A Study of Tolerability and Efficacy of Cannabidiol on Tremor in Parkinson's Disease
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|ClinicalTrials.gov Identifier: NCT02818777|
Recruitment Status : Recruiting
First Posted : June 30, 2016
Last Update Posted : April 28, 2017
|First Submitted Date ICMJE||May 6, 2016|
|First Posted Date ICMJE||June 30, 2016|
|Last Update Posted Date||April 28, 2017|
|Start Date ICMJE||July 2016|
|Estimated Primary Completion Date||December 2018 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT02818777 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Change in MDS-UPDRS tremor score (total of Items 3.17 and 3.18) in the ON state [ Time Frame: Stage 1: Baseline to day 22-27, baseline to day 36 +/-4. Stage 2: Baseline to each low dose visit (day 10-15, 78-83), baseline to each end of treatment phase (day 47+/-4, 115+/-4), baseline to day 129+/-4.] ]
There are four parts: Part I (Non-motor experiences of daily living), Part II (motor experiences of daily living), Part III (motor examination) and Part IV (motor complications).
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Study of Tolerability and Efficacy of Cannabidiol on Tremor in Parkinson's Disease|
|Official Title ICMJE||A Randomized, Double Blind, Placebo-controlled Crossover Study of Tolerability and Efficacy of Cannabidiol (CBD) on Tremor in Parkinson's Disease|
There are two stages in the study. 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.
The major purpose of Stage 2 is to assess the safety and tolerability of the GWP42003-P at the determined dose, and secondarily to study efficacy, particularly regarding tremor. Stage 2 is a crossover, double-blind, randomized controlled trial (RCT) with 50 subjects.
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.
Stage 2: Randomized, Controlled Trial
Primary Specific Aim: To evaluate the safety and tolerability of CBD, in the form of GWP42003-P, in PD.
Secondary Specific Aim: To examine the effect of CBD on severity & duration of intractable tremor 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.
The main study is a randomized, placebo controlled, double-blind crossover design with two treatment phases, each of approximately 7 weeks duration separated by a 3-week washout phase. In each 7 week treatment phase subjects will start study drug and titrated up to the maximum tolerated or targeted dose (25 mg/kg/day). Each subject will have a screening visit, baseline visit within 3 weeks, a low dose visit (when on 5 mg/kg/day for 10-15 days), a visit when on 20 mg/kg/day, a first end of 7 weeks treatment phase visit (subject reaches maximum tolerated or targeted dose), a start of second 7-week treatment phase visit, a low dose visit (when on 5 mg/kg/day for 10-15 days), a visit when on 20 mg/kg/day, a second end of 7 weeks treatment phase visit and a safety visit (10 visits total). At the start of second 7-week treatment phase, subjects are dispensed and instructed to take study drug for the next treatment phase. Subjects will be called every 3rd day during dose escalation and every 10th day during the dose maintenance period (up to 25 mg/kg/day). During phone calls subjects are monitored for adverse events, symptoms of hepatotoxicity, and changes in medical history and concomitant medications. Subjects are also called 3 days after stopping the study drug to check for signs of withdrawal. Further, in case CBD alters the reliability of self - report, repeated measures will be taken of a set of tests three times: at baseline, low dose and high dose. During the 10 days that subjects are on a low dose the measurements will be taken on the 3rd and 9th day by phone and at the visit on the 10th to 15th day. During the 28 days on high dose the measurements will be taken on the 12th and 22nd day by phone and at the visit on the 28th +/- 4 days. The phone assessments include the primary outcome (assessment of tolerability), SCOPA-sleep, Anxiety short form, Depression short form, Emotional and behavioral dyscontrol short form, and EQ-5D-5L.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Condition ICMJE||Parkinson's Disease|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||60|
|Estimated Completion Date||June 2019|
|Estimated Primary Completion Date||December 2018 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||45 Years to 78 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02818777|
|Other Study ID Numbers ICMJE||15-0929|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||University of Colorado, Denver|
|Study Sponsor ICMJE||University of Colorado, Denver|
|PRS Account||University of Colorado, Denver|
|Verification Date||April 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP