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

A Randomized, Double Blind, Placebo-controlled Parallel Study of Tolerability and Efficacy of Cannabidiol (CBD) on Motor Symptoms in Parkinson's Disease

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).

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 Katerina Venderova and colleagues 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. 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.

Parkinson's Disease, Motor symptoms, Tremor, tolerability, safety, cognition, anxiety, psychosis, mood, dyskinesia, sleep, cannabidiol, cannabis, efficacy, non-motor symptoms, quality of life, seborrhea

Change in Movement Disorders Society-Unified Parkinson's disease rating scale (MDS-UPDRS) Part III (motor examination) scores

MDS UPDRS Part III assesses the motor signs of PD. There are 33 scores based on 18 items, several with right, left or other body distribution scores.Each question is anchored with five responses that are linked to commonly accepted clinical terms: 0=normal, 1=slight, 2=mild, 3=moderate, and 4=severe. The possible change may be the scores of the total 33 scores. Higher values represent a worse outcome.

Adverse events (AEs) are collected at each dose level. AEs collection include Serious Adverse Events (SAE), withdrawal symptoms and common AEs. SAE is antoward medical occurrence that results in death, or life-threatening, or inpatient hospitalization or prolongation of existing hospitalization or significant disability or incapacity or in a congenital anomaly/birth defect. Withdrawal and common AEs include headache, anxiety, nausea/vomiting, tremor, chills, decreased concentration, increased concentration, agitation, irritability, sleep disturbances, mood changes, somnolence, fatigue, anorexia, appetite changes, weight loss or gain, diarrhea, convulsion, abdominal pain, weakness, fever and other unexpected AEs. All of the these AEs will be recorded and counted.

Liver function tests will be performed and evaluated at each clinic visit from baseline through 3 weeks.. The change may be the values of the liver function test, including aspartate aminotransferase (AST), Alanine transaminase (ALT), Gamma-glutamyl transferase (GGT), Alkaline phosphatase (Alk Phos), Total Bilirubin (TB).

Liver function impairment will be evaluated and then related to adverse events and documented at each clinic visit. The change may be the frequency and severity of liver function impairment related AEs, including nausea/vomiting, diarrhea, abdominal pain, fatigue, weakness, chills, appetite changes, weight loss or gain, fever, etc.

Blood pressure (systolic and diastolic) measurements will be assessed through 3 weeks. The change may be the value of systolic and diastolic blood pressure.

The change may be complete physical exam findings, including allergic immunologic, cardiovascular, constitutional symptoms, ENT, endocrine, eyes, gastrointestinal, genitourinary, hematologic, integumentary, musculoskeletal, neurological, psychiatric, respiratory and other symptoms clinical significant findings.

The change may be general neurological exam clinical significant findings, including cranial nerves, motor strength, sensation, reflexes, gait, and other movements.

The change may be values of Chemistry profile, including BUN, CR, Electrolyte, glucose, liver function, etc.

Montreal Cognitive Assessment (MoCA) is a rapid screening instrument for mild cognitive dysfunction. The change may be the scores of MoCA, which is ranging from 0-30. Higher values represent a worse outcome.

The change may be the scores of Intellectual functioning estimate, Paced auditory serial addition test.

The change may be the scores of Intellectual functioning estimate, Controlled oral word association test.

The change may be the scores of Intellectual functioning estimate, Hopkins verbal learning test-revised.

Comprised of 8 items which has five response options. The change may be the total scores of the 8 items. Higher values represent a worse outcome.

Valid and reliable scale to provide a means of assessing neuropsychiatric symptoms and psychopathology of patients. The change may be the scores of NPI. Higher values represent a worse outcome.

Valid, reliable short scale for assessing nighttime sleep and daytime sleepiness in patients with PD. The change may be the sub-scores, including daytime and nighttime sleepiness scores. Higher values represent a worse outcome.

Is a quick and easy way to assess how the participant is feeling. The change may be the scores of the scale 3 hours after dosing compared to pre-dosing. Higher values represent a worse outcome.

Comprised of 8 items which item has five response options. The change may be the scores of the total 8 items. Higher values represent a worse outcome.

Comprised of 8 items which item has 5 response options. The change may be the total scores of the 8 items. Higher values represent a worse outcome.

Self-report 9-item questionnaire with questions related to how fatigue interferes with certain activities and rates its severity. The change may be the total scores of the 9 items, ranging from 9-63. Higher values represent worse outcome.

Assess how much a person hurts. The change may be the score of the short form. Higher values represent a worse outcome.

Self-reported consequences of pain on relevant aspects of one's life. The change may be the scores of the short form. Higher values represent a worse outcome.

To measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. The change may be the total and sub scores of QUIP-RS (hobbyism-punding and dopamine dysregulation syndrome). The total QUIP-RS scores is 0-112, total ICD score is 0-64. Subscores Gambling 0-16, sex 0-16, buying 0-16, eating 0-16, hobbyism-punding 0-32, and PD Medication use 0-16. Higher values represent a worse outcome.

Is a suicidal ideation rating scale. The change may be the answers to the questions of C-SSRS. There are ten categories and have binary responses (yes/no). Suicidal ideation score: the maximum suicidal ideation category (1-5 on the C-SSRS) present at the assessment. Assign a score of 0 if no ideation is present. Higher values represent a worse outcome.

Movement Disorder Society Unified Parkinson Disease Rating Scale. There are four parts, non-motor experiences of daily living, motor experiences of daily living, motor examination, and motor complications. The change may be the total scores of the four parts. Higher values represent a worse outcome.

To evaluate involuntary movements often associated with treated PD. The change may be the total scores of the scale, including historical sub-score (0-60) and objective sub-score (0-44). The total score is historical sub score plus objective sub score, ranged from 0- 104. Higher values represent a worse outcome.

To evaluate balance and walking ability associated with advancing age, neurological or other disorders. The change may be the time duration of performing the tusk.

International restless legs syndrome (IRLS) study group rating scale for restless legs syndrome. The change may be the scroes of the IRLS, ranged from 0-40. Higher values represent a worse outcome.

REM sleep behavior disorder screening questionnaire (RBDSQ). The change may be the total scores of RBDSQ. Maximum total score 13 points. Higher values represent a worse outcome.

A validated self-administered questionnaire consisting of 7 questions on a 5-point Likert scale. The change may be the scores of the scale, ranged from 0-35. Higher values represent a worse outcome.

A reliable valid responsive acceptable and feasible tool for assessment of quality of life in PD, including 390multiple-choice items covering 8 dimensions: mobility (#1-10), activities of daily living (#11-16), emotional well-being (#17-22), stigma (#23-26), social support (#27-29), cognition (#30-33), communication (#34-36), and bodily discomfort (#37-39). 5-point ordinal scoring system: 0=never, 1= occasionally, 2=sometimes, 3=often, 4=always. The change may be the total scores of PDQ-39, ranged from 0-156. Higher values represent a worse outcome.

Consists of 2 pages-the EuroQol-5 Dimension-5 level (EQ-5D-5L) descriptive system and the EuroQol (EQ) Visual analogue scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The VAS records the patient's self-rated health on a vertical visual analogue-scale, where the endpoints are labelled the best health you can imagine and the worst health you can imagine. The change may be the scales of EQ-5D.

Change in Proportion of participants that discontinue the study due to study drug intolerance. The change may be the number of patients dropped out.

Rest tremor amplitude and constancy of rest tremor scores in MDS UPDRS. The change may be the sum scores of 3.17 and 3.18. Score ranged from 0-24. Higher values represent a worse outcome.

Patient's tremor experience. The change may be the scores of item 2.10. Score ranged from 0-4. Higher values represent a worse outcome.

Postural tremor of the hands and kinetic tremor of the hand. The change may be the sum scores of item 3.15 and 3.16. Score ranged from 0-16. Higher values represent a worse outcome.

Rigidity sub scores in MDS UPDRS. The change may be the sub scores of rigidity related item in MDS UPDRS (item 3.3). Score ranged from 0-20. Higher values represent a worse outcome.

Bradykinesia sub scores in MDS UPDRS. The change may be the sub scores of bradykinesia related itmes in MDS UPDRS, including items 3.4-3.8, and 3.14. The scores ranged from 0-44. Higher values represent a worse outcome.

Axial sub scores in MDS UPDRS. The change may be the sub scores of axial related items in MDS UPDRS, including items 3.9, 3.13, 3.10, 3.11, and 3.12. The sub scores ranged from 0-20. Higher values represent a worse outcome.

Bulbar sub scores in MDS UPDRS (item 3.1 and 3.2). The change may be the sub scores of bulbar related items in MDS UPDRS, ranged from 0-8. Higher values represent a worse outcome.

7-item self-report questionnaire assessing the nature, severity, and impact of insomnia. The change may be the scores of ISI. Total scores is the sum of the all seven items. 0-7=no clinically significant insomnia. 8-14=subthreshold insomnia. 15-21=clinical insomnia (moderate severity). 22-28=clinical insomnia (severe). Higher values represent a worse outcome.

Self reported questionnaire to identify and assess various sleep/insomnia-related cognition (e.g., beliefs, attitudes, expectations, appraisals, attributions). For each statement, the person rates his or her level of agreement/disagreement on a 100-mm visual analog scale anchored at one end by strongly disagree and at the other by strongly agree. The change may be the scores of the questionnaire.

To measure the quality and patterns of sleep in adults. It differentiates "poor" from "good" sleep quality by measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. The change may be the total scores, ranged from 0 to 42. The higher values represent a worse outcome.

Home sleep monitory with polysomnograph. The change may be the values of the PSG parameters compared to the value of normal population. The higher values represent a worse outcome.

Dermatology quality of life index. The change may be the scores of the questionnaire. The scoring of each question is as follows: very much=3, a lot =2, a little=1, not at all=0, not relevant =0. Question 7, prevented work or studying =3. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired.

Validated 30-item scale for the assessment of NMS in PD. Each symptom scored with respect to severity (0=none, 1=mild, 2=moderate, 3=severe), frequency (1=rarely, 2=often, 3=frequent, 4=very frequent). The change may be the total scores of NMSS, ranged from 0 to 360. The higher values represent a worse outcome.

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.