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A Study of Tolerability and Efficacy of Cannabidiol on Tremor in Parkinson's Disease

This study is currently recruiting participants.
Verified April 2017 by University of Colorado, Denver
Sponsor:
ClinicalTrials.gov Identifier:
NCT02818777
First Posted: June 30, 2016
Last Update Posted: April 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Colorado Department of Public Health and Environment
GW Research Ltd
Information provided by (Responsible Party):
University of Colorado, Denver
  Purpose

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.


Condition Intervention Phase
Parkinson's Disease Drug: cannabidiol Drug: placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind, Placebo-controlled Crossover Study of Tolerability and Efficacy of Cannabidiol (CBD) on Tremor in Parkinson's Disease

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Frequency of study-related adverse events at each dose level [ Time Frame: Stage 1: Every 3rd day on each dose level, assessed up to 5 weeks; Stage 2: Every 3rd day on each dose level, assessed up to 19 weeks. ]
    Adverse events are measured primarily by a standardized phone script administered at each dose level. The phone script starts with an open ended question (Do you notice any effects, good or bad, of the study drug?) and followed by a series of yes/no questions regarding adverse effects (including previously reported adverse effects of CBD and general common adverse effects of medications), and all the effects we hypothesize in the study. For each adverse and beneficial reported effect, further questions will be asked, such as when did the effect start and how is it progressing, etc. In addition, since a major dose limiting effect, per GW, is somnolence, the daytime sleepiness part of the SCOPA-sleep is included in the phone script.

  • Changes in Vital Signs [ Time Frame: Stage 1: Baseline to end of treatment phase up to 3 weeks. Stage 2: Baseline to end of each treatment phase up to 7 weeks and 15 weeks for each treatment period. ]
    Vital signs will be monitored at each dose level, e.g. at each study visit.

  • Changes in Physical Exam [ Time Frame: Stage 1: Baseline to end of treatment phase up to 3 weeks. Stage 2: Baseline to end of each treatment phase up to 7 weeks and 15 weeks for each treatment period. ]
    A physical exam will be performed at each dose level, e.g. at each study visit.

  • Changes in EKG [ Time Frame: Stage 1: Baseline to end of treatment phase up to 3 weeks. Stage 2: Baseline to end of each treatment phase up to 7 weeks and 15 weeks for each treatment period. ]
    A physical exam will be performed at each dose level, e.g. at each study visit.

  • Changes in Laboratory Values [ Time Frame: Stage 1: Baseline to end of treatment phase up to 3 weeks. Stage 2: Baseline to end of each treatment phase up to 7 weeks and 15 weeks for each treatment period. ]
    Laboratory tests (hematology, serum chemistry, and urinalysis) will be evaluated at each dose level, e.g. at each study visit.

  • Proportion of subjects that drop out of the study due to study drug intolerance [ Time Frame: Stage 1: Baseline to end of treatment phase up to 3 weeks. Stage 2: Baseline to end of each treatment phase up to 7 weeks and 15 weeks for each treatment period. ]
    Assessing the proportion of subjects that drop out of the study due to study drug intolerance.

  • Change in MDS-UPDRS total score [ 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).

  • Change in Montreal Cognitive Assessment (MoCA) [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    MoCA - is designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visual -constructional skills, conceptual thinking, calculation

  • Change in Cognitive Assessment Battery [ Time Frame: Stage 2: Baseline to each end of treatment phase (day 47+/-4, 115+/-4). ]
    Intellectual functioning estimate, e.g.: attention/processing speed/executive functioning, memory functioning, language functioning.

  • Change in Anxiety short form [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    This includes 8 items that assess severity of anxiety

  • Change in Neuropsychiatric Inventory (NPI) [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    Assessing neuropsychiatric symptoms and psychopathology of patients with Alzheimer's disease and other neurodegenerative disorders. It has proven to be sensitive to change and has been employed to capture treatment related behavioral.

  • Change in Depression short form [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    This includes 8 items that assess severity of depression

  • Change in Scales for Outcomes in Parkinson's disease (SCOPA)-sleep [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    A valid, reliable, short scale that is used to evaluate sleep problems (nighttime and daytime sleep) in PD.

  • Change from baseline of REM sleep behavior disorder screening questionnaire (RBDSQ) [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    10-item, patient self-rating instrument assessing the subject's sleep behavior with short questions that have to be answered by either "yes" or "no".

  • Change in emotional and behavioral dyscontrol short form [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    8 items that assess severity of emotional and behavioral dyscontrol.

  • Change in Pain severity and intensity short form [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    This will assess severity and intensity of pain

  • Change in Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    To measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD.

  • Change in Fatigue severity scale [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    A self-report 9-item questionnaire with questions related to how fatigue interferes with certain activities and rates its severity.

  • Change in International Restless Legs Syndrome Study Group Rating Scale for restless [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    This encompasses a ten-question instrument for measuring severity of restless legs syndrome (RLS)

  • Change in The 39-item Parkinson's Disease Questionnaire (PDQ-39) [ Time Frame: 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). ]
    A reliable, valid, responsive, acceptable and feasible as the tool for the assessment of quality of life in Parkinson's disease patients

  • Change in EuroQoL-5 Dimension 5 level (EQ-5D-5L) [ Time Frame: 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). ]
    Consists of 2 pages-the EQ-5D-5L descriptive system and the EQ Visual Analogue

  • Change in Rapid Paced Walk test [ Time Frame: 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). ]
    To assesses stride length, balance and overall mobility, all of which can be impaired in PD

  • Change in Unified Dyskinesia Rating Scale (UDysRS) [ Time Frame: Stage 1: Baseline to day 22-27. 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). ]
    To evaluate involuntary movements often associated with treated Parkinson's disease.


Secondary Outcome Measures:
  • 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).


Estimated Enrollment: 60
Study Start Date: July 2016
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: cannabidiol

GWP42003-P oral solution, is purified cannabidiol (purity of ≥98%, 100 mg/ml cannabidiol in sesame oil with anhydrous ethanol with added sweetener (sucralose) and strawberry flavoring).

Started at 5 mg/kg/day and is increased by 2.5-5 mg/kg at 3-5 day intervals to a target dose of 20 mg/kg/day.

Drug: cannabidiol

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 Name: GWP42003-P
Placebo Comparator: placebo
Same with GWP42003-P, except for the active product, CBD. Started at 5 mg/kg/day and is increased by 2.5-5 mg/kg at 3-5 day intervals to a target dose of 20 mg/kg/day.
Drug: placebo
Other Name: The placebo is the same with GWP42003-P, but without CBD

  Hide Detailed Description

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.

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.

Exploratory Aims:

  1. To study the effects of CBD on cognition, anxiety, psychosis, sleep, daytime sleepiness, mood, fatigue, pain, impulsivity, other motor and non-motor PD signs, restless legs syndrome and REM sleep behavior disorder.
  2. To evaluate the effects of CBD on these same conditions at a low dose.

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   45 Years to 78 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Stage 1:

Inclusion criteria:

  • Male or female subjects between 45 and 78 years of age inclusive.
  • Willing and able to give informed consent.
  • Idiopathic PD, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria
  • Rest tremor amplitude score of ≥2 in any limb on question 3.17 of the MDS-UPDRS (ON state).
  • Anti-parkinsonian medication is fixed for at least 1 month prior to study entry
  • If MoCA<22 subject must have a legally authorized representative (LAR) sign the consent, and must have a designated caregiver that agrees to ensure study protocols followed. This includes accompanying patient to study visits and being available for study phone calls.
  • Must have a driver to drive them to and from study visits
  • Has a significant other (someone who knows the subject well) that is appropriate for doing the NPI assessment, can accompany patient to study visits, and agrees to do so
  • Agrees to not take more than 1 gram per day of acetaminophen, due to a possible interaction with study drug that could increase risk of hepatotoxicity.

Exclusion criteria:

  • Known or suspected allergy to cannabinoids or excipients used in the study drug formulation.
  • Cannabinoids taken currently or in the previous 30 days.
  • History of drug or alcohol dependence; defined by prior inpatient stay(s) for this or that patient stats s/he has a history of this.
  • Use of dopamine blockers within 180 days and amphetamine, cocaine, and MAO-A inhibitors within 90 days of baseline.
  • Currently taking tolcapone, valproic acid, felbamate, niacin, isoniazid and ketoconazole due to risk of liver injury and clobazam and ketoconazole because of risk of toxic interactions with the study drug. These medications need to be stopped 90 days before the baseline visit.
  • Unstable medical condition.
  • Any of the following laboratory test results at screening:
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02818777


Contacts
Contact: Maureen A Leehey, M.D. 1-303-724-2194 maureen.leehey@ucdenver.edu
Contact: Ying Liu, M.D. 1-720-921-4815 YING.3.LIU@UCDENVER.EDU

Locations
United States, Colorado
University of Colorado School of Medicine Recruiting
Aurora, Colorado, United States, 80045
Contact: Maureen A Leehey, M.D.    303-724-2194    maureen.leehey@ucdenver.edu   
Contact: Ying Liu, M.D.    13037244337    YING.3.LIU@UCDENVER.EDU   
Principal Investigator: Maureen A Leehey, M.D.         
Sub-Investigator: Olga S Klepitskaya, M.D.         
Sub-Investigator: Lauren C Seeberger, M.D.         
Sponsors and Collaborators
University of Colorado, Denver
Colorado Department of Public Health and Environment
GW Research Ltd
Investigators
Principal Investigator: Maureen A Leehey, M.D. University of Colorado, Denver
  More Information

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT02818777     History of Changes
Other Study ID Numbers: 15-0929
First Submitted: May 6, 2016
First Posted: June 30, 2016
Last Update Posted: April 28, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by University of Colorado, Denver:
Parkinson's Disease
Tremor
tolerability
safety
cognition
anxiety
psychosis
mood
dyskinesia
cannabidiol
cannabis
efficacy
sleep
motor symptoms
non-motor symptoms
quality of life
marijuana

Additional relevant MeSH terms:
Parkinson Disease
Tremor
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Dyskinesias
Neurologic Manifestations
Signs and Symptoms