Full Title: A phase II, randomized, open-label, double-blind, two-center study to evaluate the tolerability, safety and dose-finding of oil cannabis preparation for pain in Parkinson's disease.

Short title: Cannabis oil for pain in Parkinson's disease Sample Size: N = 15 Study Population: Patients with Parkinson's disease and pain, without cognitive impairment.

Study Duration: July 2018 - July 2019

Study Agent/ Intervention: Cannabis oil: mixed oil cannabis preparation consisting of 3 different formulations of ∆-9THC and cannabidiol - 18:0; 10:10; and 1:20 respectively. Cannabis oil will be administered orally once per day, as required for pain; or taken 4h before bedtime, if no pain.

Primary objective: to determine the safety and tolerability of different formulations of Cannabis oil for pain in PD patients (incidence and severity of adverse events).

Secondary objective: to assess change from the start of treatment (V2) to end of treatment (V5) in frequency and severity of pain, sleep, dystonia and motor symptoms in PD patients.

BACKGROUND AND RATIONALE Pain is a common symptom in PD and is reported in up to 50 % of patients. Pain in PD has been classified as musculoskeletal, dystonic (particularly in OFF-periods), radicular and central pain, and is frequently associated with muscle rigidity, postural abnormalities and bradykinesia. Often, the presence of pain in PD is associated with the daily fluctuations in the motor symptoms of PD. In addition, some patients experience 'off-dystonia' which affects the toes and feet, with painful cramps and posturing. The treatment of pain in PD patients with such fluctuating symptoms involves optimizing the dose of levodopa or other dopaminergic drugs to treat the OFF periods. Frequently, the pain does not resolve on altering the PD medication and remains difficult to treat.

Cannabis Sativa (marijuana) and its major psychoactive constituent, delta-9- tetrahydrocannabinol(Δ9THC) have been used for centuries to treat pain. The mechanism of action is likely mediated via cannabinoid receptors (CB1 and CB2) in basal ganglia and spinal circuits. Because of these potential therapeutic properties, several synthetic and naturally occurring cannabinoid preparations have been manufactured. Cannabinoids have been demonstrated to alleviate allodynia or hyperalgesia in animal models of pain; the effect on pain modulation may be secondary to CB1 receptors in the amygdala, thalamus, spinal cord and dorsal root ganglion. Several recent clinical studies have demonstrated the potential efficacy of synthetic and naturally occurring cannabinoids in pain. Synthetic cannabinoids such as nabilone and nabiximols are now licensed as add-on therapy in multiple sclerosis and advanced cancer for relief of pain. A Canadian systematic review of randomized clinical trials of cannabinoids (cannabis, nabilone, dronabinol and nabiximols) for the treatment of chronic non-cancer pain (neuropathic pain, mixed chronic pain, rheumatoid arthritis, fibromyalgia) concluded that cannabinoids are modestly effective. Other cannabinoids found in cannabis sativa include cannabidiol (CBD). CBD potentially lacks a psychoactive effect, and appears to act via non-CB receptor-mediated actions including ion channels and enzymes. Pre-clinical studies suggest anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform actions. Thus, the advantage of CBD in PD is a potentially lesser risk of cognitive dysfunction and psychosis.

Currently, there is an oil preparation (CanniMed® Oil) in Canada, with the advantage of ease of administration. CanniMed® Oil is a mixed oil preparation that contains both Δ9THC and CBD, of varying proportions of Δ9THC (more psychoactive component) and CBD (18:0; 10:10; 1:20 respectively). Investigators of this study have experience in conducting trials using synthetic cannabinoids in movement disorders, including PD. Investigators have demonstrated tolerability, but limited efficacy, of short-term administration of clinically available oral tablet cannabinoids in idiopathic dystonia. More specifically in PD, investigators have assessed nabilone for the treatment of levodopa-induced dyskinesia with documented efficacy. Of interest to the current proposal, in this study, investigators also found an improvement in painful OFF-period limb dystonia in 2 out of 7 subjects. It is unknown if this effect is a specific analgesic effect or related with an anti-dystonia effect.

STUDY HYPOTHESIS Despite the major advances in understanding the pathophysiology of the endocannabinoid system, there are many unknowns in the use of cannabinoids for medical purposes. To date, clinical studies with cannabinoids in PD have been inconclusive and the use of cannabinoids remains controversial due to a lack of well-powered confirmatory clinical studies and obvious safety concerns. However, the known efficacy of cannabinoids in reducing pain suggests that PD-related pain may also be a reasonable target for cannabinoids. Combined with the potential rationale for reducing dystonia, we hypothesize that cannabinoids could reduce pain in PD, regardless of the PD-specific pain cause.

Primary Outcome

Safety:

• Incidence and severity of adverse events
• Maximum tolerated dose (MTD)

Tolerability:

• Ability to remain on assigned treatment
• Withdrawal rates due to adverse events

Secondary Outcomes: Assess change from baseline in the King's Parkinson Disease Pain scale (KPPS).

Other Outcomes: Assess change from baseline in frequency and severity of pain, sleep, dystonia and PD motor symptoms, using the following measurement tools:

• Visual Analogue Scale for Pain
• MDS-UPDRS part III
• UDysRS - Dystonia part 2 subscores
• Clinical Global Impression of pain severity (severity and improvement)
• Epworth Sleepiness Scale

Inclusion Criteria:

• Male and female subjects;
• Aged >18y
• International Parkinson and Movement Disorder Society (MDS) Clinical Diagnostic Criteria for Parkinson Disease.
• Bothersome Pain - Defined as Severity score of 2 or more (Moderate pain of some distress to the patient); and Frequency score of 2 or more (at least 1 episode/week) in at least one pain domain according to King's Parkinson Disease Pain Scale (KPPS, see supplements);
• On stable PD medications in the month prior to enrollment.
• Drugs used to treat pain, including dopaminergic drugs, analgesics, non-steroidal anti-inflammatories and opiates will be allowed to be continued during the study period but doses must be unchanged.
• Women of childbearing age must be non-pregnant and using a reliable method of contraception and have a negative pregnancy test at screening. Acceptable methods of contraception include using oral injected or implanted methods of hormonal contraceptives for at least 3 months prior to randomization and the partner should also use a barrier method (e.g. condom) with spermicidal foam/gel/film/cream/suppository during this study. Additional pregnancy testing will be completed if necessary throughout the study duration.
• Subject agrees not to drive for the duration of the study.

Exclusion Criteria:

• Secondary parkinsonism (as per MDS Diagnostic Criteria).
• Previous serious adverse event or hypersensitivity to cannabis or cannabinoids
• Current use of cannabinoids or marijuana within 90 days prior to screening.
• Cognitive impairment or dementia (Montreal Cognitive Assessment/MoCA < 24).
• Current substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorder Fifth Edition (DSM-5) and lifetime history of dependence on cannabis or diagnosis of cannabis use disorder (CUD) according to the DSM-5
• History of clinically significant impulse control disorders: QUIP-RS- part A-D ≥ 10 and part E ≥ 7.
• Current suicidal ideation within one year prior to the second Screening Visit as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the C-SSRS or attempted suicide within the last 5 years.
• Symptomatic orthostatic hypotension or drop in (standing from sitting) blood pressure of >20 mmHg (systolic) and >10 mmHg (diastolic).
• Significant hepatic disease (AST, ALT, ALP >2xUpper Normal Limit).
• Normal renal function (defined as serum creatinine level <133 µmol/L and Estimated Glomerular Filtration Rate (eGFR) greater than or equal to 60)
• Uncontrolled and severe cardiovascular disease, as per clinical judgment.
• History of problematic substance abuse, or substance use disorder, whether of alcohol, prescription drugs or illicit drugs
• Other contra-indication as per Health Canada recommendation for use of cannabis - see reference 21.
• Inability or unwillingness of subject to give written informed consent.
• Participation in another investigational study at the time of recruitment or during the prior month.
• Clinical use of any exclusionary drugs listed in Appendix I of this protocol

This will be a double-blind study. The different cannabis oil formulations have the same colour, taste and smell. Study investigators will be blind to the dose/formulation of cannabis oil. Unblinding will only be performed in the event of a Serious AE. The site PI will maintain a randomization list kept in a locked secure 24h a day accessible location for emergency unblinding.