A Study of Tolerability and Efficacy of Cannabidiol on Tremor in Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease; Tremor
Study type: Interventional
Phase: Phase 2

Summary: 
      The major purpose of the Stage 1 is to study the safety and tolerability of the proposed
      dosage regimen of the study drug. The form of cannabidiol (CBD) used in this study is
      GWP42003, supplied by GW Pharmaceuticals. The dosage regime is based on their experience.
      This is an open label study in 10 subjects, during which the dose is gradually increased to
      the manufacturers recommended target dose, with tolerability being evaluated at each dose
      level. Based on the response of subjects in the Stage 1, a target dose is determined for the
      next stage. Standardized tools will be administered to study both tolerability and efficacy.
      Efficacy assessments are simply explorative, and are done to look for an effect that warrants
      specific or different evaluation in the next stage.
    

Detailed description: 
      Persons with Parkinson's disease (PD) have progressive disabling tremor, slowness, stiffness,
      balance impairment, cognitive deficits, psychiatric symptoms, autonomic dysfunction, fatigue
      and insomnia. Tremor may interfere with necessary daily and work functions. The disorder
      affects approximately seven million people globally. The total economic cost in the US is
      around 23 billion dollars. In addition to economic costs, PD reduces quality of life of those
      affected and their caregivers.

      Cognitive impairment is a common feature and ranges from delayed recall in early stages to
      global dementia in up to 80% at end stage. PD with dementia has been associated with reduced
      quality of life, shortened survival, and increased caregiver distress.

      Depression, anxiety and psychosis are also common and are particularly disabling in PD, even
      at the earliest stages. These symptoms have important consequences for quality of life and
      daily functioning, are associated with increased carer burden and risk for nursing home
      admission. Anxiety affects up to 40% of patients with PD, and may predate motor symptoms by
      several years. The most common anxiety disorders in PD are panic attacks (often during
      off-periods), generalized anxiety disorder, and simple and social phobias. Psychotic symptoms
      vary in frequency according to the definition used. If mild forms are included, these affect
      up to 50% of patients. Visual hallucinations are the most common type. However,
      hallucinations occur in all sensory domains and delusions of various types are also
      relatively common. The impact of psychosis is substantial in that it is associated with
      dementia, depression, earlier mortality, greater caregiver strain, and nursing home
      placement.

      Current therapies are inadequate. Medications have improved the prognosis of PD, but also
      have problematic adverse effects. Since treatment of PD is often unsatisfactory and since
      marijuana has recently become legal and readily available in Colorado, persons with PD have
      been trying it. Patients have heard from the internet, support groups and other sources that
      marijuana is helpful. Most are doing so on their own, without the supervision or even
      knowledge of their neurologist. In a survey conducted in the spring of 2014 in University of
      Colorado Movement Disorders Center (UCMDC) clinic about 5% of 207 PD patients, average age
      69, reported using marijuana. In the same clinic, about 30% of the PD patients have asked
      doctors during their visits over the past 6 months about marijuana. In another study Katerina
      Venderova and colleagues reported that 25% of PD patients had taken cannabis in the General
      University Hospital in Prague.

      PD mostly affects the elderly, and with the cognitive, psychiatric and motor problems,
      subjects are prone to falls. Cannabis is well documented to cause psychosis, slowness, and
      incoordination. Studies have also shown that chronic users have structural and functional CNS
      alterations. Thus cannabis is expected to be risky in persons with PD. Further, there are
      many components of cannabis, and the cannabis preparations being sold in Colorado vary widely
      in composition. There are no definitive data regarding the benefits and risks of these
      various preparations in PD. Studies on safety and efficacy are greatly needed to protect this
      fragile Colorado population.

      Cannabidiol (CBD) is a cannabinoid that is present to a lesser extent in street marijuana,
      and limits delta-9-tetrahydrocannabinol (THC)'s psychoactive effect. CBD acts in some
      experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic,
      anxiolytic and antipsychotic agent, and therefore has potential beneficial medical uses.
      Further, animal studies suggest that CBD is neuroprotective, perhaps due to reported
      anti-oxidative and anti-inflammatory actions.

      Human trials report that CBD decreases anxiety and causes sedation in healthy individuals,
      decreases psychotic symptoms in schizophrenia and PD, and improves motor and non-motor
      symptoms and alleviates levodopa-induced dyskinesia in PD. The ratio of THC to CBD plays a
      role in the preparation's therapeutic outcome: strains of cannabis with higher concentrations
      of CBD did not produce short-term memory impairment vs. strains with higher concentrations of
      THC and lower concentrations of CBD.

      Many clinicians who suspect cannabis may have a positive effective upon a particular patient
      group have no idea of the cannabinoid profile that is being used. Without knowing the
      composition, it is impossible to draw any conclusions simply because of the huge variety of
      strains utilised.

      Given the current literature regarding CBD: possible neuroprotective effect, good
      tolerability, anxiolytic and antipsychotic effects and general lack of be well tolerated in
      PD, including its effect on tremor, the investigators hypothesize that CBD would be well
      tolerated and would reduce tremor, anxiety and psychosis, and would stabilize cognitive
      decline in PD. First the investigators will perform an open label study to determine a
      reasonable dose, and then a randomized, double-blind, placebo-controlled crossover study to
      evaluate the efficacy and tolerability of oral CBD on tremor and other important aspects of
      PD. A strength of the study is that it uses well defined form or CBD.

      Stage 1: Open Label Dose Escalation Tolerability Study

      Primary Specific Aim: To confirm that the dosage regimen of CBD, in the form of GWP42003-P
      recommended by the study drug manufacturer is safe and tolerated in 10 subjects with PD.
      GWP42003-P is started at 5 mg/kg/day and is increased by 5 mg/kg at 3 day intervals to a
      target dose of 25 mg/kg/day.

      Secondary Specific Aim: To examine the effect of CBD on severity & duration of tremor and
      other conditions that are problematic in PD.

      The dose escalation tolerability study will be conducted in 10 subjects (the investigators
      will be recruiting up to 15 subjects to end up with 10) as an open label study lasting
      approximately 3 weeks followed by a 2-week safety follow up. Subjects are closely monitored
      as the dose is titrated. Subjects will have a screening visit, a baseline visit within the
      next three weeks, a visit when subjects are on 20 mg/kg/day, a final assessment visit when
      subjects have been on the maximal tolerated or the targeted dose for 10-15 days, and a safety
      visit 2 weeks later. The subject is to be on the maximal tolerated or targeted dose for 10-15
      days. Subjects will be called on the 3rd day of each dose. During phone calls subjects are
      monitored for adverse events, especially excessive daytime sleepiness, symptoms of
      hepatotoxicity, as well as changes in medical history and concomitant medications. Subjects
      are also called 3 days after stopping the study drug to check for signs of withdrawal.
    

Intervention name(s): cannabidiol
Intervention type(s): Drug
Intervention description(s): Purified CBD, is a strawberry flavored liquid, in sesame oil, provided as 100 mg/ml, extracted from high CBD plant material.
A component of cannabis that has evidence suggesting it is relatively safe and perhaps neuroprotective, reduces tremor, anxiety and psychosis and is well tolerated in PD. Besides limiting the psychoactive effect of THC, studies support that CBD has anti-inflammatory, anticonvulsant, anti-oxidant, anxiolytic and antipsychotic properties.
Other intervention name(s): GWP42003-P
Intervention MeSH terms: Cannabidiol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Parkinson's Disease; Tremor; tolerability; safety; cognition; anxiety; psychosis; mood; dyskinesia; cannabidiol; cannabis; efficacy; sleep; motor symptoms; non-motor symptoms; quality of life; marijuana