Clinical trial NCT03582137: A Study of Tolerability and Efficacy of Cannabidiol on Motor Symptoms in Parkinson's Disease
Official title: A Randomized, Double Blind, Placebo-controlled Parallel Study of Tolerability and Efficacy of Cannabidiol (CBD) on Motor Symptoms in Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Keywords: Parkinson's Disease
Motor symptoms
Tremor
tolerability
safety
cognition
anxiety
psychosis
mood
dyskinesia
sleep
cannabidiol
cannabis
efficacy
non-motor symptoms
quality of life
seborrhea
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Colorado Department of Public Health and Environment
First posted: 2018-07-10
Enrollment: 74
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The major purpose of this study is to assess the efficacy of CBD on motor symptoms of Parkinson's Disease (PD), and secondarily to study the safety and tolerability of CBD and other efficacy, particularly regarding tremor in PD. The study has been powered to detect a clinically significant reduction in Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) Part III motor scores. This is a 1:1 parallel, double-blind, randomized controlled trial (RCT) with 60 participants. The investigators will be recruiting up to 75 participants; the goal is to have 60 participants (30 in CBD group and 30 in placebo group) complete the study. The study drug is obtained from the National Institute on Drug Abuse (NIDA).

Detailed description: Persons with 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. Community-based studies have estimated the point prevalence for dementia in PD to be 28% and 44%.

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. Thus, it is crucial to treat these symptoms in order to optimize the management of PD patients.

Generally, however, 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 cannabis 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 Hospital Movement Disorders clinic about 5% of 207 PD patients, average age 69, reported using cannabis. In another study reported that 25% of PD patients had taken cannabis in the General University Hospital in Prague. In the investigators clinics, about 30% of the PD patients have asked doctors during their clinic visits over the past 6 months about cannabis. In an anonymous web-based survey, 72% PD patients reported current or past using medical cannabis, and 48% reducing prescription medication since beginning cannabis use.

PD mostly affects the elderly, and affected persons often have cognitive, psychiatric and motor problems, such as being prone to falling. Cannabis is well documented to cause psychosis, anxiety, slowness and incoordination. Studies have also shown that chronic users have structural and functional Central Nervous System (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 in of these various preparations in PD. Studies on safety and efficacy are greatly needed to protect this fragile Colorado population.

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. Given the current literature regarding CBD: possible neuroprotective effect, good tolerability, anxiolytic and antipsychotic effects and general lack of information in PD, including its effect on tremor, the investigators feel that it is important to study its use in PD further. The investigators hypothesized that it would reduce tremor, anxiety and psychosis, and would be well tolerated in PD.

The Specific Aims are:

Primary Specific Aim: To evaluate the efficacy of CBD on motor symptoms in PD, specifically on the motor section of the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS).

Secondary Specific Aim: To assess the safety and tolerability of CBD in PD, and to examine the effect of CBD on severity \& duration of intractable tremor, night-time sleep, rigidity, emotional dyscontrol, anxiety and pain in PD.

Exploratory Analyses:

To study the efficacy of CBD on cognition, psychosis, sleep, daytime sleepiness, mood, fatigue, impulsivity, bladder function, other motor and non-motor PD signs, restless legs syndrome and Rapid Eye Movement (REM) sleep behavior disorder and quality of life. To explore the effect of CBD on plasma levels in PD.

The study is a randomized, placebo controlled, double-blind parallel design with two treatment arms, each of approximately 2-3 weeks duration. In the 2-3 week treatment phase participants will start study drug and titrate up to the maximum tolerated or targeted dose (2.5 mg/kg/day of CBD). Each participant will have a screening visit, baseline visit within 3 weeks, 1 liver function monitoring visits on 3rd to 5th day of 2.5 mg/kg/day, 2 dose assessment visit (1.25 mg/kg/day and 2.5 mg/kg/day), and a safety visit (6 visits total). Participants will be evaluated on the 3rd to 5th day at each dose level for monitoring liver function and adverse events, as well as changes in medical history and concomitant medications. Participants are called 3 days and 1 week after stopping the study drug to check for signs of withdrawal.

Eligibility criteria: Inclusion criteria:

* Male or female participants 40 - 85 years of age.
* Willing and able to give informed consent (including through use of a legally authorized representative (LAR), if necessary).
* Idiopathic PD, per UK Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria
* ON motor MDS UPDRS \>20.
* Anti-parkinsonian medication is fixed for at least one month prior to the day the participant starts study drug treatment.
* If MoCA\<22 participant 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 or available transportation (including provided Uber vouchers) to drive them to and from study visits and for other transportation needs during the treatment period.
* Has a significant other (someone who knows the participant well) that is appropriate for doing the NPI assessment, 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.
* Cannabis is detectable at the screening visit by blood testing or at the baseline visit by urine testing. If cannabis is detected at either the screening or baseline visit, then the participant is a screen fail and may return \>14 days later for a repeat screening visit. If cannabis is again detected at either the screening or baseline visit, then the participant is excluded and not allowed to rescreen.
* History of drug or alcohol dependence; defined by prior inpatient stay(s) for this or that patient states 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 (nicotinic acid) at ≥2000 mg/day or nicotinamide (nicotinic acid amide or nicotinamide) at ≥3000 mg/day, 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:

Hemoglobin \< 10 g/dL WBC \<3.0 x 109/L Neutrophils \<1.5 x 109/L Lymphocytes \< 0.5 x 109/L Platelets \<100 x 109/L Hemoglobin A1C \> 9%

* Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3 times the upper limit of normal. Persons with stable liver disease of known etiology can be included, unless total bilirubin or prothrombin time/INR is abnormal.
* Is pregnant or lactating, or has a positive pregnancy test result pre-dose.
* If a sexually active female, is not surgically sterile or at least two years post-menopausal, or does not agree to utilize an effective method of contraception from screening through at least four weeks after the completion of study treatment, using one of the following: barrier methods (diaphragm or partner using condoms plus use of spermicidal jelly or foam, preferably double-barrier methods); oral or implanted hormonal contraceptive; intrauterine device (IUD); or vasectomized male partner.
* Planned elective surgery during study participation.

Primary outcomes:
measure: Change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (Motor Examination) Scores
timeFrame: From baseline to the end of 2.5 mg/kg/day of CBD, through 3 weeks
Secondary outcomes:
measure: The Number of Participants Wtih Treatment-related Adverse Events
timeFrame: Every 3-5 days at each dose level, assessed up to 3 weeks
measure: Change in Liver Function Monitoring --Liver Function Test
timeFrame: Baseline; at the end of 2.5 mg/kg/day; and every 3-5 days at each dose level, through 3 weeks.
measure: The Number of Participants Wtih Liver Function Impairment Related Adverse Events
timeFrame: Baseline; at the end of 2.5 mg/kg/day; and every 3-5 days at each dose level, through 3 weeks.
measure: Change in Blood Pressure (Systolic)
timeFrame: Baseline; at the end of 2.5 mg/kg/day, through 3 weeks
measure: Change in Vital Signs-heart Rate
timeFrame: Baseline; at the end of 2.5 mg/kg/day, through 3 weeks
measure: Change in Vital Signs--weight
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Vital Signs--temperature (Fahrenheit Degree)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Physical Exam
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Neurological Exam
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Electrocardiograms
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Laboratory Values--hematology
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Laboratory Values--chemistry
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Montreal Cognitive Assessment (MoCA)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Wechsler Test for Adult Reading
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Grooved Pegboard Test
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Symbol Digit Modalities Test
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Paced Auditory Serial Addition Test
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Controlled Oral Word Association Test
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Hopkins Verbal Learning Test-total Learning
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change From Baseline for the Delayed Recall Trials Score of HVLT-R
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change From Baseline in Hopkins Verbal Learning Test-Delayed Recognition Trial
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Judgment of Line Orientation
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Semantic Verbal Fluency
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Anxiety Short Form Response
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Neuropsychiatric Inventory (NPI)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Scales of Outcomes in Parkinson's Disease (SCOPA) Sleep-daytime Sleepiness
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Depression Short Form
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Emotional and Behavioral Dyscontrol Short Form
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Stanford Sleepiness Scale
timeFrame: Pre- and 3 hours post- dose at baseline visit
measure: Change in Pain Intensity 3a Short Form
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Pain Interference 4a Short Form
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Fatigue Severity Scale
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Movement Disorder Society Unified Parkinson Disease Rating Scale
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Unified Dyskinesia Rating Scale
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in the Timed UP&GO (TUG)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in IRLS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Overactive Bladder Symptom Score
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Parkinson's Disease Questionnaire (PDQ-39)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in EuroQol-5 Dimension-5 Level
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Difference in Proportion of Participants That Discontinue the Study Due to Study Drug Intolerance
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Total Scores on Items 3.17 and 3.18 in MDS-UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Item 2.10 in MDS UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Item 3.15 and 3.16 in MDS UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Rigidity Sub Scores in MDS UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Bradykinesia Sub Scores in MDS UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Axial Sub Scores in MDS UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Bulbar Sub Scores in MDS UPDRS
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Insomnia Severity Index
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Pittsburgh Sleep Quality Index
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Dermatology Quality of Life Index
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in the Number of Participants With Presence of Seborrheic Dermatitis From Baseline to Final Visit.
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Non-motor Symptoms Scale for Parkinson's Disease (NMSS)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Scales of Outcomes in Parkinson's Disease (SCOPA) - Daytime Sleep (DS) Problems.
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Scales of Outcomes in Parkinson's Disease (SCOPA) - Nighttime Sleep (NS) Problems.
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Modified Dysfunctional Beliefs and Attitudes About Sleep Questionnaire (DBAS-16)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Wake After Sleep Onset
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Difference of Plasma Interleukin 6 Level Between PD and Healthy Control Population
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS) - Total Scores
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
measure: Change in The Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: From baseline to the end of 2.5 mg/kg/day, assessed up to 3 weeks
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado hospital
state: Colorado
Study officials:
affiliation: University of Colorado School of Medicine
name: Maureen Leehey
role: PRINCIPAL_INVESTIGATOR
References: