Cannabinoid Profile Investigation of Vapourized Cannabis in Patients With Osteoarthritis of the Knee

A Randomized Double Blind Placebo Controlled, Proof-of-concept, Crossover Clinical Trial of Vapourized Cannabis in Adults With Painful Osteoarthritis of the Knee

Primary Objective:

- To determine the analgesic dose-response characteristics of vapourized cannabinoids with varying degrees of delta-9-tetrahydrocannabiol (THC)/ Cannabidiol (CBD) ratios.

Secondary Objectives:

• To compare functional changes and patient preferences of different cannabinoid (THC, CBD) profiles in patients with OA (Osteoarthritis);
• To describe the Pharmacokinetics (PK) of vapourized cannabis of differing cannabinoid profiles in patients with OA;
• To explore the short term safety of vapourized cannabis with different cannabinoid profiles.
• To describe the incidence and severity of psychoactive events.

A Phase IIa randomized double blind placebo controlled crossover trial (RCT) using six different herbal cannabis drug product formulations prepared by the Sponsor, Prairie Plant Systems Inc. An initial screening period (minimum one week) will be completed for pain assessment and determination of eligibility. After screening, eligible subjects will be randomly assigned to receive all 6 different formulations in a random order.

The study will be conducted using six periods of 7 days duration, with each period consisting of one day of exposure and 6 days of washout from study drug. The study will therefore take 6 weeks to be completed for each enrolled subject with an additional week for adverse event monitoring after the final study exposure. Total time in study may therefore be a maximum of nine weeks (including screening).

Adult subjects (age ≥50y) will be recruited with chronic (>3 months) moderate to severe pain (pain score ≥40/100 on visual analogue scale) due to primary osteoarthritis (OA) of the knee as defined by American College of Rheumatology (ACR) criteria. Target enrolment for this study is 36 (18 from each site).

The study will be conducted at the Alan Edwards Pain Management Unit of the McGill University Health Centre, in Montreal, Quebec, Canada and the Pain Management Unit at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada. A dedicated ventilated room is available at these sites for cannabinoid inhalation studies as used in prior evaluation trials on medicinal cannabis.

All subjects meeting eligibility criteria after the screening period will be randomized to receive all 6 herbal cannabis drug product formulations in a randomly assigned order of treatment between Clinical Visit (CV) 2 and CV7.

A washout period of 6 days is proposed between the six different treatment periods. This will allow the pharmacological effects of each dose to be minimized prior to each subsequent dosing period to avoid confounding.

Throughout the study all subjects will remain on their stable (pharmacological and non-pharmacological) treatment regimen.

Throughout the study, subjects will be blinded to the treatment they are receiving. Once a subject has been randomized, the investigator and the subject, as well as all staff involved in the conduct or management of the study will be blinded to the treatment assignment. All dosing will be via the Volcano® Medic vapourizer (licensed for medical administration of cannabis in Canada March 2010; Licence No. 82405) and both the nurse and the patient will be familiarized with its instruction manual.

The study nurse will prepare the dose for the subject. After opening the vial of drug product formulation, its contents will be transferred to the Volcano® Medic's filling chamber (sample-holder) equipped top and bottom with fine wire mesh to retain the finely ground material. The filling chamber will be placed atop the main body of the unit and then have a, 12.5 L, heat-resistant Medic Valve balloon affixed to it (this balloon will be housed within an opaque bag that is required to ensure blinding because the placebo generates little in the way of visible vapour). Active components (THCA and CBDA decarboxylated to THC and CBD) will be vapourized out of the herbal material by a stream of hot air with an exact, predefined temperature (190 °C). The ensuing vapour will be captured in the balloon. After filling has been completed (35 seconds), a mouthpiece will be attached to the balloon for inhalation of the vapour by the study subject. The total contents of the balloon will be inhaled over five minutes by using a standardized inhalation technique. Immediately after the bag has been removed from the Volcano® Medic, inhalation will be according to the following regimen:

1. Inhale for 4 seconds
2. Hold breath for 6 seconds
3. Exhale and breathe normally for 20 seconds
4. Repeat this inhale-hold-breathe cycle (30 seconds) until the bag has been evacuated.

Inclusion Criteria:

1. Idiopathic (primary) OA of the knee as defined by American College of Rheumatology criteria
2. Age ≥50 years
3. Numerical Rating Scale (NRS) Pain intensity score ≥ 4 (on a 0-10 scale)
4. Stable medication and treatment regimen
5. Open to Canadian Residents only

Exclusion Criteria:

1. Pregnant/nursing
2. BMI >39kg/m2
3. Secondary causes of OA
4. Stage IV OA of the knee
5. Significant other cause of pain (e.g. fibromyalgia, CRPS)
6. Significant cardiac, neurological, psychiatric or respiratory disease
7. Joint infiltration in 30 days prior to trial or during study
8. Positive urine screen for THC