A Phase II, Randomized, Double-blinded, Placebo-controlled Trial of Liraglutide in Parkinson's Disease
Phase: PHASE2
Conditions: Parkinson Disease
Sponsor: Cedars-Sinai Medical Center

 
U1111-1173-0106                July 29, 2020 
Page 1 
 
A phase II, randomized, double-blinded, placebo-controlled 
trial of liraglutide in Parkinson’s disease 
 
 
 
 
 
 
INVESTIGATOR-INITIATED STUDY PROPOSAL 
 
UNIVERSAL TRIAL NUMBER (UTN): U1111-1173-0106 
 
IND Number: 133612 
 
 
 
 
Department of Neurology 
Cedars-Sinai Medical Center 
8700 Beverly Blvd., Los Angeles, CA 90048 
 
 
 
 
Correspondence to: 
 
Principal Investigator: Michele Tagliati, M.D. 
Steve D. Broidy Chair in Movement Disorders 
Professor of Neurology and Director of the Movement Disorders Program 
Cedars-Sinai Medical Center, 127 South San Vicente Blvd., Suite A6813, Los Angeles, CA 90048 
Phone numbers: 310-423-1320 (office), 917-670-9014 (cell) 
 
 

 
U1111-1173-0106                July 29, 2020 
Page 2 
 
Table of Contents 
 
Background and Significance ……………………………………………………………………..... 4-5 
 
Specific Objectives ……………………………………………………………………………………... 5 
 
Research Design and Methods ……………………………………………………………………….... 5 
 
Study hypotheses ……………………………………………………………………………………. 5 
 
Endpoints ……………………………………………………………………………………………. 5 
 
Study type …………………………………………………………………….................................... 5 
 
Study Population ……………………………………………………….……………..... 5-9 
 
Inclusion criteria …………………………………………………………………………………… 6 
 
Exclusion criteria ………………………………………………………….................................... 6-7 
 
Withdrawal criteria ……………………………………………………………............................... 7 
 
Subject replacement ……………………………………………………………………………….. 7 
 
Rationale for study population ……………………………………………………………………. 7 
 
Visit procedures ……………………………………………………………………………………. 7 
 
Assessments for efficacy ………………………………………………………………………… 7-8 
 
Assessments for safety ……………………………………………………………………………... 8 
 
Other assessments ………………………………………………………………………………….. 8 
 
Subject compliance ………………………………………………………………………...………8-9 
 
Statistical Considerations ………………………………………………………………………….. 9-12 
 
Sample size calculation …………………………………………………………………………….. 9 
 
Statistical methods ……………………………………………………………………………..…. 10 
 
Interim analysis …………………………………………………………………………………..   11 
 
Data Handling and Record Keeping …………………………………………………………………12 
 

 
U1111-1173-0106                July 29, 2020 
Page 3 
 
Table of Contents (cont’d.) 
 
Ethics …………………………………………………………………………………………………   12 
 
Study Schedule ……………………………………………………………………………………   12-13 
 
Study Drugs and Materials ……………………………………………………….……………… 13-14 
 
Study medications …………………………………………………………………………………  13 
 
Packaging and labeling of study medications ……………………………………………………. 13 
 
Storage and drug accountability of study medications …………………………………...………13 
 
Auxiliary supply …………………………………………………………………………………… 14 
 
Randomization and blinding …………………………………………………………………….... 14 
 
Breaking of blinded codes ………………………………………………………………………… 14 
 
Concomitant Illnesses and Medications …………………………………………………………….. 15 
 
Adverse Events …………………………………………………………………………………….. 15-17 
 
Collection, recording and reporting of adverse events ………………………………………….  15 
 
Follow-up of adverse events ………………………………………………………………………. 16 
 
Pregnancy ………………………………………………………………………………………….. 16 
 
Precautions/over-dosage …………………………………………………………………………... 16 
 
Liability and Subject Insurance ……………………………………………………………………... 17 
 
Premature Termination of Study ……………………………………………………………………. 17 
 
Publication Plans ………………………………………………………………………........................ 17 
 
References …………………………………………………………………………………………   18-23 
 
 

 
U1111-1173-0106                July 29, 2020 
Page 4 
 
BACKGROUND AND SIGNIFICANCE 
 
Parkinson’s disease (PD) is a progressive neurodegenerative condition affecting large numbers of people 
65 years and older. Based on prevalence and incidence of the disorder,1 more than 120,000 people in the 
U.K.1,2 and nearly a million people in the U.S.1,3 suffer from PD with 10,000 new cases in the U.K.1,4 and 
60,000 new cases in the U.S.1,5 being diagnosed with the condition each year. At present, there is no 
treatment that can slow or reverse PD progression and all agents currently licensed for the treatment of 
the disease only temporarily alleviate its motor symptoms.6-9 
 
Reduced glucose tolerance in PD is well known and predates introduction of levodopa therapy for the 
disorder.10-13 Yet the possibility that this played a role in the pathogenesis of PD was not pursued given 
several epidemiological reports contending that diabetes was not a risk factor for PD.14-18 The one 
epidemiological study on unmedicated diabetics, however, found that diabetes does increase PD risk.19 
This is also the conclusion of the largest epidemiological study on the topic,20 as well as in several 
smaller studies of that type.21-23 
 
There is reason to believe then that one or more features of diabetes accelerate pathogenesis of PD. 
One feature likely to do this is systemic insulin resistance, a prominent characteristic of type 2 diabetes 
(T2D). As noted above, PD cases commonly display impaired glucose tolerance, which is indicative of 
systemic insulin resistance.24 That systemic condition can induce brain insulin resistance25-33 which can 
also be induced by several early pathogenic factors in PD including α-synuclein,34 inflammatory 
cytokines,35,36 and mitochondrial dysfunction.37 In this manner, systemic insulin resistance could help 
drive PD pathogenesis. Indeed, impaired insulin signaling in the brain can cause or exacerbate many 
brain pathologies and behavioral abnormalities seen in PD, including diminished levels of 
mitochondrial complexes I-V,38 increased oxidative stress and apoptosis,38 elevated striatal dopamine 
turnover and monoamine oxidase A and B levels,38 reduced neurogenesis,39,40 decreased synaptic 
plasticity,39,41 impaired cognition,39,42 anxiety,38 and depression.38  
 
Brain insulin resistance is thus a promising therapeutic target in PD, treatment of which could 
efficiently slow or stop progression of the disorder. At present, the safest and most reliable means of 
reducing brain insulin resistance appears to be treatment with receptor agonists of glucagon-like 
peptide 1 (GLP-1).43 This is a naturally occurring peptide for which receptors are found throughout 
much of the brain,44 including the human cerebral cortex.45 Two currently marketed GLP-1 receptor 
agonists with good safety profiles, exenatide and liraglutide, are well known for their neuroprotective 
effects on animal models of PD.46-50 
 
Twice daily administration of exenatide has been tested in a pilot trial on PD patients with encouraging 
results.51,52 This single-blind trial on 45 patients showed that those taking the drug for 12 months 
improved to a significant degree on the Movement Disorders Society’s Unified Parkinson’s Disease 
Rating scale (MDS-UPDRS, +2.7 points) compared to a decline (-2.2 points) in control patients not 
administered the drug. It also showed a highly significant improvement in the Mattis dementia rating 
scale (MDRS, +2.8 points) in patients on exenatide compared to a decline (-3.5 points) in control 
patients. A follow-up study a year after the trial ended (i.e., a year off exenatide) found preservation of 
both the motor and cognitive benefits of the trial.52 These results suggest a disease modifying effect of 
the GLP-1 receptor agonist, providing evidence that the pathogenesis of PD can be slowed or stopped. 
These findings are being pursued in a placebo-controlled, once weekly exenatide (Bydureon) trial on PD 
cases in London (https://foxtrialfinder.michaeljfox.org/trial/3583/; http://www.ucl.ac.uk/exenatide-pd). 
 

 
U1111-1173-0106                July 29, 2020 
Page 5 
 
Once daily liraglutide, however, may prove superior to once weekly exenatide in treating PD. While 
both these GLP-1 receptor agonists can reduce systemic insulin resistance by causing weight loss, once 
daily liraglutide may be more potent in that regard because it has recently been found more effective than 
once weekly exenatide in reducing body weight.53 Liraglutide, which is currently indicated for once-daily 
administration in adults with T2D up to 1.8 mg/day and for weight management at 3.0 mg/day, is also 
more effective than exenatide (twice daily or weekly) in reducing hyperglycemia,53-55 which has diverse 
detrimental effects on neuronal function.56-58 Unlike the case for exenatide, there is direct evidence from 
ex vivo insulin stimulation studies that liraglutide applied directly to brain tissue can reduce insulin 
resistance there in mild cognitive impairment (MCI) cases in a mouse model of AD.43 Finally, liraglutide 
exerts neuroprotective effects in the mouse MPTP model of PD at 25 nmoles/kg body weight, but 
exenatide does not.59 
 
Since it crosses the blood-brain barrier,60 peripherally administered liraglutide can also reduce brain 
insulin resistance directly, as verified in studies on a mouse model of AD. Peripheral administration of the 
drug can have this effect indirectly by promoting weight loss, thereby reducing systemic insulin resistance, 
which induces brain insulin resistance noted earlier. 
 
Extracellular vesicles (EVs) are membranous particles and are secreted from nearly every cell type 
throughout the body, whereas the term exosomes refers to a subtype of EVs from 30-150 nm in size that 
have been implicated in a variety of functions. A recently developed methodology allows isolating plasma 
EVs enriched for neuronal origin85. To date, this approach has been mostly implemented to pursue 
biomarkers for Alzheimer’s disease including the main pathogenic proteins (p-tau and Aβ42) but also 
intracellular signaling molecules, such as phosphorylated IRS-1, Cathepsin-D, REST, LRP6, and others 
.81-84 Of particular interest for the study of brain insulin resistance are the findings concerning IRS-1. In 
plasma EVs enriched for neuronal origin, total pSer312- and p-PanY- (pan-Tyr phosphorylated) IRS-1 
was measured in a clinical cohort of AD patients and cognitively normal (CN) older control subjects (as 
well as patients with Frontotemporal Dementia, as a neurodegenerative disease control, and cognitively 
normal patients with diabetes, as a metabolic disease control). Two phospho-species, as well as their ratio, 
were shown to be highly significantly different in AD patients vs. all control groups. Interestingly, subjects 
with diabetes had intermediate values between AD patients and CN controls, suggesting that the peripheral 
IR that characterizes diabetes is linked to some degree to brain IR and corroborating the extensive body of 
literature suggesting that IR and diabetes are risk factors for AD, but by no means obligatory causative 
factors. Furthermore, IRS-1 phospho-species achieved remarkable classification accuracy for AD patients 
vs. controls, and in a separate smaller cohort were already abnormal up to 10 years before clinical onset of 
AD.81  
 
In a recent study, it was shown that a cohort of AD patients without systemic insulin resistance, pSer312-
IRS-1 was positively associated with MRI atrophy, whereas p-PanY-IRS-1 was negatively associated with 
it, in a highly characteristic pattern of regions. The significance of this regional pattern lies in its spatial 
correlation with the normal IRS-1 brain expression. It is speculated that neuronal-enriched plasma EVs 
containing IRS-1 may be preferentially derived from brain regions with high levels of IRS-1 expression. 
Therefore, the IRS-1 phosphorylation pattern seen in these EVs may reflect its phosphorylation status in 
specific brain regions that suffer brain atrophy in early AD in association with higher burden of brain 
insulin resistance. These findings provide hope that using these biomarkers may also possibly demonstrate 
target engagement and follow response to treatment in clinical trials that aim to reverse brain insulin 
resistance (e.g. liraglutide). 
 

 
U1111-1173-0106                July 29, 2020 
Page 6 
 
In summary, there is mounting evidence that PD pathogenesis is accelerated by brain insulin resistance 
and that liraglutide can markedly reduce this abnormality, thereby reducing the motor and non-motor 
symptoms of the disorder. 
 
SPECIFIC OBJECTIVES: 
 
The primary objective of this clinical trial is to test the therapeutic efficacy and safety of liraglutide 
treatment of patients with idiopathic PD. The secondary objective is to correlate the magnitude of any 
observed therapeutic efficacy with degree of reduction in peripheral insulin resistance over the course of 
drug treatment. 
 
RESEARCH DESIGN AND METHODS: 
 
Study Hypotheses: We hypothesize that global disease status (MDS-UPDRS) and especially cognition 
in PD patients will improve significantly by the end of daily liraglutide treatment for one year compared 
to those treated only with the placebo (i.e., drug vehicle). We also hypothesize that the improvement 
seen in each patient will be proportional to the degree of improvement in peripheral as well as neuronal 
insulin resistance seen in the treatment period.  
 
Endpoints: The primary outcomes are measures of the drug’s effects on motor (assessed by MDS-
UPDRS III) and non-motor symptoms of PD (assessed by NMSS and MDRS-2) after 52 weeks of 
treatment at full tolerated dose. The secondary outcomes are measures of the association between 
liraglutide’s effects on peripheral insulin resistance, markers of insulin resistance on plasma EVs 
enriched for neuronal origin, PD symptoms and safety.  
 
Study Type: This is a phase II, randomized, double-blinded, placebo-controlled clinical trial. 
 
STUDY POPULATION:  
 
Cases: Fifty-seven patients with a diagnosis of idiopathic PD will be recruited and randomized to 
receive once daily self-administered injections of liraglutide (1.2 or 1.8 mg, as tolerated) or placebo at 
the same dose range in a 2:1 study design. 
 
Inclusion Criteria: 
 
• Diagnosis of idiopathic PD according to the United Kingdom Parkinson's Disease Society 
Brain Bank (UKPDSBB) criteriaa for at least 2 years, and/or a DaT-confirmed diagnosis 
of PD 
• Responsive to levodopa or dopaminergic treatment 
• Male or female between 25 and 85 years of age at time of enrollment 
o Women of child-bearing potential (WOCBP) must agree to use a reliable method of 
contraception (e.g., oral contraceptive or long-term injectable or implantable hormonal 
contraceptive, double barrier methods (such as condom plus diaphragm, condom plus 
spermicide foam, condom plus sponge), or intra-uterine devices) throughout the duration of 
the trial period and must have a negative serum pregnancy test at screening  
o Male patients with female partners who have child bearing potential must agree to use 
adequate contraception throughout the duration of the trial period 

 
U1111-1173-0106                July 29, 2020 
Page 7 
 
• Capacity to give informed consent 
• Ability to self-administer, or to arrange a care partner to administer trial drug, to comply with trial 
protocol, and to attend necessary clinic visits off medication 
a: Note: the study team will not consider the UKPDSBB criterion “more than one affected relative” as exclusionary. 
According to the scientific community, family history is not regarded as exclusionary and this specific criterion is no longer 
used (reference).  
 
Exclusion Criteria: 
 
• Diagnosis or suspicion of other causes for Parkinsonism, including drug- or toxin-induced 
parkinsonism and other neurodegenerative conditions, including multiple system atrophy, 
progressive supranuclear palsy, Huntington's disease, Wilson's disease, or Alzheimer's disease 
• Active treatment with anticholinergic medications (e.g., triexyphenydil or tricyclic antidepressants) 
• Known abnormality on CT or MRI brain imaging considered to cause symptoms or signs of 
neurological dysfunction, or considered likely to compromise compliance with trial protocol 
• Concurrent dementia defined by a score lower than 120 on the MDRS-2 and/or inability to 
complete scale per neuropsychologist’s discretion 
• Concurrent severe depression defined by a score greater than 29 on the Beck Depression 
Inventory (BDI-II) 
• Prior intracerebral surgical intervention for PD, including deep brain stimulation, lesional surgery, 
growth factor administration, gene therapy, or cell transplant 
• Already actively participating in a trial of a device, drug, or surgical treatment for PD, or trial 
participation within 30 days prior to the baseline visit 
• Diagnosis of diabetes mellitus of any type, established historically or by: 
• Fasting plasma glucose levels equal or above 126 mg/dl 
• 
Hemoglobin A1c equal or above 6.5% 
• Active treatment with oral antidiabetic medications 
• History of severe cardiac disease (e.g., angina, myocardial infarction, or cardiac surgery) in the 
preceding year 
• Significant systemic illness likely to result in deterioration of the patient's condition or, in the 
Investigator’s opinion, affect the patient's safety during the study, including in particular: 
1) History of pancreatitis 
2) Personal or family history of medullary thyroid carcinoma 
3) History of multiple endocrine neoplasia syndrome type 2 
4) History of alcoholism 
5) Severe gastrointestinal disease, including gastroparesis 
6) Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within the 
last 90 days or chemotherapeutic agents for malignancy within the last 2 years 
7) Severe renal insufficiency (CrCl <30) 
8) Moderate or severe hepatic impairment 
9) Severe hypertriglyceridemia (triglycerides >500 mg/dl) 
10) Body mass index <18.5 
•  Females who are pregnant or breast feeding 
• Prior serious hypersensitivity reaction to Victoza or any of the product components 
 
Withdrawal Criteria: In the absence of a medical contraindication or significant protocol violation, 

 
U1111-1173-0106                July 29, 2020 
Page 8 
 
every effort will be made by the Principal Investigator (PI) to keep accepted subjects in the study. 
However, should the subject decide to discontinue treatment, all efforts will be made to complete and 
report the observations as thoroughly as possible, including a complete final evaluation at the time of the 
subject's withdrawal with an explanation of why the subject is withdrawing from the study. All subjects 
who prematurely withdraw from the study will receive a follow-up telephone call one month after 
discontinuation. Study treatment will be stopped if any of the following events occur: 
 
• The subject has any clinical AE, laboratory abnormality, intercurrent illness, or other medical 
condition that indicates to the PI that continued participation is not in the best interest of the subject 
or if it requires the subject to stop taking levodopa or other medications essential to the treatment of 
Parkinson’s disease. Subjects experiencing AEs that are present at the end of their participation in 
the study should receive follow-up, as appropriate. If possible, the outcome of any AE resulting in 
withdrawal from the study or that was present at the end of the study will be followed until 
resolution or return to baseline condition, particularly if the AE was considered by the PI to be 
related to the study drug; 
• The subject requires a concomitant medication that is prohibited in the study; 
• The subject wishes to withdraw consent from the study in the absence of a medical need to 
withdraw, as determined by the Investigator; 
• The PI concludes that it is in the best interest of the subject to discontinue study treatment; 
• The subject is noncompliant; or 
• If pregnancy is suspected while the subject is receiving study treatment, the study medication must 
immediately be withheld until the result of pregnancy testing is known. If pregnancy is confirmed, 
the study medication will be permanently discontinued and the subject withdrawn from the study. 
Reasonable attempts will be made to follow the pregnancy to conclusion in order to obtain 
information regarding the outcome. 
 
The PI must complete all applicable final visit procedures (e.g., safety laboratory 
parameters, ECG, physical examination, vital signs [including orthostatic BP and HR]) and study 
documentation for subjects who withdraw from the study treatment and specify the reason for their 
withdrawal. Once subjects withdraw from the study, they will revert to the care of their usual physician 
for treatment/management of their disease as appropriate. 
 
Subject Replacement: A subject who withdraws from the study may not reenter the study. 
 
Rationale for Study Population: (see Background and Significance) 
 
Visit Procedures: (see Study Schedule) 
 
Assessments for Efficacy: The efficacy of liraglutide will be assessed by measures of the drug’s effects 
versus placebo on PD motor and non-motor symptoms quantified on the following scales after study 
medication titration in active and placebo groups: 
 
• MDS-UPDRS part I, II, III and IV changes from ON medication baseline at 28 and 54 weeks  
• MDS-UPDRS part III changes from OFF medication baseline at 28 and 54 weeks  
• Non-Motor Symptoms Scale (NMSS) changes from ON medication baseline at 28 and 54 
weeks 

 
U1111-1173-0106                July 29, 2020 
Page 9 
 
• PDQ-39 Quality of Life scale changes from baseline at 28 and 54 weeks 
• MDRS-2 changes from ON medication baseline at 28 and 54 weeks. This test assesses overall 
cognitive functioning on 5 subscales measuring specific abilities including attention, 
initiation/perseveration, construction, conceptualization, and memory. 
• To complement the MDRS-2, additional neuropsychological assessment tools will include: 
o Delis-Kaplan Executive Function System (DKEFS) Verbal Fluency, a standardized 
assessment tool with robust psychometric properties. Verbal fluency has been established 
as a highly sensitive cognitive construct to neuropathology in individuals with PD (e.g., 
sensitive to striatal pathology or dorsolateral frontal dysfunction). 
o 
Geriatric Depression Scale 
o 
The Parkinson's Anxiety Scale. 
Inclusion of these brief mood measures will assist in assessing drug effects on the subjects’ health-
related quality of life. 
 
Assessments for Safety: Safety and tolerability will be assessed by changes in vital signs, weight, 
clinical laboratory measures, and adverse events. Routine laboratory studies performed at the beginning 
and the end of the study will include CBC, renal function, liver function, serum amylase, serum lipase, 
serum calcitonin77, and fasting serum glucose and insulin. In addition, an ECG will be performed at 
baseline and follow-up visits. The number of patients completing the study will be calculated and will 
establish the tolerability of the study compound at the studied doses. It is expected that over 80% (43 
subjects) will safely complete the study. 
 
Other Assessments: Measures of peripheral insulin sensitivity will be used to test the association of 
changes in such sensitivity to changes in MDS-UPDRS and MDRS-2 scores from baseline to 28 and 54 
weeks. Surrogate measures of peripheral insulin sensitivity will be used, specifically the homeostasis 
model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index 
(QUICKI).61,62 HOMA-IR is defined as fasting glucose (mmol/L) × fasting insulin (mU/L)/22.5. 
QUICKI is defined as 1/[log fasting insulin (mU/L) + log fasting glucose (mg/dL)]. 
 
Note: While the validity of HOMA-IR as a surrogate measure of peripheral insulin sensitivity has been 
questioned given its failure to correlate with diet-induced insulin sensitivity in dogs63 and its erroneous 
prediction of differences in insulin sensitivity between non-diabetic African and European Americans,64 
virtually all clinical studies report a significant correlation of HOMA-IR (or the similarly derived 
QUICKI index) with insulin sensitivity directly measured with the euglycemic-hyperinsulinemic clamp 
technique in normal, prediabetic, and diabetic cases of various ethnicities.65-74 Indeed, the only contrary 
studies are two reporting that HOMA-IR and/or QUICKI are  not correlated with insulin sensitivity in 
normal Afro-Caribbean adults75 and a small population of  normal Caucasians.73 Given the body of 
predictive evidence and to avoid the added expense of oral glucose tolerance tests, the HOMA-IR and 
QUICKI have been chosen as surrogate measures of peripheral insulin resistance.  
 
In addition, measures of insulin sensitivity in neuronal-origin enriched plasma EVs will be used to test 
the association of changes in such sensitivity to changes in MDS-UPDRS and MDRS-2 scores from 
baseline to 28 and 54 weeks. For that purpose, plasma samples will be collected and stored and -80oC to 
allow for isolation of neuronal origin EVs at the completion of the study.  
 
Subject Compliance: The PI is required to ensure that subjects comply with the drug schedule specified 
by the study protocol. 

 
U1111-1173-0106                July 29, 2020 
Page 10 
 
 
Subjects who fail to comply with the drug schedule for 70% of the days since the previous study visit on 
one occasion will be considered for termination. If the non-compliance was unrelated to an adverse 
event related to the study drug, then the Investigator will need to evaluate whether the non-compliance is 
likely to recur. Subjects judged to be high risks for continued non-compliance will terminated at the 
discretion of the principal investigator. Subjects who fail to comply with the drug schedule for 70% of 
the days preceding a study visit on a second occasion must be terminated from the study. This 
mandatory termination due to non-compliance will be reported on the end of study eCRF unless the non-
compliance was attributable to adverse effects of study drug. 
 
STATISTICAL CONSIDERATIONS: 
 
Sample Size Calculation: This is a randomized, double-blinded, placebo-controlled clinical trial that 
aims to evaluate the effects of liraglutide on motor and non-motor symptoms in patients diagnosed 
with PD. The primary outcome of this study will be the difference in MDRS-2 scores at baseline and 
follow-up (52 weeks after titration) between the active and placebo control group. The power 
analysis was performed utilizing data reported in a previous study using a similar GLP-1 agonist 
(Table 1 ). While score changes associated with active medication were not compared to a placebo 
group but to a cohort of patients treated with “conventional PD medication”, this data represent the 
closest approximation available for power analysis and sample size calculation.  
 
With a total of 57 patients (38 in the drug group and 19 in the placebo group), the study will have an 
82.7% chance of rejecting the null hypothesis of equal means, assuming an average critical 
difference of 5.1 points on the MDRS-2 and a standard deviation of 6.4 for the drug group and 5.3 for 
the placebo group with a significance level (alpha) of 0.050 using a two-sided two-sample unequal-
variance t-test.  
 
This sample allows for a 12% dropout of up to 6 subjects (e.g., if they are diagnosed with T2D 
during the course of the study) and still maintain 81.3% power with a total of 51 patients (i.e., 36 
cases in the drug group and 15 cases in the placebo group). If the rate of drop out is higher than 
anticipated, the study will enroll and randomize additional subjects; subjects will be 
enrolled/randomized in multiples of 3 subjects in order to maintain the 2:1 randomization. The 
additional enrolled subjects will aim to maintain the power of the study. In total, up to 63 patients will 
be enrolled and randomized. No more than 42 patients, including drop outs, will be exposed to the drug 
during the trial.  
 
Statistical Methods: The analysis populations for this study are defined as:  
1. Full Analysis Set (FAS): all randomized subjects who receive at least one dose of study drug and have 
a baseline and at least one post-baseline efficacy score (MDRS-2 and MDS-UPDRS).  
2. Per-Protocol (PP) population: a subset of the FAS population, excluding subjects with major 
deviations from the protocol that may substantially affect the results of the primary efficacy analysis.  
3. Safety population: all randomized subjects who receive at least one dose of study drug.  
The final determination of protocol violations, and therefore the composition of the PP population, will 
be made prior to unblinding the database and will be documented separately. Analysis of all efficacy 
 
 

 
U1111-1173-0106                July 29, 2020 
Page 11 
 
 
 
 
 
 
 
 
Table 1 (from Aviles-Olmos et al., 201351) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
variables will be performed on the FAS and PP population. The FAS population will serve as the 
primary population for the analysis of efficacy data. Analyses based on the PP population will be 
considered as a sensitivity analysis. Subjects will be analyzed for efficacy according to the treatment to 
which they were randomized.  
 
All safety outcomes will be analyzed using the Safety population. Subjects will be analyzed for safety 
according to the treatment they actually received.  
 
Descriptive statistics: The study population will be described using demographic, baseline, and subject 
characteristics. Descriptive statistics of demographic, baseline, and subject characteristics will be based 
on the Safety population. A detailed description of subject disposition will include: 
  
• 
A summary of data on subject discontinuations including reason for withdrawal  
• 
A summary of protocol violations and deviations  
 
All screened subjects will be accounted for in the disposition summaries. The number and percentage of 
subjects included in each analysis population will be summarized. 
 
Baseline and subject characteristics will include a summary of the following:  
 
• 
Subject demographics  
• 
Medical history including family history  
 

 
U1111-1173-0106                July 29, 2020 
Page 12 
 
• 
Physical examination findings  
• 
Prior and concomitant medications/therapies  
• 
HoMA-IR and QUICKI index at baseline 
• 
MDRS-2 scores at baseline  
• 
MDS-UPDRS scores at baseline  
• 
Non-Motor Symptoms Scale (NMSS) scores at baseline  
• 
PDQ-39 Quality of Life scale scores at baseline  
• 
Delis-Kaplan Executive Function System (DKEFS), Geriatric Depression Scale, and 
Parkinson's Anxiety Scale scores at baseline 
 
Inferential Statistics on Primary Efficacy Parameter(s): The primary analysis of efficacy endpoint 
(changes in UPDRS, NMSS, and MDRS-2 scores between baseline and Week 54) will be assessed using 
a two-sided, two-sample unequal-variance t-test to evaluate the differences in end points between the 
active and placebo cohorts. Multiple regression analysis will be used for comparisons of between-cohort 
differences in these outcomes over time. General linear models will be used to evaluate possible 
associations between baseline characteristics and the primary endpoints. Analysis of covariance 
(ANCOVA) will be used to evaluate possible effects of peripheral insulin sensitivity and treatment 
group (independent variables) on the primary end points (dependent variable). Hochberg’s method for 
adjustment for multiple testing separately for the primary end points and secondary endpoints will also 
be used.  
The last UPDRS, NMSS, and MDRS-2 scores prior to first drug administration will be used as the 
baseline value in the model and to calculate change from baseline clinical scores. To calculate the 
change from baseline at week 54, the clinical scores at week 54 will be used. Missing values will be 
imputed using the last observation carried forward (LOCF) method, including clinical scores on the 
discontinuation visit. Baseline values will not be carried forward. This methodology will be applied to 
all treatment groups (liraglutide and placebo).  
The assumptions of normality and homogeneity of variance will be explored using probability and 
residual plots. Data will be tested for normality using the Shapiro-Wilk test. If any of the assumptions 
are found to be violated, an appropriate transformation of the data or non-parametric test will be 
considered.  
Sensitivity analyses of the primary efficacy endpoint will be performed on the PP population using the 
same methods described for the FAS population. Summaries of clinical scores, including the change 
from baseline, will be presented at each visit (i.e., baseline, Week 28, and Week 54). No adjustments 
have been made to the Type I error rate for the multiple comparisons of the primary or secondary 
endpoints since this is a phase II study; therefore, results should be interpreted appropriately. No 
statistical testing within treatment groups will be performed.  
Inferential Statistics on Secondary Efficacy Parameter(s): Analyses of secondary efficacy endpoints will 
be conducted on the FAS and PP populations. The following secondary efficacy endpoints will be 
analyzed using an approach similar to that described for the primary efficacy endpoints:  
• 
Change in PDQ-39 scores for each domain and total score between baseline and week 54.  
• 
Change in Delis-Kaplan Executive Function System (DKEFS) between baseline and week 

 
U1111-1173-0106                July 29, 2020 
Page 13 
 
54 
• 
Change in Geriatric Depression Scale between baseline and week 54 
• 
Change in Parkinson's Anxiety Scale scores between baseline and week 54 
 
The safety outcomes of this study will be the following: 
• 
Adverse events 
• 
Serious adverse events  
• 
Clinical laboratory parameters  
• 
Geriatric Depression Scale  
• 
Vital signs  
• 
Physical examination. 
• 
12-lead ECGs  
 
Interim Analysis: No interim efficacy analyses are planned for this study. However, after intervals 
during the study (for example, when approximately 25% of the subjects (ca. 15 subjects) have been 
randomly assigned to the treatment groups and again when 25%, 50%, 75%, and 100% of the planned 
number of subjects have reached 12 weeks of dosing (week 14 visit)) the DSMB will conduct a review 
of safety data and will provide the Investigator with recommendations regarding the conduct of the 
study. In particular, the DSMB will review safety data (including thyroid and liver function, serum 
amylase, and fasting serum glucose and insulin) when the first 25% of subjects have been enrolled and 
will make recommendations to the Investigator as to whether or not there are any concerns which 
warrant discontinuation of enrollment in any given treatment arm and/or the study overall.  
 
The DSMB will be composed of four members, selected among clinicians and biostatisticians at Cedars 
Sinai Medical Center with expertise in Parkinson’s disease, glucose metabolism, pancreatitis and current 
clinical trials conduct and methodology. No member of the DSMB will have direct involvement in the 
conduct of the study. Furthermore, no member will have financial, proprietary, professional, or other 
interests that may affect impartial, independent decision-making by the DSMB. The research 
coordinator or other PI designee will prepare blinded data including interim and cumulative data 
regarding study-related adverse events; quality, completeness, and timeliness of data 
collection; adequacy of compliance with goals for recruitment and retention; adherence to the protocol 
and protocol violations. The DSMB will conclude each review with their recommendations to the PI as 
to whether the study should continue without change, be modified, or terminated. Recommendations 
regarding modification of the design and conduct of the study could include: 1) modifications of the 
study protocol based upon the review of the safety data; 2) suspension or early termination of the study 
because of serious concerns about subjects’ safety, inadequate performance or rate of enrollment. 
 
DATA/SAMPLE HANDLING AND RECORD KEEPING: The Investigator will delegate 
responsibility for data entry and quality to a named individual who will be part of the trial team, in 
accordance with the Data Protection Act of 1998. The Investigator will be responsible for data analysis 
done independently of data entry. The Cedars-Sinai Core Statistical team will be on hand with 
additional advice. 
 
The plasma samples for EV analysis will be stored in the Advanced Health Sciences Pavillion building 
in a -80oC freezer.  
 
ETHICS: The trial will comply with ICH GCP and applicable regulatory requirements and proceed in 

 
U1111-1173-0106                July 29, 2020 
Page 14 
 
accordance with the Declaration of Helsinki. Prior to the start of the study, the Investigator will apply 
for approval of the study from the Cedars-Sinai IRB. All documents required by the IRB and the 
regulatory authority will be submitted. Any notification/submission must be dated and contain sufficient 
information to identify the relevant protocol. The study will only commence after receipt of written 
approval from the Cedars-Sinai IRB. The Investigator designee is responsible for maintaining the 
approval documents in the Investigator study files. The Investigator will report promptly to the IRB any 
new information that may adversely affect the safety of the patients or the conduct of the trial. At the 
end of the study, the Investigator is obligated to inform the IRB in writing that the study has ended and 
no further activities regarding this protocol will be conducted at the site 
 
STUDY SCHEDULE: The trial will be conducted in the Neurology Department of the Cedars-Sinai 
Medical Center in Los Angeles, CA, according to the following schedule of events. Enrollment is 
expected to start (FPFV) on July 1st, 2016 and conclude (LPLV) on June 30th 2018. 
 
Screening and information visit 
The informed consent will take place after the study candidate has received extensive oral and written 
information about the study, including the risks associated with the study procedures and study-drug, 
prior to any study-related activity, including screening procedures. After consenting, detailed 
information will be collected on all study candidates, including demographics and relevant medical 
history, MDRS-2 screening, BDI-II screening, physical and neurological exams, routine vitals (height, 
weight, blood pressure in clino- and orthostatic positions), an EKG, and blood and urine tests. For 
women of child-bearing age, a serum pregnancy test will also performed.  
 
Baseline evaluation visit 
After confirmation of eligibility criteria, subjects will subsequently be randomized to one of the two 
treatment arms. They will then undergo MDS-UPDRS OFF and ON testing and Neuropsychological 
testing (ON). The practically defined OFF condition will be considered an overnight withdrawal of 
dopaminergic medications for 12 hours while ON evaluation will be performed 1 hour (+ 15 minutes) 
after the administration of the usual morning dose of dopaminergic medications. The first daily dose of 
0.6 mg and/or placebo, including injection instructions, will be administered at the end of the baseline 
visit. The baseline visit is to be conducted within 30 days of screening.  
 
Commence treatment: 2-week titration 
The following two visits will be dedicated to medication titration, up to 1.2mg (Week 1) and 1.8 mg 
(Week 2), as tolerated. At every visit, study drug compliance will be reviewed. Adverse events will be 
assessed and concomitant medications, routine vitals, and ECG, and blood and urine tests will be 
collected. A phone interview will be conducted following titration to determine which dosage (1.2 mg 
or 1.8 mg) the patient will remain on for the duration of the study.  
 
Follow-up visit 1 and 2 
4 and 12 weeks after titration is completed, a follow-up visit will establish whether the subjects are 
tolerating study medications, including an assessment of adverse events, concomitant medications, 
routine vitals, an ECG, and blood and urine tests. 
 
Follow-up visit 3 (6 month) 
26 weeks after completing titration, subjects will undergo repeat MDS-UPDRS OFF and ON testing and 

 
U1111-1173-0106                July 29, 2020 
Page 15 
 
Neuropsychological testing (ON) in addition to an assessment of adverse events, concomitant 
medications, routine vitals, an ECG, and blood and urine tests. 
 
Follow-up visit 4 (9 months) 
36 weeks after titration is completed, a follow-up visit will establish whether the subjects are tolerating 
study medications, including an assessment of adverse events, concomitant medications, routine vitals, 
and ECG, and blood and urine tests. 
 
End visit 
52 weeks after completing titration, subjects in both treatment arms will undergo an exit visit including 
MDS-UPDRS OFF and ON testing and neuropsychological testing (ON) in addition to an assessment of 
adverse events, concomitant medications, routine vitals, an ECG, and blood and urine tests. At this stage, 
study treatment will be discontinued. 
 
Post-study visit 
4 weeks after the end of the study, a phone interview will be completed to assess adverse events which 
were ongoing at the end visit (Week 54) and concomitant medications. 
 
Post-study follow-up (6 month) 
26 weeks after completing the active phase of the study (end visit), subjects originally assigned to both 
treatment arms will undergo a follow-up visit including MDS-UPDRS OFF and ON testing and 
neuropsychological testing (ON) in addition to an assessment of adverse events which were ongoing at 
the end visit (Week 54), concomitant medications, routine vitals, an ECG, and blood and urine tests. At 
this stage, enrolled subjects will no longer be on study treatment. However, the study team may continue 
to follow subjects who opt to continue liraglutide off-label. 
 
Post-study follow up (12 month) 
52 weeks after completing the active phase of the study (end visit), subjects originally assigned to both 
treatment arms will undergo a follow-up visit including MDS-UPDRS OFF and ON testing and 
neuropsychological testing (ON) in addition to an assessment of adverse events which were ongoing at 
the end visit (Week 54), concomitant medications, routine vitals, an ECG, and blood and urine tests. At 
this stage, enrolled subjects will no longer be on study treatment. However, the study team may continue 
to follow subjects who opt to continue liraglutide off-label. 
 
STUDY DRUGS AND MATERIALS: 
 
Study Medications: Liraglutide 6 mg/ml (Novo Nordisk A/S) will be self-administered 
subcutaneously once daily at a maximum dose of 1.8 mg after a 2 week titration schedule. Placebo will 
be administered according to the same schedule (Table 2). At baseline, subjects will be dispensed drug 
pens preset to deliver 0.6 mg of either liraglutide or vehicle per daily dose. At week 1 visit, after being 
assessed for tolerability by the investigator, subjects will be titrated to 1.2 mg of either liraglutide or 
vehicle per daily dose. The same procedure will be repeated at week 2, when subjects will be titrated to 
1.8 mg of either liraglutide or vehicle per daily dose, as tolerated. A subject that cannot tolerate at least a 
1.2 mg dose will be excluded from the study. Subjects that cannot tolerate the 1.8 mg dose, will be 
offered to continue at the 1.2 mg dose. The project will include a washout period at study end. 
 

 
U1111-1173-0106                July 29, 2020 
Page 16 
 
 
 
 
 
Table 2 
 
 
Titration Schedule 
Week 
Drug Group 
Placebo Group 
 
Liraglutide Dose 
Vehicle Dose 
Baseline 
0.6 mg 
0.6 mg 
Week 1 
1.2 mg 
1.2 mg 
Week 2 - 54 
1.2 or 1.8 mg 
1.2 or 1.8 mg 
 
 
Packaging and Labeling of Study Medications: Packaging and labeling of the trial products will be 
handled by the manufacturer (Novo Nordisk A/S). Liraglutide and its vehicle will be administered via 
pens supplied by the manufacturer (Novo Nordisk A/S). 
 
Storage and Drug Accountability of Study Medications: The research pharmacist will inventory and 
acknowledge receipt of all shipments of the study drug. The study drug will be kept in a locked area 
with restricted access. The study drug will be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC), 
in a secure location. After initial use, the pen can be stored for 30 days at controlled room temperature 
(59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C), with the pen cap on when 
not in use. The pen should be always protected from excessive heat and sunlight.  
 
The PI, pharmacist, or designee is responsible for maintaining accurate records of the receipt, 
dispensing, proper storage, and return of all investigational materials. Cedars Sinai Investigational Drug 
Pharmacy will be the designee to control on-site storage conditions of the drug prior to dispense. 
Temperature logs are maintained and archived indefinitely. At study closure, printed logs are provided 
in the pharmacy binder for the duration of study drug storage. The PI, pharmacist, or designee may 
dispense study drug only to subjects enrolled in the study. Under no circumstance will the PI, 
pharmacist, or designee allow study drug to be used other than as directed by the protocol. When a 
shipment is received, the research Pharmacist or designee must verify the quantities received and return 
the acknowledgement to the Drug Manufacturer or designee. The study drug accountability record 
includes the identification of the subject to whom the drug is dispensed, the lot number on the pen, the 
date of dispensing, and any returned or unused drug. An account must be given of any discrepancies. 
These records must be readily available for inspection by any relevant Health Authority at any time. The 
Investigational Drug Pharmacy will destroy unused drug following institutional drug destruction policy 
and will maintain a record of destruction of the drug incinerated off-site via the hospital’s contracted 
pharmaceutical waste vendor, Stericycle. 
 
Randomization and Blinding: The study drug will be administered according to the clinical study 

 
U1111-1173-0106                July 29, 2020 
Page 17 
 
protocol only to subjects who have signed the informed consent form (ICF).  
 
At the end of the Baseline visit (see Study schedule), each subject meeting entry criteria will be 
randomly assigned to one of the two treatment groups in a 2:1 ratio (liraglutide or placebo). 
A pre-determined randomization list generated by our biostatistics team will be given to and maintained 
by pharmacy staff. Once assigned, codes will not be reused for any other subjects in the study. In data 
collection records, subjects will be designated only by these de-identified codes. The randomization 
schedule so generated will be maintained by the investigational pharmacist, who will remain the only 
unblinded study staff member.  
 
The liraglutide and matching placebo injection pens will be identical and indistinguishable to the 
Investigators, the subjects or others assisting in treatment administration. In accordance with the double-
blind design, all these individuals will remain blinded to study treatment and will not have access to the 
randomization (treatment) codes except under the circumstances described below. 
 
Breaking of Blinded Codes: The blinding code may be broken only in exceptional circumstances when 
knowledge of the study drug is essential for treating the subject, such as in case of an adverse event. 
Code breaking can be performed by the PI or authorized designee at any time by opening a sealed 
envelope containing unblinding information provided by the pharmacy staff. The Investigator or the 
designee who breaks the blind must record the date and the reasons for doing so in the source 
documentation and in the subject's medical records 
 
CONCOMITANT ILLNESSES AND MEDICATIONS: See Inclusion and Exclusion Criteria 
 
 
 
ADVERSE EVENTS: 
Collection, Recording, and Reporting of Adverse Events (AEs): The collection of non-serious AE 
data and serious adverse event (SAE) information commences following the subject’s written consent to 
participate in the study. An AE is any untoward medical occurrence in a clinical investigation subject 
administered an investigational product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product (study drug). An 
Adverse Reaction (AR) is an AE for which a causal relationship to the trial product is at least possible, 
i.e. a causal relationship is conceivable and cannot be dismissed.  
The description of each AE will identify the subject, date of onset, the date of resolution, the severity of 
the event, the action taken regarding study drug, the outcome of the event, and the relationship of the 
event to study drug. AE information will be entered in the CRF within 7 days of the information 
becoming available in order to ensure timely reporting to the Sponsor.  
Severity of reported AEs will be evaluated using the following guidelines: 
• Mild: The subject is aware of the AE but it is easily tolerated. 
• Moderate: The AE causes the subject discomfort and interrupts the subject’s activities of daily life. 

 
U1111-1173-0106                July 29, 2020 
Page 18 
 
• Severe: The AE is debilitating or results in the inability of the subject to perform the activities of daily 
life. 
 
The Investigator will use the following definitions to evaluate the relationship of each AE to the study 
drug: 
 
Definitely: An AE that follows a reasonable temporal sequence from administration of the study drug 
(including the course after withdrawal of the study drug) and that satisfies any of the following: 
• reappearance of a similar reaction upon re-administration (positive rechallenge); 
• toxic level of the study drug as evidenced by measurement of study drug concentrations in blood or 
other bodily fluid. 
 
Probably Related: An AE that follows a reasonable temporal sequence from administration of the study 
drug (including the course after withdrawal of the study drug) and for which involvement of factors 
other than the study drugs, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments, can reasonably be excluded. This may also include positive dechallenge, in which 
the event abates upon discontinuation of the study drug. 
 
Possibly Related: An AE that follows a reasonable temporal sequence from administration of the study 
drug (including the course after withdrawal of the study drug) and for which possible involvement of the 
study drug can be suggested (for example, previous similar reports or pharmacologic actions of the study 
drug) although factors other than the study drug, such as underlying diseases, complications, 
concomitant drugs, and concurrent treatments may also be responsible. 
 
Unlikely: An AE that, while not necessarily unrelated to the study drug, does not appear to follow a 
reasonable temporal sequence from administration of the study drug or that appears to be reasonably 
explained by other factors, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments. 
 
Not related: An AE that does not follow a reasonable temporal sequence from administration of the 
drug or that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs, and concurrent treatments. 
 
The liraglutide US Prescribing Information document will be used for evaluations of expectedness, as 
agreed with the drug manufacturer. 
 
An SAE is an experience that, at any dose, results in any of the following: 
• Death; 
• A life-threatening event in which the patient is at risk of death at the time of the event. Note: it does 
not refer to an event that hypothetically might have caused death if it was more severe. 
• In-patient hospitalization or prolongation of an existing hospitalization; 
• Persistent or significant disability/incapacity; 
• Congenital anomaly or birth defect in the offspring of the subject (whether the subject is male or 
female);  
• Need of medical or surgical intervention to preclude permanent impairment of a body function or 
permanent damage to a body structure; 

 
U1111-1173-0106                July 29, 2020 
Page 19 
 
• An important medical event: Those events that may not be immediately life-threatening or result in 
death or hospitalization but based upon appropriate medical and scientific judgment may jeopardize the 
subject or may require intervention to prevent one of the serious outcomes listed above. 
• Suspicion of transmission of infectious agents must always be considered an SAE. 
 
A Serious adverse reaction (SAR) is an adverse event that fulfils both the criteria for a Serious Adverse 
Event and the criteria for an Adverse Reaction.  
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a SAE that is unexpected and regarded 
as possibly or probably related to the trial/study product by the investigator. 
SAEs require expeditious handling to comply with regulatory requirements. Any SAE, SAR or SUSAR 
occurring in a clinical study subject will be reported to the Institutional Review Board (IRB) within 10 
days of the Investigator having knowledge of the SAE. In addition, the investigator will copy Novo 
Nordisk A/S (NN) when expediting SARs or SUSARs to health authorities and will report all SARs 
related to NN Product to the local NN affiliate safety department. The submission to NN will be within 
day 15 from the investigator’s first knowledge about a valid case. The Investigator or other qualified 
individual at the investigative site will complete an SAE form including study name, name of the 
reporter, subject identification (e.g. subject number, initials, gender, age), event (preferably diagnosis), 
study drug, most recent date of administration, the Investigator’s causality assessment to study drug (as 
outlined above) and outcome.  
Follow-up of Adverse Events: If a subject experiences an SAE or AE, the subject will receive 
appropriate treatment and supportive care, as necessary, and the PI will continue to follow-up until there 
is a return to the subject’s baseline condition, or until a clinically satisfactory resolution is achieved. 
 
Pregnancy Beginning During Course of Trial: Female study subjects will be advised by the 
Investigator to inform him immediately if she suspects she may be pregnant up to 30 days after the last 
dose of study drug. 
 
Male study subjects will be advised by the Investigator to inform him immediately if he suspects his 
partner became pregnant up to 30 days after the last dose of study drug. 
 
When a study subject reports a possible pregnancy to the PI after the start of drug administration, study 
drug should be stopped immediately and a pregnancy test should be arranged for the subject (or partner) 
by the PI within 7 days of the pregnancy being reported. In the case of pregnancy, the PI must 
immediately notify the Drug manufacturer of this event and report the pregnancy in the source 
documentation. This includes a study subject as well as the partner of a study subject who becomes 
pregnant while the subject was receiving study drug. Every attempt will be made to follow the 
pregnancy to conclusion to obtain information regarding the outcome. All pregnancies in trial subjects 
exposed to the study drug will be reported to the drug manufacturer (Novo Nordisk A/S). 
 
Precautions/Over-dosage: Based on previous studies with liraglutide in patients with type-2 diabetes,76 
the following percentages of cases are expected to experience mild-to-moderate nausea (5-40%), 
diarrhea (17%), constipation (10%), and/or headache (9%). Subjects will be asked to report these or any 
other adverse effects when they arise and during each of the scheduled visits (see Study Schedule). 

 
U1111-1173-0106                July 29, 2020 
Page 20 
 
 
Overdoses have been reported in clinical trials and post-marketing use of liraglutide, with resulting 
effects including severe nausea and vomiting. In the event of over-dosage, appropriate supportive 
treatment will be initiated according to the subject's clinical signs and symptoms. 
 
LIABILITY AND SUBJECT INSURANCE: A research-related injury or illness is a direct result of 
the study drug or a procedure performed only as a part of the study and is not part of standard clinical 
medical treatment. Cedars-Sinai has no plans to pay for costs associated with the treatment of research-
related injury or illness.  If a study subject will need treatment for a research-related injury or illness, 
Cedars-Sinai Health System will make every effort to seek reimbursement from his/her health plan. The 
subject will be responsible for any deductibles and co-payments required under his/her health plan and 
for any claims ultimately denied by the health plan.  Financial assistance may be available under Cedars-
Sinai’s Charity Care Policy and Procedure. Losses such as lost wages will not be paid.  
 
PREMATURE TERMINATION OF STUDY: In case the study is terminated early due to the 
discovery of an unexpected, significant, or unacceptable risk/safety concern, regardless of how far along 
the subject has reached in their study follow-up, subjects will be asked to return all unutilized pens to the 
PI.  The study site will then return investigational drug to the drug manufacturer (See also Study Drug 
Accountability). 
 
PUBLICATION PLANS: The intention of the study will be to publish the results of the complete study 
at conclusion. All information obtained during the conduct of this study will be regarded as confidential 
but no written permission from the study funding sources is required prior to disclosing any information 
relative to this study. A formal publication of data collected as a result of the study will be considered a 
joint publication by all investigators and appropriate personnel. Authorship will be determined by 
mutual agreement. Submission to the funding source(s) for review and comment will be intended solely 
to ensure concurrence regarding data, evaluations, and conclusions, and to provide an opportunity to 
share with them any new or unpublished information of which they may be unaware.  

 
 
U1111-1173-0106         July 29, 2020 
 21 
 
Schedule of events 
Procedures 
Screening 
Baseline Week 1 
Week 2 
Week 
3 
Week 
6 
Week 
14 
Week 
28 
Week 
40 
Week 
54 
Week 
58 
Week 
80 
Week 
108 
Day  
Within 30 
days of 
baseline 
1 
8 + 3 
(7+3 days 
from Week 
1) 
(7+3 
days 
from 
Week 2) 
42 + 
7 
98 + 
7 
196 + 
7 
280 + 
7 
378 + 
7 
406 + 
7 
560 + 
7 
756 + 
7 
Sign Consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
Neuro Exam 
x 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Vitals 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Blood and Urine 
samples1 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Blood for 
Biomarker 
Analysis 
x 
 
 
 
 
 
 
x 
 
x 
 
x 
x 
Review of 
eligibility  
 
x 
 
 
 
 
 
 
 
 
 
 
 
MDS-UPDRS 
OFF2 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
x 
MDS-UPDRS 
ON 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
x 
BDI-II 
x 
 
 
 
 
 
 
 
 
 
 
 
 
NMSS 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
x 
MDRS-2 
x 
 
 
 
 
 
 
x 
 
x 
 
x 
x 
Neuropsych tests 
 
x 
 
 
 
 
 
x 
 
x 
 
x 
x 
Treatment 
Randomization 
and First Dose 
 
X (0.6) 
Placebo 
X (1.2) 
Placebo 
X (1.8) 
Placebo 
 
 
 
 
 
 
 
 
 
Drug 
Administration 
Training 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Dispense Study 
Drug 
 
x 
x 
x 
 
x 
x 
x 
x 
 
 
 
 

 
U1111-1173-0106                July 29, 2020 
Page 22 
 
Review Study 
Drug 
Compliance 
 
 
x 
x 
 
x 
x 
x 
x 
x 
 
 
 
AE Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Assessment of 
Concomitant 
Medications 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Final dosage 
determination3 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
1)Lab tests – schedule across study:  
• Screening: HbA1C, lipid panel, fasting insulin, CBC, CMP, amylase, lipase, calcitonin, urinalysis, blood for biomarker 
analysis 
• Weeks 1, 2, 6, 14, 40: CBC, CMP, amylase, lipase, calcitonin, urinalysis 
• Weeks 28, 54, 80, 108: HbA1C, fasting insulin, CBC, CMP, amylase, lipase, calcitonin, urinalysis, blood for biomarker 
analysis 
• Note: Lab tests may be repeated if the study team has concerns regarding test result accuracy or subject safety 
2)OFF Medication assessments – withhold all PD meds and Liraglutide for at least 12 hours (overnight) before clinic visit.   
3) Dosage may be changed after Week 3 per PI discretion 
 
 

 
U1111-1173-0106            July 29, 2020 
Page 23 
 
REFERENCES: 
 
1.   Wirdefeldt, K. et al. (2011) Epidemiology and etiology of Parkinson’s disease: a review of the 
evidence. European Journal of Epidemiology 26: S1-S58. 
 
2.   Dorsey, E.R. et al. (2007) Projected number of people with Parkinson disease in the most populous 
nations, 2005 through 2030. Neurology 68: 384-386. 
 
3.   Borlongan, C.V. et al. (2013) Epidemiological survey-based formulae to approximate incidence and 
prevalence of neurological disorders in the United States: a meta-analysis. PLoS One 8(10): 
e78490. 
 
4.   Foltynie, T. et al. (2004) The cognitive ability of an incident cohort of Parkinson’s patients in the 
U.K.. The CamPaIGN study. Brain 127: 550-560. 
 
5.   Hirtz, D. et al. (2007) How common are the “common” neurologic disorders? Neurology 68: 326-
337. 
 
6.   Löhle, M. and Reichmann, H. (2010) Clinical neuroprotection in Parkinson's disease - still waiting 
for the breakthrough. Journal of Neurological Sciences 289: 104-114. 
 
7.   AlDakheel, A. et al. (2014) Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. 
Neurotherapeutics 11: 6-23. 
 
8.   Schapira, A.H.V. et al. (2014) Slowing of neurodegeneration in Parkinson’s disease and 
Huntington’s disease: future therapeutic perspectives. Lancet 384: 545-555. 
 
9.   Kalia, L.V. and Lang, A.E. (2015) Parkinson’s disease. Lancet (in press). 
 
10. Schwab, R.S. (1960) Progression and prognosis in Parkinson's disease. Journal of Nervous and 
Mental Disease 130: 556-566. 
 
11. Boyd, A.E., 3rd et al. (1971) Endocrine function and glucose metabolism in patients with 
Parkinson's disease and their alternation by L-Dopa. Journal of Clinical Endocrinology and 
Metabolism 33: 829-837. 
 
12. Sandyk, R. and Awerbuch, G.I. (1992) The association of diabetes mellitus with dementia in 
Parkinson's disease. International Journal of Neuroscience 64: 209-212. 
 
13. Sandyk, R. (1993) The relationship between diabetes mellitus and Parkinson's disease. International 
Journal of Neuroscience 69: 125-130. 
 
14. Simon, K.C. et al. (2007) Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson’s 
disease. Neurology 69: 1688-1695. 
 
15. Driver, J.A. et al. (2008) Prospective cohort study of type 2 diabetes and the risk of Parkinson’s 
disease. Diabetes Care 31: 2003-2005. 

 
U1111-1173-0106            July 29, 2020 
Page 24 
 
 
16. Cereda, E. et al. (2011) Diabetes and risk of Parkinson’s disease, a systematic review and meta-
analysis. Diabetes Care 34: 2614-2623. 
 
17. Noyce, A.J. et al. (2012) Meta-analysis of early nonmotor features and risk factors for Parkinson 
disease. Annals of Neurology 72: 893-901. 
 
18. Lu, L. et al. (2014) Diabetes and risk of Parkinson’s disease: an updated meta-analysis of case-
control studies. PLoS One 9(1): e85781. 
 
19. Wahlqvist, M.L. et al. (2012) Metformin-inclusive sulfonylurea therapy reduces the risk of 
Parkinson’s disease occurring with Type 2 diabetes in a Taiwanese population cohort. 
Parkinsonism and Related Disorders 18: 753-758. 
 
20. Sun, Y. et al. (2012) Risk of Parkinson disease onset in patients with diabetes. Diabetes Care 35: 
1047-1049. 
 
21. Hu, G. et al. (2007) Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 30: 842-847. 
 
22. Schernhammer, E. et al. (2011) Diabetes and the risk of developing Parkinson’s disease in Denmark. 
Diabetes Care 34: 1102-1108. 
 
23. Xu, Q. et al. (2011) Diabetes and risk of Parkinson’s disease. Diabetes Care 34: 910-915. 
 
24. Muniyappa, R. et al. (2008) Current approaches for assessing insulin sensitivity and resistance in 
vivo: advantages, limitations, and appropriate usage. American Journal of Physiology - 
Endocrinology and Metabolism 294: E15-E26. 
 
25. Mielke, J.G. et al. (2005) A biochemical and functional characterization of diet-induced brain insulin 
resistance. Journal of Neurochemistry 93: 1568-1578. 
 
26. Clegg, D.J. et al. (2011) Consumption of a high-fat diet induces central insulin resistance 
independent of adiposity. Physiology and Behavior 103: 10-16. 
 
27. Pratchayasakul, W. et al. (2011) Effects of high-fat diet on insulin receptor function in rat 
hippocampus and the level of neuronal corticosterone. Life Sciences 88: 619-627. 
 
28. Agrawal, R. et al. (2012) ‘Metabolic syndrome’ in the brain: deficiency in omega-3 fatty acid 
exacerbates dysfunctions in insulin receptor signaling and cognition. Journal of Physiology  590: 
2485-2499. 
 
29. Heyward, F.D. et al. (2012) Adult mice maintained on a high-fat diet exhibit object location memory 
deficits and reduced SIRT1 gene expression. Neurobiology of Learning and Memory 98: 25-32. 
 
30. Bhat, N.R. et al. (2013) Increased tau phosphorylation and impaired brain insulin/IGF signaling in 
mice fed a high fat/high cholesterol diet. Journal of Alzheimer’s Disease 36: 781-189. 
 

 
U1111-1173-0106            July 29, 2020 
Page 25 
 
31. Castro, G. et al. (2013) Diet-induced obesity induces endoplasmic reticulum stress and insulin 
resistance in the amygdala of rats. FEBS Open Bio 3, 443-449. 
 
32. Calvo-Ochoa, E. et al. (2014) Short-term high-fat-and-fructose feeding produces insulin signaling 
alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat 
hippocampus. Journal of Cerebral Blood Flow and Metabolism 34: 1001-1008. 
 
33. Djordjevic, A. et al. (2015) The impact of different fructose loads on insulin sensitivity, 
inflammation, and PSA-NCAM-mediated plasticity in the hippocampus of fructose-fed male rats. 
Nutritional Neuroscience 18: 66-75. 
 
34. Gao, S. et al. (2015) Alpha-synuclein overexpression negatively regulates insulin receptor substrate 
1 by activating mTORC1/S6K1 signaling. International Journal of Biochemistry and Cell Biology 
64: 25-33. 
 
35. Kwon, H. and Pessin, J.E. (2013) Adipokines mediate inflammation and insulin resistance. Frontiers 
in Endocrinology 4: 71. 
 
36. Lourenco, M.V. et al. (2013) TNF-α mediates PKR-dependent memory impairment and brain IRS-1 
inhibition induced by Alzheimer’s β-amyloid oligomers in mice and monkeys. Cell Metabolism 18: 
831-843. 
 
37. Szendroedi, J. et al. (2011) The role of mitochondria in insulin resistance and type 2 diabetes 
mellitus. Nature Reviews Endocrinology 8: 92-103. 
 
38. Kleinridders, A. et al. (2015) Insulin resistance in brain alters dopamine turnover and causes 
behavioral disorders. Proceedings of the National Academy of Sciences (U.S.A.) 112: 3463-3468. 
 
39. Ghasemi, R. et al. (2013) Insulin in the brain: sources, localization and functions. Molecular 
Neurobiology 47: 145-171. 
 
40. Ramos-Rodriguez, J.J. et al. (2014) Central proliferation and neurogenesis is impaired in type 2 
diabetes and prediabetes animal models. PLoS One 9(2): e89229. 
 
41. van der Heide, L.R.P. et al. (2006) Insulin signaling in the central nervous system: learning to 
survive. Progress in Neurobiology 79: 205-221. 
 
42. Talbot, K. et al. (2012) Demonstrated brain insulin resistance in Alzheimer’s disease patients is 
associated with IGF-1 resistance, dysregulated IRS-1, and cognitive decline. Journal of Clinical 
Investigation 122: 1316-1338. 
 
43. Talbot, K. and Wang, H.-Y. (2014) The nature, significance, and GLP-1 analogue treatment of brain 
insulin resistance in Alzheimer’s disease. Alzheimer’s and Dementia 10: S12-S25. 
 
44. Heppner, K.M. et al. (2015) Expression and distribution of glucagon-like peptide-1 receptor mRNA, 
protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology 156: 
255-267). 

 
U1111-1173-0106            July 29, 2020 
Page 26 
 
 
45. Alvarez, E. et al. (2005) The expression of GLP-1 receptor mRNA and protein allows the effect of 
GLP-1 on glucose metabolism in the human hypothalamus and brainstem. Journal of 
Neurochemistry 92: 798-806. 
 
46. Harkavyi, A. et al. (2008) Glucagon-like peptide 1 receptor stimulation reverses key deficits in 
distinct rodent models of Parkinson's disease. Journal of Neuroinflammation 5:19. 
 
47. Kim, S. et al. (2009) Exendin-4 protects dopaminergic neurons by inhibition of microglial activation 
and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. Journal of 
Endocrinology 202: 431-439. 
 
48. Li, Y. et al. (2009) GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons 
in cellular and rodent models of stroke and Parkinsonism. Proceedings of the National Academy of 
Sciences (U.S.A.) 106: 1285-1290. 
 
49. Bertilsson, G. et al. (2008) Peptide hormone exendin-4 stimulates subventricular zone neurogenesis 
in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. Journal 
of Neuroscience Research 86: 326-338. 
 
50. Liu, W-Z. et al. (2015) Neuroprotective effects of lixisenatide and liraglutide in the MPTP mouse 
model of Parkinson’s disease (submitted). 
 
51. Aviles-Olmos, I. et al. (2013) Exenatide and the treatment of patients with Parkinson’s disease. 
Journal of Clinical Investigation 123: 2730-2736. 
 
52. Aviles-Olmos, I. et al. (2014) Motor and cognitive advantages persist 12 months after exenatide 
exposure in Parkinson’s disease. Journal of Parkinson’s Disease 4: 337-344. 
 
53. Buse, J.B. et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes 
(DURATION-6): a randomized, open label study. Lancet 381: 117-124. 
 
54. Blonde, L. and Montanya, E. (2012) Comparison of liraglutide versus other incretin-related anti-
hyperglycaemic agents. Diabetes, Obesity and Metabolism 14 (suppl. 2): 20-32. 
 
55. Lee, W.C. et al. (2014) Improved real-world glycaemic outcomes with liraglutide versus other 
incretin-based therapies in type 2 diabetes. Diabetes, Obesity and Metabolism 16: 819-826. 
 
56. Tomlinson, D.R. (2008) Glucose neurotoxicity. Nature Reviews Neuroscience 9: 36-45. 
 
57. Macauley, S.L. (2015) Hyperglycemia modulates extracellular amyloid-β concentrations and 
neuronal activity in vivo. Journal of Clinical Investigation (in press). 
 
58. Cox, D.J. et al. (2005) Relationships between hyperglycemia and cognitive performance among 
adults with type 1 and type 2 diabetes. Diabetes Care 28: 71-77. 
 
59. Liu, W.-Z. et al. (2015) Neuroprotective effects of lixesenatide and liraglutide in the MPTP mouse 

 
U1111-1173-0106            July 29, 2020 
Page 27 
 
model of Parkinson’ disease. (in press) 
 
60. Hunter, K. and Hölscher, C. (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, 
cross the blood brain barrier and enhance neurogenesis. BMC Neuroscience 13: 33. 
 
61. Muniyappa, R. et al. (2008) Current approaches for assessing insulin sensitivity and resistance in 
vivo: advantages, limitations, and appropriate usage. American Journal of Physiology – 
Endocrinology and Metabolism 294: E15-E26. 
 
62. Borai, A. et al. (2011) Selection of the appropriate method for the assessment of insulin resistance. 
BMC Medical Research Methodology 11: 158. 
 
63. Ader, M. et al. (2014) Failure of homeostatic model assessment of insulin resistance to detect 
marked diet-induced insulin resistance in dogs. Diabetes 63: 1914-1919. 
 
64. Pisprasert, V. et al. (2013) Limitations in the use of indices using glucose and insulin levels to 
predict insulin sensitivity. Diabetes Care 36: 845-853. 
65. Emoto, M. et al. (1999) Homeostasis model assessment as a clinical index of insulin resistance in 
type 2 diabetic patients treated with sulfonylureas. Diabetes Care 22: 818-822. 
66. Katsuki, A. et al. (2001) Homeostasis model assessment is a reliable indicator of insulin resistance 
during follow-up of patients with type 2 diabetes. Diabetes Care 24: 362-365. 
67. Mather, K.J. et al. (2001) Repeatability characteristics of simple indices of insulin resistance: 
implications for research applications. Journal of Clinical Endocrinology & Metabolism 86: 5457-
5464. 
68. Yokoyama, H. et al. (2003) Quantitative insulin sensitivity check index and the reciprocal index of 
homeostasis model assessment in normal range weight and moderately obese type 2 diabetic 
patients. Diabetes Care 26: 2426-2432. 
69. Strączkowski, M. et al. (2004) Comparison of simple indices of insulin sensitivity using the 
euglycemic hyperinsulinemic clamp technique. Medical Science Monitor 10:8. 
70. Sarafidis, P.A. et al. (2007) Validity and reproducibility of HOMA-IR, 1/HOMA-IR, QUICKI and 
McAuley’s indices in patients with hypertension and type II diabetes. Journal of Human 
Hypertension 21: 709-716. 
71. George, L. et al. (2011) Surrogate estimates of insulin sensitivity in obese youth along the spectrum 
of glucose tolerance from normal to prediabetes to diabetes. Journal of Clinical Endocrinology & 
Metabolism 96: 2136-2145. 
72. Henderson, M. et al. (2011) Measuring insulin sensitivity in youth: how do the different indices 
compare with the gold-standard method? Diabetes & Metabolism 37: 72-78. 

 
U1111-1173-0106            July 29, 2020 
Page 28 
 
73. Trikudanathan, S. et al. (2013) Comparison of insulin sensitivity measures in south Asians. 
Metabolism Clinical and Experimental 62: 1448-1454. 
74. Abbasi, F. et al. (2014) Evaluation of fasting plasma insulin concentration as an estimate of insulin 
action in nondiabetic individuals: comparison with the homeostasis model assessment of insulin 
resistance (HOMA-IR). Acta Diabetologica 51: 193-197. 
75. Thompson, D.S. et al. (2014) Limitations of fasting indices in the measurement of insulin sensitivity 
in Afro-Caribbean adults. BMC Research Notes 7: 98. 
 
76. Montanya E, Sesti G. (2009) A review of efficacy and safety data regarding the use of liraglutide, a 
once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. 
Clin Ther 31: 2472-88.  
 
77. Daumerie C, Maiter D, Gruson D. (2013) Serum calcitonin estimation in medullary thyroid cancer: 
basal or stimulated levels? Thyroid Research 6(Suppl 1): S4 
 
78. 
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin 
secretion and resistance. Am J Physiol. 1979;237(3):E214-23. 
 
79. 
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis 
model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin 
concentrations in man. Diabetologia. 1985;28(7):412-9. 
 
80. 
Le DS, Brookshire T, Krakoff J, Bunt JC. Repeatability and reproducibility of the 
hyperinsulinemic-euglycemic clamp and the tracer dilution technique in a controlled inpatient setting. 
Metabolism. 2009;58(3):304-10. 
 
81. 
Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, Masharani U, Frassetto L, 
Petersen RC, Miller BL, Goetzl EJ. Dysfunctionally phosphorylated type 1 insulin receptor substrate in 
neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J. 2015;29(2):589-96. 
 
82. 
Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Kapogiannis D. Altered 
lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 
2015;85(1):40-7. 
 
83. 
Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Carlson OD, Mustapic M, 
Kapogiannis D. Low neural exosomal levels of cellular survival factors in Alzheimer's disease. Ann Clin 
Transl Neurol. 2015;2(7):769-73. 
 
84. 
Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, Abner EL, Petersen 
RC, Federoff HJ, Miller BL, Goetzl EJ. Identification of preclinical Alzheimer's disease by a profile of 
pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 
2015;11(6):600-7 e1. 
 
85. 
Mustapic M, Eitan E, Werner JK, Jr., Berkowitz ST, Lazaropoulos MP, Tran J, Goetzl EJ, 

 
U1111-1173-0106            July 29, 2020 
Page 29 
 
Kapogiannis D. Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into 
Brain Pathologic Processes. Front Neurosci. 2017;11:278. 
 
86. 
Mullins RJ, Mustapic M, Goetzl EJ, Kapogiannis D. Exosomal biomarkers of brain insulin 
resistance associated with regional atrophy in Alzheimer's disease. Hum Brain Mapp. 2017;38(4):1933-
40. 
 
87. Stumvoll, M., Mitrakou, A., Pimenta, W., Jenssen, T., Yki-Järvinen, H. A. N. N. E. L. E., Van 
Haeften, T., ... & Gerich, J. (2000). Use of the oral glucose tolerance test to assess insulin release 
and insulin sensitivity. Diabetes care, 23(3), 295-301. 
 
88. Preitner, F., Ibberson, M., Franklin, I., Binnert, C., Pende, M., Gjinovci, A., ... & Thorens, B. (2004). 
Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and 
GIP receptors. Journal of Clinical Investigation, 113(4), 635. 
 
89. Massano, J.,  Bhatia, K. (2012). Clinical Approach to Parkinson’s Disease: Features, Diagnosis, and 
Principles of Management. Cold Spring Harbor Perspectives in Medicine, 2:a008870.