A Pilot Study of Terazosin for Parkinson's Disease
Phase: PHASE1
Conditions: Parkinson Disease
Sponsor: Jordan Schultz

FULL PROTOCOL TITLE 
A Pilot Study of Terazosin for Parkinson’s Disease 
SHORT PROTOCOL TITLE 
TZ-PD 
Protocol Version: 2.0 
Protocol Date: 12th November 2019
 
Protocol Principal Investigator (PPI); 
Jordan Schultz, PharmD 
Assistant Professor of Psychiatry and Neurology 
Carver College of Medicine at the University of Iowa 
Nandakumar Narayanan, MD, PhD 
Associate Professor of Neurology 
Assistant Director: Clinical Neuroscientist Training Program in Neurology 
Assistant Director: Residency Program in Neurology 
University of Iowa – Carver College of Medicine 
NCT03905811
Supported by: 
Institute of Clinical and Translational Science at the University of Iowa  

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LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
AZ 
Alfuzosin 
CCC 
Clinical Coordination Center 
CDE 
Common Data Elements 
CFR 
Code of Federal Regulations 
CIRB 
Central Institutional Review Board 
CRF 
Case report form 
CS 
Clinically Significant 
CSS PI 
Clinical Study Site PI 
DCC 
Data Coordination Center 
DM 
Data Management 
DSMB 
Data Safety Monitoring Board 
DZ 
Doxazosin 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA   
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization  
IMM 
Independent Medical Monitor 
MDS-UPDRS TMS 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale 
Total Motor Score  
MedDRA 
Medical Dictionary for Regulatory Activities 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NINDS  
National Institute of Neurological Disorders and Stroke
PD 
Parkinson’s Disease
Pgk1 
Phosphoglycerate kinase 1
PPI 
Protocol Principal Investigator
PPMI 
Parkinson’s Progression Markers Initiative
PSC 
Protocol Steering Committee
SAE 
Serious adverse event
SNc 
Substantia nigra pars compacta
SOA 
Schedule of Activities
TZ 
Terazosin
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SYNOPSIS 
Rationale: 
Parkinson’s disease (PD) is a devastating neurodegenerative disease affecting ~1 million 
Americans with ~60,000 new diagnoses made annually1. There are no interventions that slow the 
inexorable progression of PD. Thus, there is a critical need to develop novel disease-modifying 
therapies for PD. We have discovered that activation of phosphoglycerate kinase 1 (Pgk1) can 
reverse energy deficits that contribute to the pathology of PD.  More importantly, we have 
discovered that terazosin (TZ) can activate Pgk1 through a novel mechanism that is independent 
of its predicted α-adrenergic receptor antagonism and slow the progression of PD.  The 
procedures outlined in the protocol will allow us to 1) quantify energy deficits in the brains of 
patients with PD and 2) determine if the administration of TZ can alter energy deficits over a short 
time period and longer time period. This study will test the safety and tolerability of TZ in 
patients with PD as well as test the feasibility of this protocol while providing vital 
information to guide future clinical trials of TZ in PD.   
Study Title 
A FeASibiliTy study of TeraZosin as a disease modifying treatment for PD: FAST TZ-PD 
Objectives 
Primary objective: 
To assess the safety of TZ in patients with PD as well as the feasibility of the study protocol.  The 
active treatment group (TZ 5mg daily) will be compared to a placebo group. The primary outcome 
measure will be the safety and tolerability of TZ in the select patient population.  This will be 
assessed by comparing the number of participants in each group that experience drug-related 
adverse drug events as well as assessing the rate of drop out in each group. 
Secondary objective: 
Orthostatic hypotension is more common in PD2, so it is possible that TZ could exacerbate this 
symptom of PD. To assess the change in blood pressure (systolic and diastolic) from baseline to 
week 6 and from baseline to week 12.   
Exploratory Objective: 
To quantify ATP levels in 1) red blood cells and 2) in the brain before and after the administration 
of TZ and after taking TZ for 12 weeks. 
Design and Outcomes 
We will randomize 20 PD patients to receive TZ or placebo. Ten of the participants will be 
randomized to receive TZ 5mg daily for 12 weeks and 10 participants will be randomized to 
receive a daily placebo for 12 weeks. This aim will generate data on safety and tolerability of TZ 
in a population of patients with PD. As an exploratory outcome, we aim to determine if treatment 
with TZ in patients with PD improves markers of energy metabolism.  Furthermore, we will 
determine if cellular and cerebral ATP levels correlate with disease severity and progression. 
Participants will also participate in an assessment that will include, but is not limited to a motor 
exam, a neuropsychological assessment, and functional assessments. Clinical findings will be 
used to guide future clinical trials.  
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Interventions and Duration 
Participants in this study will be randomized to receive either TZ 5 mg by mouth once daily or a 
matched placebo once daily.  Once randomized, each participant will receive their assigned 
treatment for 12 weeks.  Participants will be assessed via telephone for 3 weeks after their 2 
week visit, then 6 weeks months after their baseline visit, then via telephone 9 weeks after 
their baseline visit, and their last visit will occur 12 weeks from their baseline visit.  We 
anticipate that this study can be completed (study open to end of data analyses) within 9 
months. 
= Study Visit
X = Telephone call
Sample Size and Population 
This study will randomize 20 participants: 10 participants will be randomized to receive 5mg of TZ 
daily and 10 participants will be randomized to the placebo group.  It is anticipated that no more 
than 35 participants will need to be screened to enroll these participants. 
This study will include participants who are ≥ 40 years old who have a confirmed diagnosis of PD 
made by a neurologist and a Hoehn & Yahr score at baseline of < 4.  Participants will be excluded 
from this study if any of the following are true: 
•
Participants has orthostatic hypotension or a sitting blood pressure of ≤90/60
•
Participant is pregnant
•
Participant has a deep brain stimulation device implanted
•
Participant has a known allergy or sensitivity to terazosin
•
Participant is concomitantly taking doxazosin, alfuzosin, prazosin, urapadil, or tamsulosin
•
Participant has active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements
•
Participant is unable or unwilling to give written informed consent
Day 0
1 wk
2 wk
3 wk
4 wk
5 wk
6 wk
7 wk
8 wk
9 wk
10 wk
11 wk
12 wk
 
X 
 
X 

 
X 
X 
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1 
STUDY OBJECTIVES 
1.1 
Primary Objectives 
To assess the safety and efficacy of TZ in patients with PD as well as the feasibility of the study 
protocol.  The primary outcome measure will be the safety and tolerability of TZ in the select 
patient population.   
1.2 
Secondary Objectives 
To assess the mean change in systolic and diastolic blood pressures at 6 weeks and 12 weeks 
between the active and placebo groups. 
1.3 
Exploratory Objectives 
1) To utilize magnetic resonance spectroscopy (MRS) to quantify ATP levels in the brain at
baseline, after a single dose of study drug, and after 12 weeks of treatment with study
drug
2) To explore the effect of TZ on ATP levels in red blood cells.
2 
BACKGROUND 
2.1 
Rationale 
Parkinson’s disease (PD) is a devastating neurodegenerative disease affecting ~1 million 
Americans with ~60,000 new diagnoses made annually1. Patients with PD suffer debilitating motor 
symptoms affecting all aspects of their ability to function, communicate, and care for themselves3. 
In addition, PD patients can suffer non-motor symptoms including dementia, depression, sleep 
disorders, and a range of autonomic dysfunctions4. Because age is a primary risk factor for PD, 
PD-related morbidity and mortality will surge in the coming decades as Americans live longer5. 
There are no interventions that slow the inexorable progression of PD. Thus, there is a critical 
need to develop novel disease-modifying therapies for PD.  
A key pathogenic factor in Parkinson’s disease is impaired energy metabolism5.  Several 
observations support this conclusion.  a) Aging, a major risk factor for PD, impairs cerebral 
glucose metabolism, reduces mitochondrial biogenesis, and decreases ATP levels6, 7.  b) 
Glycolysis and mitochondrial function and numbers are decreased in people with PD8-12.  c) 
Mitochondrial toxins (MPTP & rotenone) induce PD and PD-like phenotypes in cells and animals, 
including humans13.  d) Mutations associated with familial PD (PINK1, Parkin, DJ-1, CHCHD2, α-
synuclein, LRRK2) disrupt various aspects of mitochondrial function and/or energy balance14.  
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We recently discovered that terazosin (TZ) binds and 
activates phosphoglycerate kinase 1 (Pgk1), the first 
ATP-generating enzyme in glycolysis (Fig. 1)15.  TZ 
is an α1-adrenergic antagonist that is prescribed to 
treat benign prostatic hypertrophy and rarely 
hypertension16. 
 
However, 
biochemical 
and 
functional studies show that TZ has an additional 
target, Pgk1, that is independent of α1-adrenergic 
antagonism15.  Our earlier crystal structure of Pgk1 
with 
TZ 
revealed 
that 
the 
2,4-diamino-6,7-
dimethoxyisoquinazoline motif of TZ binds Pgk1 
adjacent to the ADP/ATP binding site15.  In earlier 
work and our current unpublished data, we found 
that TZ increases glycolysis and cellular levels of 
ATP in cultured cells and in vivo in mice and rat 
brain15.  Measurements of brain TZ levels also 
indicate that TZ readily crosses the blood-brain 
barrier.  These findings and the impaired energy 
production in PD, suggested the possibility that TZ 
activation of Pgk1 might improve cellular energy metabolism, prevent progressive cell death, and 
restore dopamine production and motor function in PD.  Of note, case reports have identified 
mutations in the PGK1 gene that are associated with early onset PD17. 
Based on this information, we believe that TZ has the potential to be repurposed for use as the 
first disease modifying treatment of PD.  This would have enormous implications for patients and 
society.  TZ has the potential to provide a safe and low-cost treatment option for patients with PD.  
The information collected in this study will provide vital information to guide future clinical trials of 
TZ in PD.   
Regarding the chosen treatment regimen, oral administration was chosen based on the existence 
of Phase 1 studies that have evaluated the safety of oral TZ in healthy subjects.  The decision to 
utilize a dose of 5mg daily of TZ was primarily based on information obtained from human data 
(see Section 2.2).  Two separate databases were evaluated (Parkinson’s Progression Markers 
Initiative and Truven) to test the effect of TZ on PD.  In both datasets, TZ was associated with 
improvements in progression and complications of PD. The mean dose of TZ being used by 
participants in both databases was approximately 5mg daily.  Based on results from the Truven 
data, the use of TZ at this dose was not associated with a significantly increased risk of falls or 
orthostatic hypotension.  TZ can be used at higher doses (up to 20 mg/day) for the treatment of 
benign prostatic hyperplasia and (rarely) hypertension.  However, the antihypertensive action of 
TZ could potentially exacerbate the autonomic instability that can occur in PD18.  Therefore, 5mg 
daily that was chosen represents a dose that is 1) already FDA approved, 2) is used safely in 
patients with PD, and 3) has been shown to provide benefit for the treatment of PD. After 
randomization, patients will remain on therapy for 12 weeks in this study.   
Fig. 1. Aging, genetic mutations & 
predispositions, and environmental 
factors contribute to PD in several 
ways. A common feature is energy 
deficits. Terazosin (TZ) enhances 
phosphoglycerate kinase (PGK1) 
activity to decrease energy deficits and 
halt neurodegeneration in models of 
PD. 
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2.2 
Supporting Data 
a) Preclinical Data
TZ increases brain ATP levels in vivo. 
We recently discovered that terazosin (TZ) binds and 
enhances PGK1 activity in cell lines, thereby increasing ATP 
levels15.  To test if TZ increases brain energy production in 
vivo, we administered it to mice.  TZ increased levels of 
pyruvate, the product of glycolysis, increased oxidative 
phosphorylation, and elevated ATP levels (Fig. 2a-2c).  Like 
previous in vitro data, the dose-response was biphasic; at low 
but not high concentrations, TZ may enhance ATP release 
from PGK1.   
We also asked if TZ would increase energy production in mice 
that received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
(MPTP), which is often used to model PD in mice.  Seven 
days after administering MPTP to mice, ATP levels, pyruvate 
levels (Fig. 2d,2e), and mitochondrial numbers fell, consistent 
with impaired energy production.  TZ partially prevented the 
energy deficits, and mitochondrial content was partially 
maintained.  These data indicate that TZ activates glycolysis 
in vivo.  Together with measurements of brain TZ levels, they 
also indicate that TZ readily crosses the blood-brain barrier.   
TZ enhances PGK1 activity to protect dopamine neurons 
in toxin-induced models of PD. 
MPTP causes PD in humans19.  We delivered MPTP to mice, 
administered 
TZ for the next 
7 days, and then assayed on day 7 (Fig. 3a).  
Because PD patients present after onset of neuron 
degeneration, we also asked if delayed TZ 
administration would slow neuron loss and 
functional decline.  Therefore, we also delivered 
MPTP to mice, waited 7 days, then started 7 days 
of TZ treatment, and assayed on day 14 (Fig. 3a).  
Over the course of 14 days, MPTP progressively 
decreased levels of TH protein, dopamine content, 
numbers of TH-positive cells in the substantia nigra 
pars compacta (SNc), TH staining of their striatum 
projections, and increased apoptosis of the TH-
positive SNc neurons in vehicle-treated mice (Fig 
3b).  Initiating TZ treatment when MPTP was 
delivered, attenuated these defects at day 7. 
Delayed TZ delivery also improved the day 14 
abnormalities.  Accordingly, TZ prevented deficits 
in motor function at day 7 and improved motor 
performance at day 14 after delayed administration 
(Fig. 3c). 
Fig. 2. TZ increases striatum 
pyruvate and ATP levels in vivo.  
Mice were given vehicle or MPTP 
and then TZ once a day for 1 week.  
Data points are individual mice.
Fig. 3. TZ slows cell death, increases 
dopamine levels, and improves motor 
peformance in mice given MPTP (a-c) and 
rats given 6-OHDA (d-g). 
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6-hydroxydopamine (6-OHDA) is delivered to rats can model dopamine neuron degeneration20.
We injected 6-OHDA into the right striatum, waited 2-5 weeks, and then initiated a two-week
course of TZ (Fig. 3d).  In vehicle-treated rats, evidence of SNc cell apoptosis progressively
increased from 2 to 7 weeks (Fig. 3e).  However, irrespective of the delay until beginning
treatment, TZ protected against further cell loss.  Correspondingly, dopamine content and TH
reverted toward control values (Fig. 3f).  Seven weeks after injecting 6-OHDA into the right
striatum, use of the left forepaw had fallen (Fig. 3g).  However, when rats received TZ between
weeks 5 and 7, they used both forepaws equally.
As an additional model of PD, we treated Drosophila with rotenone, a mitochondrial complex I 
inhibitor implicated in sporadic PD21.  Rotenone exposure reduced brain ATP levels and disrupted 
motor function.  PGK1 is highly conserved in flies, and supplying TZ together with rotenone 
minimized decrements in ATP content and motor performance.  Knocking-down Pgk1 by RNAi in 
TH-neurons abolished the protective effect of TZ.  Conversely, overexpressing PGK1 in 
Drosophila and rat TH neurons phenocopied TZ’s energy effects15, 22.  These in vivo results 
suggest that TZ slows or prevents neurodegeneration by enhancing PGK1 activity and increasing 
ATP15, 22. 
TZ prevents or slows neurodegeneration in genetic models of PD. 
We tested Drosophila 
PINK15 and LRRKex1 
mutants; PINK1 and 
LRRK2 
mutations 
cause PD in humans23,
24.
TZ 
attenuated
biochemical and motor
deficits in these models.
Abnormal accumulation 
of α-synuclein, a major 
constituent 
of 
Lewy 
bodies, is a key feature 
of 
PD25. 
Transgenic 
mice 
overexpressing 
wild-type 
human 
α-
synuclein 
(mThy1-
hSNCA) exhibit PD-like 
neurodegeneration26.  When they were 3 months-old, we began 
treating mice with vehicle or TZ.  When 15 months old, vehicle-
treated mice had substantial α-synuclein in the striatum and SNc 
and impaired motor performance on the rotarod and pole test (Fig. 
4).  TZ partially reversed these abnormalities. 
We also tested the effect of TZ on dopamine neurons differentiated 
from induced pluripotent stem cells (iPSCs).  LRRK2G2019S is the 
most common LRRK2 mutation and is associated with ~4% of 
familial and ~1% of sporadic PD27.  Dopamine neurons derived 
from LRRK2G2019S iPSCs recapitulate PD features including 
abnormal α-synuclein accumulation28.  We studied such neurons 
generated from two Spanish patients.  After thirty days of 
Fig. 4. TZ reduces accumulation of α-
synuclein in transgenic mice over-
expressing WT human α-synuclein. 
Fig. 5. TZ reduces SNCA 
aggregation in DA neurons 
derived from human iPSCs 
(LRRK2G2019S and normal).  
30-day old DA neurons
received TZ and were
studied 3d later.
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differentiation, ~60% of the LRRK2G2019S dopamine neurons had accumulated α-synuclein 
compared to ~15% of dopamine neurons from healthy individuals (Fig. 5).  Adding TZ for 24 hr 
reduced the percentage of LRRK2G2019S dopamine neurons with increased α-synuclein 
accumulation.   
b) Clinical Data
TZ use is associated with slower disease progression in people with PD.
PD incidence increases markedly after age 6029.
TZ is prescribed for benign prostatic hyperplasia,
which also affects older men.  Therefore, to
determine if some patients with PD used TZ, we
interrogated the Parkinson’s Progression Markers
Initiative (PPMI) database.  Compared to PD
patients not taking TZ (n=269), patients taking TZ
had a slower rate of motor function decline
assayed by the Movement Disorder Society’s
Unified Parkinson’s Disease Rating Scale Part 3.
Although statistically significant (P=0.039), only 7
patients with PD used TZ.  To increase the sample
size, we tested related drugs with quinazoline
structures and found that  doxazosin and alfuzosin
increased glycolysis and tyrosine hydroxylase in
MPTP-treated mice.  In patients using TZ,
doxazosin, 
or 
alfuzosin 
(TZ/DZ/AZ, 
n=13),
progression of motor disability slowed (P=0.012)
(Fig. 6).  In contrast, the non-quinazoline α1-
adrenergic antagonist tamsulosin did not rescue
tyrosine hydroxylase levels in MPTP-
treated mice and failed to slow motor 
function decline.  These data also support 
the conclusion that enhanced glycolytic 
activity and attenuation of cell death are 
mediated by TZ’s effect on PGK1 and not 
α1-adrenergic receptors. 
We 
also 
interrogated 
the 
IBM 
Watson/Truven 
Health 
Analytics 
MarketScan database from 2011 to 2016. 
The database includes longitudinal, de-
Fig. 6. TZ/DZ/AZ reduced motor function 
decline assayed by MDS-UPDRS Part 3. Data 
are scores at PPMI entry through ~1 year for 
patients taking TZ/DZ/AZ (n=13, red), 
tamsulosin (n=24, green), or neither (n=269, 
blue). Lines are linear mixed effect regression 
analyses. Slopes of TZ/DZ/AZ group differed by 
maximum likelihood estimation compared to 
controls (p=0.012). 
Fig. 7.  TZ reduces risk of ICD9 diagnostic codes 
associated with PD.  Data are means and 
confidence intervals for relative risk in PD patients 
taking TZ/DZ/AZ vs.  tamsulosin.  Codes were a 
curated set developed by physicians treating PD.  
2,885 enrollees were taking TZ/DZ/AZ; 15,417 were 
on tamsulosin. 
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identified diagnoses (ICD-9/ICD-10 codes) and pharmaceutical claims.  We identified 2,880 PD 
patients taking TZ/DZ/AZ and 15,409 taking tamsulosin.  Among 79 PD-related diagnoses, we 
found a reduced relative risk in 69 codes among patients taking TZ/DZ/AZ vs. tamsulosin.  
Moreover 41 were significantly decreased, whereas only 2 were significantly increased.  To 
estimate PD-related benefits/risks attributable to TZ/DZ/AZ vs. tamsulosin, we calculated the odds 
ratio for each of the 79 PD-related codes.  Relative to PD patients taking tamsulosin, those on 
TZ/DZ/AZ had reduced clinic/hospital encounters for motor symptoms (odds ratio 0.77 (95% 
CI:0.70-0.84)), non-motor symptoms (odds ratio 0.78 (95% CI:0.73-0.83)), and PD complications 
(odds ratio 0.76 (95% CI:0.71-0.82)) (Fig. 7).  These data suggest that under real-world 
conditions, TZ and related drugs that enhance PGK1 activity reduced PD signs, symptoms and 
complications. 
Relationship between PGK1 enhancement and PD. 
PGK1 mutations cause recessive hemolytic anemia, myopathy, seizures, and intellectual 
disability; Parkinsonism has also been reported17, 30.  The authors speculated that reduced ATP 
generation in the SNc was responsible.  It may also be worth noting that PD occurs 1.5 times 
more frequently in men than women31, and PGK1 is located on the X-chromosome. 
Finding that TZ increases glycolysis and prevents progressive neurodegeneration supports the 
concept that energy deficits are a critical factor in the pathogenesis of PD5, 14.  The increased ATP 
levels produced by TZ may be key.  ATP has properties of a hydrotrope32, 33.  It can prevent 
aggregate formation and dissolve previously formed protein aggregates, and the transition 
between aggregate stability and dissolution occurs in a narrow range of physiological ATP 
concentrations.  We speculate that by elevating ATP levels, TZ facilitates solubilization of 
aggregates, including α-synuclein, and prevents the neurodegeneration of PD.  However, other 
mechanisms are possible, including ATP-dependent chaperones (such as HSP90) and 
disaggregases15, 32, 33. 
Summary of supporting data. 
It is uncertain which preclinical models of PD will accurately predict therapeutic benefit.  These 
data have the advantage that they identify TZ efficacy in multiple different animal models of PD, 
including toxin-induced and genetic.  Moreover, probing two independent databases suggested 
efficacy in humans with PD.  As a potential PD therapeutic, TZ has the advantages of a defined 
mode of action, blood-brain barrier penetration, oral availability, and extensive safety experience 
in humans suggesting feasibility of long-term administration. 
2.3 
Risk/Benefit Assessment 
As mentioned previously, TZ is associated with an increased risk for orthostatic hypotension (OH). 
This is especially important in the setting of PD where the prevalence of OH is significantly 
increased compared to healthy controls.  Patients with PD are also more susceptible to calls, 
which could also be exacerbated by the presence of OH.  The results from the Truven database 
outlined above demonstrated that patients with PD who were using TZ did not have significantly 
increased prevalence of ICD-9 codes related to falls compared to PD patients who were not using 
TZ.  However, this study will directly assess whether or not the use of TZ in PD significantly 
increases the occurrence of orthostatic hypotension and related events, such as falls.  TZ is 
associated with additional adverse effects, such as peripheral edema, palpitations, nausea, 
asthenia, dizziness, headache and somnolence.  Despite these risks, the potential benefit that TZ 
may provide is significant given that there are no currently available treatments to slow the 
progression of PD.   
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3 
STUDY DESIGN 
3.1 
Scientific Rationale for Study Design 
The primary goal of this study is to assess the safety and efficacy of TZ in PD and to assess the 
feasibility of using TZ in patients with PD.  Our hope is that the results of this pilot study will guide 
future clinical trials of TZ in PD. 
3.2 
Justification for Dose 
Terazosin is used as an α1-adrenergic antagonist in humans with benign prostatic hyperplasia 
or, largely in the past, hypertension.  The typical dosing range for use in these conditions is 1mg 
per day up to 20 mg/day.  The average daily dose of TZ that participants from the PPMI and 
Truven databases were using was approximately 5 mg/day.  In both of these databases, TZ was 
associated with beneficial outcomes for patients with PD.  Therefore, it is reasonable to assume 
that a dose of 5 mg/day of TZ in patients with PD will provide benefit.  This also represents a dose 
that will minimize antagonism of α-1 receptors that could lead to a decrease in BP, which could 
potentially exacerbate the autonomic instability that can occur in PD18.   
As outlined in Figure 2c, the dose of TZ that produced the optimal results was approximately 1 
microgram/kg to 100 micrograms/kg.  This translates into a dose of 0.001 mg/kg to 0.1 mg/kg.  If 
we assume that the average participant will weight approximately 100 kg, a reasonable dose 
would be 0.1 to 10 mg/day.  Figure 2c also demonstrates that the benefits of TZ are still significant 
at higher doses but begin to decrease.  Taken together, our pre-clinical and clinical data suggest 
that the choice of optimal dose would most reasonably be between doses of 1mg, 5mg or 10mg 
daily.  The choice to eliminate a dose of 10 mg/day was based on 1) the increased risk of 
orthostatic hypotension in PD at higher doses and 2) the fact that higher doses may blunt the 
potential benefit of TZ relative to lower doses.  Because the average dose of TZ used in both the 
PPMI and Truven datasets was ~ 5mg/day, and this dose is very reasonable based on the pre-
clinical data, this dose was chosen.  
3.3 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit shown in the Schedule of Activities (SoA).   
4 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 
Inclusion Criteria 
1. Men or women aged 40 and older with the diagnosis of idiopathic PD per UK Brain Bank
criteria
2. Hoehn-Yahr Stage I-III, on stable dopaminergic treatment regimen for ≥4 weeks prior to
baseline.
4.2 
Exclusion Criteria 
1. Subjects unwilling or unable to give informed consent
2. Secondary parkinsonism (e.g., drug induced)
3. Parkinson-plus syndromes
4. History of brain surgery for PD such as deep brain stimulation
5. No confounding acute or unstable medical, psychiatric, orthopedic condition. Subjects
who have hypertension, diabetes mellitus, depression, or other common age-related

illness will be included if their disease under control with stable treatment regimen for at 
least 30 days.  
6. Neurogenic orthostatic hypotension defined as symptomatic decrease in BP > 20mmHg
systolic or > 10mmHg diastolic and HR increase < 20bpm on supine to sitting or standing.
7. Clinically significant traumatic brain injury or post-traumatic stress disorder
8. Presence of other known medical or psychiatric comorbidity that in the investigator’s
opinion would compromise participation in the study
9. Presence of dementia per Movement Disorder Society Level I criteria
10. Major depression, bipolar affective disorder, or other mental health disorders that are
sufficiently severe to increase adverse event risk or impact neuropathy assessment in the
opinion of the responsible site principal investigator.
11. Current suicidal ideation within one year prior to the baseline visit as evidenced by
answering “yes” to Questions 4 or 5 on the suicidal ideation portion of the Columbia-
Suicide Severity Rating Scale (C-SSRS), Beck Depression score >21, Beck Anxiety score
>22.
12. History of exposure to typical or atypical antipsychotics or other dopamine blocking agents within
6 months prior to the baseline visit
13. Use of investigational drugs within 30 days before screening
14. Subjects have to be on a stable regimen of central nervous system acting medications
(benzodiazepines, antidepressants, hypnotics) for 30 days prior to the baseline visit
15. Use of doxazosin, alfuzosin, prazosin, or tamsulosin
16. For female participant, pregnancy, or plans for child-bearing during study period
17. Participant is restricted from traveling to and from the study site
4.3 
Lifestyle Considerations 
No specific restrictions on lifestyle and/or diet will be placed on the subject during the study.  If a 
participant is prescribed an α-1 antagonist that is indicated for their care, they will be withdrawn 
early from the study to 1) avoid the risk for harmful side effects and 2) to maintain the integrity of 
blinding.  
4.4 
Subject Withdrawal Criteria 
Subjects are free to withdraw from the study at any point.  Subjects will be withdrawn from the 
study if they experience serious and/or persistent side effects during the study that, in the opinion 
of the site PI, are thought to be related to the study drug.  Examples include but are not limited to 
persistent and symptomatic orthostatic hypotension, persistent peripheral edema, persistent 
drowsiness that significantly affects activities of daily living, significant weakness, or falls.  If any 
of these side effects occur, the site PI will be asked to make a recommendation regarding whether 
continuation of the study treatment will place the subject at any undue risk.  If so, the subject will 
be immediately withdrawn from the study.   
Withdrawn subjects will not be replaced.  Should a subject withdraw from the study despite all 
efforts to maintain follow-up every effort should be made to obtain an in-person final visit, which 
should include all assessments that would be obtained in the final drug visits (see Section 6). 
4.5 
Study Enrollment Procedures 
Only subjects who meet all the inclusion and none of the exclusion criteria will be eligible for 
enrollment and subsequent randomization in the study.  No protocol waivers will be allowed for 
eligibility criteria.  Subjects will be deemed eligible for enrollment by the PI.  If eligible for 
enrollment, the site investigators will review the informed consent documents with the subject.  If 
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the subject signs the informed consent document, they will be considered as being enrolled in the 
study.   
Once a participant has been enrolled, they will be assigned a Subject Identification Number by 
the site.  After a subject is enrolled and has a Subject Identification Number, they will undergo a 
screening visit.  If they fail the screening, their Subject Identification Number will be documented 
and their reason for screening failure will be documented.  If a subject fails their initial screening 
visit, they will not be eligible for re-screening for the study.  If a subject is deemed eligible after 
their screening visit, they will be randomized to treatment. 
4.5.1 
Subject Recruitment and Retention 
Subjects will be recruited from the University of Iowa Neurology clinic as well as from referrals 
from other providers within the University of Iowa.   
4.5.2 
Screening Logs 
Screening logs will be collected for all enrolled participants.  Screening logs to document reasons 
for ineligibility and reasons for nonparticipation of eligible subjects will be stored by the PIs.  
Screening logs of all participants will include information regarding how the subject learned of the 
trial, reasons for screen failure (if applicable), and reasons for not participating in study (if 
applicable). 
4.5.3 
Informed Consent 
Written informed consent will be obtained from each study subject before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, 
and potential hazards are explained. The subject’s willingness to participate in the study 
will be documented in writing in a consent form approved by the IRB at the University of Iowa, 
which will be signed by the subject with the date of that signature indicated. The investigator 
will keep the original consent forms and a copy will be given to the subject. It will also be 
explained to the subject that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. Written and/or oral 
information about the study in a language understandable by the subject will be given to all 
subjects. 
If a participant is unable to read the consent forms, the consent form will be read in its 
entirety to the subject.  If the subject is willing and able to provide verbal consent to 
participate in the study, but is physically unable to provide their signature, the subject’s 
authorized representative may sign the subject’s name while also providing their name 
and relationship to the study participant.   
4.5.4 
Randomization/Treatment Assignment 
Participants will be randomized in a 1:1 fashion to TZ 5mg daily and placebo.  
Randomization will 
be 
performed 
by 
NuCara Pharmacy in Coralville, Iowa.   
Randomization codes will be made available only to the dispensing pharmacist.  
The randomization code will not be made available to the investigators, study centers, study 
subjects, or other representatives.  Only after the study is complete, will randomization 
codes be made available to the investigators.   
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5 
STUDY INTERVENTIONS/STUDY MEDICATION/STUDY DRUG OR DEVICE 
5.1 
Study Medications/Interventions, Administration, and Duration 
Once randomized, all participants will receive a one-month titration packet.  For participants 
who are randomized to receive TZ, it is important to titrate the dose slowly to avoid higher 
incidences of orthostatic hypotension.  All participants will undergo a dummy titration schedule 
to maintain blinding.  The titration schedule is outlined below: 
Placebo 
TZ 5mg per day 
Week 1 (days 1-7) 
P 
A 
Week 2 (days 8-14) 
P + P 
A + A 
Week 3 (days 15-21) 
P + P + P 
A + A + A 
Week 4 (days 22-28) 
P + P + P + P 
A + A + A + A 
Day 28 and beyond 
P 
AA 
P = 1 Placebo Capsule 
A = 1 capsule containing 1mg of TZ 
AA = 1 capsule containing 5mg of TZ 
Participants will be informed of the titration schedule at randomization and all participants will 
be informed that they will be switched to a single capsule starting on Day 28 and beyond.  This 
will maintain blinding and avoid the need for participants to have a 4 capsule pill burden for 
the remainder of the study.   
Participants will be provided with the entire study supply of 1mg and 5mg terazosin or 
placebo. The first bottle will contain a one month supply of 1mg capsules for the titration 
period. The second bottle will contain a two month supply of 5mg capsules. The participant 
will be instructed to take their dose of medication once daily.  The participant will be 
instructed to take their dose of medication before bedtime to maintain the same dosing 
schedule, as doses should be separated by at least 23 hours. Each treatment will be 
administered by the participant in their home by mouth. Each participant will be maintained 
on their dosage schedule for the duration of the study (3 months).  Dose escalation 
schedules will not be employed.   
5.2 
Handling of Study Medications/Interventions 
Study treatment will be compounded and shipped to the University of Iowa IDS Pharmacy 
by NuCara Pharmacy. All treatment capsules will be compounded to have similar 
appearance, color, taste, and markings between active treatment capsules and placebo 
capsules. The NuCara Pharmacy will be responsible for all regulatory requirements for 
dispensing of treatment, including packaging and labeling requirements. A d d i t i o n a l l y ,  
the NuCara Pharmacy will be responsible for documenting the codes of the treatment 
bottles that are dispensed.
On Day 1 of the study, the participant will be given a 1 month supply for their initial titration 
medication, either terazosin or placebo per randomization, and a 2 month supply of the 5mg 
capsules. At each visit, participants will bring their medication bottles to the investigator 
who will be responsible for counting the reamining capsules and checking medication 
compliance.
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An investigator is responsible for ensuring product accountability records are maintained 
throughout the course of the study. The inventory will include details of treatment bottles received 
and dispensed to subjects, batch, and ID numbers. All unused capsules must be kept 
until reconciliation of delivery records with accountability logs by the monitor. An accounting 
must be made of any drug deliberately or accidentally destroyed. Discrepancies between the 
number of capsules received and dispensed drug must be reconciled. 
5.3 
Concomitant Interventions 
5.3.1 
Required Concomitant Medications/Interventions 
No specific concomitant medications/interventions are required for this study.  Participants will 
continue to receive their normal level of care from their providers, and any concomitant 
medications initiated by outside providers will be dispensed by the subject’s preferred pharmacy. 
Any time that a new medication is prescribed to a participant, they are to contact their site to report 
this change in therapy to ensure that it is allowed. 
5.3.2 
Prohibited Medications/Interventions 
Subjects are prohibited from taking doxazosin, alfuzosin, prazosin, terazosin, urapadil, or 
tamsulosin during this study.  If one of these medications is prescribed during the course of the 
study, the participant will be informed that initiation of any of these treatments will result in their 
immediate withdrawal from the study.  They may decide if they wish to receive the prescribed 
treatment from their outside provider.  If the subject decides to not initiate the prohibited treatment, 
they may remain in the study.   
5.4 
Subject compliance 
Subject compliance will be assessed at each study visit via pill counts. Specifically, study 
intervention will be dispensed in prescription bottles and subjects will be asked to bring 
their bottles to each visit so that compliance can be assessed.    See section 5.2 for additional 
information. 
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6 
CLINICAL AND LABORATORY EVALUATIONS/STUDY PROCEDURES 
6.1 
Schedule of Activities 
Evaluation 
Screening 
(-90 days) 
Day 
1 
2 
 wks
6 
wks 
9 
wks 
12 
wks 
Written Informed Consent 
X 
Inclusion/Exclusion Review 
X 
X 
Documentation of Disease/Disorder 
X 
X 
Hoehn & Yahr 
X 
X 
X 
X 
Medical History 
•
Overall Medical History
•
Medical History of PD
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
Orthostaticsa 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
Randomizationc
X 
Dispense Study Drugd
X 
Blood Draw 
Xc
MRI
Xc
Neurological examination 
X 
X 
X 
X 
Body weight and height 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
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X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS Motor assessmentb
X 
X 
X 
X 
X 
3
 wks
4
 wks
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 wks

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X 
X 
X 
Behavioral Assessments 
• Columbia Suicide Severity
Rating Scale Questionnaire for
Compulsive Disorders (C-SSRS)
• Beck Anxiety Inventory
• Beck Depression Inventory
• Parkinson's Disease
Questionnaire (PDQ-39)
X 
X 
X 
Sleep assessment 
•
Pittsburgh Sleep Quality Index
X 
X 
X 
Recent Falls 
X 
X 
X 
X 
Cognitive Assessments 
Xe
X 
X 
X 
Auditory/Speech Assessment 
X 
X 
X 
Pregnancy Test for Women of Child-Bearing 
potential 
X 
X 
X 
Drug Accountability/ Compliance 
X 
X 
X 
X 
Adverse Event Review 
X 
X 
X 
X 
a) Participants will lie in the supine position for 5 minutes and have their blood pressure checked.  The patient will then sit up for
1 minute and have their blood pressure re-checked.  The patient will then stand for 3 minutes and have their blood pressure
checked.  If the participant has a decrease in the systolic blood pressure by 20 or more mmHg after standing for 3 minutes, or
a decline of 10 or more mmHg in the diastolic blood pressure, they will be considered to have orthostatic hypotension.
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•
Hopkins Verbal Learning Test (HVLT)
•
Symbol Digit Modalities Test (SDMT)
•
MoCa
X 
Xf 
X 
Finger Tapping Assessments 
Timed Up and Go Assessment
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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b) All MDS-UPDRS Motor Assessments will be collected when the participant is in the practically defined OFF state, meaning
they have not taken their dopaminergic PD medications for > 6 hours at the time of assessment; this assessment will be video
recorded to ensure rater reliability
c) Baseline assessments on day 1 will occur PRIOR to randomization or the study drug being dispensed after the site
coordinator has determine the subject is still eligible for participation.
d) This will be performed twice at the baseline visit: prior to administration of TZ and 3 hours after administration of TZ
e) Only the Beck Depression, Beck Anxiety, and C-SSRS will be assessed at the screening visit, per exclusion criteria
f) At the Week 2 visit only the PDQ-39 will be assessed.
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6.2 
Timing of Study Activities 
6.2.1 
Screening/Pre-Randomization Evaluations/procedures 
Individuals identified at each site to potentially be eligible for inclusion will first be informed about the study and 
asked if they wish to receive more information.  If the subject answers in the affirmative, approved staff will first 
go through the informed consent document with the subject and answer any questions that the subject may 
have.  Specifically, the participant will be informed that signing this informed consent document does not 
guarantee that they will included in the study.  It simply allows the study sites to perform the necessary screening 
procedures to determine if the participant is eligible for randomization.  If the participant signs the informed 
consent document, the participant will then be screened.  This will include the following assessments: 
•
Review of inclusion/exclusion criteria
•
Documentation of PD
•
Hoehn & Yahr
•
Review of concomitant medications/prohibited medications
•
Orthostatics
•
Medical history
•
A physical exam
•
Neurological exam
•
Body weight and height
•
Vital signs
•
MDS-UPDRS Motor assessment
•
Beck Depression Inventory, Beck Anxiety Inventory, Columbia-
Suicide Severity Rating Scale
If the participant is found to be eligible for randomization based on this screening visit, their first baseline visit 
will be scheduled.  The baseline visit must be scheduled within 90 days of the initial screening visit.  If 
the participant is unable to schedule their baseline visit within 90 days of the screening visit, they may still be 
eligible for inclusion, but they will need to be re-screened. 
After all assessments are completed, the site investigator will review the available data and ensure that the 
participant is eligible for randomization.  If so, the participant will be randomized at Day 1.  They will then be 
dispensed their study treatment packs.  The participants will then have their blood drawn and then have their 
MRI. Immediately following this initial MRI, they will take their first dose of TZ 1mg or placebo.  They will then 
wait 3 hours from that time, during which the other study assessments may be completed.  After three hours 
from the time that they took their TZ, they will have their blood drawn again, and will then undergo another MRI 
study.  
6.2.2 
On-Study/On-Interventions Evaluations/procedures 
At each study visit, subjects will undergo the following assessments: 
•
Hoehn & Yahr
•
Concomitant medication review
•
Orthostatics
•
Height and weight
•
Vital signs
•
Physical examination
•
Neurological examination
•
MDS-UPDRS Motor Assessment
•
Cognitive Assessments
•
Behavioral Assessments
•
Sleep Assessments
•
Fall Assessments
•
Speech Assessments
•
Motor Assessments
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•
Blood Draw
•
Drug accountability/compliance
•
Adverse Event Review
The likelihood of adverse events is highest near the initiation of study drug
or at the time of dose escalation34.  
Therefore, subjects will be contacted via telephone the following 3 weeks (weeks 3, 4 & 5) after starting study 
drug and after the 2 week visit.  They will then be seen halfway through the study at 6 weeks.  They will again 
be contacted 9 weeks after their baseline visit via telephone by the research coordinator, and their final visit will 
be 12 weeks after their baseline visit.  
6.2.3 
Study Medication Discontinuation Evaluations/procedures 
Study medication discontinuation will occur under the following circumstances: 
•
Completion of study
•
Presence of orthostatic hypotension
•
Blood pressure of ≤90/60
•
Participant initiates prohibited medication
•
Participant reports unwillingness to continue with study due to intolerable side effects
If any of the above occurs, participants will be asked to come in for an end-of-study visit as soon as possible. 
All assessments outlined in the SoA will be performed at the end-of-study visit.  Participants will not be required 
to continue for future follow-up appointments after discontinuation of treatment.  Participants who experience 
adverse effects will immediately discontinue study treatment and will not be considered for inclusion in further 
evaluations. 
6.2.4 
On Study/Off-Intervention Evaluations 
This trial will follow an intention-to-treat design.  Subjects who discontinue study medication (see section 6.2.3) 
will be asked to continue to be followed for the remainder of the study, but will not be taking a study intervention. 
The following assessments will be performed at all on study/off-intervention visits: 
•
Hoehn & Yahr
•
Concomitant medication review
•
Orthostatics
•
Height and weight
•
Vital signs
•
Physical examination
•
Neurological examination
•
MDS-UPDRS Motor Assessment
•
Cognitive Assessments
•
Behavioral Assessments
•
Sleep Assessments
•
Fall Assessments
•
Speech Assessments
•
Motor Assessments
•
Blood draw
If participants are unable or unwilling to continue with the regularly-scheduled assessments after discontinuation 
of the study intervention, they will be encouraged to return to the study site for a final evaluation that will include 
the same assessments as listed above.  
6.2.5 
Final On-Study Evaluations 
The final On-Study Evaluation will be comprised of the following assessments: 
•
Hoehn & Yahr
•
Concomitant medication review
•
Orthostatics
•
Height and weight
•
Vital Signs
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•
Physical examination
•
Neurological examination
•
MDS-UPDRS Motor Assessment
•
Cognitive assessments
•
Behavioral Assessments
•
Sleep assessments
•
Fall Assessments
•
Speech Assessment
•
Motor Assessments
•
Blood draw
•
Drug accountability/compliance
•
Adverse Event Review
6.2.6 
Off-Study Requirements 
No off-study requirements after the final evaluation will be employed for this study. 
6.2.7 
Pregnancy 
Per the exclusion criteria, female who are pregnant will be excluded from this study.  Terazosin has been 
designated a pregnancy category C medication by the FDA.  Therefore, if a subject were to become pregnant 
while taking the active treatment, it is unclear if this would pose a risk to the developing fetus.  As a result, 
females who are capable of becoming pregnant during the study should be screened with a urine-
dipstick pregnancy test at their screening visit, prior to randomization, and at their 6-week visit.  Females 
participants must also practice a highly effective method of contraception (i.e., oral contraceptives, a barrier 
method of birth control such as condoms or a diaphragm, intrauterine devices, partner with vasectomy, or 
sexual abstinence). 
6.3 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS 
6.3.1 
Informed Consent 
Written informed consent will be obtained from each subject before any study-specific procedures 
or assessments are performed and after the aims, methods, anticipated benefits, and potential hazards 
are explained. Written informed consent will be obtained from each participant by authorized personnel 
prior to undergoing screening and prior to randomization.  The subject’s willingness to participate in the 
study will be documented in writing in a consent form, which will be signed by the subject with the date of 
that signature indicated. The investigator will keep the original consent forms and copies will be given to the 
subjects. It will also be explained to the subjects that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. Written and/or oral information 
about the study in a language understandable by the subject will be given to all subjects. HIPAA guidelines for 
confidentiality and the principles of medical ethics will be adhered to during the study. 
6.3.2 
Protocol Violations 
Protocol violations will be defined as any of the following: 
•
Inadequate or delinquent informed consent
•
Inclusion/exclusion criteria not met
•
Unreported serious adverse events
•
Improper breaking of blinding
•
Use of prohibited medications
•
Missed visits
•
Inadequate record keeping
•
Non-compliance with study requirements
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6.3.3 
Documentation of Parkinson’s Disease 
Participants must have a documented diagnosis of PD that fits with the UK Brain Bank Diagnostic Criteria 
(Appendix A). 
6.3.4 
Medical History 
As part of the initial screening for inclusion in the study, participants will provide all comorbidities and their 
approximate time of diagnosis (Appendix B).  At each visit, the participant will be asked to provide any newly 
diagnosed comorbidities.   
6.3.5 
Treatment History 
Participants will be asked to provide a full history of any medications, over-the-counter products, herbal 
supplements, nutraceuticals, or devices that have been used for the treatment of PD or PD-related symptoms.  
They will also be asked to recollect (to the best of their knowledge) the timing of these treatments (i.e. when did 
they start the medication, when were dosage adjustments made, when was the treatment stopped).  For 
medications that were used specifically for the treatment or relief of symptoms of PD, participants will be asked 
what the reason for discontinuation was, if applicable.  Participants will also be asked to provide information 
about dosages, dosage form (capsule, tablet, etc) route of administration, dosing schedule (Appendix C) 
6.3.6 
Concomitant Medications/Treatments 
In addition to PD-related treatment history, all concomitant medications they are currently taking.  Participants 
will also be asked to provide information about dosages, dosage form (capsule, tablet, etc) route of 
administration, dosing schedule(Appendix D). 
6.3.7 
Protocol Amendments and Study Termination 
All revisions and/or amendments to this protocol must be approved in writing by IRB. The Investigator will not 
make any changes to the conduct of the study or the protocol without first obtaining written approval from the 
IRB, except where necessary to eliminate an apparent immediate hazard to a study subject. 
Any revisions to the protocol that will change the number or frequency of evaluations that a participant undergoes 
will require the participant to sign an updated written informed consent. 
6.3.8 
Clinical Assessments 
•
Hoehn & Yahr
o
Collected to measure disease severity as well as progression throughout study
•
Orthostatics
o
Collected to measure if participants are having worsening orthostatic hypotension.
o
If orthostatic hypotension is present, this assessment will NOT be able to determine if it is
secondary to the study medication or autonomic failure that occurs in PD.
•
Physical examination
o
This will be a simple physical exam to measure the general health of the participant independent
of their PD
•
MDS UPDRS Part 3
o
This portion of the MDS-UPDRS specifically measures motor function.  This will only be collected
when subjects are in the practically defined “off-period” meaning that they have not taken their
PD medications within 6 hours of the assessment
•
MDS-UPDRS Part 4
o
This portion of the MDS-UPDRS will use historical and objective information to assess the motor
complications of dyskinesia and motor fluctuations including off-state dystonias
•
Vital signs/Height & Weight
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o
Participants will have their heart rate, respiratory rate, blood pressure, and core body
temperatures measured as well as their height and weight
•
Neurological Exam
6.3.9 
Laboratory Evaluations 
Women of child-bearing potential will have a urine-dipstick pregnancy test performed at their screening visit, 
their baseline/randomization visit, and at their 6 week visit.  The site PI must verify each result and indicate 
that the results are “Negative” or “Positive”.  If the results are “negative”, this indicates that the subject is not 
pregnant. If the results are “positive” this indicates that the subject is pregnant and must discontinue study 
drug. 
The MRI studies are being conducted to perform MR Spectroscopy in an attempt to quantify ATP levels in the 
brain. 
The blood draws are being conducted to collect red blood cells.  These samples will be sent immediately to 
the lab of Dr. Michael Welsh, where they will be analyzed to quantify ATP levels in the red blood cells. 
6.3.10 Pharmacokinetic Studies 
N/A 
6.3.11 Other Laboratory Studies 
All randomized participants will have the option of having their blood drawn at each visit.  Within the 
informed consent documents, subjects will have the option to donate blood or not.  The subjects will be 
informed that the blood samples are being collecting for the sake of bio-banking meaning that the blood is 
being collected without a specific assay in mind.  It is possible that these samples will be used for genome-
wide studies in the future as well as assays aimed at quantifying ATP levels in red blood cells.   
6.3.12 Questionnaires 
•
MDS-UPDRS Part 1
o
This will measure Non-motor experiences of daily living
•
MDS-UPDRS Part 2
o
This will measure Motor experiences of daily living
•
The following cognitive assessments will be performed
o
Hopkins Verbal Learning Test (HVLT)
o
Symbol Digit Modalities Test (SDMT)
o
Montreal Cognitive Assessment (MoCA)
•
Pittsburgh Sleep Quality Index
o
Assessment of sleep quality
•
The following behavioral assessments will be performed to test depression, compulsiveness & anxiety
o
Beck Depression Inventory (BDI)
o
Beck Anxiety Inventory (BAI)
o
Columbia Suicide Severity Rating Scale (C-SSRS)
o
Parkinson's Disease Questionnaire (PDQ-39)
6.3.13 Subject Adherence Assessments 
The site pharmacies will document subject adherence at each visit by pill count.  
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7 
MANAGEMENT OF ADVERSE EXPERIENCES 
The expected adverse experiences from use of TZ include orthostatic hypotension, palpitations, peripheral 
edema, nausea, asthenia, dizziness, headache, somnolence, nasal congestion, syncope, intraoperative floppy 
iris syndrome, and priapism.  Participants who experience side effects that are found to be intolerable by the 
subject or the site investigator will discontinue study drug.  If discontinuation of the study drug occurs in between 
visits, subjects will be encouraged to return to the site for their end of study assessment.   
8 
CRITERIA FOR INTERVENTION DISCONTINUATION 
Study medication discontinuation will occur under the following circumstances: 
•
Completion of study
•
Presence of orthostatic hypotension
•
Blood pressure of ≤90/60
•
Participant initiates prohibited medication
•
Participant reports unwillingness to continue with study due to intolerable side effects
Participants who discontinue study medication will be encouraged to undergo all remaining study assessments.  
9 
STATISTICAL CONSIDERATIONS 
9.1 
Outcomes 
9.1.1 
Primary Outcome (including definition) 
The primary outcome measure will be the safety and tolerability of TZ in the select patient population.  This will 
be assessed by comparing the number of participants in each group that experience drug-related adverse drug 
events as well as assessing the rate of drop out in each group. 
To assess the mean change in systolic and diastolic blood pressures at 6 weeks and 12 weeks between the 
active and placebo groups. 
9.1.2 Secondary Outcome(s) 
•
Mean change in systolic and diastolic blood pressure from baseline to 6 weeks and 12 weeks
•
Prevalence of falls between placebo and active group
•
Prevalence of intolerable side effects between placebo and active group
•
Prevalence of study discontinuation between placebo and active group
•
Differences in overall compliance between placebo and active group
9.1.3 Exploratory Outcome(s) 
•
Difference in ATP levels in red blood cells and brain within subjects before and after taking study drug
on day 1
•
Difference in ATP levels in red blood cells and brain within subjects at 6 and 12 weeks compared to
baseline reading
•
Difference in ATP levels in red blood cells and brain between groups at 6 weeks and 12 weeks
•
Slope of change over 12 weeks of the MDS-UPDRS Part 1
•
Slope of change over 12 weeks of the MDS-UPDRS Part 2
•
Slope of change over 12 weeks of the MDS-UPDRS Part 3 (OFF)
•
Slope of change over 12 weeks of the MDS-UPDRS Part 4 (OFF)
•
Absolute change over 12 weeks of the MDS-UPDRS Parts 1, 2, 3, 4, and TMS (OFF)
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•
Slope of change over 12 weeks of MDS-UPDRS TMS (OFF) (direct comparison for efficacy)
•
Slope of change over 12 weeks of the Hoehn & Yahr Score
•
Slope of change over 12 weeks of all cognitive assessments between placebo and active group
•
Slope of change over 12 weeks of sleep assessments between placebo and active group
•
Slope of change over 12 weeks of behavioral assessments between placebo and active group
9.2 
Sample Size and Accrual 
This is a pilot study and the sample size was chosen based on available funding and resources 
9.3 
Data Monitoring 
All aspects of the study will be monitored by the PI of the study.  Monitoring will be conducted according to Good 
Clinical Practice and applicable government regulations.  The investigator agrees to allow monitors access to 
the clinical supplies, dispensing and storage areas, and to the clinical files of the study subjects, and, if requested, 
agrees to assist the monitors. 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with a study, use of a drug product 
or device whether or not considered related to the drug product or device.  FDA and Office of Human Research 
Protection (OHRP) requirements for reporting AEs will be followed. Subjects will be monitored for AEs from the 
time they sign consent until 30 days following permanent discontinuation of study drug. At that point, all ongoing 
AEs will be followed to resolution, but no new AEs will be recorded.  
The PI and research team (co-Investigators, research nurse, clinical trial coordinator) are responsible for 
identifying and reporting AEs and determining the relationship of the event to the study drug/study procedures.  
9.4 
Data Analyses 
The following outcome measures will be analyzed under an intention-to-treat protocol.  All randomized individuals 
will be included regardless of their final treatment status.   
•
Primary Outcome
o
Rate of drop out between groups

Chi-square
o
Rate of adverse events between groups

Chi-square
•
Secondary outcomes
o
Prevalence of orthostatic hypotension between placebo and active group

Chi-square
o
Prevalence of falls between placebo and active group

Chi-square
o
Differences in overall compliance between placebo and active group

Linear mixed effect models that includes compliance at each study visit for each
participant
•
Exploratory outcomes
o
Difference in ATP levels in red blood cells and brain within subjects before and after taking study
drug on day 1

Paired samples t-test
o
Difference in ATP levels in red blood cells and brain within subjects at 6 and 12 weeks compared
to baseline reading
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
Paired samples t-test
o
Difference in ATP levels in red blood cells and brain between groups at 6 weeks and 12 weeks

Independent samples t-test
o
Slope of change over 12 weeks of the MDS-UPDRS Part 1

LMER
o
Slope of change over 12 weeks of the MDS-UPDRS Part 2

LMER
o
Slope of change over 12 weeks of the MDS-UPDRS Part 3

LMER
o
Slope of change over 12 weeks of the MDS-UPDRS Part 4

LMER
o
Absolute change over 12 weeks of the MDS-UPDRS Parts 1, 2, 3, 4, and TMS

Independent samples t-tests
o
Slope of change over 12 weeks of MDS-UPDRS TMS (direct comparison for efficacy)

LMER
o
Slope of change over 12 weeks of the Hoehn & Yahr Score

LMER
o
Slope of change over 12 weeks of all cognitive assessments between placebo and active group

LMER
o
Slope of change over 12 weeks of sleep assessments between placebo and active group

LMER
o
Slope of change over 12 weeks of behavioral assessments between placebo and active group

LMER
10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING 
10.1 Data Management 
Site personnel will collect, transcribe, correct, and transmit the data onto source documents, CRFs, and other 
forms used to report, track and record clinical research data.  The PI will monitor clinical sites to ensure 
compliance with data management requirements and Good Clinical Practices. The PI is responsible for 
developing, testing, and managing clinical data management activities. 
10.1.1 Data Entry 
Data will be entered in RedCap. Data quality assurance and analyses will be performed by the PI.  
Data collection for this study will be accomplished with paper forms that will be transcribed into RedCap.  The 
paper forms will be stored in a locked filing cabinet in a locked office, in a badge-access area.   
10.2 Role of Data Management 
Data Management (DM) is the development, execution and supervision of plans, policies, programs, and 
practices that control, protect, deliver, and enhance the value of data and information assets. 
All data will be managed in compliance with University of Iowa policies, and applicable Sponsor and regulatory 
requirements. 
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10.3 Adverse Experience Reporting 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with all applicable 
United States Food and Drug Administration (FDA) regulations and International Conference on Harmonization 
(ICH) guidelines.  The PI will carefully monitor each subject throughout the study for possible adverse events. 
All AEs will be documented on CRFs designed specifically for this purpose.  It is important to report all AEs, 
especially those that result in permanent discontinuation of the investigational product being studied, whether 
serious or non-serious. 
Receipt will be kept in the investigator’s study file. 
An adverse event is defined as: “an unfavorable and unintended sign, symptom, or disease associated with a 
subject’s participation in this research trial.” 
Serious adverse events include those events that:  “result in death; are life-threatening; require inpatient 
hospitalization or prolongation of existing hospitalization; create persistent or significant disability/incapacity, or 
a congenital anomaly/birth defects.”  
Unexpected adverse event is defined as any adverse experience…the specificity or severity of which is not 
consistent with the risks described in the protocol.  
Expected adverse events are those that are known to be associated with or have the potential to arise as a 
consequence of participation in the study. 
On-line Adverse Event Reporting System 
Serious adverse events: The site investigator determines causality (definitely not related, probably not related, 
possibly related, probably related, definitely related) of the adverse event. The PI will prepare a Medwatch safety 
report for submission to the FDA.  
Non-serious adverse events: Non-serious adverse events that are reported to or observed by the investigator or 
a member of his research team will be submitted to the PI within 24 hours.   
10.3.1 Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious Adverse Events 
10.3.1.1 Adverse Event and Suspected Adverse Drug Reactions 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with a study, use of a drug product 
or device whether or not considered related to the drug product or device.  
Adverse drug reactions (ADR) are all noxious and unintended responses to a medicinal product related to any 
dose.  The phrase “responses to a medicinal product” means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
Therefore, a subset of AEs can be classified as suspected ADRs, if there is a causal relationship to the medicinal 
product. 
Examples of adverse events include: new conditions, worsening of pre-existing conditions, clinically significant 
abnormal physical examination signs (i.e. skin rash, peripheral edema, etc), or clinically significant abnormal test 
results (i.e. lab values or vital signs), with the exception of outcome measure results, which are not being 
recorded as adverse events in this trial (they are being collected, but analyzed separately). Stable chronic 
conditions (i.e., diabetes, arthritis) that are present prior to the start of the study and do not worsen during the 
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trial are NOT considered adverse events. Chronic conditions that occur more frequently (for intermittent 
conditions) or with greater severity, would be considered as worsened and therefore would be recorded as 
adverse events. 
Adverse events are generally detected in two ways: 
Clinical  symptoms reported by the subject or signs detected on examination. 
Ancillary Tests  abnormalities of vital signs, laboratory tests, and other diagnostic procedures (other than the 
outcome measures: the results of which are not being captured as AEs). 
If discernible at the time of completing the AE log, a specific disease or syndrome rather than individual 
associated signs and symptoms should be identified by the Site Investigator and recorded on the AE log. 
However, if an observed or reported sign, symptom, or clinically significant laboratory anomaly is not considered 
by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a 
separate AE on the AE log.  Clinically significant laboratory abnormalities, such as those that require intervention, 
are those that are identified as such by the Site Investigator. 
An unexpected adverse event is any adverse event, the specificity or severity of which is not consistent with the 
current Investigators Brochure or package insert or described in the protocol.  An unexpected, suspected 
adverse drug reaction is any unexpected adverse event that, in the opinion of the Site Investigator or Sponsor, 
there is a reasonable possibility that the investigational product caused the event. 
10.3.1.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets any of the following criteria: 
1. Results in death.
2. Is life threatening: that is, poses an immediate risk of death as the event occurred.
a. This serious criterion applies if the study subject, in the view of the Site Investigator or Sponsor, is at
immediate risk of death from the AE as it occurs.  It does not apply if an AE hypothetically might have
caused death if it were more severe.
3. Requires inpatient hospitalization or prolongation of existing hospitalization.
a. Hospitalization for an elective procedure (including elective PEG tube/g-tube/feeding tube placement)
or a routinely scheduled treatment is not an SAE by this criterion because an elective or scheduled
“procedure” or a “treatment” is not an untoward medical occurrence.
4. Results in persistent or significant disability or incapacity.
a. This serious criterion applies if the “disability” caused by the reported AE results in a substantial
disruption of the subject’s ability to carry out normal life functions.
5. Results in congenital anomaly or birth defect in the offspring of the subject (whether the subject is male or
female).
6. Necessitates medical or surgical intervention to preclude permanent impairment of a body function or
permanent damage to a body structure.
7. Important medical events that may not result in death, are not life-threatening, or do not require
hospitalization may also be considered SAEs when, based upon appropriate medical judgment, may
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed
in this definition.  Examples of such medical events include blood dyscrasias or convulsions that do not result
in inpatient hospitalization, or the development of drug dependency or drug abuse.
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical adverse event may 
meet criteria for "seriousness" but is not an adverse experience, and will therefore, not be considered an SAE. 
An example of this would include a social admission (subject admitted for other reasons than medical, e.g., lives 
far from the hospital, has no place to sleep). 
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A serious, suspected adverse drug reaction is an SAE that, in the opinion of the Site Investigator or Sponsor, 
suggests a reasonable possibility that the investigational product caused the event. 
The Site Investigator is responsible for classifying adverse events as serious or non-serious. 
10.3.1.3 Assessment and Recording of Adverse Events 
Assessment of Adverse Events 
At each visit (including telephone interviews), the subject will be asked “Have you had any problems or symptoms 
since your last visit?” in order to determine the occurrence of adverse events. If the subject reports an adverse 
event, the Investigator will determine: 
1. Type of event
2. Date of onset and resolution (duration)
3. Severity (mild, moderate, severe)
4. Seriousness (does the event meet the above definition for an SAE)
5. Causality, relation to investigational product and disease
6. Action taken regarding investigational product
7. Outcome
Relatedness of Adverse Event to Investigational Product 
The relationship of the AE to the investigational product should be specified by the Site Investigator, using the 
following definitions: 
1. Not Related: Concomitant illness, accident or event with no reasonable association with treatment.
2. Unlikely: The reaction has little or no temporal sequence from administration of the investigational product,
and/or a more likely alternative etiology exists.
3. Possibly Related: The reaction follows a reasonably temporal sequence from administration of the
investigational product and follows a known response pattern to the suspected investigational product; the
reaction could have been produced by the investigational product or could have been produced by the
subject’s clinical state or by other modes of therapy administered to the subject. (suspected ADR)
4. Probably Related: The reaction follows a reasonably temporal sequence from administration of
investigational product; is confirmed by discontinuation of the investigational product or by re-challenge; and
cannot be reasonably explained by the known characteristics of the subject’s clinical state. (suspected ADR)
5. Definitely Related: The reaction follows a reasonable temporal sequence from administration of
investigational product; that follows a known or expected response pattern to the investigational product; and
that is confirmed by improvement on stopping or reducing the dosage of the investigational product, and
reappearance of the reaction on repeated exposure. (suspected ADR)
Recording of Adverse Events 
All clinical adverse events are recorded in the Adverse Event (AE) Log in the subject’s study binder. The site 
should fill out the AE Log and enter the AE information into the online Adverse Event Reporting System within 5 
working days of the site learning of a new AE or receiving an update on an existing AE.   
Please Note: Serious Adverse Events (SAEs) must be reported to the NeuroNEXT Data Coordinating Center 
within 24 hours of the site learning of the SAE.  
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Entries on the AE Log (and into the online Adverse Event Reporting System) will include the following: name 
and severity of the event, the date of onset, the date of resolution, relationship to investigational product, action 
taken, and primary outcome of event. 
Adverse Events and Serious Adverse Events - Reportable Events 
The following are considered reportable events and must be reported to the PI within 24 hours of the site being 
notified of the event.  
•
All events that meet the above criteria for Serious Adverse Events (SAEs)
All occurrences of Serious Adverse Events (SAEs) must be reported within 24 hours of discovery of the event.  
All other Adverse Events (AEs) must be reported within insert timeline for reporting (of discovery of the event). 
11 HUMAN SUBJECTS 
Documented approval from the IRB will be obtained for all participating centers prior to clinical trial start, 
according local laws, regulations and organization. When necessary, an extension, amendment or renewal of 
the IRB approval must be obtained. 
Evidence of training in responsible conduct of research shall be on file for each PI and co-investigator. 
11.1 Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document (Appendix A) and any subsequent modifications will be 
reviewed and approved by the University of Iowa IRB responsible for oversight of the study.  A signed consent 
form, approved by the IRB, will be obtained from the subject.   For subjects who cannot provide consent for 
themselves, such as those below the legal age, a parent, legal guardian, or person with power of attorney, must 
sign the consent form; additionally, the subject's assent must also be obtained if he or she is able to understand 
the nature, significance, and risks associated with the study.  The consent form will describe the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation.  A copy of the consent form will 
be given to the subject, parent, or legal guardian, and this fact will be documented in the subject’s record. 
11.2 Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave the clinical 
study site will be identified only by the study specific Subject Identification Number (SID) to maintain subject 
confidentiality.  All records will be kept in a locked file cabinet.  All computer entry and networking programs will 
be done using study specific SIDs only.  Clinical information will not be released without written permission of 
the subject, except as necessary for monitoring by IRB, the FDA, the OHRP, the sponsor, or the sponsor’s 
designee. 
11.2.1  Certificate of Confidentiality 
To further protect the privacy of study subjects, a Certificate of Confidentiality will be issued by the National 
Institutes of Health (NIH).  This certificate protects identifiable research information from forced disclosure. It 
allows the investigator and others who have access to research records to refuse to disclose identifying 
information on research participation in any civil, criminal, administrative, legislative, or other proceeding, 
whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to 
disclose information that would identify research subjects, Certificates of Confidentiality help achieve the 
research objectives and promote participation in studies by helping assure confidentiality and privacy to subjects. 
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11.3 Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the IRB, the sponsor, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research subjects are protected. If the study 
is terminated or suspended, the PI will promptly inform study subjects, the IRB, and sponsor and provide 
the reason(s) for the termination or temporary suspension. 
12  FUTURE USE OF STORED SPECIMENS AND DATA 
Within the informed consent documents, participants will have the options to either opt in or opt out of 
having their blood drawn and stored for future use.  For subjects who opt to have their blood drawn and 
stored, the biospecimens will be stored at the University of Iowa.  The tubes will be stored with only the 
subject’s ID number to protect confidentiality.  Future studies that will require use of clinical data that was 
obtained during the course of this study will require review by the institutional IRB to ensure proper actions 
are taken to protect confidentiality.  All clinical data will be deidentified and include only the subject ID as the 
primary identifier.  Samples will be stored for up to five years.  
13 STUDY RECORDS RETENTION 
All records pertaining to this study will be made publicly available, in accordance with NIH Policies.  
Therefore, all available data will be made electronically available for a time period specified by the NIH.  In 
addition, all records related to this study will be kept for a minimum of five years by the investigator.  
Destruction of records after five years will be done only after permission has been requested and granted from 
the NINDS.   
14 PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies of the ICTS at the University of Iowa. 
15 CONFLICT OF INTEREST POLICY 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to their participation in 
the design and conduct of this trial.  The study leadership in conjunction with the NINDS has established 
policies and procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
16 REFERENCES 
1.
de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. The Lancet Neurology 2006;5:525-535.
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Senard JM, Rai S, Lapeyre-Mestre M, et al. Prevalence of orthostatic hypotension in Parkinson's
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3.
Chaudhuri KR, Odin P. The challenge of non-motor symptoms in Parkinson's disease. Prog Brain Res
2010;184:325-341.
4.
Collier TJ, Kanaan NM, Kordower JH. Ageing as a primary risk factor for Parkinson's disease: evidence
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5.
Saxena U. Bioenergetics failure in neurodegenerative diseases: back to the future. Expert Opin Ther
Targets 2012;16:351-354.
6.
Cunnane S, Nugent S, Roy M, et al. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition
2011;27:3-20.
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Hoyer S. Brain glucose and energy metabolism during normal aging. Aging (Milano) 1990;2:245-258.
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Firbank MJ, Yarnall AJ, Lawson RA, et al. Cerebral glucose metabolism and cognition in newly
diagnosed Parkinson's disease: ICICLE-PD study. J Neurol Neurosurg Psychiatry 2017;88:310-316.
9.
Hattingen E, Magerkurth J, Pilatus U, et al. Phosphorus and proton magnetic resonance spectroscopy
demonstrates mitochondrial dysfunction in early and advanced Parkinson's disease. Brain 2009;132:3285-3297.
10.
Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I
deficiency in Parkinson's disease. J Neurochem 1990;54:823-827.
11.
Pyle A, Anugrha H, Kurzawa-Akanbi M, Yarnall A, Burn D, Hudson G. Reduced mitochondrial DNA
copy number is a biomarker of Parkinson's disease. Neurobiol Aging 2016;38:216 e217-216 e210.
12.
Mortiboys H, Johansen KK, Aasly JO, Bandmann O. Mitochondrial impairment in patients with
Parkinson disease with the G2019S mutation in LRRK2. Neurology 2010;75:2017-2020.
13.
Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson's
disease. J Biomed Biotechnol 2012;2012:845618.
14.
Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. The Lancet
Neurology 2008;7:97-109.
15.
Chen X, Zhao C, Li X, et al. Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat
Chem Biol 2015;11:19-25.
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Achari R, Laddu A. Terazosin: a new alpha adrenoceptor blocking drug. J Clin Pharmacol 1992;32:520-
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17.
Sakaue S, Kasai T, Mizuta I, et al. Early-onset parkinsonism in a pedigree with phosphoglycerate kinase
deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism? NPJ
Parkinsons Dis 2017;3:13.
18.
Kaufmann H, Goldstein DS. Autonomic dysfunction in Parkinson disease. Handb Clin Neurol
2013;117:259-278.
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Heikkila RE, Hess A, Duvoisin RC. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-
tetrahydropyridine in mice. Science 1984;224:1451-1453.
20.
Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J
Pharmacol 1968;5:107-110.
21.
Coulom H, Birman S. Chronic exposure to rotenone models sporadic Parkinson's disease in Drosophila
melanogaster. J Neurosci 2004;24:10993-10998.
22.
Boyd PJ, Tu WY, Shorrock HK, et al. Bioenergetic status modulates motor neuron vulnerability and
pathogenesis in a zebrafish model of spinal muscular atrophy. PLoS Genet 2017;13:e1006744.
23.
Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and
interacts genetically with parkin. Nature 2006;441:1162-1166.
24.
Lee SB, Kim W, Lee S, Chung J. Loss of LRRK2/PARK8 induces degeneration of dopaminergic
neurons in Drosophila. Biochem Biophys Res Commun 2007;358:534-539.
25.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous
inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci U S A
1998;95:6469-6473.
26.
Rockenstein E, Mallory M, Hashimoto M, et al. Differential neuropathological alterations in transgenic
mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res
2002;68:568-578.
27.
Lill CM. Genetics of Parkinson's disease. Mol Cell Probes 2016;30:386-396.
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Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased
susceptibility to oxidative stress. Cell Stem Cell 2011;8:267-280.
29.
Driver JA, Logroscino G, Gaziano JM, Kurth T. Incidence and remaining lifetime risk of Parkinson
disease in advanced age. Neurology 2009;72:432-438.
30.
Sotiriou E, Greene P, Krishna S, Hirano M, DiMauro S. Myopathy and parkinsonism in
phosphoglycerate kinase deficiency. Muscle Nerve 2010;41:707-710.
31.
Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J. Are men at greater risk for Parkinson's disease
than women? J Neurol Neurosurg Psychiatry 2004;75:637-639.
32.
Patel A, Malinovska L, Saha S, et al. ATP as a biological hydrotrope. Science 2017;356:753-756.
33.
Hayes MH, Peuchen EH, Dovichi NJ, Weeks DL. Dual roles for ATP in the regulation of phase
separated protein aggregates in Xenopus oocyte nucleoli. Elife 2018;7.
34.
Lowe FC. Safety assessment of terazosin in the treatment of patients with symptomatic benign prostatic
hyperplasia: a combined analysis. Urology 1994;44:46-51.
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17 Appendix A 
UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria 

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18 Appendix B 
Medical History of PD 
Date Medical History Taken (m m/dd/yyyy): 
1. Year of first symptoms as confirmed by history obtained by the physician?
2. Year of Initial Diagnosis?
3. Diagnostic Features/Criteria (as evident on clinical assessment of the patient):
a.
4-6 Hz Rest Tremor:
 Present 
 Absent 
 Unknown 
b. Bradykinesia: 
 Present 
 Absent 
 Unknown 
c.
Rigidity:
 Present 
 Absent 
 Unknown 
d. Asymmetric Onset:
 Present 
 Absent 
 Unknown 
e.
Substantial Response to Dopaminergic Therapy:
 Present 
 Absent 
 Unknown 
4. Degree of Certainty of Diagnosis of PD:
90-100% Certain 
 50-89% Certain 
 10-49% Certain
0-9% Certain
Other important diagnostic alternative(s) (give reason): 
5. Initial motor symptoms, i.e., as described by the patient (Please check all that apply):
 Tremor (including internal tremor) 
 Stiffness 
 Change in facial expression 
 Disturbances of dexterity 
 Micrographia 
 Weakness 
 Dystonia (specify symptoms) 
a.
Ambulatory/Axial Difficulties:
 Freezing 
 Lack of arm swing 
 Leg Dragging 
 Shuffling of gait 
 Postural imbalance (excluding falls) 
 Falls 
 Slowness of gait 
 Other abnormality of posture or gait (other, 
specify) 
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6. Side of Body of Initial Symptoms:
 Right 
 Left 
 Bilateral 
 Midline 
 Unknown 
7. Motor symptoms developing over the course of illness (Please check all that applies):
 Tremor (including internal tremor) - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Stiffness - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Micrographia - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Change in facial expression - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Disturbances of dexterity - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Weakness - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Dystonia - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
a.
Ambulatory/Axial Difficulties:
 Freezing - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Lack of arm swing - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Leg Dragging - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Shuffling of gait - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Postural imbalance (excluding falls) - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Falls - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Slowness of gait - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Stooped posture - Approximate date of onset (m m/dd/yyyy): 
 Unknown 
 Other abnormality of posture or gait (other, specify) – Approximate date of onset (m m/dd/yyyy): 
Unknown 
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General Instructions 
Medical history data are collected to help verify the inclusion and exclusion criteria (e.g., no history of 
cognitive disabilities), ensure the participant/subject receives the appropriate care, and describe the study 
population. The Parkinson’s disease Medical History CRF captures conditions specifically related to PD as 
opposed to a more general Medical History which captures conditions that occurred at some point in time 
within a protocol-defined period. 
Important note: None of the data elements included on this CRF Module are classified as Core (i.e., strongly 
recommended for all Parkinson’s disease clinical studies to collect). The remaining data elements are classified 
as supplemental (i.e., non Core) and should only be collected if the research team considers them appropriate 
for their study. Please see the Data Dictionary for element classifications. 
Specific Instructions 
Please see the Data Dictionary for definitions for each of the data elements included in this CRF Module. 
History can also be obtained from a family member, friend, or chart/ medical record. If the informant is unable 
to answer the question or is deemed unreliable (e.g., the participant/ subject has dementia) the history should be 
obtained from the medical record. 
Additional instructions for the elements are already included on the CRF. 
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19 Appendix C 
PD Medication History 
Did the subject ever take any non-study PD medications?  
 Yes (Follow instructions below)  
 No  
 Unknown 
Please record all PD medications the subject has ever taken (including PD medications the subject has taken 
while participating in the study). Enter each dose change on a new line. All other medications (i.e., non-PD 
medications) should be recorded on the Non-PD Medications Log. 
PD Medication Class Reference 
Parkinson’s Disease-Medication Class Reference. 
Class Reference Table 
Levodopa 
Dopamine 
agonists 
MAO-B 
inhibitors 
COMT 
inhibitors 
Antiglutamat 
agents 
Anticholinergics 
Other, 
specify 
PD Medication Name Reference 
Parkinson's Disease Medication Name Reference 
Name Reference Table 
1 Alpha-
Dihydroergocryptine 
Budipine 
L-Dopa
Methylester
Lisuride 
Pramipexole 
Selegiine 
standard 
oral 
Amantadine 
Cabergoline 
L-Dopa Slow
Release
Mematine 
Rasagiline 
Selegiline 
patch 
Apomorphine 
Entacapone 
L-Dopa
Soluble
Pergolide 
Ropinirole 
Selegiline 
sublingual 
Bromocriptine 
L-Dopa Duel
Release
L-Dopa
Standard
Piribedil 
Rotigotine 
Tolcapone 
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Parkinson's Disease Medication Log. 
Medication Log Table 
Line 
# 
Medication 
Class 
Medication 
Name 
(Trade or 
generic 
name) 
Maximum 
Dose 
(Specify 
units) 
Estimated Total 
Duration of 
Exposure (Check 
units) 
Medication 
Use Ongoing? 
If Applicable, 
Reason for 
Discontinuation 
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
*Side Effect:
Other:
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
*Side Effect:
Other:
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
 1Side Effect: 
 Other: 
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
 2Side Effect: 
 Other: 
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
 3Side Effect: 
 Other: 
1 Common Side Effects 
2 Common Side Effects 
3 Common Side Effects 
FAST TZ-PD 
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Version date: 11/12/2019 

Page 40 of 44 
Line 
# 
Medication 
Class 
Medication 
Name 
(Trade or 
generic 
name) 
Maximum 
Dose 
(Specify 
units) 
Estimated Total 
Duration of 
Exposure (Check 
units) 
Medication 
Use Ongoing? 
If Applicable, 
Reason for 
Discontinuation 
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
 4Side Effect: 
 Other: 
Data 
to be 
filled 
out 
by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
Data to be 
filled out by 
site 
 Years 
 Months 
 Weeks 
 Days 
 Yes 
 No 
 Unknown 
 Lack of efficacy 
 5Side Effect: 
 Other: 
Side Effects Table 
AA = Motor offs 
(including wearing off 
and sudden off) 
DD = 
Cognitive 
impairment – 
not dementia 
GG = 
Autonomic 
dysfunction 
JJ = ICD (including 
Gambling, 
Hypersexuality, Binge 
eating, Shopping) 
MM=Dopamine 
agonist 
withdrawal 
BB = Dyskinesia 
EE= Non-
motor offs, 
specify: 
HH= Daytime 
sleep 
abnormalities 
KK=Punding 
OT = Other 
important side 
effects, specify 
CC = 
Hallucination/psychosis 
FF - Behavioral 
disturbances 
specify: 
II = Nighttime 
sleep 
abnormalities 
LL=Dopadysregulation 
syndrome 
4 Common Side Effects 
5Common Side Effects from Medication 
FAST TZ-PD 
Version 2.0 
Version date: 11/12/2019 

Page 41 of 44 
General Instructions 
The Parkinson’s disease medication log provides information about current non-study PD medications the 
participant/ subject has taken in his/her lifetime. Study PD medications should not be listed on this CRF. 
The PD Medication Log was created as an alternative to the Prior and Concomitant Medication CDEs that are 
available under the General CDE Data Standards. For example, in a PD population, patients may be able to 
recall ‘duration’ with greater accuracy than they can recall specific medication start and stop dates. 
Important note: Three of the data elements included on this CRF Module are classified as Core (i.e., strongly 
recommended for all Parkinson’s disease clinical studies to collect). The remaining data elements are classified 
as supplemental (i.e., non Core) and should only be collected if the research team considers them appropriate 
for their study. Please see the Data Dictionary for element classifications. 
Specific Instructions 
Please see the Data Dictionary for definitions for each of the data elements included in this CRF Module. 
The majority of the data elements on the CRF have the following instructions: 
History can be obtained from participant/ subject, family member, friend, or chart/ medical record. In some 
studies it may be possible to ask the subject/ participant or a family member to bring in the pill bottles for all 
current medications. 
Medication name – Please refer to the PD Medication Name Reference Chart. Additionally, please include the 
genric name or trade name of the medication. 
Side effects – Please refer to the Common Side Effects chart for the codes of the possible side effects 
experienced from PD medications. Only capture the side effects code on this form. Specifics of the side effect 
(i.e., Severity, Relatedness, Outcome, etc) should be recorded on the General Adverse Events form if they occur 
during the study. 
There are no other specific instructions for the data elements not already included on the CRF. 
FAST TZ-PD 
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Version date: 11/12/2019 

Page 42 of 44 
20 Appendix D 
Non-PD Medication Log 
Note: This is a template form. Please consider whether your study needs to collect additional data (e.g., exact 
timing for PRN medications) and if additional data are required add fields to this template or capture them on a 
separate form. 
Did the subject take any medications before or during the study? (days): 
FAST TZ-PD 
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Version date: 11/12/2019 

Page 43 of 44 
 Yes (Follow instructions below)  
 No 
 Unknown 
In the table below please record all non-Parkinson’s Disease medications the participant/subject was taking at the time of the protocol-specified 
period indicated above. These can include prescription medications, over the counter drugs, vitamins, supplements, minerals, 
complementary/alternative medications etc. 
Table 1: Non-Parkinson’s Disease medications 
Line # 
Medication 
Name (Trade or 
generic name) 
Total Daily 
Dose or PRN 
Dose (with 
units) 
Start Date 
(M M/D 
D/Y Y Y 
Y) 
End Date 
(M M/D 
D/Y Y Y 
Y) 
Medication Use 
Ongoing? 
*PRN Med?
If PRN, Average 
Frequency (with 
units e.g., times 
per month) 
Indication 
Data to 
be filled 
in by site 
Data to be filled 
in by site 
Data to be 
filled in by site 
Data to be 
filled in by 
site 
Data to be 
filled in by 
site 
 Yes 
 No 
 Unknown 
 Yes 
 No 
 Unknown 
Data to be filled 
in by site 
Data to be 
filled in by 
site 
Data to 
be filled 
in by site 
Data to be filled 
in by site 
Data to be 
filled in by site 
Data to be 
filled in by 
site 
Data to be 
filled in by 
site 
 Yes 
 No 
 Unknown 
 Yes 
 No 
 Unknown 
Data to be filled 
in by site 
Data to be 
filled in by 
site 
Data to 
be filled 
in by site 
Data to be filled 
in by site 
Data to be 
filled in by site 
Data to be 
filled in by 
site 
Data to be 
filled in by 
site 
 Yes 
 No 
 Unknown 
 Yes 
 No 
 Unknown 
Data to be filled 
in by site 
Data to be 
filled in by 
site 
Data to 
be filled 
in by site 
Data to be filled 
in by site 
Data to be 
filled in by site 
Data to be 
filled in by 
site 
Data to be 
filled in by 
site 
 Yes 
 No 
 Unknown 
 Yes 
 No 
 Unknown 
Data to be filled 
in by site 
Data to be 
filled in by 
site 
Data to 
be filled 
in by site 
Data to be filled 
in by site 
Data to be 
filled in by site 
Data to be 
filled in by 
site 
Data to be 
filled in by 
site 
 Yes 
 No 
 Unknown 
 Yes 
 No 
 Unknown 
Data to be filled 
in by site 
Data to be 
filled in by 
site 
* “PRN Med?” asks whether the medication is taken on an as needed basis. NO should be answered for chronic medications that are taken on a
regular basis.
FAST TZ-PD 
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Version date: 11/12/2019 

Page 44 of 44 
General Instructions 
The non-Parkinson’s disease medication log provides information about non-PD medications the 
participant/ subject was taking prior to or during the study. Collecting non-PD medications taken 
prior to the study in a defined time window is important when there may be potential interactions 
with the study intervention. Thus, a potential subject may need to stop a medication prior to 
starting the study intervention (washout period). The study exclusion criteria may identify drugs 
that cannot be taken during the study and so prior medications are identified to determine 
whether an individual may be eligible for the study. 
Important note: None of the data elements included on this CRF Module is classified as Core 
(i.e., strongly recommended for all Parkinson’s disease clinical studies to collect). All data 
elements are classified as supplemental (i.e., non Core) and should only be collected if the 
research team considers them appropriate for their study. Please see the Data Dictionary for 
element classifications. 
Specific Instructions 
Please see the Data Dictionary for definitions for each of the data elements included in this CRF 
Module. 
The majority of the data elements on the CRF have the following instructions: 
History can be obtained from participant/ subject, family member, friend, or chart/ medical 
record. In some studies it may be possible to ask the subject/ participant or a family member to 
bring in the pill bottles for all non-PD medications. 
There are no other specific instructions for the data elements not already included on the CRF. 
FAST TZ-PD 
Version 2.0 
Version date: 11/12/2019