for Cannabidiol and Metabolite 7-OH Cannabidiol for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Volume of Distribution (Vz/F) of Cannabidiol for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Metabolite to Parent Ratio for AUC(0-inf) [MRAUC(0-inf)] on Day 1 for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

MRAUC(0-inf) was adjusted for molecular weight differences between cannabidiol (341.46) and 7-OH cannabidiol (330.46).

Metabolite to Parent Ratio for AUC(0-12) [MRAUC(0-12)] on Day 10Day 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

MRAUC(0-12) was adjusted for molecular weight differences between cannabidiol (341.46) and 7-OH cannabidiol (330.46).

Accumulation Ratio for Cmax (RCmax) on Day 10 for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

RCmax is the ratio of Cmax at Day 10 compared to Cmax at Day 1.

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Dose Normalized AUC(0-12) [AUC (0-12)/D] for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 1Day 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 1 at 2, 4, 8, 12 hours post-dose; Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose.

AUC From Time 0 to Infinity [AUC(0-inf)] for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 1 for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Metabolite (7-OH Cannabidiol) to Parent (Cannabidiol) Ratio for Cmax [MRCmax] on Day 1Day 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 1 at 2, 4, 8, 12 hours post-dose; Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose.

MRCmax was adjusted for molecular weight differences between cannabidiol (341.46) and 7-OH cannabidiol (330.46).

AUC(0-12) for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 10Day 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Cmax for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Dose Normalized Cmax (Cmax/D) for Cannabidiol and Metabolite 7-OH CannabidiolDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2: Day 1 at 2, 4, 8, 12 hours post-dose; Participants ages 2 to \<6: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17: Day 1 pre-dose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose.

Dose Normalized AUC(0-inf) [AUC(0-inf)/D] for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 1 for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Cmax/D for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Time to Cmax (Tmax) for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Oral Clearance (CL/F) for Cannabidiol for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

MRCmax on Day 10Day 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

MRCmax was adjusted for molecular weight differences between cannabidiol (341.46) and 7-OH cannabidiol (330.46).

Metabolite to Parent Ratio for AUC(0-12) [MRAUC(0-12)] on Day 1Day 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 1 at 2, 4, 8, 12 hours post-dose; Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose.

MRAUC(0-12) was adjusted for molecular weight differences between cannabidiol (341.46) and 7-OH cannabidiol (330.46).

Minimum Plasma Concentration (Cmin) for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Maximum Plasma Concentration (Cmax) for Cannabidiol and Metabolite 7-hydroxy (7-OH) CannabidiolDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 1 at 2, 4, 8, 12 hours post-dose; Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose.

Area Under the Plasma-Concentration Time Curve From 0 to 12 Hours Post-dose [AUC(0-12)] for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 1Day 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 1 at 2, 4, 8, 12 hours post-dose; Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose.

AUC From Time 0 to the Last Quantifiable Concentration [AUC(0-last)] on Day 1 for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 1 for Participants ≥2 Years of AgeDay 1 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Dose Normalized AUC(0-12) [AUC (0-12)/D] for Cannabidiol and Metabolite 7-OH Cannabidiol on Day 10Day 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Accumulation Ratio for AUC(0-12) [RAUC(0-12)] on Day 10 for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

RAUC(0-12) is the ratio of AUC(0-12) at Day 10 compared to AUC(0-12) at Day 1.

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)From the first dose of study drug up to Day 17

An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product. It does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event not present prior to the initiation of the treatment or any event already present that worsens. Any laboratory (clinical chemistry, hematology, urinalysis), 12-lead electrocardiograms, vital signs (temperature, blood pressure, pulse rate, respiratory rate) and physical examination findings deemed by the investigator to be clinically significant were captured as AEs. A SAE is any untoward medical occurrence that results in death, is life-threatening, requires the participant be at a risk of death at the time of the event, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect, or other serious event that requires medical or surgical intervention.

Average Plasma Concentration (Cavg) for Cannabidiol and Metabolite 7-OH CannabidiolDay 10 at age-specific times

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 1 to \<2 years: Day 10 pre-dose and at 2, 4, 8 and 12 hours post-dose; Participants ages 2 to \<6 years: Day 10 pre-dose and at 1, 2, 3, 4, 8, 12 and 24 hours post-dose; Participants ages 6 to ≤17 years: Day 10 pre-dose and at 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

Time Linearity Index for Cannabidiol and Metabolite 7-OH Cannabidiol in Participants ≥2 Years of AgeDay 1 and Day 10

Time linearity index is calculated as the ratio of AUC(0-12) on Day 10/AUC\[0-inf\] on Day 1.

Serial blood sample collection times for pharmacokinetic (PK) analysis were based on the participant's age as follows:

Participants ages 2 to \<6 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24 and 48 hours post-dose; Participants ages 6 to ≤17 years: Day 1 pre-dose and at 1, 2, 3, 4, 8, 12, 16, 24, 36, 48 and 72 hours post-dose; Participants ages 1 to \<2 years were not included in this analysis.

Number of Participants With Suicide Related Thoughts and Behaviors Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)Day 11

The C-SSRS captured the occurrence, severity, and frequency of suicide related thoughts and behaviors at Day 11. The C-SSRS was only used for participants ≥ 7 years of age. The number of participants with results of "Yes" for Suicidal Ideation (Wish to be Dead and Non-Specific Active Suicidal Thoughts) and Suicidal Behavior (Actual Attempt, Interrupted Attempt, Aborted Attempt, Preparatory Acts or Behavior, and Suicidal Behavior) are reported.

Clinical Global Impression of Improvement (CGI-I) AssessmentDay 11

The CGI-I was completed by the parents/caregivers and the investigator and was used to assess participants global status of their condition on Day 11 using a 7-point scale, where 1=very much improved and 7=very much worse since the initiation of treatment.

Change From Baseline in Clinical Global Impression of Severity (CGI-S) AssessmentBaseline and Day 11

The CGI-S was completed by the parents/caregivers and the Investigator and was used to rate participant's mental illness status at Baseline (Screening) and Day 11 using a 7-point scale, where 1=normal, not mentally ill, and 7=among the most extremely mentally ill participants. This rating is based upon observed and reported symptoms, behavior, and function in the past seven days. The change in CGI-S score at Day 11 relative to Baseline is reported. A negative change from Baseline indicates improvement (decreased severity in illness).

Change From Baseline in Daily Seizure ActivityBaseline and Day 11

The specific number of tonic and atonic seizures per study day were recorded in a diary. The change in number of seizures at Day 11 relative to Baseline is reported. A negative change from Baseline indicates an improvement based on Daily Seizure Activity.

Secondary Outcome Measures
NameTimeMethod

Trial Locations

Locations (10)

University of Chicago Medical Center

🇺🇸

Chicago, Illinois, United States

Children's Hospital of Philadelphia

🇺🇸

Philadelphia, Pennsylvania, United States

Miami Children's Hospital

🇺🇸

Miami, Florida, United States

Child Neurology Center - NW F

🇺🇸

Pensacola, Florida, United States

Texas Scottish Rite Hospital for Children

🇺🇸

Dallas, Texas, United States

Mary Bridge Children's Hospital

🇺🇸

Tacoma, Washington, United States

Clinical Research Center of Nevada LLC

🇺🇸

Las Vegas, Nevada, United States

University of California San Francisco Medical Center

🇺🇸

San Francisco, California, United States

Oregon Health Services University

🇺🇸

Portland, Oregon, United States

Le Bonheur Children's Hospital

🇺🇸

Memphis, Tennessee, United States

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