Clinical trial NCT02240160: A Randomised, Open-label, Three-way Crossover Study to Assess the Pharmacokinetics and Safety of Single Doses of Four Sprays of Sativex® in a Range of Oral pH Environments in Healthy Subjects
Official title: A Randomised, Open-label, Three-way Crossover Study to Assess the Pharmacokinetics and Safety of Single Doses of Four Sprays of Sativex® in a Range of Oral pH Environments in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Sativex
Pharmacokinetics
Oral pH
Lead sponsor: GWPharm
Sponsor class: UNKNOWN
First posted: 2014-09-15
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: To evaluate the effect of oral pH on the pharmacokinetics (PK) of a single oromucosal dose of Sativex (four sprays containing 10.8 mg Δ9 tetrahydrocannabinol (THC) and 10 mg cannabidiol (CBD)) by comparing the PK profile of Sativex in healthy subjects.

The primary clinical hypothesis is that there will be an effect of oral pH on the PK of Sativex when administered as a single oromucosal dose (four sprays).

Detailed description: This is a Phase I, randomised, open-label, three-way crossover study to assess the effects of oral pH on the PK of Sativex. Subjects will receive each of the following treatments in a random order across three residential treatment visits:

* Treatment A (acidic oral pH): Sativex (four sprays) after pre-treatment with Coca-Cola;
* Treatment B (neutral oral pH): Sativex (four sprays) after pre-treatment with tap water;
* Treatment C (alkaline oral pH): Sativex (four sprays) after pre-treatment with an oral suspension of magnesium hydroxide (milk of magnesia).

The target pH for each treatment will be determined from the results of a pilot study.

Each dose administration will be separated by at least seven days. Study subjects will participate in a total of five study visits.

Eligibility criteria: Inclusion Criteria:

* Subject is willing and able to give informed consent for participation in the study;
* Male and/or female subjects aged 18 to 50 years, inclusive;
* Subject must weigh at least 50.0 kg and have a body mass index (BMI) between 19.0 and 35.0 kg/m2, inclusive;
* Subject must be a non-smoker for at least three months prior to screening and must be willing to abstain from smoking during the study;
* Subject must be in good health as determined by the investigator from medical history, physical and oral examination findings, 12-lead standard ECG findings and clinical laboratory test results (laboratory results outside of the reference range must be documented as acceptable by both the investigator and sponsor);
* Subject is able (in the investigator's opinion) and willing to comply with all study requirements;
* Subject is willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study.

Exclusion Criteria:

* Use of any prescription medications or herbal supplements within 2 weeks prior to Day 1 of the first treatment visit or any over the counter medications or supplements within 72 hours prior to first study medication administration;
* Subject has oral issues/condition likely, in the opinion of the investigator, to affect the assessment of the oromucosal absorption of Sativex;
* Subject is physically dependent on alcohol, has a history of drug or alcohol abuse within the 12 months prior to dose administration or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations;
* Subject has a positive result for the presence of hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCAb) or human immunodeficiency virus (HIV) antibodies;
* Subject is currently using or has used cannabis, cannabinoid-based medications (e.g. Marinol®, Nabilone®, Cannador®) or Acomplia (rimonabant) or taranabant within 30 days of study entry (first treatment visit) and is unwilling to abstain for the duration of the study;
* Subject consumes more than five caffeinated beverages per day (e.g., five cups of tea or coffee or cans of cola) or is unwilling to abstain from consumption of caffeine-containing food and beverages throughout the study period;
* Subject has any known or suspected history or family history of schizophrenia, or other psychotic illness, history of severe personality disorder or other significant psychiatric disorder;
* Subject has any history of epilepsy as evidenced by one or more seizures in the last 12 months;
* Subject has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the investigational medicinal product (IMP), Coca-Cola or antacid medications;
* Subject who has received an IMP within the 12 weeks prior to the screening visit, or who has received the last dose of an IMP greater than three months ago but is on extended follow-up;
* Subject with any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, may influence the result of the study or the subject's ability to participate in the study;
* Following a physical examination, the subject has any abnormalities that, in the opinion of the investigator would prevent the subject from safe participation in the study;
* Travel outside the country of residence planned during the study;
* Subjects who are vegans or have medical dietary restrictions.
* Subject has a positive urine drug (including THC), cotinine or alcohol result at screening or at Day -1 of first treatment visit; or positive urine drug (excluding THC), cotinine or alcohol result at Day -1 of subsequent treatment visits;
* Female subjects of child bearing potential and male subjects whose partner is of child bearing potential, unless willing to ensure that they or their partner use two effective forms of contraception e.g, oral contraception, double barrier or intra-uterine device (IUD), during the study and for three months thereafter (however a male condom should not be used in conjunction with a female condom);
* Female subject who is pregnant, lactating or planning pregnancy during the course of the study and for three months thereafter;
* Subjects who have donated or lost more than 450 mL of blood in the 60 days prior to screening or are unwilling to abstain from donation of blood during the study;
* Subject has previously been randomised into this study.

Primary outcomes:
measure: Pharmacokinetic parameters of THC: Cmax, AUC(0-t), and AUC(0-∞)
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of CBD: Cmax, AUC(0-t), and AUC(0-∞)
timeFrame: 0-24 hours post-dose
Secondary outcomes:
measure: Pharmacokinetic parameters of 11-hydroxy-CBD (11-OH-CBD): Cmax, AUC(0-t), and AUC(0-∞)
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of 7-hydroxy-CBD (7-OH-CBD): Cmax, AUC(0-t), and AUC(0-∞)
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of 6-hydroxy-CBD (6-OH-CBD): Cmax, AUC(0-t), and AUC(0-∞)
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of THC: t½ and Tmax
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of 11-OH-CBD: t½ and Tmax
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of CBD: t½ and Tmax
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of 7-OH-CBD: t½ and Tmax
timeFrame: 0-24 hours post-dose
measure: Pharmacokinetic parameters of 6-OH-CBD: t½ and Tmax
timeFrame: 0-24 hours post-dose
measure: Total body clearance (CL/F) of THC and CBD from plasma
timeFrame: 0-24 hours post-dose
measure: The incidence of adverse events as measure of subject safety
timeFrame: From screening to follow-up, an expected average of 35 days
measure: The number of subjects with a clinically significant change in physical and oral examination results, relative to pre-treatment baseline
timeFrame: From screening to follow-up, an expected average of 35 days
measure: The number of subjects with a clinically significant change in 12-lead electrocardiogram (ECG) results, relative to pre-treatment baseline
timeFrame: From screening to follow-up, an expected average of 35 days
measure: The number of subjects with clinically significant changes in laboratory test parameters, relative to pre-treatment baseline
timeFrame: From screening to follow-up, an expected average of 35 days
measure: The number of subjects with a clinically significant change in vital signs, relative to pre-treatment baseline
timeFrame: From screening to follow-up, an expected average of 35 days
measure: The number of subjects with a clinically significant change in body temperature, relative to pre-treatment baseline
timeFrame: From screening to follow-up, an expected average of 35 days
measure: The number of subjects with a clinically significant change in body weight, relative to pre-treatment baseline
timeFrame: From screening to follow-up, an expected average of 35 days
Other outcomes:
Locations:
Study officials:
affiliation: Quintiles Drug Research Unit at Guy's Hospital, Quintiles Ltd, 6 Newcomen Street, London SE1 1YR, United Kingdom
name: James Ritter, DPhil, FRCP, FMedSci
role: PRINCIPAL_INVESTIGATOR
References: