Clinical trial NCT02818777
Conditions: Parkinson's Disease
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
Sponsor: University of Colorado, Denver
Start date: 2016-10-01; Completion date: 2017-11-01
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief 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.

Arms: arm 1: 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.
Interventions: intervention 1: cannabidiol
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
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w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #:15-0929 
Project Title: A randomized, double blind, placebo-controlled crossover study of tolerability and efficacy 
of Cannabidiol (CBD) on tremor in Parkinson’s disease 
 
 
 
 
Principal Investigator: Maureen Anne Leehey, MD 
 
Version Date:  12May2017 
 
 
 
 
 
  
 
I. 
Hypotheses and Specific Aims:  
 
Parkinson disease (PD) is a relatively common, progressive, disabiling disorder that responds partially to 
symptomatic treatments. Since cannabis has become legal in Colorado, many persons with PD have been 
trying it to see if it relieves any of their symptoms. According to published and anecdotal reports cannabidiol 
(CBD), is a component of cannabis, has potential beneficial medical uses. However, the safety, tolerability, 
dose and benefits are unknown. 
 
There are many forms of CBD being marketed. In this study we are using Epidiolex, because it is >99% pure 
CBD with only a trace amount of THC (<0.15%) and because it has more data on it regarding safety, 
tolerability, dosing and efficacy than most other forms. It is manufactured by GW Pharmaceuticals and 
currently it is being used in four FDA approved epilepsy studies. GW has determined a dose range that is best 
tolerated and effective in psychosis and seizure disorders. These studies are described in the Investigational 
Brochure (IB) Edition 8, Section 7.3.1. The largest cohort of subjects have been in epilepsy studies, and the 
majority of them were pediatric. Because there is no definitive published data on what dose of Epidiolex is 
best tolerated and effective in an adult population with a neurodegenerative disease, PD, this study is 
conducted in two stages.  
• 
The major purpose of the Stage 1 is to study the safety and tolerability of the proposed dosage 
regimen, which is based on GW Pharmaceutical’s 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 Epidiolex 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.   
 


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Our Hypotheses are:  
 
Stage 1: Open Label Dose Escalation Tolerability Study 
(1) Epidiolex, a purified form of cannabidiol (CBD) manufactured by GW Pharmaceuticals, is safe and 
tolerated in Parkinson disease (PD) patients using the dosing regimen recommended by GW. 
(2) Epidiolex has some beneficial effect on PD tremor and other conditions that occur in PD.  
 
Stage 2: Randomized, Controlled Trial 
(1) CBD, in the form of Epidiolex, is safe and tolerated in PD. 
(2) CBD has a significant treatment effect on PD tremor. 
(3) CBD has a some beneficial effect on other conditions that occur in PD - 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. 
(4) CBD has some beneficial effect on these same conditions, particularly on anxiety, at a low dose. 
 
Our Specific Aims are: 
 
Stage 1: Open Label Dose Escalation Tolerability Study 
Primary Specific Aim: To confirm that the dosage regimen of CBD, in the form of Epidiolex recommended 
by the study drug manufacturer is safe and tolerated in 10 subjects with PD. Epidiolex is started at 5 
mg/kg/day and is increased every 3 days by 2.5 mg/kg/day to 10 mg/kg/day. Then increase the dosage every 
5 days by 5 mg/kg/day to a target dose of 20 mg/kg/day. 
Secondary Specific Aim: To examine the effect of CBD on severity & duration of tremor and other 
conditions that occur in PD. 
  
Stage 2: Randomized, Controlled Trial 
Primary Specific Aim: To evaluate the safety and tolerability of CBD, in the form of Epidiolex, in PD. 
Secondary Specific Aim: To examine the effect of CBD on severity & duration of intractable tremor in PD. 
Exploratory Analyses:   
(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.  
   


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II.    Background and Significance:  
 
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 [Yao, S.C, et al. 2013; de Lau LM, et al. 2006]. The total economic cost in the US is around 23 
billion dollars [Findley LJ. 2007]. 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 [Schrag A, et al. 
2000], shortened survival [Nussbaum M, et al. 1998], and increased caregiver distress [Aarsland D, et al. 
1999]. Community-based studies have estimated the point prevalence for dementia in PD to be 28% and 44% 
[Mayeux R, et al. 1992; Aarsland D, et al. 1996; Hobson P, et al. 2004; Marttila RJ, et al. 1976]. 
 
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 [Menza MA, et al. 1993; Richard IH. 2005; Leentjens AF, et al. 2008; Stein MB, et al. 1990; Nuti A, et al. 
2004; Lauterbach EC, et al. 2004; Aarsland D, et al. 2009], 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. [Aarsland D, et al. 2009, Soulas 
T, et al. 2008.] 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 identify these symptoms in order to optimize the management of PD patients.  
 
Current therapies are inadequate. Medications have improved the prognosis of PD, but also have problematic 
adverse effects [Poewe W. 2006]. 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 [Finseth TA. et al. 2015]. In another study Katerina Venderova and 
colleagues reported that 25% of PD patients had taken cannabis in the General University Hospital in Prague 
[Venderova K, et al. 2004]. In UCMDC, about 30% of the PD patients have asked doctors during their clinic 
visits over the past 6 months about marijuana. 
 
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, slowness, and 
incoordination. Studies have also shown that chronic users have structural and functional CNS alterations 
[Sneider JT., et al. 2013; Matochik JA., et al. 2005; Jager G., et al. 2010; James A, et al. 2011; Battistella G., 
et al. 2014; Gruber SA., et al. 2005; Stone JM., et al. 2012]. Thus cannabis is expected to be risky in persons 


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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.  
 
Cannabis is composed of many cannabinoid compounds and other substances. Cannabidiol (CBD) is a 
cannabinoid that is present to a lesser extent in street marijuana, and limits Delta-9-tetrahydrocannabinol 
(THC)’s psychoactive effect [Bhattacharryya S et al, 2010; Hayakawa K, et al. 2008; Atakan Z. 2012]. 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 [Zhornitsky S, et al. 2012; Crippa 
JA, et al. 2011; Iuvone T, et al. 2009]. Further, animal studies suggest that CBD is neuroprotective, perhaps 
due to reported anti-oxidative [Lastres-Becker I, et al. 2005; García-Arencibia M et al. 2007; Hayakawa K, et 
al. 2007] and anti-inflammatory actions [Mecha M, et al. 2013].  
 
Human trials report that CBD decreases anxiety and causes sedation in healthy individuals, decreases 
psychotic symptoms in schizophrenia [Zuardi AW, et al, 2006; Leweke FM et al. 2012] and PD [Zuardi AW, et 
al. 2009], and improves motor and non-motor symptoms and alleviates levodopa-induced dyskinesia in PD 
[Venderova K., et al. 2004; Lotan I, et al. 2014; Chaqas MH, et al. 2014; Zuardi AW, et al. 2009]. 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 similar concentrations 
of THC, but lower concentrations of CBD [Englund A et al. 2013]. 
 
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 information in PD, including its effect on tremor, we hypothesize that 
CBD would reduce tremor, anxiety and psychosis, stabilize cognitive decline and would be well tolerated in 
PD. This is 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.  
 
III.   Preliminary Studies/Progress Report:  
 
American Academy of Neurology (AAN) Guideline Development Subcommittee performed a systematic 
review of medical marijuana to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and 
movement disorders [Koppel BS, et al. 2014]. In patients with MS, oral cannabis extract is effective, and 
nabiximols (Sativex, GW Pharmaceuticals, 1:1 ratio of CBD to THC, with a fixed dose of 2.7 mg THC and 2.5 
mg CBD) and THC are probably effective for spasticity, central pain or painful spasms; nabiximols is probably 
effective for reducing bladder voids/day. Oral cannabis extract is probably ineffective for treating levodopa-


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induced dyskinesia in patients with PD. Oral forms of cannabis are of unknown efficacy in non-chorea-related 
symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy.  
 
CBD is a cannabinoid that is present to a lesser extent in street marijuana, and limits THC’s psychoactive 
effect [Bhattacharryya S et al, 2010; Hayakawa K, et al. 2008; Atakan Z. 2012]. 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 [Zhornitsky S, et al. 2012; Crippa JA, 
et al. 2011; Iuvone T, et al. 2009]. Further, animal studies suggest that CBD is neuroprotective, perhaps due 
to reported anti-oxidative [Lastres-Becker I, et al. 2005; García-Arencibia M et al. 2007; Hayakawa K, et al. 
2007] and anti-inflammatory actions [Mecha M, et al. 2013].  
 
CBD undergoes a significant first-pass effect leading to the formation of a number of metabolites, most 
notably, 7-hydroxy-CBD and CBD-7-oic acid [Agurell, S. et al. 1986; Harvey, D.J. 1990]. The half-life of CBD 
in humans was found to be between 18–33 hours following intravenous administration, 27–35 hours following 
smoking, and 2–5 days following oral administration. Bioavailability of oral and smoked CBD in humans was 
found to be around 6% and 31%, respectively, providing further support for a substantial first-pass effect 
[Agurell, S. et al. 1986; Consroe, P. et al. 1991; Ohlsson, A. et al. 1986; Guy, GW. et al. 2004]. Oral 
administration of CBD (~700 mg) over six weeks to 14 Huntington’s disease patients resulted in a low, narrow 
plasma range of 5.9–11.2 ng/mL [Consroe, P. et al. 1991]. Oral cannabis extract (10 mg ∆9-THC; 10 mg CBD) 
produced markedly lower levels of CBD (range = 0–2.6 ng/mL) at 30–120 minutes after administration and 
absorption was increased with food [Nadulski, T. et al. 2005a; Nadulski, T. et al. 2005b].  
 
Human trials report that CBD decreases anxiety and causes sedation in healthy individuals, decreases 
psychotic symptoms in schizophrenia [Zuardi AW, et al, 2006; Leweke FM et al. 2012] and PD [Zuardi AW, et 
al. 2009], and may improve motor and non-motor symptoms and alleviate levodopa-induced dyskinesia in PD 
[KaterˇinaVenderova´, et al. 2004; Lotan I, et al. 2014; Chaqas MH, et al. 2014; Zuardi AW, et al. 2008]. 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 similar concentrations 
of THC, but lower concentrations of CBD [Englund A et al. 2013].  
 
 
A few studies have been reported that tested varied cannabis compositions in PD. A Class I double-blind 
crossover study examined the effectiveness of an extract of cannabis sativa standardized to 2.5 mg of Δ9 -
THC and 1.25 mg of cannabidiol per capsule in the treatment of levodopa-induced dyskinesias in 19 patients 
[Carroll CB, et al. 2004] and concluded that cannabis is probably ineffective. Note that the CBD dose used 
was very low. In an open-label observational study, 22 patients with PD were evaluated at baseline and 30 
minutes after smoking cannabis to assess the clinical effect of cannabis on motor and non-motor symptoms of 
PD. There was significant improvement of sleep and pain scores. No significant adverse effects of the drug 
were observed [Lotan I, et al. 2014]. An anonymous questionnaire sent to all PD patients attending the Prague 
Movement Disorder Centre revealed that 85 (25%) out of 339 respondents had taken cannabis and 39 
patients (45.9%) described mild or substantial alleviation of their PD symptoms in general, 26 (30.6%) 
improvement of rest tremor, 38 (44.7%) alleviation of bradykinesia, 32 (37.7%) alleviation of muscle rigidity, 
and 12 (14.1%) improvement of L-dopa-induced dyskinesias. Only 4 patients (4.7%) reported that cannabis 
actually worsened their symptoms [Venderová K, et al. 2004]. In another study, 5 patients with PD and severe 


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tremor were given marijuana smoked as a cigarette in addition to other medications, including diazepam, 
levodopa/carbidopa and apomorphine. None of the patients experienced relief or demonstrated improvement 
of tremor following marijuana [Frankel J.P., et al. 1990]. 
 
Also, a few studies have been reported that tested CBD in PD. In a double-blind trial [Chagas MH, et al. 
2014], 21 PD patients without dementia or comorbid psychiatric conditions were assigned to three groups of 
seven subjects each who were treated with placebo, CBD 75 mg/day or CBD 300 mg/day for 6 weeks. The 
study found that significant improvements in measures of functioning and well-being of PD patients treated 
with CBD 300 mg/day compared to a group that received placebo, with no psychiatric comorbidities. In 
another study, six PD patients with psychosis symptoms for at least 3 months were recruited in an open-label 
pilot study to evaluate the efficacy, tolerability and safety of CBD on PD patients who had psychosis. All 
patients received CBD in flexible dose (start with an oral dose of 150 mg/day) for 4 weeks, in addition to their 
usual therapy. The psychotic symptoms showed a significant decrease under CBD treatment. CBD did not 
worsen the motor function and decreased the total scores of the UPDRS. No adverse effect was observed 
during the treatment [Zuardi A.W., et al. 2009].  
 
There are more than 30 reported human trials testing CBD, but doses, cannabinoid compositions and results 
vary widely. Generally the studies find CBD is well tolerated. Several studies suggest that CBD does not affect 
food intake, affect physiological parameters (heart rate, blood pressure and body temperature), affect 
gastrointestinal transit or alter psychomotor or psychological functions [Zuardi AW, et al. 2009; Riedel G, et al. 
2009; Scopinho AA, et al. 2011; Gomes FV, et al. 2013; Bergamaschi MM, et al. 2011; Bhattacharyya S, et al. 
2010]. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans 
[Zuardi AW, et al. 1995]. Conversely, some studies reported that this cannabinoid has adverse effects, 
including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, and decreased fertilization 
capacity [Bergamaschi MM, et al. 2011; Bornheim LM, et al. 1994; Narimatsu S, et al. 1990]. 
 
Extensive reports of CBD administration across a wide range of concentrations did not detect important 
adverse or toxic effects [Bergamaschi MM, et al. 2011]. With a median Lethal Dose (LD50) of 212 mg/kg in 
rhesus monkeys, CBD has a low toxicity [Rosenkrantz H, et al. 1981]. Some studies investigated mutagenic or 
teratogenic effects and describe no such events [Matsuyama SS, Fu TK. 1981; Dalterio S, et al. 1984]. We 
reviewed the tolerability of CBD doses used in human studies to date – one study suggested over 300 mg per 
day may exacerbate bradykinesia [Consroe P, et al. 1986], but other studies used 7.5 to 1500 mg per day 
without significant adverse effects [Bergamaschi MM, et al. 2011; Zuardi AW, et al. 1995]. Most studies used 
doses in the range of 200 - 600 mg/day.  
 
In this study we are using Epidiolex, which is >99% pure CBD with only a trace amount of THC (<0.15%). GW 
conducted a single ascending dose study in which four groups of six healthy volunteers received single oral 
doses of either 1500mg, 3000mg, 4500mg or 6000mg purified CBD oral solution (Ref: GWEP1544 safety 
assessment following dose administration of cannabidiol to healthy volunteers, 2015). Each single oral dose 
was well tolerated. In a 70kg individual these doses are equivalent from 21 mg/kg to 85mg/kg in a single daily 
dose.  Currently Epidiolex is being used in four FDA approved epilepsy studies. GW has determined a dose 
range that is best tolerated and effective in psychosis and seizure disorders. These studies are described in 
the Investigational Brochure (IB) Edition 8, Section 7.3.1. Open label study results have recently been 
published and are described in section C.1. 


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IV. Research Methods 
 
A.  Outcome Measure(s):   
 
Stage 1: Open Label Dose Escalation Tolerability Study 
Primary Specific Aim: To confirm that the dosage regimen of CBD, in the form of Epidiolex recommended 
by the study drug manufacturer is safe and tolerated in 10 subjects with PD. Epidiolex is started at 5 
mg/kg/day and is increased every 3 days by 2.5 mg/kg/day to 10 mg/kg/day. Then increase the dosage every 
5 days by 5 mg/kg/day to a target dose of 20 mg/kg/day. 
Primary Outcome Measures: The safety and tolerability of Epidiolex is measured in 4 ways: 
1. By examining the frequency of study-related adverse events at each dose level.  
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 advere 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 addtition, 
since a major dose limiting effect, per GW, is somnolence, the daytime sleepiness part of the SCOPA-
sleep is included in the phone script.     
 
The phone script is administered before each dose increase. This phone call is done by a RN, MD or 
an advanced practice practitioner (APP). Tolerability is judged by the appropriate clinical staff (APP, 
neurologist) under the supervision of the PI and sub-I (who are MDs), based on their clinical 
expertise. 
 
2.  By monitoring vital signs, orthostatic blood pressures, physical exam, EKG and labs (hematology,  
complete metabolic profile, and urinalysis) during study visits. 
 
3. By conducting standardized assessment tools on cognition, anxiety, psychosis, sleep, daytime 
sleepiness, mood, fatigue, pain, impulsivity, suicidality, and motor and non-motor PD signs during 
study visits. In addition, since many patients with PD also have restless legs syndrome and REM 
sleep behavior disorder, assessments for these are also done. The assessment tools are:  
Cognition: 
• 
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, calculations, and orientation. [Freitas S, et al. 
2013]. 
Anxiety: 


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• 
Anxiety short form - is component of the Neurol-QOL (Quality of Life in Neurological Disorders) 
Measurement System, which is a collaborative effort of the National Institute of Neurological 
Disorders and Stroke and a number of partnering institutions. This measurement system was 
designed to be responsive to the needs of researchers in a variety of neurological disorders and 
to facilitate comparisons of data across clinical trials in different diseases. The short form is 
comprised of 8 items that were selected from the respective item bank. Items have five response 
options (e.g., 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always). Respondents generally can 
answer 5 questions per minute. 
Psychosis: 
• 
Neuropsychiatric Inventory (NPI) - is a valid and reliable scale. It was developed to provide a 
means of 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. The NPI is administered 
to a caregiver/significant other who has detailed knowledge of the subject’s behavior. 
Sleep & daytime sleepiness: 
• 
Scales for Outcomes in Parkinson’s disease (SCOPA)sleep - is a valid, reliable, short scale for 
assessing nighttime sleep (NS) and daytime sleepiness (DS) in patients with PD [Marinus J, et al. 
2003]. The SCOPA-Sleep consists of two parts. The NS subscale addresses sleep problems and 
includes five items with four response options. Subjects have to indicate how much they were 
bothered by particular sleep problems, ranging from 0 (not at all) to 3 (a lot). The five items 
address sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, and early wakening. 
The maximum score of this scale is 15, with higher scores reflecting more severe sleep problems. 
One additional question evaluates overall sleep quality on a 7-point scale. The DS subscale 
evaluates daytime sleepiness and includes six items with four response options, ranging from 0 
(never) to 3 (often). Subjects indicate how often they fell asleep unexpectedly, fell asleep in 
particular situations, how often they had difficulty staying awake, and whether falling asleep in the 
daytime was considered a problem. The maximum score is 18, with higher scores reflecting more 
severe sleepiness. The average score for PD is 5.2 ± 4 for DS and 4.9 ± 4 for NS. 
Mood: 
• 
Depression short form - is component of the Neurol-QOL (Quality of Life in Neurological 
Disorders) Measurement System, which is a collaborative effort of the National Institute of 
Neurological Disorders and Stroke and a number of partnering institutions. This measurement 
system was designed to be responsive to the needs of researchers in a variety of neurological 
disorders and to facilitate comparisons of data across clinical trials in different diseases. The 
short form is comprised of 8 items that were selected from the respective item bank. Items have 
five response options (e.g., 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always). Respondents 
generally can answer 5 questions per minute. 
• 
Emotional and behavioral dyscontrol short form - is component of the Neurol-QOL Measurement 
System, which is a collaborative effort of the National Institute of Neurological Disorders and 
Stroke and a number of partnering institutions. This measurement system was designed to be 
responsive to the needs of researchers in a variety of neurological disorders and to facilitate 
comparisons of data across clinical trials in different diseases. The short form is comprised of 8 
items that were selected from the respective item bank. Items have five response options (e.g., 
1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always). Respondents generally can answer 5 
questions per minute. 


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Fatigue: 
• 
Fatigue Severity Scale (FSS) - is a self-report 9-item questionnaire with questions related to how 
fatigue interferes with certain activities and rates its severity. The items are scored on a 7 point 
scale with 1= strongly disagree and 7= strongly agree. The minimum score =9 and maximum 
score possible =63. Higher the score= greater fatigue severity. 
Pain: 
• 
Pain Intensity 3a short form and Pain Interference 4a short form - are components of the Patient 
Reported Outcome Measurement Information System (PROMIS), which was developed by the 
NIH to provide a standardized metric for measuring physical, mental, and social health across 
chronic diseases. PROMIS instruments were developed using item response theory, and have 
been tested in more than 20,000 individuals drawn from the general US population. The Pain 
Intensity instrument assesses how much a person hurts. The Pain Interference instrument 
measures the self-reported consequences of pain on relevant aspects of one’s life. This includes 
the extent to which pain hinders engagement with social, cognitive, emotional, physical, and 
recreational activities. Each question has five response options ranging in value from one to five.  
Impulsivity: 
• 
Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS) is a rating scale 
designed to measure severity of symptoms and support a diagnosis of impulse control disorders 
and related disorders in PD. QUIP-RS has 4 primary questions (pertaining to commonly reported 
thoughts, urges/desires, and behaviors associated with ICDs), each applied to the 4 ICDs 
(compulsive gambling, buying, eating, and sexual behavior) and 3 related disorders (medication 
use, punding, and hobbyism). It uses a 5-point Likert scale (score 0-4 for each question) to gauge 
the frequency of behaviors, and instructs patients to answer questions based on behaviors that 
occurred in the preceding 4 weeks (or any 4-week period in a designated time frame). Scores for 
each ICD and related disorder range from 0 to 16, with a higher score indicating greater severity 
(ie, frequency) of symtoms. The total QUIP-RS score for all ICDs and related disorders combined 
ranges from 0 to 112. [Weintraub D, et al. 2012] 
Suicidality: 
• 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a suicidal ideation rating scale. It rates 
an individual’s degree of suicidal ideation on a scale, ranging from “wish to be dead” to “active 
suicidal ideation with specific plan and intent.” The scale identifies behaviors which may be 
indicative of an individual’s intent to commit suicide. The C-SSRS has been found to be reliable 
and valid in the identification of suicide risk in several research studies. 
Motor & non-motor PD signs: 
• 
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS)- The MDS 
UPDRS has 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). Part I has two 
components: IA concerning a number of behaviors that are assessed by the investigator with all 
pertinent information from patients and caregivers and IB that is completed by the patient with or 
without the aid of the caregiver, but independently of the investigator. It can, however, be 
reviewed by the rater to ensure that all questions are answered clearly and the rater can help 
explain any perceived ambiguities. Part II is designed to be a self-administered questionnaire like 
Part IB, but can be reviewed by the investigator to ensure completeness and clarity. Part III has 
instructions for the rater to give or demonstrate to the patient; it is completed by the rater. Part IV 
has instructions for the rater and also instructions to be read to the patient. This part integrates 


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patient-derived information with the rater’s clinical observations and judgments and is completed 
by the rater. Rater involvement time for administering the MDS-UPDRS is estimated to require 
less than 10 min for the interview items of Part I, 15 min for Part III, and 5 min for Part IV, resulting 
in an equivalent rater time investment to the original scale and meeting the 30-min goal.  
• 
Unified Dyskinesia Rating Scale (UDysRS) is developed to evaluate involuntary movements often 
associated with treated Parkinson’s disease. There are two primary sections: Historical [Part 1 
(On-Dyskinesia) and Part 2 (Off-Dystonia)] and Objective [Part 3 (Impairment) and Part 4 
(Disability)]. On-Dyskinesia refers to the choreic and dystonic movements described to the patient 
as “jerking or twisting movements that occur when your medicine is working.” Off-Dystonia should 
be described to the patient as “spasms or cramps that can be painful and occur when your 
Parkinson’s disease medications are not taken or are not working. 
Restless Legs Syndrome: 
• 
International Restless Legs Syndrome Study Group Rating Scale for restless legs syndrome 
(IRLS): IRLS is a ten-question instrument for measuring severity of restless legs syndrome (RLS). 
The scale reflects subjective assessment of the primary features (reflected in questions 1 through 
3 and 6 of the scale), intensity and frequency of the disorder (questions 7 and 8 of the scale) and 
associated sleep problems (reflected in questions 4 and 5 of the scale). The scale also includes 
questions which probe the impact of symptoms on the patients’ mood and daily functioning 
(question 9 and 10 of the scale). Each question has a set of five response options graded from no 
RLS or impact (score=0) to very severe RLS or impact (score=4). This produced a total scale 
whose overall score could range from 0 to 40. IRLS sum score and subscales (symptoms in 
questions 1,2,4, and 6 through 8; symptoms impact in questions 5, 9 and 10) at every time point 
will be recorded. Item 3 is used for the total score for overall RLS severity. 
REM Sleep Behavior Disorders: 
• 
REM sleep behavior disorder screening questionnaire (RBDSQ) – is a 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”.  Items 1 to 4 address the frequency and content of dreams and their 
relationship to nocturnal movements and behavior. Item 5 asks about self-injuries and injuries of 
the bed partner. Item 6 consists of four sub items assessing nocturnal motor behavior more 
specifically, e.g., questions about nocturnal vocalization, sudden limb movements, complex 
movements, or bedding items that fell down. Items 7 and 8 deal with nocturnal awakenings. Item 
9 focuses on disturbed sleep in general and item 10 on the presence of any neurological disorder. 
The maximum total score of the RBDSQ is 13 points. 
 
4. By assessing the proportion of subjects that drop out of the study due to study drug intolerance. 
 
Secondary Specific Aim: To examine the effect of CBD on severity & duration of tremor and other conditons 
that occur in PD. 
Secondary Outcome Measures:  
The effect of CBD on tremor is measured by the change from baseline to the end of treatment phase (week 4) 
change in total of scores on items 3.17 and 3.18 in part III of the MDS-UPDRS in the ON state (when anti-PD 
medication is working). Item 3.17 is rest tremor amplitude. Extremity ratings range from 0: Normal, No tremor 
to 4: Severe, >10 cm in maximal amplitude. Lip/Jaw ratings are similar but smaller amplitudes. Item 3.18 is 
constancy of rest tremor: 0 (no tremor) to 4 (present >75% of the exam). 
 


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The effect of CBD on other conditions that occur in PD, 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, are measured by the same standardized tools used for safety and tolerability 
assessments (listed above). The effect of CBD are also measurend by Clincial Global Impression (CGI) and 
Patient Global Impression-improvement (PGI-I) and Change (PGI-C). CGI is a 3-item observer-rated scale 
that measures illness severity (CGIS), global improvement or change (CGIC) and therapeutic response. The 
CGI is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) 
through to 7 (amongst the mose severely ill patients). CGI-C scores range from 1 (very much improved) 
through to 7 (very much worse). Treatment response ratings should take account of both therapeutic efficacy 
and treatment-related adverse events and range from 0 (marked improvement and no side-effects) and 4 
(unchanged or worse and side-effects outweigh the therapeutic effects). Each component of the CGI is rated 
separately. PGI-I is a global index that may be used to rate the response of a condition to a therapy (transition 
scale). It is a simple, direct, easy to use scale that is intuitively understandable to clinicans. PGI-C is rated on 
a 7-point scale, evaluating all aspects of patient’ health and determining if there has been an improvement or 
not.  
 
Stage 2: Randomized, Controlled Trial 
Primary Specific Aim: To evaluate the safety and tolerability of CBD, in the form of Epidiolex, in PD. 
Primary Outcome Measures: The primary objective, to evaluate the safety and tolerability of CBD in PD is 
assessed in 4 ways: 
1. By examining and comparing the frequency of study-related adverse events at each dose level 
between the two groups (treatment vs. placebo). Adverse events are measured by  assessments at 
study visits and by the standardized phone script administered at each dose level (as in Stage 1). 
 
2. By monitoring and comparing vital signs, orthostatic blood pressures, physical exam, EKG and labs 
(hematology, complete metabolic profile, and urinalysis) between the two groups. These are collected 
during study visits. 
 
3. By conducting and comparing standardized assessment tools on cognition, anxiety, psychosis, sleep, 
daytime sleepiness, mood, fatigue, pain, impulsivity, suicidality, and motor and non-motor PD signs, 
restless legs syndrome, REM sleep behavior disorder and quality of life. These are the same tools 
used in the Stage 1 safety and tolerability evaluation, except that a more detailed cognitive 
assessment, an additional motor test and measures of quality of life are done. These are collected 
during study visits. The change from baseline to 10th day of 5 mg/kg/day (low dose analysis) and from 
baseline to the maximum tolerated or targeted dose is compared. The additional tools that are  
Cognition: 
• 
Cognitive assessment battery: 
Intellectual Functioning Estimate 
1)Wechsler Test of Adult Reading (WTAR) - Word reading tests are an established method of 
establishing a premorbid estimate of verbal intellectual functioning, which will serve as an 
estimate of premorbid cognitive reserve. 
Visuospatial construction 


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2) Rey-Osterrieth Complex Figure (ROCF) Test-  is a widely used neuropsychological test for the 
evaluation of visuospatial constructional ability (Copy trial) and visual memory (Immediate Recall, 
Delayed Recall, and Recognition trials). It consists of three test conditions: Copy, Immediate 
Recall and Delayed Recall.  
Attention/Processing Speed/Executive Functioning 
3) Trail making tests – is a neuropsychological test of visual attention and task switching. It 
consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as 
possible while still maintaining accuracy. It can provide information about visual search speed, 
scanning, speed of processing, mental flexibility, as well as executive functioning.  
4) Symbol Digit Modalities Test (SDMT) - The SDMT is a measure of processing speed and 
working memory that has proven to be sensitive to cognitive impairment in MS that has both oral 
and written trials (only the oral trial will be administered given the anticipated difficulty patients will 
have with tremor). Subjects are presented with a key at the top of a page pairing unique symbols 
with single digits. Subjects are required to provide the correct digit with symbols that are 
presented on the rest of the page. The number of correct responses provided in 90 seconds on 
the oral and written trials, respectively, is recorded.  
5)Paced Auditory Serial Addition Test (PASAT) - The PASAT is a more complex measure of 
processing speed and working memory in which a series of digits is presented to subjects at 
varying intervals (i.e., 2 seconds, 3 seconds). Subjects must add each digit to the immediately 
preceding digit for the duration of each trial. The number of correct responses for each trial is 
recorded. 
6)Controlled Oral Word Association Test (COWAT) - The COWAT is a measure of speeded 
verbal fluency and word retrieval in which subjects are asked to say as many words as they can 
that begin with each of three letters for 60 seconds. The total number of words generated across 
all three trials is recorded. 
Memory Functioning 
7)Hopkins Verbal Learning Test-Revised (HVLT-R) - The HVLT-R is a measure of verbal learning 
and memory in which subjects are asked to learn a 12-item word list over three trials (total 
immediate learning). A delayed free recall trial is administered after 20 minutes, followed by a 
yes/no recognition trial. 
Language functioning  
8)Semantic Verbal Fluency – Semantic Verbal fluency is a measure of speeded verbal fluency 
and word retrieval in which subjects are asked to say as many animal names/fruits and 
vegetables for 60 seconds. The total number of words generated across all three trials is 
recorded 
Motor testing 
• 
Rapid Paced Walk (RPW) test: The RPW assesses stride length, balance and overall mobility, all 
of which can be impaired in PD [Crizzle AM, et al. 2013]. 
Quality of Life 
• 
Parkinson’s Disease Questionnaire (PDQ-39): is a reliable, valid, responsive, acceptable and 
feasible as the tool for the assessment of quality of life in Parkinson’s disease patients. There are 


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39 questions in the long form Parkinson’s Disease Questionnaire, with 8 discrete scales: mobility 
(10 items), activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), 
social support (3 items), cognitions (4 items), communication (3 items), and bodily discomfort (3 
items). Patients are asked to think about their health and general well-being and to consider how 
often in the last month they have experienced certain events. Patients are asked to indicate the 
frequency of each event by selecting one of 5 options (likert Scale): 
never/occasionally/sometimes/often/always or cannot do at all. 
• 
EuroQoL-5 Dimension-5 level (EQ-5D-5L): consists of 2 pages-the EEQ-5D-5L descriptive system 
and the EQ Visual Analogue Scale (EQ VAS). The descriptive system comprises 5 dimensions: 
mobility, self care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 
levels: no problem, slight problems, moderate problems, severe problems, and extreme problems. 
This is a widely used well validated simple assessment that is comparable across disease 
populations. 
 
4. By assessing and comparing the proportion of subjects that drop out of the study due to study drug 
intolerance in the two groups (treatment vs. placebo). 
 
Secondary Specific Aim: To examine the effect of CBD on severity & duration of tremor in PD. 
Secondary Outcome Measure: Tremor is measured by the change from baseline to 10th day of 5 mg/kg/day 
(week 2 and week 12) and the end of each treatment phase (week 7 and week 17) change in total of scores 
on items 3.17 and 3.18 in part III of the MDS-UPDRS in the ON state (when anti-PD medication is working). 
Item 3.17 is rest tremor amplitude. Extremity ratings range from 0: Normal, No tremor to 4: Severe, >10 cm in 
maximal amplitude. Lip/Jaw ratings are similar but smaller amplitudes. Item 3.18 is constancy of rest tremor: 0 
(no tremor) to 4 (present >75% of the exam). 
 
Exploratory Analyses: 
(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 and global impression of patients and clinicians.  
(2) To evaluate the effects of CBD on these conditions at a low dose.  
Exploratory Outcome Measures: The effects of CBD on cognition, anxiety, psychosis, sleep, daytime 
sleepiness, mood, fatigue, pain, impulsivity, and motor and non-motor PD signs, restless legs syndrome, 
REM sleep behavior disorder and quality of life are evaluated using the aforementioned assessment tools. 
The change from baseline to 10th day of 5 mg/kg/day (low dose analysis) and from baseline to the maximum 
tolerated or targeted dose is compared. 
 
Table 1. Measurement tools performed in Stage 1 and Stage 2.  
Assessments 
Stage 1 
Stage 2 
Primary 
Secondary 
Primary 
Secondary 
Exploratory 


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*Specifically items 3.17 and 3.18 in part III 
 
B. Description of Population to be Enrolled:   
Parkinson disease - 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 [Yao, S.C, et al. 2013; de Lau LM, et al. 2006]. PD usually begins around age 60, but it can 
start earlier. Treatment, typically medications such as levodopa and dopamine agonists, improve early stage 
MoCA 
X 
X 
X 
 
X 
Detailed cognitive battery 
 
 
X 
 
X 
Anxiety short form 
X 
X 
X 
 
X 
NPI 
X 
X 
X 
 
X 
SCOPA-Sleep 
X 
X 
X 
 
X 
Depression short form 
X 
X 
X 
 
X 
Emotional and Behaviroral dyscontrol 
short form 
X 
X 
X 
 
X 
Fatigue Severity Scale 
X 
X 
X 
 
X 
Pain Intensity 3a and Interference 4a 
short forms 
X 
X 
X 
 
X 
QUIP-RS 
X 
X 
X 
 
X 
MDS UPDRS total 
X 
X 
X 
X* 
X 
Unified Dyskinesia Rating Scale 
(UDysRS) 
X 
X 
X 
 
X 
Rapid Paced Walk (RPW) test 
 
 
X 
 
X 
REM Sleep Behavior Disorder Screening 
Questionnaire (RBDSQ) 
X 
X 
X 
 
X 
The Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
X 
 
X 
 
 
International Restless Legs Syndrome 
Study Group Rating Scale (IRLS) 
X 
X 
X 
 
X 
PDQ-39 
 
 
X 
 
X 
EQ-5D 
 
 
X 
 
X 
CGI 
 
X 
 
 
X 
PGI 
 
X 
 
 
X 


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symptoms. As the disease progresses and dopaminergic neurons continue to be lost, these drugs become 
less effective, and levodopa produces disabling motor fluctuations in most patients. PD invariably progresses 
with time. Untreated individuals are expected to lose independent ambulation after an average of eight years 
and be bedridden after ten years [Poewe W. 2006]. In people taking levodopa the progression of symptoms to 
a stage of high dependency from caregivers is on average 15 years.  
 
C. Study Design and Research Methods   
 
C.1 Study design and study drug dose determination 
 
The study is conducted in two stages. The major purpose of the Stage 1 is to study the safety and tolerability 
of the proposed dosage regimen, which is based on GW Pharmaceutical’s 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. We will be recruiting up to 20 subjects in Stage 1 to end up 
with 10. 
 
The major purpose of Stage 2 is to assess the safety and tolerability of the Epidiolex at the determined dose, 
and secondarily to study efficacy, particularly regarding tremor. The study has been powered to detect a 
clinically significant reduction in tremor, all other efficacy analyses are exploratory. Stage 2 is a crossover, 
double-blind, randomized controlled trial (RCT) with 50 subjects. We will be recruiting up to 60 subjects in 
Stage 2 to end up with 50.   
 
See Appendix 1 Schedule of Events for each Stage for more detail on study design. 
 
The study drug is obtained from GW Pharmaceuticals and is called Epidiolex. How the dose is started and 
escalated and what target dose is chosen is based on human literature but primarily on recommendations 
from GW staff. Animal data supports the use of CBD dosing up to 24 mg/kg/day. In human literature CBD has 
been well tolerated up to 1500 mg/day (~21 mg/kg/day).  Studies using Epidiolex are described in GW’s 
Investigational Brochure (IB) Edition 8, Section 7.3.1. Epidiolex has been used in six Phase 2 studies (mostly 
related to pain).  Presently a study of patients with psychosis are taking 1000 mg per day. Also GW has 
initiated a clinical program of Phase 1-3 studies to investigate its effect in severe forms of epilepsy, i.e., 
Davet’s syndrome and Lenox Gastaut syndrome. Based on their experience, GW has recommended the dose 
escalation and target used in this study. As noted, the purpose of Stage 1 study, n=10, is to check for 
tolerability of this dose regimine in PD patients. If Stage 1 shows that the maximal dose tolerated is less than 
20 mg/kg/day, then the maximal targeted dose for the RCT study will be reduced accordingly.  
 
A recent publication, Lancet Neurol 2016; 15: 270-78, shows evidence for using this dose.  The study reported 
on the safety (n=128) and efficacy (n=137) of the study drug we are using, but in a pediatric (aged 1-30; mean 


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10) population with severe epilepsy. Subjects were evaluated after 12 weeks on study drug, mean dose of 
~23 mg/kg/day.  Adverse events were reported in 128 (79%) of the 162 patients within the safety group.  
Adverse events reported in more than 10% of patients were somnolence (25%), decreased appetite (19%), 
diarrhea (19%), fatigue (13%), and convulsion (11%). Somnolence and fatigue were not dose related, 
diarrhea and weight loss occurred more often in subjects taking >15 mg/kg/day.  Of note, the concomitant use 
of clobazam (an anticonvulsant medication) was highly associated with somnolence, meaning somnolence 
was less in those not on clobazam (21%) compared to those taking it (51%).  Most adverse events were 
moderate and transient.  SAEs deemed related to the study drug occurred in 12% of subjects, including 9 who 
had status epilepticus.  However, of note, the study showed a ~50% reduction in seizures on study drug, and 
status epilepticus is a common problem in the population studied.  Five subjects (3%) stopped the study drug 
due to an adverse event.  Please see the article regarding clinically significant changes in safety blood 
analyses.  Hepatotoxicity (< 1%), hyperammonemia (<1%), and thrombocytopenia (<1%) occurred only in 
subjects also taking valproate.   
 
The maximum tolerated doses, in mg/kg/day, of the 10 subjects will be averaged, and adjusted to the next 
highest 5 mg/kg/day. That dose will be used as the targeted dose for the RCT. For example if the average of 
the maximal tolerated doses in Stage 1 subjects is 17.4 mg/kg per day, the targeted dose in the RCT will be 
20 mg/kg/day. Or if the average of the maximal tolerated doses in stage 1 subjects is 22.7 mg/kg per day, the 
targeted dose in the RCT will be 25 mg/kg/day.  
 
C.2 Stage 1: Open Label Dose Escalation Tolerability Study 
 
The dose escalation tolerability study will be conducted in 10 subjects (we will be recruiting up to 20 subjects 
to end up with 10) as an open label study lasting 4 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 4 
weeks, a final assessment visit when they have been on the maximal tolerated or the targeted study drug 
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, and  return for the final assessment visit on that dose on any of days 10-15. The reason 
for a range of 10-15 days instead of exactly 10 days is to allow for some flexibility in getting subjects in for the 
study visit. Subjects will be called on the 3rd day of each dose between 5-10 mg/kg/day and the fifth day of 
each dose between 10-20 mg/kg/day. 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. At the final assessment visit, urinary CBD and metabolites will be tested. 
Subjects are also called 3 days after stopping the study drug to check for signs of withdrawal.  
 
To increase compliance with taking study drug, subjects will be asked to fill out a diary at home. The diary will 
be a record of the date and time subjects take study drug, adverse and beneficial events, and whether they 
talked to study staff on the phone that day, and if so what they were told to do with the dose. To make sure 
the diary is recorded correctly, subjects will be asked to mail, email or fax a copy or image of the diary they 
filled out within 3 days of increasing from 5 to 7.5 mg/kg/day. This is so that diary errors can be corrected 
early. 
 
 


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Urine collection, storage and transfer for cannabis and metabolites test: The purpose of the urine cannabis 
and metabolites test is to develop a methodology to quantitate CBD metabolites. Subjects will be given two 
urine cups, 100 mL each, at the baseline visit. On the phone call before the day of the final assessmen visit, 
subjects will be reminded to collect urine in the morning of the study visit. They are asked to fill each up at 
least 3/4 full if possible, and to bring them to the visit (no refrigeration needed). Upon arrival of the visit the 
study coordinator will collect and store the urine cups in a -80°C freezer until shipment. For shipment, samples 
for each individual will be placed onto a sealable plastic bag together with an absorption pad. All the individual 
bags will be placed into a large sealable plastic bag with contains absorption material. Samples will be placed 
onto a Styrofoam box and will be shipped on dry ice. Urine samples will be labeled with the name of the study 
and the date and time of collection. Urine samples will be shipped for analysis to Dr. Jost Klawitter at iC42 
Clinical Research & Development.         
 
Inclusion & Exclusion criteria 
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 the day the subject starts study drug 
treatment.  
• 
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, 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.  
 
**Note: the LAR (required for those with MOCA<22), caregiver (required for those with MOCA<22), and 
significant other (required for all subjects) may be the same person in some cases. In other cases, these 
may be different people. 
 
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 subject 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 subject 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. 


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• 
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 2 years post-menopausal, or does not agree 
to utilize an effective method of contraception from screening through at least 4 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. 
 
Dose escalation strategy 
 
Study product will be started at 5 mg/kg/day and increased every 3 days by 2.5 mg/kg/day to 10 mg/kg/day. 
Then increase the dosage every 5 days by 5 mg/kg/day until the subject reaches a maximum targeted dose 
(20 mg/kg/day) or experiences intolerable adverse effects, in which case the dose will be dropped to the last 
tolerated dose, for 10-15 days. Tolerability will be assessed on the third day of each dose between 5-10 
mg/kg/day and the fifth day of each dose between 10-20 mg/kg/day and the subject is instructed whether or 
not to change the dose starting the next day. Once a subject has been on a specific dose for at least 3 days 
(5-10 mg/kg/day) or 5 days (10-20 mg/kg/day), that dose can be changed for less or more than 3 (5-10 
mg/kg/day) or 5 days (10-20 mg/kg/day) and can be changed by a smaller increment (2.5-5 mg/kg/day) as 
needed for tolerability. The maximal tolerated dose is determined by the PI or co-Investigator that is an MD, 
based on their clinical expertise. 
Assessment of tolerability of each dose level 
Tolerability will be assessed at each dose via collection of adverse events during administration of the 
standardized phone script by appropriate study staff. Severity of adverse events will be graded according to 
the Common Terminology Criteria for Adverse Events (CTCAE), which is published by the National Cancer 
Institute (NCI) of the National Institutes of Health (NIH):  
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLs. Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc.  
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADLs. Self care ADLs refer to 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.  
Grade 4:  Life-threatening consequences; urgent intervention indicated.  
Grade 5:  Death related to AE.  
 


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The protocol for dose adjustments, maintenance and discontinuation based on adverse effects is a follows: 
• 
For subjects with a grade 1 adverse event the dose will be increased by up to 5 mg/kg/day, or if they are 
on the maximal targeted dose (20 mg/kg/day) it will be continued.  
• 
For subjects with a grade 2 adverse event the dose will be reduced by 5 mg/kg/day or less.  
• 
For subjects with a grade 3 or 4 adverse event that the Investigator determines is unrelated, the dose will 
be continued. When the adverse event is stabilized or resolved, e.g., subject is stable after a hip fracture 
repair, the dose will be increased unless they are already on the maximum targeted dose.  
• 
For subjects with a grade 3 or 4 adverse event that the Investigator determines is related the study drug 
will be stopped and not restarted.  
The Investigaor will determine relatedness as described in Section IV. C.8, and will consider the adverse 
event related if she determines there is at least a reasonable possibility. 
 
The major dose limiting effect, per GW, is somnolence. To monitor for this closely, the daytime sleepiness part 
to the SCOPA-sleep will be administered during each phone call, thus before each increase in dose. A score 
of >7 (note that the average score for PD is 5.2 ± 4), if greater than before and considered problematic by the 
appropriate clinical staff, would result in the subject being instructed to drop to the prior dose for three more 
days before increasing the dose.  
 
Additional assessments of safety and tolerability is done at the study visit when the subject is on the 
maximum tolerated or targeted dose. The same protocol for dosing is applied for both adverse events found 
during phone assessments and during study visits.  
 
The results of safety and tolerability assessments in Stage 1 will be studied to determine if additional 
evaluations during Stage 2 are warranted. For example, if grade 1 or 2 advere events occur in ≥ 2 subjects 
then additional surveillence will be conducted during Stage 2. Further, safety and tolerability Stage 1 results 
determine participant and study stopping parameters, described in Section IV C.7. 
 
The CTCAE criteria are used to determine dose level adjustments and for participant and study stopping rules 
(Section IV C.7).  Adverse events for both Stage 1 and 2 will be collected and reported as discussed in 
Section IV C.8. 
 
To mitigate potential risk during the study, the subjects will be told not to drive cars or operate dangerous 
machinery while taking study drug in the Open Label Dose Escalation Tolerability study (Stage 1). Instructions 
to subjects in the Randomized Controlled Trial (Stage 2) will be developed after Stage 1 is completed, with 
COMIRB guidance.   
 
Procedures at each visit 
Visit 1-Screening visit: Consent, demographics, family medical history, concomitant medications, formal drug 
interaction assessment, vital signs, orthostatic blood pressures, history & physical examination (complete 
physical exam and detailed neurological exam), tremor evaluation (question 3.17 of the MDS-UPDRS), 
MOCA, MDS-UPDRS III, H&Y rating, Drug, alcohol and tobacco abuse screening test, safety assessments 
(as listed in section IV A, except for RBDSQ, IRLS), EKG and safety labs (complete blood count,  hemoglobin 
A1C, complete metabolic profile and urinalysis), blood cannabis analysis testing, serum pregnancy test (for 
women childbearing potential), and inclusion/exclusion criteria are done. Study subjects are instructed not to 
take cannabis from outside source throughout the study. 


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Visit 2-Baseline visit: Eligibility confirmation, medical history, and concomitant medications, formal drug 
interaction assessment, vital signs, orthostatic blood pressures, brief physical exam (heart and lung 
auscultation), MDS-UPDRS, UDysRS, and inclusion/exclusion criteria, RBDSQ, IRLS, C-SSRS, urine drug 
(THC) test (urine dipstick testing), urine pregnancy test (women childbearing potential), safety assessments, 
and drug and home diary dispensing are done. Subjects will take the first dose in clinic and will be monitored 
and vital signs (including orthostatic blood pressure and pulse) will be taken to check for study drug tolerability 
at 1 hour after taking the study drug. Subjects are instructed on how to take the medication and how to fill out 
the diary at home. To make sure the diary is recorded correctly, subjects will be asked to mail, email or fax a 
copy or image of the diary they filled out within 3 days of increasing from 5 to 7.5 mg/kg/day. This is so that 
diary errors can be corrected early. Subjects will be told not to take the study drug on the day of the next visit, 
as they will take it upon arrival under instruction by study staff. Subjects are also instructed to bring in empty, 
partially used and unused bottles of study drug at next clinical visit. Subjects will be given two urine cups, 100 
mL each, and will be instructed to collect their urine the morning of the final assessment visit. They are asked 
to fill each cup at least 3/4 full, if possible, and to bring them to the visit (no refrigeration needed). 
Visit 3-Final Assessment visit: Medical history and concomitant medications collection, formal drug interaction 
assessment, vital signs, orthostatic blood pressures, complete physical exam and detailed neurological exam, 
and all efficacy and safety assessments are repeated that were done in the screening, baseline and 20 
mg/kg/day assessment visit, except for the cannabis, drug, alcohol and tobacco abuse questionnaire. Adverse 
event check is done. Subjects will take the study drug upon their arrival to the clinic and record the time. On 
the morning of the visit, subjects will collect their urine and bring it to the visit. Study coordinator will collect 
and store the urine cups in a -80°C freezer until shipment. Blood draw is performed 3 hours after the dose is 
taken, for cannabis testing and safety labs. Subjects will be monitored and vital signs and orthostatic blood 
pressures will be checked at 1 and 3 hours after taking the study drug. Returned study drug is counted. 
Compliance will be checked by study drug count and cannabis analysis testing. Home diary is collected and 
reviewed. 
Visit 4-Safety follow up: Concomitant medications, formal drug interaction assessment, vital signs, orthostatic 
blood pressures, history & complete physical examination, MDS UPDRS, H&Y rating, UDysRS, MoCA, QUIP-
RS,  C-SSRS, NPI, SCOPA-sleep, RBDSQ, Anxiety short form, Depression short form, Emotional and 
behavioral dyscontrol short form, Fatigue Severity Scale, Pain Intensity and Interference short form, IRLS, 
adverse event check, blood cannabis lab testing and urine pregnancy test (women childbearing potential). 
Safety labs and EKG will be done if there was a clinically significant change at the assessment visit compared 
to baseline visit. The PI will evaluate the subject for signs of withdrawal.  
 
C.3 Stage 2: RCT 
 
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 titrate up to the maximum tolerated or targeted dose (20 
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), an assessment visit while 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), an assessment 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. To 
maximize compliance the coordinator calls the subject to remind them the next day’s clinical visit. Subjects will 
be called every 3rd day during dose escalation and every 10th day during the dose maintenance period (up to 


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25 mg/kg/day). During phone calls subjects are monitored for adverse events, 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. 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) and symptoms of hepatotoxicity, SCOPA-sleep, Anxiety short form, Depression short form, 
Emotional and behavioral dyscontrol short form, and EQ-5D-5L. At low dose visit (end of 10 days on 5 
mg/kg/day), each 20 mg/kg/day visit and each end of treatment phase assessment visits, urinary CBD and 
metabolites will be tested. To increase compliance with taking study drug, subjects will be asked to fill out a 
diary at home. The diary will be a record of the date and time subjects take study drug, adverse and beneficial 
events, and whether they talked to study staff on phone that day, and if so what they were told to do with the 
dose. Study drug is dispensed at the baseline visit and at the start of the second 7-week treatment phase visit 
so that subject has enough to take until they return for the low dose visit.  At that visit they are given enough to 
last through 20 mg/kg/day. At the 20 mg/kg/day visit they are given enough for the time on 25/mg/kg/day. As 
in Stage 1, the purpose of the visit at 20 mg/kg/day is to limit the amount of study drug that is dispensed at 
any one time and facilitate compliance, safety and drug control. In the instance that a subject does not reach 
the 20 mg/kg/day dose, due to intolerance, then they will come in when and if they need more study drug to 
complete 10-15 days on their maximal tolerated dose.  If they have enough to last through the 10-15 days 
then they return for the Final Asssessment visit, and therefore have fewer total visits. 
 
Inclusion & Exclusion criteria:  
These are the same as in stage 1, except an additional exclusion criteria is: Participated in Stage 1.  Criteria 
for driving will be decided based on results from Stage 1, with COMIRB guidance. 
 
Dose escalation strategy: 
In each of the two 7-week periods, study product (CBD or placebo) will be started at 5 mg/kg/day and 
increased as tolerated to a maximum weight-adjusted target dose that is determined as a result of the Stage 1 
study. The dose escalation strategy is the same as in Stage 1 for each treatment phase, except that subjects 
will take 5 mg/kg/day for 10 -15 days, and have a study visit before increasing further. The reason for a range 
of 10-15 days instead of exactly 10 days is to allow for some flexibility in getting subjects in for the study visit. 
Then the dose is escalated at 3-day intervals (with 5 mg/kg/day increased each interval) until the subject 
reaches the maximum target dose or experiences intolerable adverse effects, in which case the dose will be 
dropped to the last tolerated dose. Tolerability will be assessed on the third day of each dose and the subject 
is instructed whether or not to change the dose on the next day. The maximal tolerated dose is the dose at 
which 5 mg/kg/day higher was not tolerated on two trials.  When subject achieves the maximal tolerated dose 
or the maximum targeted dose, they will maintain that dose for 28 +/-4 days. 
 
Urine collection, storage and transfer for cannabis and metabolites test protocol is as described in Stage 1. 
 
Procedures at each visit 
Visit 1- Screening visit: Consent, demographics, concomitant medications, formal drug interaction 
assessment, family medical history, medical history & physical examination (complete physical exam and 


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detailed neurological exam), vital signs, orthostatic blood pressures, tremor evaluation, MDS-UPDRS III, H&Y 
rating, MOCA, Drug, alcohol and tobacco abuse screening test, safety assessments (as listed in section IV A, 
except for RBDSQ, IRLS, PDQ-39 and EQ-5D), EKG and safety labs (as in dose escalation study), blood 
cannabis analysis testing, serum pregnancy test (for women childbearing potential) and inclusion/exclusion 
criteria are done. Study subjects are instructed not to take cannabis from outside source throughout the study.  
Visit 2- Baseline visit: Eligibility confirmation (including tremor evaluation), medical history, concomitant 
medications collection, formal drug interaction assessment, vital signs, orthostatic blood pressures, brief 
physical exam, MoCA, MDS-UPDRS, H&Y rating, UDysRS, RPW, cognitive assessment battery (including 
tests of verbal intellectual function, attention, processing speed, executive function, verbal learning and 
memory, visuospatial memory, speeded verbal fluency and word retrieval), RBDSQ, C-SSRS, IRLS, PDQ-39, 
EQ-5D, urine drug (THC) test (urine dipstick test), urine pregnancy test (women childbearing potential) and 
study drug dispensing is done and, if appropriate, randomization. Home diary is also dispensed. Subjects take 
the first dose and are instructed on how to take the medication and how to fill out the diary at home. Subjects 
will be monitored and vital signs and orthostatic blood pressures will be checked at 1 hour after taking the 
study drug. Subjects are also told to bring in empty, partially used and unused bottles of study drug at next 
clinical visit. Subjects will be told not to take the study drug on the day of the next visit, as they will take it upon 
arrival under instruction by study staff. Subjects will be given two urine cups, 100 mL each, and will be 
instructed to collect their urine the morning of the low dose visit. They are asked to fill each cup at least 3/4 
full, if possible and to bring them to the visit (no refrigeration needed). 
Visit 3 and Visit 7-Low dose visit (end of 10 days on 5 mg/kg/day): On the morning of the visit, subjects will 
collect their urine and bring it to the visit. Study coordinator will collect and store the urine cups in a -80°C 
freezer until shipment. Concomitant medications, formal drug interaction assessment, change in medical 
history, vital signs, orthostatic blood pressures, brief physical exam, MDS-UPDRS, UDysRS, H&Y rating, 
RPW, Anxiety short form, Depression short form, Emotional and behavioral dyscontrol short form, Fatigue 
Severity Scale, Pain Intensity and Interference short form, MoCA, RBDSQ, QUIP-RS, C-SSRS, NPI, SCOPA-
sleep, IRLS, EQ-5D, PDQ-39, CGI, PGI, and urine pregnancy test are done. Study drug compliance check, 
adverse event check and blinding assessment are done. Subjects will take their study drug upon their arrival 
to the clinic and record the taking time. Blood is drawn for cannabis testing and safety labs 3 hours after the 
dose. Subjects will be monitored and vital signs and orthostatic blood pressures will be checked at 1 and 3 
hours after taking the study drug. Home diary is collected and reviewed. The next study drug supply and home 
diary are dispensed. Subjects are instructed on how to fill out the diary at home and are told to bring in empty, 
partially used and unused bottles of study drug at next clinical visit. Subjects will again be given urine cups 
and instructions. 
Visit 4 and Visit 8-20 mg/kg/day Assessment visit: Subjects will be on 20 mg/kg/day for 5 days. They will come 
back to clinic on either day from 2nd through 5th day while on 20 mg/kg/day. On the morning of the visit, 
subjects will collect their urine and bring it to the visit. Study coordinator will collect and store the urine cups in 
a -80°C freezer until shipment. Medical history and concomitant medications collection, formal drug interaction 
assessment, vital signs, orthostatic blood pressures, brief physical exam, CGI, PGI, and adverse event 
(including SCOPA-Sleep and C-SSRS) check are done. Blood is drawn for complete metabolic profile. Study 
drug is collected and counted.  Study drug is dispensed: and subject is instructed in how to take it. Home diary 
is collected and reviewed. The next home diary is dispensed. Subjects will be told not to take the study drug 
on the day of the next visit, as they will take it upon arrival under instruction by study staff. Subjects will again 
be given urine cups and instructions. 
Visit 5-End of first 7-week (47 days) and Visit 9-second 7-week (115 days) treatment phase assessment visits: 
Same procedures are conducted as at the previous low dose visit, except for study drug and home diary 
dispensation. In addition, complete physical exam, detailed neurological exam, blood draw, urinalysis, ECG, 
and full cognitive assessment battery are done. Subjects will take their study drug upon their arrival to the 


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clinic and record the taking time. Blood is drawn for cannabis testing and safety labs 3 hours after the dose. 
Subjects will be monitored and vital signs and orthostatic blood pressures will be checked at 1 and 3 hours 
after taking the study drug.   
Visit 6-Start of second 7-week treatment phase: Study drug and home diary dispensation and instruction will 
be performed. Formal drug interaction assessment will be done. Subjects take the first dose of study drug. 
Subjects will be monitored and vital signs and orthostatic blood pressure will be taken at 1 hour after taking 
the study drug. Subjects are also told to take study drug and record the taking time upon their arrival to clinic 
on the next clinical visit day. 
Visit 10-Safety follow up: Vital signs, orthostatic blood pressures, history & complete physical examination, 
concomitant medications collection, formal drug interaction assessment, MDS-UPDRS, H&Y rating, UDysRS, 
RPW, MoCA, RBDSQ, QUIP-RS, C-SSRS, NPI, SCOPA-sleep, Anxiety short form, Depression short form, 
Emotional and behavioral dyscontrol short form, Fatigue Severity Scale, Pain Intensity and Interference short 
form, IRLS, PDQ-39, EQ-5D-5L, adverse event check, urine pregnancy test and cannabis lab testing are 
done. Hematology,  complete metabolic profile, urinalysis and EKG will be done if there was a clinically 
significant change at the high dose evaluation visit compared to baseline visit. The PI will evaluate the subject 
for signs of withdrawal. 
 
C.4 Study Drug: Epidiolex: 
 
Purified CBD from GW is a strawberry flavored liquid, in sesame oil, provided as 100 mg/ml, extractd from 
high CBD plant material. The placebo is the same, but without CBD. The study drug is best taken fasted, as 
food will increase Cmax and delay Tmax. The study drug could be taken with a small amount of food as 
needed if the subjects experience nausea. It is to be taken twice daily at a standard time, minimum of 6 hours 
apart. Subjects are instructed to take it before breakfast (30 to 60 minutes) and the same before dinner. 
Further detail is proprietary.  Subjects are instructed not to drink grapefruit for 7 days prior to the first dose of 
study medication and during the rest of the study (both Stages). 
 
The study drug is taken as normal on the mornings of assessments. As far as practical, the same assessor 
carries out assessments at each visit. Assessment data are stored and not made available at subsequent 
visits. 
 
Subjects take their routine anti-PD medication on the day of clinical visit, and when ON (PD medications are 
working) the testing is done. 
 
CBD and metabolite levels will be measurements: 
 
• 
In Stage 1, blood CBD and metabolite levels will be measured at the screening visit,  final assessment 
visit and safety follow up visit. Urinary CBD and metabolites levels will be tested at the final assessment 
visit. 
• 
In Stage 2, blood CBD and metabolite levels will be measured at screening visit, baseline, low dose visit 
(end of 10 days on 5 mg/kg/day) and end of each treatment phase assessment visits. Urinary CBD and 
metabolites levels will be tested at the low dose visit, 20 mg/kg/day visit and the end of each treatment 
phase assessment visit. 


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Potential drug-drug interactions 
The PI has worked with Jacci Bainbridge, Pharm D, and GW to study possible drug interactions.  See GW 
Pharmaceutical’s Investigator Brochure on CBD, especially pages 4-5, 47-51 and 105-106 and their 
CBD;CBD BDS Development Core Safety Information dated August 2015 pages 2-4 for detailed information.  
Also, Appendix 2 is a list of drugs with potentially interactions with CBD, thus the PI will monitor for clinical 
effects. CBD concentrations and adverse events will be monitored in the presence of concomitant medications 
which are inhibitors of CYP3A4 and 2C19. 
 
There are many possible interactions, but some are more likely and clinically relevant.  Thus, the PI will 
especially monitor for clinical symptoms that may be associated with these particular interactions.  The 
following drugs may increase the level of CBD: fluoxetine, fluvoxamine, fluconazole, ticlopidine and 
nefazodone.  The following dugs may decrease the level of CBD: carbamazine, phenytoin, phenobarbital, 
rifampin and St. John’s Wort.  The following drugs may interact with CBD to cause their levels to 
increase: alprazolam, clonazepam, lorazepam, oxazepam, temazepam, zolpidem, clopidigrel, narcotics 
(codeine, methadone, oxycodone, hydromorphone, morphine), cyclosporine A, tacrolimus, propranolol 
and acetaminophen.  Subjects will be instructed not to take more than 1 gram per day of acetaminophen.  
 
CBD is a potent inhibitor of CYP2C19.  The plasma level of clobazam, which is metabolized by 
CYP2C19, therefore is expected to increase if CBD is added.  Clobazam, per Micromedix, causes 
somnolence (16-25%).  In a recent study, Lancet Neurology 2016;15:270-278, using the same study drug 
as in our trial at similar doses there was ~twice as much somnolence AEs reported in subjects on both 
CBD and clozabam than in subjects on CBD and not clobazam.  Thus clobazam will be exclusionary in 
this study. 
 
The following is additional information relevant to the population of this study, Parkinson disease (PD).  
CBD is metabolized by the hepatic CYP450 enzymes 2C19 and 3A4 and an inhibitor of these isoenzymes.  
Thus the expectation is that selegiline levels could increase.  CBD may mildly induce the expression of 1A2, 
2B6, and 3A4.  Thus the expectation is that levels of rasagiline, ropinirole and selegiline may decrease.   
CBD is a relatively potent inhibitor of UGT1A9 and UGT2B7 and has no significant effect on other UGT 
isoenzymes.  The expectation is that the level of rotigotine may increase. 
 
CBD is highly protein bound, so rasagiline, selegiline and rotigotine levels may increase transiently. 
Checking plasma concentration levels of these anti-PD medications is not a routine clinical practice.  Thus the 
PI will monitor subjects on these medications for clinical changes.  The most important and likely adverse 
effects of a clinically significant increase in the level of selegiline is anxiety, dyskinesia, agitation, insomnia 
and hallucinations.  The most important and likely adverse effects of a clinically significant decrease in the 
levels of rasagiline, ropinirole and selegiline is an increase in the motor symptoms of Parkinson disease, 
which are resting tremor, bradykinesia, rigidity and postural instability.  The most important and likely adverse 
effects of a clinically significant increase in rotigotine is low blood pressure, somnolence and impulse control 
disorders. 


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Instructions to Subjects at the End of Each Stage: 
We wil provide the following instructions about continued marijuana use at the end of the study to facilitate 
safety: 
Cannabis (marijuana) is composed of many substances. Street cannabis is high in tetrahydrocannabinol 
(THC), which casues the “high” feeling.  Street cannabis has lower concentrations of cannabidiol (CBD). The 
cannabis preparations sold at dispensaries have various concentrations of THC and CBD. The ratio of THC to 
CBD plays a role in a preparation’s beneficial and adverse effects.  Studies to date suggest that THC is 
especially risky in person with PD, because it may worsen thinking and coordination and cause psychiatric 
symtoms.  The precise effects of all the substances in cannabis is unkown.  In this study we are using 
Epidiolex.  It is >99% pure CBD with only a trace amount of THC (<0.15%) and it has more data regarding 
safety, tolerability, dosing and efficacy than most other forms.  Using marijuana should be under the 
supervision of your physician, with monitoring the symptoms of PD and other diseases, as well as the 
interactions of marijuana and other drugs you take. 
 
C.5 Randomization and drug dispensation: 
 
Patients who consent will be stratified by age (45 – 60 and 61-78) and disease severity (H&Y 1 – 2.5, 3 – 5) 
and divided into blocks of a few patients each, depending on order of recruitment.  Equal numbers from each 
block will be assigned to each of two sequence groups. One group will receive the control first and the 
treatment second, and the other group will receive the treatment first and the control second. Since all 
subjects receive both treatments randomization and stratification are less critical then in studies with fixed 
treatment groups, unless order effects are important or an expectedly large number of patients drop out. 
 
The study drug, Epidiolex, and matching placebo will be provided by GW Pharmaceuticals.  GW will ship the 
drug according to British and US regulations. Initially enough study drug will be provided for the Stage 1 open 
label study, and replenishment shipments will follow. Dr. Leehey, the PI, will obtain a Schedule 1 license and 
all procedures of drug handling will be according to  DEA specifications. Briefly, designated study personnel 
will receive the study drug, store it,  measure and label it (Jacci Bainbridge, PharmD and her fellow) and 
dispense to the subject (study coordinator).  
 
C.6 Blinding assessment and Un-blinding procedures:  
 
Blinding assessment: 
Active drug and placebo will look and taste the same. Subjects and all study personnel except for Drs. Sillau, 
Bainbridge and her fellow, are blinded. 
 
During each visit when on study drug and at the safety follow up visit, participants will be asked  


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about the treatment allocation they think they were assigned. The answers are taken in forms with five 
responses of “strongly believe the treatment is drug”, “Somewhat believe the treatment is drug”, “Somewhat 
believe the treatment is placebo”, “Strongly believe the treatment is placebo”, and “Don’t know”.  
 
Un-blinding procedures: 
The identity of the treatment assigned to individual subjects can be revealed in an emergency only. The PI is 
responsible for ensuring that the instructions on how to request unblinding of treatment are stored safely, that 
their location is known, and that access is readily available to the relevant staff in case of an emergency. Dr. 
Sillau, the statistician will provide the information when un-blinding is requested by the PI.  As a back up, Dr. 
Sillau will provide a file of sealed envelopes to the PI, which is kept in a locked file in her office. The location is 
known to the PI, sub-I and coordinator. A sealed envelope coded with each subject number is provided. In the 
event that Dr. Sillau is not available to provide break the blind the PI and designated staff can do so. 
 
A subject’s treatment assignment should only be un-blinded when knowledge of the treatment is essential for 
the safety of the subject. Un-blinding for any other reason will be considered a protocol deviation. 
 
C.7 Stopping rules: 
Note there are no interim analyses planned. 
 
Participant stopping rules (Both Stages): 
• 
If subject cannot tolerate the study drug at any dose level 
• 
if subject develops a CTCAE criteria grade 3 or 4 adverse event per that the Investigator determines is 
related the study drug 
• 
Pregnancy or breast-feeding  
• 
Requested by subject to terminate treatment 
• 
Failure by the subject to attend consecutive study visits; 
• 
Subject is at significant risk of failing to comply with the provisions of the protocol as to cause harm to self 
or seriously interfere with the validity of the study results; 
• 
At the discretion of the IRB, Food and Drug Administration (FDA). 
 
If a subject is withdrawn from the study, all efforts will be made to complete the early termination visit that 
includes efficacy assessments and safety follow-up. In addition, women of childbearing potential will have a 
post-study pregnancy test performed at the early termination visit.   
 
Withdrawals and the reason for withdrawal will be tabulated by treatment group.  The number and percentage 
of subjects who complete the study will be summarized by treatment group. The number and percentage of 
subjects who withdraw from the study will be tabulated by original treatment group and last treatment taken at 
time of withdrawal. Study medication discontinuations will be summarized in a similar fashion. 
 


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Subjects will be advised that they are free to withdraw from the study at any time. Reasons that subjects may 
be withdrawn from the study include the following:  
Subject discontinued study medication and wishes to withdraw. 
Subject consent is withdrawn. 
 
Study stopping rules (Both Stages) 
• 
Subjects are unable to be recruited 
• 
Study drug becomes unavailable 
• 
Subjects are unable to tolerate the study drug at any dose level  
• 
Discovery (from this or other studies) of an unexpected, serious, or unacceptable health 
hazard to subjects, i.e., development of the same adverse event, CTCAE criteria grade ≥3, related to 
study drug in ≥2 subjects 
• 
At the discretion of the IRB, Food and Drug Administration (FDA). 
 
Any of the above occurring during Stage 1 will lead to a hold and reassessment of starting Stage 2. 
 
C.8 Adverse events assessments: 
 
Adverse events will be classified according to ICH Good Clinical Practice (GCP) definitions. Any adverse 
event or abnormal laboratory test value that is serious  (see definition below) and occurs after administration 
of the investigational product will be documented by the Sponsor-Investigator within 24 hours of discovery of 
the event. 
 
Severity of Adverse Events  
The severity of each AE/SAE will be classified into one of three defined categories as follows:  
• 
Mild: the AE is easily tolerated by the subject, causes minimal discomfort, and does not interfere in a 
significant manner with the subject’s normal functioning level or activities;  
• 
Moderate: the AE is sufficiently uncomfortable to interfere with normal everyday activities, but is not 
hazardous to health;  
• 
Severe: the AE produces significant impairment of functioning or incapacitation and is a definite hazard to 
the subject’s health.  
These three categories are based on the investigator’s clinical judgment, which in turn depends on 
consideration of various factors such as the subject’s reports, the physician’s observations, and the 
physician’s prior experience. The severity of the AE will be recorded in the appropriate section on the AE page 
of the CRF.  
 
Serious Adverse Events (SAEs) 


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The evaluation of severity will be distinguished from the evaluation of “seriousness”. A severe event might not 
meet the criteria for seriousness and a serious event might be evaluated as mild or moderate. For example, a 
subject might have a severe headache that does not require hospitalization and is consequently not serious; 
or a subject might have a mild myocardial infarction that requires hospitalization and is therefore serious. 
 
An SAE is any untoward medical occurrence at any dose that: 
• 
Results in death during the period of protocol-defined surveillance. Death due to PD will not be considered 
an SAE. However, if a patient requires hospitalization due to an AE related to PD, the specific sign or 
symptom leading to hospitalization will be reported as an SAE. If death due to PD occurs outside of 
hospitalization and is considered to be due solely to the patient's PD, no SAE report is required. The 
death will be recorded as part of PD and patient disposition. 
• 
Is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refersto an event in 
which the subject, in the view of the Investigator, is at risk of death at thetime of the event; it does not 
refer to an event that hypothetically might cause death if itwas more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization* 
• 
Results in persistent or significant disability or incapacity 
• 
Results in a congenital anomaly/birth defect. 
*  Hospitalization: Out-patient treatment in an emergency room is not in itself an SAE, although the 
reasons for it might be (e.g., bronchospasm, laryngeal edema). Hospital admission and/or surgical 
operations planned before or during a study are not considered SAEs if the illness or disease existed 
before the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. It should be noted that for this study, subjects with planned or anticipated surgery should 
not be enrolled into the study. 
 
Important Medical Events: Medical and scientific judgment will be exercised in deciding whether a case is 
serious in situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the subject or may require medical or 
surgical intervention to prevent one or more outcomes listed in the definition of serious. These should usually 
be considered as serious, and examples of such events are: 
• 
Angioedema not severe enough to require intubation but requiring intravenous hydrocortisone treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with N-
acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Development of drug dependency or drug abuse. 
 
Unanticipated Adverse Events 
An unanticipated problem is any event or information that was unforeseen and indicates that the research 
procedures caused harm (including physical, psychological, economic, or social harm) to participants or 
others or indicates that participants or others are at increased risk of harm than was previously known or 
recognized.  An "unexpected" adverse reaction is one in which the nature or severity of which is not consistent 
with information in the relevant source document(s). Until source documents are amended, expedited 
reporting is required for additional occurrences of the reaction.  


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Relationship to Study Drug  
The relationship or association of the AE/SAE to study drug will be characterized as “related” or “not related”. 
An AE/SAE will be considered to be not related to the use of the study drug if any of the following criteria are 
met:   
• 
An unreasonable temporal relationship between administration of the product and the onset on the AE 
(e.g., the event occurred either before, or too long after administration of the product for it to be 
considered product-related);   
• 
A causal relationship between the product and the AE is biologically implausible (e.g., death as a 
passenger in an automobile accident);   
• 
A clearly more likely alternative explanation for the AE is present (e.g., typical adverse reaction to a 
concomitant drug).  
Adverse events will be considered “related” to the use of the study drug if none of the “not related” criteria are 
met. The Investigator will use clinical judgment to determine the relationship of the AE/SAE to study drug. An 
AE/SAE may be related to the study drug, other concomitant medications, intercurrent illness, a procedure 
performed in the course of the study, or another reason. Among the potential etiologies, the Investigator will 
make a determination based on the most likely causal relationship. Alternative causes, such as the natural 
history of any underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the event to the study drug will be considered. The Investigator will also take into account the Investigator’s 
Brochure in the causality assessment. There may be situations when an SAE has occurred and the 
Investigator has minimal information to include in the initial report to the Sponsor. However, the Investigator 
will make an assessment of causality prior to transmission of the SAE report to the Sponsor, as the causality 
assessment is one of the criteria used when determining regulatory reporting requirements. The Investigator 
may change the causality assessment in light of follow-up information, by amending the SAE report 
accordingly. 
 
SAEs that are considered related (i.e., determined to be possibly, probably, or definitely related) to the 
investigational product by the Sponsor-Investigator will be followed until the event resolves or stabilizes. Any 
SAE that occurs after treatment completion, and is considered by the Sponsor-Investigator to be related to the 
investigational product, will be documented and reported as appropriate. 
 
Reporting Serious Adverse Events to Regulatory Agencies 
Events meeting the following criteria will be submitted to the Food and Drug Administration (FDA) as 
expedited IND Safety Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report 
The Sponsor-Investigator will notify the appropriate review division at the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the Sponsor-Investigator to be possibly related to the use 
of the investigational product. An unexpected adverse event is one that is not already described in the 
investigational product’s Investigator Brochure. Such reports are to be telephoned or faxed to the appropriate 
review division at FDA and to the manufacturer of the investigational product within 7 calendar days of first 
learning of the event. 


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15 Calendar Day Written Report 
The Sponsor-Investigator will notify the appropriate review division at the FDA, in a written IND Safety Report, 
of any serious, unexpected AE that is considered reasonably or possibly related to the use of the 
investigational product.  
 
Written IND Safety reports will include an Analysis of Similar Events in accordance with regulation 21 CFR § 
312.32. All safety reports previously filed by the Sponsor-Investigator with the IND concerning similar events 
will be analyzed and the significance of the new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events will be submitted to the appropriate review division 
at the FDA, and the manufacturer of the investigational product within 15 calendar days of first learning of the 
event, using FDA Form 3500A. 
 
Written IND Safety Reports will be submitted to the IRB(s) of record per IRB Guidelines. 
 
IND Annual Reports 
The Sponsor-Investigator will provide annual reports to the appropriate review division at the FDA within 60 
days of the IND’s anniversary date, until the IND is withdrawn or terminated. 
 
C.9 Risks of Study Drug: 
 
A review of 25 studies on the safety and efficacy of CBD did not identify significant side effects across a wide 
range of dosages, including acute and chronic dose regimens, using various modes of administration. 
[Bergamaschi  M.M., et al. 2011] There are no rare but serious side effects reported. The most frequently 
occurring side effect was somnolence (i.e.drowsiness) (21%). Other side effects, in order of prevalence, 
include: fatigue (17%), diarrhea (17%), increased appetite (17%), decreased appetite (16%), and weight loss 
(9%). [Devinsky O, et al. 2014] Other side effects include extrapyramidal symptoms, increased prolactin 
levels, weight gain increased serum concentrations of antiepileptic drugs and elevated liver function tests .   
 
Table 2 and 3 show the adverse reactions of CBD from the IB (CBD) provided by GW Research Ltd.  
 
Table 2. The adverse reactions with a plausible causal relationship to purified CBD solution—reported at a 
daily maximum of 25 mg/kg/day 
Adverse Reactions 
Related causality CBD (n=213) 
Most frequently (5 to 10%) 


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Somnolence 
44 (21%) 
Fatigue 
36 (17%) 
Decreased appetite 
31 (15%) 
Diarrhoea 
29 (14%) 
Lethargy 
12 (6%) 
Increased appetite 
15 (7%) 
Weight increased 
12 (6%) 
Convulsion 
11 (5%) 
Weight decreased 
10 (5%) 
Gait disturbance 
10 (5%) 
Less frequently (1 to 5%) 
Drug level increased 
9 (4%) 
Sedation 
7 (3%) 
 
Table 3. Most frequently adverse reactions of purified CBD reported at 200, 400, and 800 mg/day  
Adverse reactions 
CBD 200 
mg/day 
(n=7) 
CBD 400 
mg/day 
(n=6) 
CBD 800 mg/day 
(n=7) 
Diarrhoea 
4 (57%) 
3 (50%) 
5 (71%) 
Dyspepsia 
0 
1 (17%) 
1 (14%) 
Defaecation urgency 
0 
0 
1 (14%) 
Eructation 
0 
0 
1 (14%) 
Frequent bowel 
movements 
0 
0 
1 (14%) 
Gastritis 
1 (14%) 
0 
0 
Gastrointestinal 
hypermotility 
0 
1 (17%) 
0 
Vomiting 
1 (14%) 
0 
1 (14%) 
Fatigue 
1 (14%) 
1 (17%) 
0 
Product size issue 
1 (14%) 
0 
0 


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Aspartate 
aminotransferase 
increased 
1 (14%) 
0 
0 
Gamma-
glutamyltransferase 
increased 
1 (14%) 
0 
0 
Platelet count 
decreased 
1 (14%) 
0 
0 
Decreased appetite 
1 (14%) 
0 
1 (14%) 
Dysgeusia 
0 
0 
1 (14%) 
Headache 
1 (14%) 
2 (33%) 
0 
Pollakiuria 
0 
0 
1 (14%) 
Rash generalised 
0 
0 
1 (14%) 
Rash maculo-papular 
0 
0 
1 (14%) 
 
Based on data of Epidiolex and previous studies, some side effects, such as diarrhea, weight loss, and 
decreased appetite, required reduction of the dose resulting in improvement of symptoms. The large majority 
of adverse events were mild to moderate and transient. No significant laboratory abnormalities were 
observed. 
 
D.   Description, Risks and Justification of Procedures and Data Collection Tools: 
 
 
Patients could be uncomfortable about their survey of cannabis, drug, alcohol and tobacco use that is 
administered during screening in both Stages. However, this information is essential for their safety, to check 
for history of addiction. If this is found then subject could be harmed by participating and thus would be 
excluded. Also this information is needed for scientific rigor. Federal funding sources are likely to want this 
information to understand the relevance and importance of future cannabis studies. The importance of having 
the information will be explained and the subject will be reminded that participation is voluntary.   
 
CBD’s effect on many aspects of PD are being studied, besides the primary and major secondary outcome 
measures. This makes the visits longer and may be tiring for some subjects. To minimize discomfort subjects 
will be offered sufficient breaks and maximal efforts for efficiency will be made to minimize visit time. The 
reason for the many assessments is twofold. First, PD is a complex disorder with many different disabling 
symptoms, and secondly, it is prudent to maximize the information from this study. Studies on cannabis are 
sorely needed, since many PD patients are taking this potentially dangerous drug as it becomes more 
available. Access is becoming more available throughout the US as more states are considering legalizing 
use of medical and recreational marijuana. Besides this lack of vital information, obtaining funding and getting 
through all the regulatory steps required for study of cannabis is very hard, thus we want to obtain maximal 
information when such a study (as this one) can be done. This information is vital to guide future studies. 


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To minimize the risk in the study, the following procedures will be complied with: 
1. The study will be conducted in compliance with the COMIRB approved protocol, GCP and the applicable 
regulatory requirements. 
2. The study will be overseen by COMIRB and a Data Safety Monitoring Board (DSMB) at University of 
Colorado. 
3. Each patient will be contacted by phone every 3rd or 10th day and the 3rd day following discontinuation of 
study drug as described in Section C during in both the dose escalation safety study and the RCT to 
monitor for adverse effects or withdrawal, as well as changes of medical history and concomitant 
medications. These phone calls will be done by a RN, APP or MD. 
4. Adverse events and serious adverse events will be reported from the time of study drug administration 
until the last study visit or death, whichever occurs first, according to mandated guidelines. 
5. All adverse events and serious adverse events will be followed until resolution (or return to baseline 
status), or until the condition stabilizes or is otherwise explained, or until subject dies or is lost to follow-
up. 
6. Safety assessments are comprehensive and include vital signs, history & physical examination, 
concomitant medications collection, EKGs, safety labs, blood and urinary cannabis and metabolites 
analysis, MoCA, QUIP-RS, C-SSRS, NPI, SCOPA-sleep, Anxiety short form, Depression short form, 
Emotional and behavioral dyscontrol short form, Fatigue Severity Scale, Pain Intensity and Interference 
short form, study drug compliance check, adverse event check and urine and blood pregnancy testing. 
 
We will follow the FDA’s Guidance for evaluating and monitoring potential drug-induced hepatotoxicity. 
Subjects with stable liver disease can be included if they have a normal total bilirubin and prothrombin 
time/INR at baseline. Liver function tests (ALT, AST, ALP and bilirubin) will be drawn at baseline and at each 
visit while subjects are on study drug.  In addition, if these labs are abnormal at the end of study visit they will 
be repeated at the safety follow up visit two weeks later and repeated until back to baseline values.  During 
each phone call that assesses effects of study drug, nonspecific symptoms of Drug Induced Liver Injury (DILI) 
will be checked, e.g., anorexia, nausea, fatigue, right upper abdominal discomfort, and vomiting.  If symptoms 
indicative of DILI occur the subject will return to clinic immediately for measurement of laboratory signs of 
hepatic injury, regardless of when the next visit or monitoring interval is scheduled.  At any time if 
aminotransferase enzymes are greater than 3x upper limit of normal (ULN), we will repeat ALT, AST, ALP 
and bilirubin within 48-72 hours.  If symptoms persist or repeat testing shows aminotransferase >3xULN for 
subjects with normal baseline measures or 2-fold increases above baseline values for subjects with elevated 
values before drug exposure, we will initiate close observation to determine whether the abnormalities are 
improving or worsening. Per the FDA, close observation includes:  
• 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of retesting can 
decrease to once a week or less if abnormalities stabilize or the trial drug has been discontinued and the 
subject is asymptomatic.  
• 
Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
• 
Obtaining a history of concomitant drug use (including nonprescription medications and herbal and 
dietary supplement preparations), alcohol use, recreational drug use, and special diets.  
• 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; 
hypoxic/ischemic hepatopathy; and biliary tract disease.  


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• 
Obtaining a history of exposure to environmental chemical agents.  
• 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin).  
• 
Considering gastroenterology or hepatology consultations.  
 
We will gather further history as recommended.  Unless we find that the repeat testing shows the 
aminotransferase levels decline to baseline, we will consult the UCH Hepatology team to determine further 
management. 
 
The FDA advises that since transient fluctuations of ALT or AST are common, and progression to severe liver 
injury or failure is uncommon, automatic discontinuation of trial drug upon finding a greater than 3xULN 
elevation of ALT or AST may be unnecessary.  The decision of whether to stop study drug will be affected by 
information on related drugs, the accumulating clinical experience, the clinical status of the patient, and many 
other factors.  We will consult the UCH hepatology service and keep the following FDA guidance in mind.  
The FDA states that discontinuation of treatment should be considered if:  
ALT or AST >8xULN  
ALT or AST >5xULN for more than 2 weeks  
ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)  
 
Data collection tools:  
To protect the privacy of patients, the data collected in the study is stored completely de-identified. A code will 
be linked to the information provided, and answers are entered into a computer database using this code. No 
personal identifiers will be linked to the subject’s information in the database. All of this information in the 
computer is password protected. The code will be linked to the subject’s University of Colorado Hospital 
medical record number in a separate computer database. The PI will keep the surveys completed on paper in 
a locked cabinet. 
 
 
E.   Potential Scientific Problems:   
 
To maximize scientific intergrity this study was peer reviewed by the Colorado Department of Health & Safety 
(CDPHE) before receiving funding. In addition it has been reviewed in detail by scientific members of the 
company providing study drug, GW Research, Ltd. We do not expect problems with recruitment because of 
the high level of interest and publicity regarding cannabis research, especially the CDPHE funded studies. In 
addition, we have a large population of PD patients, since we see over 1500 PD patients in our UCH 
Movement Disorders clinic annually, and our 8 Movement Disorders providers also cover the VAMC and 
Denver Health. We do not expect problems with unblinding because the placebo will be identical and does not 
taste or smell different from active drug and because CBD is generally well tolerated. Also, to reduce risk of 


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unblinding if the dose escalation study shows that the maximal dose tolerated is less than 25 mg/kg/day, then 
the maximal dose for the RCT study will be reduced accordingly.  
 
F.   Data Analysis Plan:   
Intention to treat concept is followed. In order to minimize data entry errors a double data entry system will be 
used.  
If study subject agrees, the de-identified data would be shared within CDPHE Marijuana grantee consortium 
for future research.   
Stage 1: Open Label Dose Escalation Tolerability Study 
 
Primay Specific Aim: To confirm that the dosage regimen of CBD, in the form of Epidiolex, is safe and 
tolerated in 10 subjects with PD. 
 
The primary outcome is safety and tolerability of the proposed dose of CBD and will be assessed in 4 ways: 
 
1. Frequency of study-related adverse events at each dose level collected at standardized phone script 
administration and at study visits. Analysis of frequency will be mostly descriptive, and proportions 
and confidence intervals will be calculated. Comparisons on repeated measures can be analyzed with 
McNemar’s test, for binary outcomes at 2 time points, or GEE models/GLMMs. Logistic or relative risk 
models can be used for binary outcomes, and Poisson models for counts. 
 
2. Vital signs, orthostatic blood pressures, physical exam, EKG and labs (hematology,  complete 
metabolic profile, urinalysis) during study visits. For vital signs and labs, means and their confidence 
intervals will be calculated at the two time points (baseline and the end of the open label dose 
escalation tolerability study), and a paired T-test will compare them. Physical exam and EKG will be 
descriptive. 
 
3. Standardized assessment tools (MoCA, Anxiety short form, NPI, SCOPA-Sleep, RBDSQ, QUIP-RS, 
C-SSRS, Depression short form, Emotional Behaviroral dyscontrol short form, Fatigue severity scale, 
MDS UPDRS, UDysRS, Pain Intensity 3a short form and Pain Interference 4a short form, IRLS) 
during study visits. Means and their confidence intervals will be calculated for each outcome at the 
two time points (baseline and the end of the open label dose escalation tolerability study), and paired 
T-tests will compare them. 
 
4. Proportion of subjects drop out of the study due to study drug intolerance. It will be descriptive and 
proportions and confidence intervals will be calculated. No tests are applicable since there is nothing 
to compare to. 
 


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The Secondary Specific Aim is to examine the effect of CBD on severity & duration of intractable tremor and 
other symptoms of PD. 
 
The secondary outcomes are tremor and the changes from baseline to the end of the open label study 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. In this open label study the 
aim is to obtain preliminary data on the effect of CBD on severity & duration of intractable tremor in PD.  This 
study is not intended to be powered to obtain a clinically significant result.  A paired T-test is applied to 
compare the data at the two time points. Analysis of binary outcomes can be performed with McNemar’s test, 
generalized estimating equations models, and generalized mixed models.   
 
Stage 2: Randomized Controlled Trial 
 
For the RCT the analysis will be performed in accordance with the analysis plan devised prior to unblinding. 
Baseline variables will be examined for equality between the two sequence groups.  The primary, secondary 
and exploratory outcomes will be analyzed as below for both the low dose (5 mg/kg/day) and highest 
tolerated dose. 
 
Primary Specific Aim: To evaluate the safety and tolerability of CBD, in the form of Epidiolex, in PD. 
 
The primary outcome is safety and tolerability and will be assessed in 4 ways: 
 
1.  Frequency of study-related adverse events at each dose level collected at standardized phone script 
administration and at study visits. Analysis (frequency of study-related adverse events at each dose 
level in the two groups, treatment vs. placebo) will be mostly descriptive, and proportions and 
confidence intervals will be calculated. Contrasts involving repeated measures on the same subjects 
can be tested with McNemar’s test (for two correlated proportions) or GEE models/GLMMs. Contrasts 
for independent data can be tested with standard two sample proportions test and with GLMs. 
Proportions, logistic regression, and relative risk regression can be applied to binary outcomes over a 
fixed period of time, and Poisson models can be applied to counts or events over time. 
 
2. Vital signs, orthostatic blood pressures, physical exam, EKG and labs (hematology, complete 
metabolic profile, urinalysis) during study visits. For vital signs and labs, data will be analyzed as a 
simple two-period crossover trial. Means and confidence intervals will be presented for each group * 
treatment, and for the change scores in each group. A two sample T-test will compare the means of 
the two groups, those in the CBD-placebo group vs. those in the placebo-CBD group, on the change 
scores between period 1 to period 2. The difference between the means of the two group will be 
equal to twice the treatment effect. Physical exam and EKG will be descriptive between the two 
groups (treatment vs. placebo).  More complex situations, including testing for treatment * order 
interaction, can be analyzed with longitudinal regression models. 
 


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3. Standardized assessment tools (MoCA, Cognition assessment battery, Anxiety short form, NPI, 
SCOPA-Sleep, RBDSQ, QUIP-RS, C-SSRS, Depression short form, Emotional Behaviroral 
dyscontrol short form, Fatigue severity scale, MDS UPDRS, UDysRS, Pain Intensity 3a short form 
and Pain Intensity 4a short form, IRLS, PDQ-39 and EQ-5D-5L) and lab tests, the data will be 
analyzed as a simple two-period crossover trial. Means and confidence intervals will be presented for 
each group * treatment, and for the change scores in each group. A two sample T-test will compare 
the means of the two groups, those in the CBD-placebo group vs. those in the placebo-CBD group, 
on the change scores between period 1 to period 2. The difference between the means of the two 
group will be equal to twice the treatment effect.  More complex situations, including testing for 
treatment * order interaction, can be analyzed with longitudinal regression models.   
 
4. Proportion of subjects drop out of the study due to study drug intolerance. Analysis (proportions of 
subjects drop out of the study due to study drug intolerance in the two groups, treatment vs. placebo) 
will be mostly descriptive, and proportions and confidence intervals will be calculated.  Proportion 
differences between groups can be compared with the standard test. 
 
The difference between the mean change scores of the two group will be equal to twice the treatment effect. 
We will test the null hypothesis of no treatment effect. To test and control for a possible time/order effect, 
longitudinal regression models will be fit with a time/order variable included. 
 
Secondary Specific Aim is to examine the effect of CBD on severity & duration of intractable tremor in PD. 
 
For the secondary outcome, tremor, the data will be analyzed as a simple two-period crossover trial.  Means 
and confidence intervals will be presented for each group * treatment, and for the change scores in each 
group.  A two sample T-test will compare the means of the two groups, those in the CBD–placebo group vs. 
those in the placebo–CBD group, on the change scores between period 1 to period 2.  The difference 
between the means of the two groups will be equal to twice the treatment effect.  We will test the null 
hypothesis of no treatment effect.  To test and control for a possible time/order effect, longitudinal regression 
models will be fit with a time/order variable included.  Covariates, such as age or baseline disease severity 
(H&Y) may be adjusted for as covariates, especially if unbalanced between the sequence groups.   
 
Exploratory Outcome Measures: The effects of CBD on cognition, anxiety, psychosis, sleep, daytime 
sleepiness, mood, fatigue, pain, impulsivity, and motor and non-motor PD signs, restless legs syndrome, 
REM sleep behavior disorder and quality of life are evaluated using the aforementioned assessment tools. 
The change from baseline to 10th day of 5 mg/kg/day (low dose analysis) and from baseline to the maximum 
tolerated or targeted dose is compared. 
 
Exploratory analyses: (1) To study the effect 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 conditions at a low dose.  
 


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Exploratory outcomes includes assessments of 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. The effect of CBD at both a low dose (5 mg/kg/day) and the maximum tolerated or targeted 
dose is studied.  Continuous outcomes will be analyzed in the same way as tremor.  Transforms or non-
parametric methods will be applied as necessary.  Non-continuous outcomes will be analyzed with 
generalized estimating equations models, and generalized mixed models, and with McNemar’s test for binary 
outcomes.   
 
Sample Size Justification 
Stage 1. Open Label Dose Escalation Tolerability Study 
Ten patients are recruited to the safety study. A 95% confidence interval derived from the T distribution, for a 
continuous outcome, would have a total width of 1.43 times the standard deviation of the change score. For 
the test for a difference, with an alpha level of 0.05, an effect size of 1.00 relative to the standard deviation 
would be required for 80% power, and an effect size of 1.16 would be required for 90% power. For a binary 
event, the probability of no “success” in 10 independent runs is less than 5% if the true probability is 26% or 
greater, and less than 2.5% if the true probability is 31% or greater.   
Stage 2: Randomized Controlled Trial 
The primary outcome, safety and tolerability, will mostly be analyzed descriptively.  For the main secondary 
outcome, testing for a treatment effect on tremor, a sample size of 38 patients would achieve 90% power with 
an alpha level of 0.05, a standard deviation of the differences of 3 units on the outcome scale, and an 
absolute value mean effect on the outcome scale of 1.625, approximately 25% (this would be a clinically 
significant effect). We anticipate a dropout rate of 10%, necessitating 43 patients, and we then increase to 48 
for safety, rounding and because of the 2x2 stratification plan.  Note that each patient serves as his/her own 
matched control.   
Since other outcomes are either descriptive and/or exploratory, and sample size is limited, there will be no 
adjustment for multiple testing adjustments are not planned. 
 
G.  Summarize Knowledge to be Gained:   
 
Marijuana is one of the most used alternative medications. Since it became legal and readily available in 
Colorado, Parkinson disease (PD) and other movement disorders patients have been trying it, usually without 
the knowledge of or supervision of their neurologist. This study will promote the safety of our patients and 
provide data useful in evaluating the effect and safety of CBD on tremor, cognition, anxiety, psychosis, and 
other symptoms, including sleep, impulsivity, suicidality, mood, fatigue, restless legs syndrome, pain, 
bradykinesia, rigidity, balance, and dyskinesia in PD patients. Data from this study are essential to aid in 
designing future marijuana research.   
 
 H. References 
 


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APPENDIX 1: Schedule of Events—Stage 1 
 
Screening
Baseline
Week
1
4
5-6
6
day
< negative 21
1
1-3
4-6
7-11
12-16
17-19
20-25
26-31 (k)
27-29
30-39
40 (+/- 4)
Clinic visit
1
2
3
4
Telephone call*
1
2
3
4
5
6 (h)
7(i)
8(h)
Dosage of CBD or placebo mg/kg
0
5(take the 
first dose in 
clinic)
5
7.5
10
15
20
20
20 (take the 
study drug prior 
to clinic visit)
0
0
0
Informed consent
√
Eligibility Criteria
√
√
Demographics
√
Medical History (a)
√
Family medical history
√
Medical History - interval
√
√
√
√
√
√
√
√
√
√
Concomitant Medications
√
√
√
√
√
√
√
√
√
√
Study drug compliance check
√
Dispense study drug and instruction
√
Adverse Events (b)
√
√
√
√
√
√
√
√
Formal drug interaction assessment
✓
✓
✓
✓
Vital Signs(c)
√
√ (l)
√ (n)
√
Orthostatic Blood Pressures check
√
√ (l)
√ (n)
√
Height and Weight
√
√
√
√
Complete Physical Exam (d)
√
√
√
Neurological exam
✓
√
Brief physcial exam (heart and lung 
ausculation)
✓
Hematology (e)
√
√ 
√ (j)
Hemoglobin A1C
✓
Complete metabolic profie (f)
√
√ 
√ (j)
Blood cannabis analysis
√
√ (m)
√
Urinalysis (g)
√
√
√ (j)
Urine Drug (THC) test
✓
Urine CBD and metabolites levels test (o)
✓
Urine cups dispense and urine collection 
instruction
✓
ECG (12-LEAD)
√
√
√ (j)
Serum Pregnancy Test (for women 
childbearing potential)
√
Urine Preganancy Test (for women 
childbearing potential)
√
√
√
Assessment of past marijuana use
√
Drug, alcohol and tobacco abuse screening 
test
√
MOCA 
√
√
√
MDS-UPDRS part III
√
MDS-UPDRS
√
√
√
Unified Dyskinesia Rating Scale (UDysRS)
√
√
√
H & Y rating 
√
√
√
QUIP-RS 
√
√
√
C-SSRS
√
√
√
√
NPI
√
√
√
SCOPA-sleep 
√
√
√
√
√
√
√
√
√
RBDSQ
√
√
√
IRLS
√
√
√
Anxiety short form
√
√
√
Depression short form
√
√
√
Emotional behavioral dyscontrol short form
√
√
√
Fatigue severity scale
√
√
√
Pain intensity and interference short form
√
√
√
CGI
√
PGI
√
Home diary dispense & instruction
√
Home diary collection & review
√
Fax, mail or email a copy or image of the 
diary filled out
√
Appendix A Schedule of events Stage 1 Open label dose escalation tolerability study
Treatment Period
Safety Followup
1-4
* phone call is made on the third day of each dose (between 5-10 mg/kg/day) and fifth day of each dose (between 10-20 mg/kg/day)


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 Schedule of Event- Stage 1 note 
 
 
 
Note: regarding the rows of days and weeks, it is variable, because of note k and also because some patients will take shorter or longer to get to their maximum tolerated dose than those that titrated 
to 20 mg/kg/day. 
a. A complete medical history (including PD history, mental health history, alcohol and drug use) will be obtained from the subject at the Screening Visit and recorded on the appropriate CRF. The 
medical history and other enrollment criteria will be reviewed and updated at the Baseline/Day 1 visit to determine continued eligibility for the study.
b. Adverse events will be recorded from the time of the first dose of study drug. Any subject with an ongoing AE will be followed until the AE is resolved, returns to baseline or deemed stable by the 
investigator.
c. Vital signs obtained after the subject has been sitting for at least 5 minutes. Body temperature will be obtained at screening, Day 1, and at the final follow up visit. Blood pressure, respiratory rate 
and heart rate will be measured once each day assessed. During screening only, after the seated blood pressure has been obtained, the blood pressure will be repeated within 3 minutes of the 
subject standing up. This procedure may be repeated, if appropriate, following hydration. If repeated, a total of two additional pairs of BP assessments (sitting/standing) should be obtained, and the 
results of the last attempt should be reported.
d. Complete PE to include: skin, head-neck, eyes-ears-nose-throat, lungs-chest, heart, abdomen, extremities, neurological.
e. Hematology consists of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red blood cell count (RBC), white blood cell (WBC) count, 
WBC differential (absolute), and numerical platelet count.
f. Serum chemistry (fasting not required) consists of alkaline phosphatase, albumin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine (MDRD formula for eGFR, to be done by the 
central laboratory), γ-glutamyltransferase, glucose, inorganic phosphorus, potassium, alanine aminotransferase, lactate dehydrogenase, aspartate aminotransferase, sodium, total bilirubin, and total 
protein.
g. Urinalysis will be performed locally using sponsor-supplied dipsticks, including leukocytes, specific gravity, pH, protein, ketones, glucose, nitrite, blood, urobilinogen, and bilirubin. If nitrite, blood, 
or protein tests are positive, a microscopic examination will be performed at the central laboratory.
h. Call patient to remind them the clinical visit next day
i. Call patient to collect adverse events and information of signs of withdrawal
o. Clean catch urine collection after taking the study drug. Urine is collected in a 500 mL container and stored in 3-4 samll cups (120 mL, fill up to 3/4). 
j. Hematology, chemistry, urinalysis and EKG will be done if there was a clincally significant change at the end of study visit compared to baseline visit.
k.  For some patients, the visit can occur during 10-15 days on max dose, not just on the 10th day.
l. Subject will be monitored and vital signs will be checked at before and 1 hour after taking the study drug.
m. Blood draw will be performed 3 hours after taking the study drug of the clinical visit day.
n.  Subject will be monitored and vital signs will be checked at before and 1 and 3 hours after taking the study drug.


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Schedule of Event—Stage 2 
 
 
 
 
screening
baseline
week (number of days)
1
17
17 to 19(10 days)
19
Days
< negative 21
1
1-3
4-9
10 (+5) (k)
11-13
14-16
17-21
22-24
25-34
35-44
45-48
49 (+/-4) (l)
50-52
53-69
70
71
71-73
75-79
80 (+5) (k)
81-83
84-86
87-91
92-94
95-104
105-114 115-118 119 (+/- 4) (l)
120-122
123-132
133 (+/- 4) 
Dosage of CBD or placebo mg/kg
0
5 (take the 
first dose in 
clinic)
5
5
5 (take the 
study drug 
prior to 
clinic vist)
10
15
20
25
25
25
25
25 (take the 
study drug 
prior to clinic 
vist)
0
0
0
5
5
5
5 (take the 
study drug 
prior to 
clinic vist)
10
15
20
25
25
25
25
25 (take the 
study drug 
prior to clinic 
vist)
0
0
0
clinical visit*
1
2
3
4
5
6
7
8
9
10
telephone call**
1
2 (i)
3
4(q)
5
6
7
8 (i)
9 (j)
10 (i)
11
12 (i)
13
14(q)
15
16
17
18 (i)
19 (j)
20 (i)
Informed consent
√
Eligibility Criteria
√
√
Demographics
√
Medical History (a)
√
Medical History
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Family medical history
√
Concomitant Medications
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Randomization
√
Blinding assessment
√
√
√
√
Study drug compliance check
√
√
√
√
Dispense study drug and instruction
√
√
✓
√
√
✓
Adverse Events (b)
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Formal drug interaction assessment
√
√
√
√
√
√
√
√
√
√
Vital Signs (c) 
√
√ (n)
√(p)
✓
√(p)
√ (n)
√(p)
✓
√(p)
√
Orthostatic Blood Pressures check
√
√ (n)
√(p)
✓
√(p)
√ (n)
√(p)
✓
√(p)
√
Height and Weight
√
√
√
✓
√
√
✓
√
√
Complete Physical Exam (d)
√
√
√
√
Neurological exam (e)
√
✓
✓
Brief physcial exam (heart and lung ausculation)
√
√
√
√
√
Hematology (f)
√
√ 
√ 
√ (m)
Hemoglobin A1C
√
Complete metabolic profie (g)
√
✓
✓
√ 
✓
✓
√ 
√ (m)
Blood cannabis analysis
√
√ (o)
√ (o)
√ (o)
√ (o)
√
Urinalysis (h)
√
√
√
√ (m)
Urine drug (THC) test
√
Urinary CBD and metabolites levels test ®
√
✓
√
√
✓
√
Urine cups dispense and urine collection 
instruction
√
✓
√
√
✓
√
ECG (12-LEAD)
√
√
√
√ (m)
Serum Pregnancy Test (for women childbearing 
potential)
√
Urine Preganancy Test (for women childbearing 
potential)
√
√
√
✓
√
√
Assessment of past marijuana use
√
Drug, alcohol and tobacco abuse screening test
√
MOCA 
√
√
√
√
√
√
√
Cognitive assessment battery
√
√
√
MDS-UPDRS part III
√
MDS-UPDRS (all 4 parts)
√
√
√
√
√
√
H & Y rating 
√
√
√
√
√
√
√
RPW
√
√
√
√
√
√
QUIP-RS 
√
√
√
√
√
√
C-SSRS
√
√
√
√
√
√
√
RBDSQ 
√
√
√
√
√
√
NPI
√
√
√
√
√
√
Anxiety short form
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Depression short form
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Emotional and behavioral dyscontrol short form
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
SCOPA-sleep 
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
IRLS
√
√
√
√
√
√
Fatigue severity scale
√
√
√
√
√
√
Pain intensity and interference short form
√
√
√
√
√
√
PDQ-39
√
√
√
√
√
√
EQ-5D
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
CGI
√
√
√
√
√
√
PGI
√
√
√
√
√
√
Unified Dyskinesia Rating Scale (UDysRS)
√
√
√
√
√
√
Home diary dispense & instruction
√
√
✓
√
√
✓
Home diary collection & review
√
✓
√
√
✓
√
Note: regarding the rows of days and weeks, it is variable, because of note (k) and note (l), and because some patients will take shorter or longer to get to their maximum tolerated dose than those that titrate to the target dose (determined in stage 1). 
1-7 (47 days)
7 to 10 (21 days)
10 to 17 (47 days)
*Clinical visit: visit 3 and 5 are low dose vists, 10th day of 5 mg/kg/day; visit 4 and 6: end of first and second treatment phase.
**phone call is made on the third day of each dose; x means the phone call is only to remind subject to come in for visit the next day.
Appendix B schedule of event Stage 2 RCT
schedule of events
Treatment Period
Washout
Treatment Period
Safety Followup


Protocol Template 
Page  
CF-146, Effective 7/10/11 
 
46
Schedule of Event—Stage 2 note 
 
o.  Blood drawn will be performed 3 hours after taking the study drug of the clinical visit day.
p.  Subject will be monitored and vital signs will be checked at before and 1 and 3 hours after taking the study drug.
q. Regular phone call, also remind patient the clinical visit on either day from 2nd to 5th day while they are on 20 mg/kg/day
r. Clean catch urine collection after taking the study drug. Urine is collected in a 500 mL container and stored in 3-4 samll cups (120 mL, fill up to 3/4). 
j. Call patient to collect adverse events and information of signs of withdrawal
k. Visits 3 and 5 can occur on 5 mg/kg/day for 10 -15 days (not just on the 10th day).
l. Visits 4 and 6 can occur on the max tolerated or the target dose, whichever patient get to, on the 28 +/- 4 days. (not just on the 28th day)
m. Hematology, chemistry, urinalysis and EKG will be done if there was a clinically significant change at the high dose evaluation visit compared to baseline visit.
n.  Subject will be monitored and vital signs will be checked again at before and 1 hour after taking the study drug.
e. Targeted PE to include: skin, lungs-chest, heart, abdomen, neurological, extremities.
f. Hematology consists of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red blood cell count (RBC), white blood cell (WBC) count, WBC differential (absolute), and numerical platelet count.
g. Serum chemistry (fasting not required) consists of alkaline phosphatase, albumin, blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine (MDRD formula for eGFR, to be done by the central laboratory), γ-glutamyltransferase, glucose, inorganic phosphorus, potassium, alanine aminotransferase, lactate dehydrogenase, aspartate aminotransferase, sodium, total bilirubin, and total protein.
h. Urinalysis  dipsticks including leukocytes, specific gravity, pH, protein, ketones, glucose, nitrite, blood, urobilinogen, and bilirubin. If nitrite, blood, or protein tests are positive, a microscopic examination will be performed at the central laboratory.
i. Call patient to remind them the clinical visit next day
Note: regarding the rows of days and weeks, it is variable, because of note (k) and note (l), and because some patients will take shorter or longer to get to their maximum tolerated dose than those that titrate to the target dose (determined in stage 1). 
a. A complete medical history (including PD history, mental health history, alcohol and drug use) will be obtained from the subject at the Screening Visit and recorded on the appropriate CRF. The medical history and other enrollment criteria will be reviewed and updated at the Baseline/Day 1 visit to determine continued eligibility for the study.
b. Adverse events will be recorded from the time of the first dose of study drug. Any subject with an ongoing AE will be followed until the AE is resolved, returns to baseline or deemed stable by the investigator.
c. Vital signs obtained after the subject has been sitting for at least 5 minutes. Body temperature will be obtained at screening, Day 1, and at the final follow up visit. Blood pressure, respiratory rate and heart rate will be measured once each day assessed. During screening only, after the seated blood pressure has been obtained, the blood pressure will be repeated within 3 minutes of the subject 
standing up. This procedure may be repeated, if appropriate, following hydration. If repeated, a total of two additional pairs of BP assessments (sitting/standing) should be obtained, and the results of the last attempt should be reported.
d. Complete PE to include: skin, head-neck, eyes-ears-nose-throat, lungs-chest, heart, abdomen, extremities, neurological.


APPENDIX 2 
Protocol Template 
Page  
CF-146, Effective 7/10/11 
 
47
 
If subject is on this & CBD 
(which is metabolized by this 
enzyme) is added, the CBD 
level may be reduced
If subject is on this & CBD (which 
is metabloized by this enzyme) is 
added then the CBD level may be 
higher
If subject is on this & CBD (which 
is metabolized by this enzyme) is 
added, the CBD level may be 
reduced
If subject is on this & CBD 
(which is metabloized by this 
enzyme) is added then the CBD 
level may be higher
Add CBD (which inhibits this 
enzyme) and the drug level may 
be increased
Add CBD (which inhibits this 
enzyme) and the drug level may 
be increased
Add CBD (which inhibits 
this enzyme) and the 
drug level may be 
increased
Add CBD (which 
inhibits this enzyme) 
and the drug level may 
be increased
If subject is on this & 
CBD (which is 
glucurondated  by this 
enzyme) is added then 
the CBD level may be 
higher
If subject is on this & 
CBD (which is 
glucurondated by this 
enzyme) is added then 
the CBD level may be 
higher
If subject is on this & 
CBD (which is 
glucurondated by this 
enzyme) is added then 
the CBD level may be 
higher
If subject in on CBD 
and starts any of these 
medications, CBD 
levels may decrease 
(CBD is glucurondated 
by this enzyme)
If subject in on CBD 
and starts any of these 
medications, CBD 
levels may decrease 
(CBD is glucurondated 
by this enzyme)
Highly Protein Boud 
drugs (serum 
concentrations can 
fluctuate between 
both drugs)
CYP 3a4 inducers
CYP 3a4 inhibitors
CYP 2c19 inducers
CYP 2c19 inhibitors
CYP 3a4 substrates
CYP 2c19 substrates
UGT1A9 substrates
UGT2B7 substrates
UGT1A7 inhibitors
UGT1A9 inhibitor
UGT2B7 inhibitor
UGT1A9 Inducers
UGT2B7 Inducers
Highly Protein Bound 
Carbamazepine
Amiodarone
Aminoglutethimide
Chloramphenicol
Alfentanil (Alfenta)
Aripiprazole (abilify)
Acetaminophen
Azidothymidine
--
Cyclosporin A
ketoconazole
--
Gancyclovir
Phenobarbital
armodafinil
alprazolam
Artemisinin
amitriptyline
Alfuzosin (Uroxatral)
Carisoprodol (Soma)
diclofenac
clofibrate
Milk Thistle (Silymarin) valproic acid
Phenobarbital
Phenytoin
bosentan
amlodipine
phenobarbital
armodafinil
Almotriptan (Axert)
Citalopram (Celexa)
ethinyl estidol
clorampehnicol
Niflumic acid
spironaldactone
Rifampin
Rasagiline
cisplatin
amprenavir
Carbamazepine (eg. Tegretol)
carbamazine
Alprazolam (Xanax)
Clobazam (Onfi)
flavipirido
Codeine
Tacromlimus (Prograf) canreone
Tobacco Smoking
Rotigitine
cyclophosphamide
Anastrozole
Phenytoin (eg. Dilantin)
Cimetidine (Tagamet)
Amiodarone (Cordarone)
Clomipramine (Anafranil)
ibuprofen
Cyclosporin A
Amitryptline
Selegiline
Dexamethasone
aprepitant
Primidone
Clopidogrel (Plavix)
Amlodipine (Norvasc)
Clopidogrel (Plavix)
kampferol
Cyclosporin A
Ketoconazole
Valproic Acid
efavirenz
atanazanavir
Rifampin (eg. Rifadin)
Delavirdine (Rescriptor)
Aprepitant (Emend)
Clozapine (Clozaril)
ketoprofen
diclofenac (Voltaren)
chloramphenicol
Ethosuximide
atorvastatin
Rifapentine
Efavirenz (Sustiva)
Atazanavir (Reyataz)
Desipramine (Norpramin)
labetolol
Entacapone
clofibrate
etravirine
Azithromzcin
ST. John's wort
Esomeprazole (Nexium)
Atorvastatin (Lipitor)
Diazepam (Valium)
naproxen
Hydromorphone (Dilaudid)
codeine
felbamate
bicalutimde
prednisone
esomeprazole (Nexium)
Bepridil (Vascor)
Diphenhydramine (Benadryl)
Propranolol
ibuprofen
diazepam
Glucocorticoids
boceprevir
ritonavir
etravirine
Bexarotene (Targretin)
Doxepin (Sinequan)
Propofol 
ketoconazole?
dicofenac
Griseofulvin
bromocriptine
valproic acid
Felbamate (Felbatol)
Bosentan (Tracleer)
Escitalopram (Lexapro)
 phenylbutazone
ketoprofen
ibuprofen
ifsofamide
Cannabinoids
Fluconazole (Diflucan)
Bromocriptine (Parlodel)
Fluoxetine (Prozac)
quercetin
Lorazepam (Ativan)
fluconazole
lopinavir
chloroquine
Fluoxetime (Prozac)
Budesonide (Entocort)
Lansoprazole (Prevacid)
valproic acid
losartan
guanfacine
methadone
cilostazol
Fluvoxamine
Buprenorphine (Subutex)
Lmipramine (Tofranil)
morphine
ketoprofen
methlyprednisolone
Cimetidine
imipramine
Bupropion (Zyban, Wellbutrin, VoMephenytoin (Mesantoin)
morphine
methadone
Modafinil
ciprofloxin
indomethacin
Carbamazepine (eg, Tegretol)
Methadone
nalaxone
morphine
Nafcillin
ciprofloxin
Isoniazid
Cevimeline (Evoxac)
Moclobemide (Manerix)
nalorphin
naproxen
Nelfinavir
Clarithromycin
ketoconazole
Cilostazol (Pletal)
Nelfinavir (Viracept)
naltrexone
oxazepam
Nevirapine
Clotrimazole
lansoprazole
Cisapride (Propulsid)
Olanzapine (Zyprexa)
naproxen
probenacid
Oxcarbazepine
conavapin
Moclobemide (Manerix)
Clarithromycin (Biaxin)
Omeprazole (Prilosec)
Oxazepam
propofol
Phenobarbital
conivaptan
Modafinil (Provigil)
Clonazepam (Klonopin)
Pantoprazxole(Protonix)
Oxycodone 
ranitidine
Phenylbutazone
crizotinib
norfluoxetine
Clopidogrel (Plavix)
Pentamidine
Tacrolimus (Prograf)
temazepam
Phenytoin
crizotinib
Omeprazole (Prilosec)
Colchicine
Phenobarbital
temazepam
trimethoprim
pioglitazone
Cyclosporine
oral contraceptives
Cyclophosphamide (Cytoxan)
Phenytoin (eg. Dilantin)
Tolcopone
prednisone
Danazol
Oxcarbazepine (Trileptal)
Cyclosporine (Neoral)
Proguanil
zidovudine
prednisone
darunavir
paroxetine
Dapsone (Avlosulfon)
Propranolol (Inderal)
Primidone
Delavirdine
ranitidine
Darunavir (Prezista)
R-warfarin (less active isomer)
primidone
Dexamethasone
ritonavir
Dasatinib (Sprycel)
Rabeprazole (Aciphex)
Progesterone
Diethyldithiocarbamate
Ticlopidine (Ticlid)
Delavirdine (Rescriptor)
Sertraline (Zoloft)
our PD patients are more likely to be taking these 
Rifabutin
Diltiazem
topiramate
Dexamethasone (Decadron)
Thalidomide
Rifampin
Dirithyromycin
Voriconazole (Vfend)
Dihydroergotamine
Voriconazole (Vfend)
strong
rifapentine
Disulfiram
Diltiazem (Cardizem)
moderate 
ritonavir
efavarinz
Disopyramide (Norpace)
weak
ritonavir
Entacapone (high dose)
Docetaxel (Taxotere)
Rofecoxib (mild)
Erythromycin
Donepezil (Aricept)
St John’s wort
Ethinyl estradiol
Doxorubicin (Adriamycin)
Sulfadimidine
fasoamprinavir
Droperidol
Sulfinpyrazone
Fluconazole
Dutasteride (Avodart)
Troglitazone
Fluoxetine
Ebastine (Kestine)
Fluvoaxamine
Efavirenz (Sustiva)
Gestodene
Eletriptan (Relpax)
ginkgo
Eplerenone (Inspra)
goldenseal
Ergotamine (Ergomar)
Grapefruit juice
Erlotinib (Tarceva)
haloperidol
Erythromycin
imitinib
Estazolam (ProSom)
Indinavir
Eszopiclone (Lunesta)
Isoniazid
Ethinyl Estradiol
itraconazole
Ethosuximide (Zarontin)
itraconazole
Etoposide (Vepesid)
Ketoconazole
Exemestane (Aromasin)
lapatinib
Felodipine (Plendil)
lopinavir
Fentanyl (Sublimaze)
methadone
Finasteride (Proscar)
methlyprednisolone
Flurazepam (Dalmane)
Metronidazole
Fosamprenavir (Lexiva)
Mibefradil
Galantamine (Reminyl)
Miconazole
Gefitinib (Iressa)
most ***ivir meds
Granisetron (Kytril)
Nefazodone
Halofantrine (Halfan)
Nelfinavir
Ifosfamide (Ifex)
Nevirapine
Imatinib (Gleevec)
nifedipine
Indinavir (Crixivan)
nilobinib
Irinotecan (Camptosar)
Norfloxacin
Isradipine (DynaCirc)
Norfluoxetine
Itraconazole (Sporanox)
Omeprazole
Ixabepilone (Ixempra)
oral contraceptives
Ketoconazole (Nizoral)
Oxiconazole
Lapatinib (Tykerb)
Paroxetine (weak)
Levomethadyl (Orlaam)
pazopanib
Loperamide (Imodium)
phenobarbital
Lopinavir (Kaletra)
posaconazole
Loratadine (Claritin)
primaquine
Lovastatin (Mevacor)
Propoxyphene
Maraviroc (Selzentry)
prosaconazole
Mefloquine (Lariam)
Quinidine
Methylprednisolone
Quinine
Midazolam (Versed)
Quinupristine and dalfopristin
Mifepristone (Mifeprex)
Ranitidine
Modafinil (Provigil)
ranolazine
Nefazodone
riton
Nevirapine (Viramune)
Ritonavir
Nicardipine (Cardene)
ritonavir
Nifedipine (Adalat)


APPENDIX 2 
Protocol Template 
Page  
CF-146, Effective 7/10/11 
 
48
 
 
Saquinavir
Nimodipine (Nimotop)
saquinavir
Nisoldipine (Sular)
Sertindole
Nitrendipine (Baypress)
Sertraline
Oxybutynin (Ditropan)
tacrolimus
Oxycodone (Percodan)
tamoxifen
Paclitaxel (Taxol)
telaprevir
Paricalcitol (Zemplar)
telithromycin
Pimozide (Orap)
ticagrelor
Pioglitazone
tipranavir
Praziquantel (Biltricide)
Troglitazone
Prednisolone
Troleandomycin
Prednisone
Valproic acid
Propoxyphene (Darvon)
verapamil
Quazepam (Doral)
voriconizole
Quetiapine (Seroquel)
zafirlukast
Quinacrine
zileuton
Quinidine
Quinine
Ranolazine (Ranexa)
Repaglinide (Prandin)
Rifabutin (Rimactane)
Ritonavir (Norvir)
Saquinavir (Invirase)
Sibutramine (Meridia)
Sildenafil (Viagra)
Simvastatin (Zocor)
Sirolimus (Rapamune)
Solifenacin (Vesicare)
Sufentanil (Sufenta)
Sunitinib (Sutent)
Tacrolimus (Prograf)
Tadalafil (Cialis)
Tamoxifen (Nolvadex)
Tamsulosin (Flomax)
Teniposide (Vumon)
Testosterone
Tiagabine (Gabitril)
Tinidazole (Tindamax)
Tipranavir (Aptivus)
Topiramate (Topamax)
Triazolam (Halcion)
Vardenafil (Levitra)
Verapamil (Calan)
Vinblastine (Velbane)
Vincristine (Oncovin)
Ziprasidone (Geodon)
Zolpidem (Ambien)
Zonisamide (Zonegran)
Zopiclone (Imovane)