A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects With Primary Autonomic Failure
Phase: PHASE3
Conditions: Symptomatic Neurogenic Orthostatic Hypotension, MSA, Parkinson's Disease (PD), Pure Autonomic Failure (PAF)
Sponsor: Theravance Biopharma

Protocol Number: 0170 
 
 
NCT Number:  NCT03829657 
 
 
A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD˗9855 in Treating 
 Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure 
 
 
Document Date: 05 August 2020 

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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, 22-week, Multi-center, Randomized Withdrawal 
Study of TD˗9855 in Treating Symptomatic Neurogenic 
Orthostatic Hypotension in Subjects with Primary Autonomic 
Failure 
Study Short Title: 
Phase 3 Clinical Effect Durability of TD-9855 for Treating 
symptomatic nOH in Subjects with Primary Autonomic Failure 
(Redwood Study) 
Sponsor Study No.: 
0170 
Date: 
05 August 2020, Amendment 4 
Replaces:  
Amendment 3, Date: 
20 March 2020 
Amendment 2, Date: 
04 December 2019  
Amendment 1, Date: 
04 March 2019 
Original Protocol Date:  05 November 2018 
Test Product: 
TD-9855 (ampreloxetine hydrochloride) tablets 
US IND: 
129797 
EudraCT No.: 
2018-003941-41 
Sponsor: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4   
D04 C5Y6 
Ireland 
Clinical Study Director: 
Michael Markowitz, MD 
Executive Director, Clinical Development, Neurology 
Theravance Biopharma Ireland Limited 
Telephone: +1-919-414-9948 
Email: mmarkowitz@theravance.com 
This study will be conducted according to the principles of Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be 
copied or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
© Theravance Biopharma (Unpublished Work). All rights reserved. 

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Confidential – Property of Theravance Biopharma, Inc. 
 
PROTOCOL SYNOPSIS 
Study Number and Title:  Study 0170: A Phase 3, 22-week, Multi-center, Randomized 
Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic 
Hypotension in Subjects with Primary Autonomic Failure 
Study Short Title:  Phase 3 Clinical Effect Durability of TD-9855 for Treating symptomatic 
nOH in Subjects with Primary Autonomic Failure (Redwood Study) 
Estimated Number of Study Centers and Countries or Regions:  Approximately 
150 clinical research sites in approximately 25 countries 
Background and Rationale:  
In healthy individuals, changes in blood pressure (BP) are highly regulated and well 
controlled- with systolic blood pressure (SBP) being transiently and minimally reduced upon 
standing. This is reflective of the normal physiological response in which neuronally 
mediated pathways remain intact, thereby maintaining the appropriate cerebral perfusion. 
Individuals with impaired compensatory mechanisms may develop orthostatic hypotension 
(OH), which reduces cerebral perfusion pressure and may lead to a sensation of 
lightheadedness, dizziness, or syncope, amongst other symptoms. In disorders with primary 
or secondary autonomic impairment, OH is accompanied by the profound reduction in or 
failure of norepinephrine (NE) neurotransmission and is said to be neurogenic in nature1. 
Disorders with prominent autonomic impairment include neurodegenerative diseases, such 
as Parkinson’s disease (PD), multiple system atrophy (MSA) and pure autonomic failure 
(PAF). Common amongst these conditions are the reported loss of peripheral sympathetic 
nerves containing NE in PD and PAF patients, or the central mechanism controlling NE 
release becoming dysfunctional in patients with MSA. When neurogenic orthostatic 
hypotension (nOH) becomes symptomatic, the experienced sudden drop in BP can cause 
dizziness, visual problems and fatigue, which greatly interfere with the daily activities of 
patients. This interference is highly debilitating and may cause severe injuries through 
frequent falling leading to potential increases in disability and morbidity2,3. 
Recent developments in the understanding of the underlying pathophysiology of various 
clinical forms of autonomic failure have revealed that patients with MSA are characterized 
by impairment of central autonomic pathways crucial for autonomic cardiovascular control 
but have intact peripheral postganglionic noradrenergic fibers. This is evidenced by the near 
normal levels of circulating plasma NE in these patients, and by the observation that cardiac 
uptake of labeled catecholamines is intact4. This latter observation implies the presence of 
both intact noradrenergic nerve terminals and catecholamine reuptake mechanisms. Thus, 
patients with MSA have peripheral residual sympathetic tone that is no longer modulated by 
central autonomic centers and is not under baroreflex control, which cannot be harnessed to 
improve orthostatic hypotension. 
It is now recognized that the continual degeneration of dopaminergic neurons in the 
substantia nigra is preceded by the loss of non-dopaminergic neurons including NE neurons 
of the locus coeruleus in patients with PD. These losses ultimately result in the tremor, 
rigidity, akinesia and postural instability associated with PD5,6. In the early stages of the 
disease, PD and MSA follow similar pathophysiology and may be difficult to distinguish 
clinically.  

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Patients with PAF are also characterized by neurodegeneration and loss of peripheral 
noradrenergic fibers, as evidenced by lower levels of plasma NE and absent cardiac uptake 
of labeled catechols. However, the presence of residual sympathetic tone principally means 
that NE reuptake inhibition may serve as a useful treatment in this subset of both PAF and 
PD patients. 
Pharmacological inhibition of NE transporters (NET) may prove beneficial toward the 
treatment of primary autonomic disorders by permitting patients to take advantage of their 
own remaining residual sympathetic tone. Norepinephrine transport inhibition increases 
tonically released synaptic NE by preventing its reuptake, resulting in increased BP and 
relief from the symptomatic effects ensuing from critical falls in BP. This mechanism of 
action (i.e., inhibition of NE uptake) may also offer an improved safety profile relative to 
other mechanisms of action, such as the addition of exogenous NE or NE prodrug.  For 
example, published proof-of-concept studies indicate that the NET inhibitor atomoxetine is 
an effective pressor agent in these patients, and acutely improves standing SBP and 
symptoms of orthostatic intolerance7,8.  
TD-9855 (ampreloxetine hydrochloride), a new chemical entity, is a potent NE reuptake 
inhibitor (NRI) being developed for a range of medical treatments.  It has a high affinity for 
binding to NE and serotonin (5-HT) transporters and is designed to demonstrate selectivity 
for inhibition of NE versus 5-HT uptake. 
TD-9855 is orally bioavailable with pharmacokinetic (PK) properties supportive of once 
daily dosing. The safety and tolerability of TD-9855 have been demonstrated in a single 
ascending dose (SAD) study in healthy subjects at doses ranging from 2 to 50 mg and a 
multiple ascending dose (MAD) study in healthy subjects at daily doses of 4, 10, 20, and 
40 mg for up to 14 days. In healthy subjects, a single dose up to 50 mg and multiple doses 
up to 20 mg daily (QD) of TD-9855 were generally well tolerated. The PK of TD-9855 was 
linear with near dose proportional exposure in terms of Cmax and AUC across the anticipated 
therapeutic range. TD-9855 has an elimination half-life (t1/2) of approximately 30 to 
40 hours achieving steady state by 6 days. Consistent with the elimination half-life, 3- to 
4-fold accumulation of TD-9855 was observed at steady state. Based on clinical PK studies 
in healthy subjects, TD-9855 is >90% eliminated through metabolism and CYP1A2 is the 
primary enzyme driving TD-9855 metabolism. Accordingly, drug-drug interactions are 
expected with strong inhibitors and inducers of CYP1A2 impacting TD-9855 exposure. 
The safety, tolerability, and efficacy of TD-9855 were also evaluated in two Phase 2 studies 
including subjects with attention-deficit hyperactivity disorder (ADHD) and Fibromyalgia 
(FM). TD-9855 doses of 5 mg and 20 mg QD were administered for 6 weeks in both studies 
and was generally well tolerated with no clinically significant safety signals.  
Theravance conducted a study in adult subjects with primary autonomic failure (including 
MSA, PD, and PAF) in which TD-9855 was investigated for the treatment of symptomatic 
neurogenic orthostatic hypotension (symptomatic nOH). In the 0145 Study, TD-9855 was 
administered to subjects once daily in doses up to 20 mg for a duration of 20 weeks to 
evaluate the effect on symptoms of symptomatic nOH, pressor response, safety, and 
tolerability. 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
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Objectives:   
The primary objectives of the study are: 
• To evaluate the durability of effect of TD-9855 in subjects with symptomatic 
neurogenic orthostatic hypotension (symptomatic nOH) due to multiple system 
atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) 
compared with placebo (PBO) over a double-blind, randomized withdrawal 
period of 6 weeks following an open label (OL) treatment of 16 weeks.  
• To evaluate the safety and tolerability of TD-9855 when taken for up to 
22 weeks. 
The secondary objective(s) of the study (during the 6-week randomized withdrawal period) 
are as follows: 
• To evaluate the durability of effect of TD-9855 by symptom and activity 
assessments using Orthostatic Hypotension Symptom Assessment (OHSA) and 
Orthostatic Hypotension Daily Activity Scale (OHDAS) 
• To evaluate subject’s symptomatic improvement as measured by a wearable 
device 
The exploratory objectives of the study are: 
• To evaluate the effect of TD-9855 using disease-specific instruments and generic 
quality of life assessment   
• To evaluate the effect of TD-9855 using standing blood pressure during 
orthostatic standing test. 
• To evaluate the effect of TD-9855 using generic quality of life assessment 
EuroQol-5D-5L (EQ-5D-5L), Non-Motor Symptom Scale (NMSS), and Hospital 
Anxiety and Depression Scale (HADS) 
• To evaluate pharmacodynamic markers (NE and dihydroxyphenylglycol 
[DHPG]) 
• To inform population PK modeling through collection of sparse PK samples 
• To assess caregiver burden in caring for subjects with primary autonomic failure 
using Burden Scale for Family Caregivers - short version (BSFC-s). 
Study Design:  
This is a Phase 3, multi-center, randomized withdrawal study to evaluate the sustained 
benefit in efficacy and safety of TD-9855 in subjects with primary autonomic failures 
(MSA, PD, or PAF) and symptomatic nOH after 22 weeks of treatment.  Given the 
challenges presented by the COVID-19 pandemic the trial utilizes an operational design 
featuring the ability to conduct protocol required visits as either in clinic or remote visits.  
Investigators, in discussion with each individual subject at their site, will be required to elect 
to conduct study visits either in the clinic or remotely. Sites must conduct the randomization 
withdrawal visits 6 through 9 (V6/D113 - V9/D155) for a given subject in a consistent 
manner to reduce the possibility of variability in data collection and reporting. Tools and 
systems are available to sites and subjects to support remote visits (e.g., direct to subject 

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shipping of study medication and other study supplies, standardized HIPAA/GDPR 
compliant telemedicine platform, in-home health nurses).  
 
Due to the potential for resurgence of COVID-19 and its impact on both sites and subjects, 
the Sponsor will allow Investigators to request exceptions to the selected type of study visit 
modality for V6/D113 through V9/D155 due to COVID-19 or COVID-19 related 
circumstances.  Approved exceptions will be recorded as COVID-19 related protocol 
deviations.  
All sites are allowed at Investigator discretion to conduct either in clinic or remote 
unscheduled visit(s) for subject safety or unexpected subject medical needs outside of the 
regular visit schedule. In this case, unscheduled visits are not considered protocol deviations 
and the Investigator is not required to obtain pre-approval from the Sponsor. Data collected 
during these visits may include any protocol-specified assessments which will be captured in 
the clinical database. 
For De Novo subjects that have previously completed the Screening visit at the time 
regulatory and ethics approval for Amendment 4 is received, sites must reconsent the subject 
using the most recently approved version of the Informed Consent Form to obtain subject 
consent for remote study visits, if that modality is selected by the Investigator and 
subject. For those subjects who are already randomized into the randomized withdrawal 
portion of Study 0170 and active in the study at the time regulatory and ethics approval for 
Amendment 4 is received, the Investigator and subject should continue the remaining study 
visits in the same visit modality as the Randomization Visit (V6, D113). 
Refer to Appendix 9 and the Study Reference Manual for detailed instructions for 
conducting subject assessments in clinic and remotely. These instructions have been 
provided to ensure the method and conduct of each assessment is consistent across sites and 
subjects for both in clinic and remote visits. 
Eligible subjects are either (i) completers of Study 0169 (0169 Completers Group), or 
(ii) symptomatic nOH subjects meeting all applicable study inclusion criteria and none of the 
applicable exclusion criteria (De Novo Group). 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
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Symptomatic neurogenic orthostatic hypotension is defined as: 
• A sustained reduction of BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) 
within 3 minutes of standing or tilted-up to ≥60o elevation from a supine position. 
• A score of at least a 4 on the Orthostatic Hypotension Symptom Assessment 
Question #1 
The study consists of 3 periods: (i) 16-week open-label (OL) treatment with TD-9855, 
(ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up (only for 
patients who do not enroll in Study 0171). A 4-week screening period will apply to the 
De Novo Group only and the Screening visit must be conducted in clinic for ALL De Novo 
group subjects. The schematic representation is as shown below: 
 
 
Subjects entering from Study 0169 (0169 Completers Group) 
Following signing of the informed consent, subjects will enter Study 0170 Visit 1 (V1), 
which will be conducted on the same day as V6/D29 of Study 0169. Sponsor preference is 
the visit modality for Study 0170, either in-clinic or remote for each subject, should be 
consistent with the visit modality selected by the given subject for Study 0169.  
Study 0169 procedures conducted at V6/D29 will serve as the baseline assessments for 
V1/D1 of Study 0170. 
Beginning on Day 2, subjects will receive a single dose of 10-mg TD-9855 once daily (QD) 
and continue thereafter for the 16-week duration of the OL treatment period. Following this 
16-week OL treatment period, subjects will be randomized to either continue on the active 
treatment or PBO for a period of 6 weeks. 
Subjects not participating in Study 0169 (De Novo Group)  
Following signing informed consent, subjects will enter a screening period of up to 4 weeks 
to confirm eligibility. At the Screening visit (Visit S), which must be performed in the clinic, 
subjects will provide a comprehensive medical history of their disease and treatments. The 

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subjects’ disease will be characterized and documented by the principal Investigator (PI) or 
sub-Investigator. 
Subjects will receive an assessment of their physical condition, including safety and 
laboratory evaluations and related aspects of their disease states according to the Schedule of 
Study Procedures. The presence of symptomatic nOH must be confirmed using a tilt-table 
test. 
Eligible subjects will undergo training of accurate scoring of their sensation of dizziness, 
lightheadedness, feeling faint or feeling like blacking out, as outlined by Orthostatic 
Hypotension Symptom Assessment Question 1 (OHSA#1). 
Following the screening period, subjects will proceed to V1 to further confirm the additional 
eligibility criteria prior to proceeding. This includes the completion of the Orthostatic 
Hypotension Questionnaire (OHQ) in which a minimum score of 4 points in OHSA#1 is 
required. 
Subjects meeting all inclusion criteria, none of the exclusion criteria and whose disease 
characterization is confirmed by the independent Enrollment Steering Committee (ESC) will 
receive TD-9855 in the OL period. 
Beginning on Day 2, subjects will receive a single dose of 10-mg TD-9855 once daily (QD) 
and continue thereafter for the 16-week duration of the OL treatment period. Following this 
16-week OL treatment period, subjects will be randomized to either continue on the active 
treatment or PBO for a period of 6 weeks. 
Enrollment Steering Committee (for De Novo Group only) 
The Investigator must obtain approval from the ESC prior to randomizing the subject in the 
study.  The ESC is a committee of independent neurologists that will make a 
predetermination of the subject’s appropriateness for study inclusion by reviewing medical 
information provided by the site. The ESC will review both the medical history 
to support the diagnosis (MSA, PD, or PAF), and confirm the presence of symptomatic nOH 
based on the results of the tilt-table test. Review of the tilt-table test results may include 
confirmation that the subject maintains a sustained fall in blood pressure to a level that is 
consistent with cerebral hypoperfusion. The ESC will consult with the Investigator to 
address any outstanding questions. The ESC review is recommended to be completed within 
48 hours and the Investigator will be informed in writing (e.g., by e-mail) of the decision. 
Following ESC approval of the subject, the Investigator will determine eligibility based 
upon the protocol Inclusion and Exclusion criteria for randomization. In cases where the 
ESC determines subject ineligibility based on tilt-table test findings that are not consistent 
with symptomatic neurogenic orthostatic hypotension, the decision will be accompanied by 
rationale. A dedicated charter has been implemented to address the mode of operations of 
the ESC to ensure the protection of the study integrity. The communication from the ESC, 
documenting review and approval of the subject, will serve as ESC documentation for 
inclusion into the study. 
Open Label Period (Weeks 1 to 16) 
Subjects enrolled into the OL period of the study will have visits scheduled for Day 15, 
Day 29, and every 4 weeks thereafter for assessments as outlined in the Schedule of Study 
Procedures. At V3 (Week 4), following the initial 4-week OL treatment, subjects must 
demonstrate a reduction in OHSA#1 of at least 2 points compared to the baseline value, as 

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determined in Study 0169 for subjects entering from Study 0169 and from V1 for De Novo 
Group subjects, in order to continue in Study 0170. Those subjects not meeting this 
continuation criterion must be discontinued and undergo an end of study visit. The end of 
study visit must be completed within 2 weeks from the date of the last dose. 
All subjects completing the initial 4-week OL treatment period and meeting the continuation 
criterion will continue receiving OL TD-9855 tablets for 12 additional weeks (16 weeks 
total). 
Double-blind Period (Weeks 17 to 22) 
Following the completion of a total of 16 weeks OL treatment with TD-9855 (V6) subjects 
will be assessed for randomization in a 1:1 manner.  Eligible subjects will receive 6 weeks of 
double-blind treatment of TD-9855 or PBO once daily. Only subjects with OHSA#1 score of 
≤7 will be eligible for randomization for the double-blind treatment period.  
Treatment period (Weeks 1 to 22): 
No dose reduction is permitted during the treatment period.  
Subjects unable to tolerate 10-mg TD-9855 will be discontinued from the study. 
At any time during the study, if a subject meets at least one of the following stopping rules, 
they should be discontinued and undergo an end of study visit: 
• A determination from the PI that further administration of the investigational 
product may pose a safety concern to the subject 
• Sustained (at least 4 hours) SBP ≥180 mmHg or diastolic BP (DBP) ≥110 mmHg 
after 3 min of standing or after 5 min in the sitting position, or a sustained (at 
least 4 hours) SBP ≥180 mmHg or DBP ≥110 mmHg measured in the supine 
state (head/torso elevated at approximately 30o from horizontal position).  
• Intolerable adverse event (AE) as determined by the PI 
• Subject becomes pregnant 
Safety assessments will include a physical examination, neurological examination, vital 
signs (body temperature, HR, respiratory rate [RR], and BP), body weight, 12-lead 
electrocardiograms (ECGs), laboratory tests (hematology, chemistry, and urinalysis), 
Columbia Suicide Severity Rating Scale (C-SSRS) and monitoring of AEs.  
Safety will be periodically reviewed by an Independent Data Monitoring Committee 
(IDMC). 
Subjects will be requested to refrain from making any significant dietary changes throughout 
the duration of the study. During their scheduled visits, subjects should be reminded to 
maintain an adequate fluid intake.  
Subjects completing the 6-week double-blind treatment period will be eligible to continue 
into the OL, long-term safety study (Study 0171). Those subjects who do not complete the 
6-week double-blind treatment period or who choose not to continue into Study 0171 will 
complete the Early Termination Visit (V9) or Follow-up visit (V10), respectively. The 
Follow-Up Visit must be completed 2 weeks from the date of the last dose. 

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Duration of Study Participation:  Up to 24 weeks for subjects coming from Study 0169 
and up to 28 weeks for de novo subjects. 
Number of Subjects:  The total number of subjects participating in this study will be 
approximately 258. After the 16-week OL phase, at least 154 subjects are expected to be 
randomized to either the TD-9855 or the PBO group, stratified by the subject’s background 
disease type (MSA, PD, or PAF), assuming 60% are eligible for randomization at the end of 
the OL phase.  
For the De Novo Group, the goal is to enroll at least 40% of MSA subjects.  
All completers from study 0169 will be eligible to participate in study 0170. Assuming 10% 
early discontinuation, approximately 170 subjects are anticipated to be eligible for the 0169 
Completers Group.   
Study Population:  
This study will enroll adult subjects with confirmed symptomatic nOH due to MSA, PD or 
PAF and who meet the inclusion and exclusion criteria defined below. Eligible subjects may 
be de novo or completers from Study 0169. 
Inclusion Criteria (For 0169 Completers Group): 
101. Completion of 4 weeks of double-blind treatment in Study 0169 (V6) and, in the 
opinion of the Investigator, could benefit from continued treatment with TD-9855. 
No minimum score of OHSA#1 is required to enter V1 of Study 0170. 
102. The subject has a minimum of 80% study medication compliance in Study 0169. 
103. The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study procedures (including an 
understanding that entry to Study 0170 may result in changes occurring in the 
subject’s current therapeutic regimen). 
104. The subject must be willing to continue on treatment regardless of the possibility of 
randomization to either TD-9855 or PBO during the randomized withdrawal phase 
and must continue to meet the inclusion criteria for the preceding study (Study 0169) 
with the exception that tilt-table test, ESC review and approval of eligibility are not 
required for entry into Study 0170. 
Inclusion Criteria (For De Novo Group): 
1. Subject is male or female and at least 30 years old. 
2. If subject is female, the subject must be non-pregnant and non-lactating. A woman of 
childbearing potential must have a documented negative pregnancy test at screening. 
NOTE: A woman is considered to be of childbearing potential unless she is 
postmenopausal (amenorrheic for at least 2 years) or documented to be surgically 
sterile (bilateral tubal ligation or total hysterectomy). A female subject may be 
admitted to the study on the basis of a negative urine pregnancy test. If the urine beta 
human chorionic gonadotropin (bHCG) test is positive, a serum bHCG test must be 

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performed. The pregnancy test must be confirmed negative for a subject to be 
eligible for this study. 
3. During the study and for 30 days after receiving the last dose of the study drug, 
females of childbearing potential or males capable of fathering children must agree to 
use highly effective birth control measures (failure rate <1% when used consistently 
and correctly) or agree to abstain from sexual intercourse (Refer to Section 4.3). 
4. Subject must meet the diagnostic criteria of nOH, as demonstrated by a sustained 
reduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) within 3 min of 
being tilted up ≥60o from a supine position as determined by a tilt-table test. 
5. Subject must score at least a 4 on the OHSA#1 at V1. 
6. For subjects with PD only: Subject has a diagnosis of PD according to the United 
Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria (1992). 
7. For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of 
the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The 
Gilman Criteria (2008). 
8. For subjects with PAF only: Subject has documented impaired autonomic reflexes, 
including the Valsalva maneuver performed within 24 months from the date of 
randomization. 
9. Subject has plasma NE levels ≥ 100 pg/mL after being in seated position for 
30 minutes. 
10. Subject is willing and able to provide signed and dated written informed consent to 
participate prior to initiation of any study related procedures. 
11. Subject is able to communicate well with the Investigator and understand clinic staff, 
understands the expectations of the study and is able to comply with the study 
procedures, requirements, and restrictions. 
Exclusion Criteria (For 0169 Completers Group): 
101. Subject may not be enrolled in another clinical trial (other than exiting Study 0169). 
102. Subject has psychiatric, neurological, or behavioral disorders that may interfere with 
the ability of subjects to give informed consent or interfere with the conduct of the 
study. 
103. Medical, laboratory, or surgical issues deemed by the Investigator to be clinically 
significant. 
104. Uncooperative attitude or reasonable likelihood of non-compliance with the protocol. 
105. Subject has a concurrent disease or condition that, in the opinion of the Investigator, 
would confound or interfere with study participation or evaluation of safety, 
tolerability, or pharmacokinetics of the study drug. 
Exclusion Criteria (For De Novo Group): 
1. Subject has a known systemic illness known to produce autonomic neuropathy, 
including, but not limited to, amyloidosis and autoimmune neuropathies.  Subject has 

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diabetes mellitus and diagnosis of PAF. Subject with diabetes mellitus and either 
MSA or PD, will be evaluated on a case by case basis by the medical monitor and 
considered ineligible unless they meet all of the following criteria: 
a. Well controlled type-2 DM in treatment with only oral medications and diet  
b. HgbA1C of ≤7.5% performed during screening or up to 12 weeks before 
screening 
c. No clinically evident peripheral neuropathy (e.g., normal sensory examination on 
peripheral extremities) 
d. No known retinopathy (e.g., annual ophthalmic exam is sufficient)  
e. No nephropathy (e.g., absence of albuminuria and GFR >60) 
2. Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake 
inhibitors (SNRIs). 
3. Subject currently uses concomitant antihypertensive medication for the treatment of 
essential hypertension. 
4. Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, 
whichever is longer, prior to V1 or requires concomitant use until the follow-up visit. 
5. Subject has changed dose, frequency, or type of prescribed medication for orthostatic 
hypotension within 7 days prior to V1.  
• Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior 
to V1. 
6. Subject has known or suspected alcohol or substance abuse within the past 
12 months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 
Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse). 
7. Subject has a clinically unstable coronary artery disease or has had a major 
cardiovascular or neurological event in the past 6 months. 
8. Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to 
V1. 
9. Subject has a history of untreated closed angle glaucoma, or treated closed angle 
glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk 
to the subject. 
10. Subject has any significant uncontrolled cardiac arrhythmia. 
11. Subject has a Montreal Cognitive Assessment (MoCA) ≤23. 
12. Subject is unable or unwilling to complete all protocol specified procedures 
including questionnaires. 
13. Subject had a myocardial infarction in the past 6 months or has current unstable 
angina. 
14. Subject has known congestive heart failure (New York Heart Association [NYHA] 
Class 3 or 4). 
15. Subject has had any malignant disease, other than carcinoma in situ of the cervix or 
basal cell carcinoma, within the past 2 years prior to screening. 

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16. Subject has a known gastrointestinal (GI) condition, which in the Investigator’s 
judgment, may affect the absorption of study medication (e.g., ulcerative colitis, 
gastric bypass). 
17. Subject has psychiatric, neurological, or behavioral disorders that may interfere with 
the ability of the subject to give informed consent or interfere with the conduct of the 
study. 
18. Subject is currently receiving any investigational drug or has received an 
investigational drug within 30 days of dosing. An investigational drug is defined as 
drug that is not approved by a regulatory agency (e.g., Food and Drug Administration 
[FDA]). 
19. Subject has a clinically significant abnormal laboratory finding(s) (e.g., alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of 
normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration 
rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could 
interfere with safety of the subject). 
20. Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal 
behavior, as outlined by the C-SSRS (Baseline/Screening Version). Subject should 
be assessed by the rater for risk of suicide and the subject’s appropriateness for 
inclusion in the study.  
21. Subject has a concurrent disease or condition that, in the opinion of the Investigator, 
would confound or interfere with study participation or evaluation of safety, 
tolerability, or pharmacokinetics of the study drug. 
22. Subject has known hypersensitivity to TD-9855 (ampreloxetine hydrochloride), or 
any excipients in the formulation. 
23. Subject has (i) confirmed severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) documented with coronavirus disease 2019 [COVID-19] positive test 
result, OR (ii) is suspected of SARS-CoV-2 infection (clinical features without 
documented test results two weeks after resolution of symptoms and remains 
asymptomatic until Day 1), OR (iii) has been in close contact with a person with 
known (or suspected) SARS-CoV-2 infection and remains asymptomatic until Day 1. 
Continuation Criteria  
• At V3 (Week 4), following the initial 4-week OL treatment, subjects must 
demonstrate a reduction in OHSA#1 of at least 2 points compared to the baseline 
value, as determined in Study 0169 for subjects entering from Study 0169 and from 
V1 for de novo subjects, in order to continue in Study 0170. 
Randomization Criteria for Double-Blind Period  
201. Subject has OHSA#1 score of <7.  
202. Subject’s unused OL study medications (10-mg TD-9855 tablets) are returned to site. 
203. The subject has a minimum of 80% study medication compliance in OL treatment 
period. 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
204. Subjects with excessive deterioration of disease or symptoms during the OL phase 
and in the opinion of the Investigator, would not benefit from the continual 
participation in the study. 
The following are prohibited or restricted during study participation as specified: 
• Subjects must stop the concomitant use of strong CYP1A2 inhibitors and inducers 
7 days or 5 half-lives, whichever is longer, prior to randomization. This restriction 
applies to concomitant medications, herbal supplements (e.g., St John’s Wort), and 
ordinary dietary intake. Please refer to Appendix 7 for a list of prohibited 
medications. 
• Prescribed medications for OH other than fludrocortisone are prohibited  
• Alpha blockers are prohibited (e.g., Prazosin, Terazosin, Doxazosin, Silodosin, 
Alfuzosin, Tamsulosin) 
• Norepinephrine reuptake inhibitors (NRIs) and serotonin and norepinephrine reuptake 
inhibitors (SNRIs) are prohibited 
− NRIs (e.g., atomoxetine and reboxetine) and SNRIs (e.g., duloxetine, 
milnacipran, levomilnacipran, venlafaxine, desvenlafaxine) 
• Psychostimulants (e.g., amphetamine, dextroamphetamine, methylphenidate, 
pemoline) are prohibited 
• Subjects will be requested to refrain from making any significant dietary changes 
throughout the duration of the study. Subjects should be reminded to maintain an 
adequate fluid intake during their scheduled visits 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
For OL treatment period: 
All subjects will receive TD-9855 and continue to take the study medication once daily 
starting on Day 2 through the end of the treatment period. The test product will be TD-9855 
supplied as a 10-mg tablet in 35-count high-density polyethylene bottles. 
For randomized treatment period: 
Subjects randomized to TD-9855 will receive TD-9855 tablets and continue to take the study 
medication once daily starting in the morning post randomization (Day 2) through the end of 
the treatment period. The test product will be TD-9855 supplied as a 10-mg tablet in 
35-count or 5-count high-density polyethylene bottles labeled in a blinded fashion (i.e., 
bottle label for test product will be indistinguishable from reference product except for a 
coded, unique bottle number).  
For both treatment periods: 
TD-9855 will be administered orally without regard to food at approximately the same time 
each morning and be taken with approximately 8 ounces of water. 
 
 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
Reference Product, Dose, and Route of Administration; Regimen; Duration of 
Treatment:  
For OL treatment period 
No subjects will receive the reference product. 
For randomized treatment period  
Subjects randomized to PBO will receive PBO tablets that match TD-9855 tablets in 
excipient content (except for absence of TD-9855), appearance, tablet count, and in 
packaging (i.e., bottle label for reference product will be indistinguishable from test product 
except for a coded, unique bottle number). 
The PBO tablet will be administered orally without regard to food at approximately the same 
time each morning and be taken with approximately 8 ounces of water. 
Study Evaluations 
Efficacy Assessments: 
• OHQ and PGI-S 
• Subject’s symptomatic improvement as measured by a wearable device 
Exploratory Assessments: 
• Orthostatic standing test 
• NMSS 
• EQ-5D-5L 
• HADS 
• BSFC-s 
For subjects with PD: 
• Unified Parkinson’s Disease Rating Scale (UPDRS) 
• Parkinson’s Disease Questionaire-8 (PDQ-8) 
For subjects with MSA: 
• Unified Multiple System Atrophy Rating Scale (UMSARS) 
• Composite Autonomic Symptom Score-31 (COMPASS-31) 
Safety and Tolerability Assessments: 
• Physical examination including weight 
• Neurological examination 
• Vital signs including ambulatory BP 
• Resting ECGs 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
• Clinical laboratory assessments including serum chemistry, hematology, and 
urinalysis 
• Concomitant medications 
• AEs 
• C-SSRS 
Pharmacokinetic Assessments: 
A sparse PK sampling strategy is being employed in this study where samples will be taken 
at select study visits as defined in the Schedule of Study Procedures. Time of ingestion of 
study medication will be accurately documented the day before and the day of each study 
visit when PK samples will be collected. 
Pharmacodynamic Assessments: 
Blood samples for pharmacodynamic markers ([dihydroxyphenylglycol] DHPG and NE) 
will be collected at select study visits as defined in the Schedule of Study Procedures after 
the subject has been seated for 30 minutes. This is applicable to all consenting subjects. 
Statistical Methods  
Sample Size: 
A total sample size of 154 at randomization will provide an overall power of 90% to detect a 
difference of 25% (25% TD-9855 vs. 50% PBO) in the primary endpoint of the proportion 
of subjects that meet the criteria of treatment failure at Week 6 (V9, D155) during the 
double-blind randomized withdrawal phase at two-sided alpha level of 0.05. 
Assuming that 60% are eligible for randomization at the end of the 16-week OL period, 
approximately 258 subjects will be enrolled such that 154 subjects are expected to continue 
into the randomized treatment period. For the De Novo Group, the goal is to enroll at least 
40% of MSA subjects. 
Study Endpoints: 
The primary study endpoint is the proportion of treatment failure at Week 6 during the 
double-blind randomized withdrawal phase. Treatment failure is defined as subjects who 
meet the following criteria at Week 6 following randomization (V9, D155): 
Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening 
of disease severity as assessed by a 1-point change in PGI-S. 
The assessments done at the Week 16 (V6, D113) visit in the OL phase prior to 
randomization are considered baseline for the double-blind randomized withdrawal phase of 
the study.  Subjects who withdraw for any reason prior to V9 (D155) or subjects who fail to 
provide assessment at V9 (D155) will be considered as treatment failures. 
The secondary endpoints include: 
• Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155) 
• Change from baseline in OHSA composite score at Week 6 post randomization 
(V9, D155) 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
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• Change from baseline in OHDAS composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in PGI-S at Week 6 post randomization (V9, D155) 
• Change from baseline in percent of time spent in standing position as measured 
by a wearable device at Week 6 post randomization (V9, D155) 
• Change from baseline in average number of steps taken as measured by a 
wearable device at Week 6 post randomization (V9, D155) 
Exploratory endpoints include: 
• Standing SBP during orthostatic standing test at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHQ overall composite score at Week 6 post 
randomization (V9, D155) 
• Change from baseline in EQ-5D-5L at Week 6 post randomization (V9, D155) 
• NMSS at Week 6 post randomization (V9, D155) 
• HADS at Week 6 post randomization (V9, D155) 
• BSFC-s at Week 6 post randomization (V9, D155) 
For subjects with PD 
• Change from baseline in UPDRS at Week 6 post randomization (V9, D155) 
• Change from baseline in PDQ-8 at Week 6 post randomization (V9, D155) 
For subjects with MSA 
• Change from baseline in UMSARS at Week 6 post randomization (V9, D155) 
Change from baseline in COMPASS-31 at Week 6 post randomization 
(V9, D155) 
Safety and tolerability endpoints include: 
• Physical examination 
• Neurological examination 
• Vital signs including ambulatory BP 
• Resting ECGs 
• Clinical laboratory assessments including biochemistry, hematology, urinalysis. 
• Concomitant medication  
• Adverse events (AEs) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Exploratory Endpoints include: 
• PK and pharmacodynamic parameters 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
Analysis: 
All efficacy analyses in the double-blind randomized withdrawal phase will be performed 
based on the Full Analysis Set (FAS) using the assigned randomized treatments.  The FAS 
of the double-blind randomized withdrawal phase is defined as all randomized subjects who 
have received at least 1 dose of study medication post randomization.  
The safety analysis set (Safety) of the double-blind randomized withdrawal phase is 
comprised of all randomized subjects who have receive at least 1 dose of study medication 
and subjects will be analyzed according to actual study treatments they receive.  
The FAS and Safety for OL phase will be identical and is defined as all enrolled subjects 
who have received at least one dose of TD-9855. 
In the double-blind randomized withdrawal phase, unless specified otherwise, all data will 
be summarized by treatment group.  In the OL phase all data will be summarized for all 
subjects and by enrollment group (De Novo Group or 0169 Completers Group). Continuous 
variables will be presented using descriptive statistics. Categorical variables will be 
summarized using subject counts and percentage of subjects in corresponding categories. 
The primary study endpoint is the proportion of treatment failure at Week 6 during the 
double-blind randomized withdrawal phase. Treatment failure is defined as subjects who 
meet the following criteria at Week 6 following randomization (V9, D155): 
Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening 
of disease severity as assessed by a 1-point change in PGI-S. 
The assessments done at the Week 16 (V6, D113) visit in the OL phase prior to 
randomization are considered baseline for the double-blind randomized withdrawal phase of 
the study.  Subjects who withdraw for any reason prior to V9 (D155) or subjects who fail to 
provide assessment at V9 (D155) will be considered as treatment failures. 
The Logistic regression model will be used to compare treatment differences based on the 
FAS. The model will include fixed effect class terms of treatment, baseline disease type 
(MSA, PAF, PD), and continuous covariate of baseline OHSA#1 score, and baseline PGI-S 
score. Odds ratio with 95% confidence intervals will be calculated and presented, 
least-square proportion and 95% confidence intervals on the differences between TD-9855 
and PBO groups will be calculated and presented. In addition, the proportion of subject with 
treatment failure along with proportion of subjects failing separately due to worsening of 
OHSA#1 and PGI-S will be reported. 
Sensitivity analyses on the primary endpoint will be carried out (1) using per-protocol set 
which excludes subjects with major protocol deviations, (2) using multiple imputation for 
subject missing OHSA#1 and/or PGI-S score at Week 6 post randomization (V9, D155) and 
(3) by excluding subjects with missing data on primary endpoint. 
The primary analysis will be repeated on a set of pre-specified subgroups (e.g., disease type) 
and presented in graphical format. Details will be specified in the Statistical Analysis Plan 
(SAP).  
Secondary efficacy endpoints involving assessment of change from baseline at multiple time 
points such as OHSA#1, OHSA composite score, OHDAS composite score, and percent of 

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PROTOCOL SYNOPSIS (CONTINUED) 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
time spent in supine, sitting, and standing position as measured by a wearable device, will be 
analyzed using mixed model for repeated measures (MMRM) to compare treatment 
differences based on the FAS. The model will include fixed effect class terms of treatment, 
baseline disease type (MSA, PD, PAF), week, and continuous covariate of baseline score of 
the respective scale, a random subject effect, with an unstructured covariance structure. If 
the model doesn’t converge, compound symmetry or other covariance structures will be used 
as alternative covariance structure. Least-square means and 95% confidence intervals on the 
differences between TD-9855 and PBO will be calculated and presented.  
Exploratory endpoints involving assessment of change from baseline at multiple time points 
such as standing SBP during orthostatic standing test will be analyzed similarly. 
Exploratory endpoints involving assessment of change from baseline but only at Week 6 
post randomization (V9, D155) such as PDQ-8, UPDRS, UMSARS, and COMPASS-31, an 
analysis of covariance (ANCOVA) will be used to compare treatment differences based on 
the FAS. The model will include fixed effect of treatment, baseline disease type (MSA, PD 
and PAF) and continuous covariate of baseline score of the respective scales. 
Secondary efficacy endpoints will be tested via a statistical testing procedure, to be 
described in the statistical analysis plan (SAP), that will protect the family-wise Type I error 
rate at 2-sided significance level of 5%.  
• Change from baseline in OHSA composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHSA item 1 score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHDAS composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in PGI-S at Week 6 post randomization (V9, D155) 
• Change from baseline in percent of time spent standing position as measured by a 
wearable device at Week 6 post randomization (V9, D155) 
• Change from baseline in average number of steps taken as measured by a 
wearable device at Week 6 post randomization (V9, D155) 
For all supportive analyses including sensitivity analyses of the primary efficacy endpoint 
and other efficacy endpoints, p-values and confidence intervals will be evaluated 
descriptively at two-sided 5% level with no adjustment for multiplicity. 
In addition, descriptive analysis of efficacy data collected during OL phase will be carried 
out for all subjects and by enrollment group (De Novo Group or 0169 Completers Group). 
Safety data will be listed by subject and summarized using the frequency of event or 
descriptive statistical summaries, as appropriate. Summaries and listings will be presented 
separately for OL phase and double-blinded randomized withdrawal phase. Summary tables 
will be provided for vital signs, body weight, ECGs, safety laboratory tests, C-SSRS, AEs, 
and concomitant medications. 
 

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SCHEDULE OF STUDY PROCEDURES 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
Table 1: 
Schedule of Study Procedures 
Study Period: 
Screenin
g a 
(De Novo 
Group 
Only – in 
clinic )  
Open Label Treatment 
(Visits either in clinic or remote for each subject) 
Randomized Withdrawal Period 
(For each subject, Visits 6 through 9, 
all either in clinic or remote) 
Follow-
upc 
Study Day (Visit): 
-28 to -7 
(Visit S) 
Day 1  
(Visit 1)b 
Day 15  
(Visit 2) 
+/- 3  days 
Day 29  
(Visit 3) 
+/- 3  days 
Day 57  
(Visit 4) 
+/- 3  days 
Day 85  
(Visit 5) 
+/- 3  days 
Day 113  
(Visit 6) 
+/- 3  days 
Day 127  
(Visit 7) 
+/- 3  days 
Day 141  
(Visit 8) 
+/- 3  days 
Day 155  
(Visit 9) / ET 
+/- 3  days 
Day 169  
(Visit 10) 
+/- 3  days 
Procedure 
Informed consentd 
X 
X 
 
 
 
 
 
 
 
 
 
Inclusion /exclusion criteriad 
X 
Xe 
 
 
 
 
 
 
 
 
 
Medical history (including 
smoking history)f 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
(including smoking usage) 
Xf 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
OHQ subject trainingg 
X 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
OHQ (OHSA and OHDAS) 
 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
PGI-S 
 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
X 
Tilt-table testh 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
 
 
 
 
 
X 
 
 
 
 
Recommended Order of Procedures (when applicable) 
NMSS 
 
Xe 
 
 
X 
 
X 
 
 
X 
 
HADS 
 
Xe 
 
 
X 
 
X 
 
 
X 
 
UPDRSj (PD Subjects only) 
 
Xe 
 
 
X 
 
X 
 
 
X 
 
PDQ-8 (PD Subjects only) 
 
Xe 
 
 
X 
 
X 
 
 
X 
 
UMSARS (MSA Subjects 
only) 
 
Xe 
 
 
X 
 
X 
 
 
X 
 

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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
Table 1: 
Schedule of Study Procedures 
Study Period: 
Screenin
g a 
(De Novo 
Group 
Only – in 
clinic )  
Open Label Treatment 
(Visits either in clinic or remote for each subject) 
Randomized Withdrawal Period 
(For each subject, Visits 6 through 9, 
all either in clinic or remote) 
Follow-
upc 
Study Day (Visit): 
-28 to -7 
(Visit S) 
Day 1  
(Visit 1)b 
Day 15  
(Visit 2) 
+/- 3  days 
Day 29  
(Visit 3) 
+/- 3  days 
Day 57  
(Visit 4) 
+/- 3  days 
Day 85  
(Visit 5) 
+/- 3  days 
Day 113  
(Visit 6) 
+/- 3  days 
Day 127  
(Visit 7) 
+/- 3  days 
Day 141  
(Visit 8) 
+/- 3  days 
Day 155  
(Visit 9) / ET 
+/- 3  days 
Day 169  
(Visit 10) 
+/- 3  days 
COMPASS-31 (MSA 
Subjects only) 
 
Xe 
 
 
X 
 
X 
 
 
X 
 
EQ-5D-5L 
 
Xe 
 
 
X 
 
X 
 
 
X 
 
BSFC-s 
 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
Orthostatic standing testk 
X 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (BP, HR, RR 
and body temperature)l 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
Xe 
 
 
 
 
X 
 
 
X 
X 
Physical examinationm 
X 
Xe 
X 
 
 
 
X 
 
 
X 
 
Neurological examination 
X 
Xe 
 
 
 
 
X 
 
 
X 
 
12-lead electrocardiogramn 
X 
Xe 
 
X 
 
 
X 
 
 
X 
 
Pregnancy testo 
X 
Xe 
 
 
 
 
X 
 
 
X 
 
Norepinephrine (NE) 
X 
 
 
 
 
 
 
 
 
 
 
Safety laboratory test 
(chemistry, hematology, and 
urinalysis) 
X 
Xe 
X 
 
X 
 
X 
 
 
X 
 
Pharmacokinetic samplingp 
 
 
 
 
X 
 
X 
X 
 
 
 
Pharmacodynamic 
samplingq 
 
Xe 
 
 
X 
 
 
 
 
 
 

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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
Table 1: 
Schedule of Study Procedures 
Study Period: 
Screenin
g a 
(De Novo 
Group 
Only – in 
clinic )  
Open Label Treatment 
(Visits either in clinic or remote for each subject) 
Randomized Withdrawal Period 
(For each subject, Visits 6 through 9, 
all either in clinic or remote) 
Follow-
upc 
Study Day (Visit): 
-28 to -7 
(Visit S) 
Day 1  
(Visit 1)b 
Day 15  
(Visit 2) 
+/- 3  days 
Day 29  
(Visit 3) 
+/- 3  days 
Day 57  
(Visit 4) 
+/- 3  days 
Day 85  
(Visit 5) 
+/- 3  days 
Day 113  
(Visit 6) 
+/- 3  days 
Day 127  
(Visit 7) 
+/- 3  days 
Day 141  
(Visit 8) 
+/- 3  days 
Day 155  
(Visit 9) / ET 
+/- 3  days 
Day 169  
(Visit 10) 
+/- 3  days 
ESC (for confirmation of 
diagnosis)a 
X 
 
 
 
 
 
 
 
 
 
 
24-hour ambulatory BP 
device provisionr 
X 
Xe 
 
X 
 
 
 
 
 
 
 
24-hour ambulatory BP 
device collectionr 
 
Xe 
X 
 
X 
 
 
 
 
 
 
Wearable device 
provision/collections 
X 
Xe 
 
X 
X 
X 
X 
X 
X 
X 
 
Incidence of Falls and 
ABPM position Diaries 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing and Midodrine 
rescue medication Diaries 
 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication 
 
Xe 
 
 
 
 
 
 
 
 
 
Study medication dosingt 
 
X 
 
Collect, review, and 
dispense study medication 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Collect and review study 
medication 
 
 
 
 
 
 
 
 
 
X 
 
Valsalva maneuveru 
X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: BSFC-s: Burden Scale for Family Caregivers - short version; BP: Blood Pressure; COMPASS-31: Composite Autonomic Symptoms Score-31; 
C-SSRS: Columbia Suicide Severity Rating Scale; ESC: Enrollment Steering Committee; ET: Early Termed; EQ-5D-5L: EuroQol-5D-5L; HADS: Hospital 
Anxiety and Depression Scale; HR: Heart Rate; MoCA: Montreal Cognitive Assessment; MSA: Multiple System Atrophy; NMSS: Non-motor Symptom Scale; 
OHDAS: Orthostatic Hypotension Daily Activity Scale; OHSA: Orthostatic Hypotension Symptom Assessment; OHQ: Orthostatic Hypotension Questionnaire; 
OL: Open Label; PAF: Pure Autonomic Failure; PD: Parkinson’s Disease; PDQ-8: Parkinson’s Disease Questionaire-8; PGI-S: Patient Global Impression of 

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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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Severity; RTSM: Randomization and trial supply management; RR: Respiratory Rate; UMSARS: Unified Multiple System Atrophy Rating Scale; UPDRS: 
Unified Parkinson’s Disease Rating Scale. 
 
a. Screening Visit must be conducted in clinic for ALL De Novo group subjects. Subject eligibility will be assessed by the Investigator during screening and 
primary diagnosis will be verified by the ESC prior to Day 1 (for De Novo Group subjects only); subjects meeting OHSA#1 criterion on Day 1 and who 
otherwise meet eligibility criteria may be enrolled via RTSM. 
b. For 0169 Completers Group, Study 0169 procedures conducted at D29 will serve as the baseline assessments for D1 of Study 0170 .  
c. Follow-up visit is only applicable for those subjects that do not proceed to Study 0171 and will be completed two weeks from the date of the last dose. Those 
subjects proceeding to Study 0171 will enter from V9.  
d. The De Novo Group subjects would sign the consent before screening, thus screening visit is only applicable for De Novo Group subjects, and the 0169 
Completers Group would sign the consent before V1 and would start with Day 1 of Study 0170. 
e. The assessments or procedures will be performed within 24-hours prior to subject taking the study medication (pre-dose). Following completion of study 
assessments, the subjects will take study medication on Day 2 in the morning.   
f. A complete medical and medication history evaluation will be performed during screening (for de novo subjects only). 
g. During the screening visit, subjects will receive thorough training on the OHQ disease instrument and will receive refresher training prior to completing the 
OHQ during each applicable study visit that occurs during treatment with study medication. Subjects should be rested prior to beginning the training. 
h. The tilt-table test should be performed following at least 12-hours of withdrawal from vasoactive medications. The tilt-table test should be performed at least 
2 hours after meals and with an empty bladder.   
i. Subjects will be randomized via RTSM once they meet the randomization criteria 
j. The UPDRS scale should be completed in an ON state, and within 1-4 hours of taking the PD medications. All UPDRS Parts will be completed on Day 1 for 
De Novo Group subjects, while only Parts 2 and 3 of the questionnaire would be completed for 0169 Completers Group, and for subsequent visits for 
De Novo Group subjects. 
k. The assessment should be performed at approximately (±2 hour) the same time of day on Day 1 (except Screening). Subjects should abstain from eating for at 
least 90mins prior to this assessment.   
l. The vital sign measurements should be performed after the subject has rested sufficiently as determined by the appropriate site staff. The BP and HR collected 
at 10 minutes supine and seated from the orthostatic standing test can be used for safety vital signs assessment. Vitals can be performed as part of the 
mandated procedures, if needed. 
m. A full physical examination at the Screening visit will be performed (for de novo subjects only). Subsequent physical examinations, per discretion of the 
Investigator, can be abbreviated and symptomatic. 
n. ECGs are done in triplicate after the subject has been resting for at least 5 minutes in a seated or supine position before the first reading, with each replicate 
separated by at least 1 minute. The total time to conduct ECGs ideally would not exceed 15 minutes 
o. In women of childbearing potential only. First, urine beta human chorionic gonadotropin (bHCG) test will be performed and if positive, confirmation with 
serum bHCG test is required. The pregnancy test must be confirmed negative for a subject to be eligible for this study. 
p. Blood samples will be collected for TD-9855 PK on the days specified.  All PK sampling times will be accurately recorded by collection date, hour, and 
minute. Study medication dosing time on the day before each PK collection and on the day of each PK collection will be accurately recorded by dosing date, 
hour, and minute by the study staff using time recorded in Dosing Diary by Subjects.  

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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
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q. Blood samples for pharmacodynamic markers (norepinephrine (NE) and dihydroxyphenylglycol (DHPG)), will be collected after the subject has been seated 
for 30 minutes. Blood sample for NE will be collected at screening (for De Novo Group subjects only) while samples for both NE and DHPG will be 
collected on Day 1 and Day 57. Note that all pharmacodynamic marker samples should be collected at approximately (±1 hour) the same time of day on 
Day 1 and Day 57 so that time-matched analysis can be performed. 
r. Ambulatory blood pressure monitoring (ABPM) equipment will be provided to the De Novo Group subjects during the screening visit and on Day 1 to 0169 
Completers Group. Beginning approximately 72 to 24-hours before a subject returns to the clinic for visits, subjects will put on the 24-hour blood pressure 
monitoring equipment and initiate the recording. Once the 24-hour session is complete, subjects will remove and return the equipment to the research center 
during the next visit. During each 24-hour session, the blood pressure monitoring device will be programmed to automatically measure blood pressure every 
2 hours beginning at the top of the hour. During each 24-hour session, subjects will also log their posture in the ABPM Position Diary at the time of each 
blood pressure measurement. Details regarding the ambulatory monitoring will be provided in a separate manual. The assessment on D1 is only for De Novo 
Group subjects. 
s. For wearables, in countries where the wearable devices are available, 2 consecutive days of device usage will be required on the days shown. The 
2 consecutive days of device usage should take place within 5 days before the subsequent visit. Site coordinators will monitor subject compliance. If the site 
coordinator becomes aware that a subject has not performed the required device usage, they will contact the subject and remind them to use the device. 
t. Study medication will be ingested orally without regard to food at approximately the same time each morning and taken with approximately 8 ounces of 
water. The exact time and day of dosing will be recorded by the subject in the Dosing Diary on the mornings of study visits. 
During their scheduled visits, subjects should be reminded to maintain an adequate fluid intake.  For OL treatment period, subjects would start taking 
medications starting on Day 2. 
u. Valsalva maneuver is to be performed for PAF subjects only if no results are available within 24 months from the date of randomization. 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 29 
1. 
INTRODUCTION ................................................................................... 33 
1.1. 
Background and Rationale ....................................................................... 33 
1.2. 
Nonclinical Profile ................................................................................... 34 
1.2.1. 
Nonclinical Pharmacology ....................................................................... 34 
1.2.2. 
Safety Pharmacology ............................................................................... 35 
1.2.3. 
Nonclinical Pharmacokinetics ................................................................. 35 
1.2.4. 
Toxicology ............................................................................................... 35 
1.3. 
Clinical Experience .................................................................................. 36 
1.3.1. 
Clinical Pharmacokinetics ....................................................................... 38 
1.4. 
Risks and Benefits ................................................................................... 38 
2. 
OBJECTIVES .......................................................................................... 40 
2.1. 
Primary Objective .................................................................................... 40 
2.2. 
Secondary and Other Objectives ............................................................. 40 
3. 
STUDY DESIGN .................................................................................... 41 
3.1. 
Overview .................................................................................................. 41 
3.2. 
Rationale for Study Design ...................................................................... 45 
3.3. 
Selection of Dose and Duration of Treatment ......................................... 45 
3.4. 
Study Endpoints ....................................................................................... 46 
3.4.1. 
Primary Endpoint ..................................................................................... 46 
3.4.2. 
Secondary Endpoints ............................................................................... 46 
3.4.3. 
Safety and Tolerability Endpoint ............................................................. 47 
3.4.4. 
Exploratory Endpoints ............................................................................. 47 
3.5. 
Minimization of Bias ............................................................................... 47 
3.5.1. 
Blinding ................................................................................................... 48 
3.5.2. 
Treatment Assignment ............................................................................. 48 
3.5.3. 
Enrollment Steering Committee (for De Novo Group only) ................... 49 
4. 
STUDY POPULATION .......................................................................... 50 
4.1. 
Inclusion Criteria ..................................................................................... 50 
4.2. 
Exclusion Criteria .................................................................................... 51 
4.3. 
Pregnancy and Contraception .................................................................. 53 
4.3.1. 
Females of Childbearing Potential........................................................... 53 
4.3.2. 
Contraception for Male and Female Subjects .......................................... 53 

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4.4. 
Continuation Criteria ............................................................................... 54 
4.5. 
Randomization Criteria for Double-Blind Period .................................... 54 
5. 
STUDY MEDICATION .......................................................................... 55 
5.1. 
Description of Study Medications ........................................................... 55 
5.1.1. 
TD-9855 Test Product ............................................................................. 55 
5.1.2. 
Placebo Reference Product ...................................................................... 55 
5.2. 
Dosage and Administration ..................................................................... 55 
5.3. 
Treatment Compliance ............................................................................. 56 
5.4. 
Drug Accountability and Reconciliation ................................................. 56 
6. 
STUDY PROCEDURES ......................................................................... 57 
6.1. 
Schedule of Study Procedures ................................................................. 57 
6.2. 
Total Blood Volume ................................................................................ 57 
6.3. 
Procedures by Visit (Recommended Order) ............................................ 57 
6.3.1. 
Screening – Visit S (De Novo Group Only) ............................................ 57 
6.3.2. 
Treatment Day 1 – Visit 1 ....................................................................... 58 
6.3.3. 
Treatment Day 15 – Visit 2 ..................................................................... 60 
6.3.4. 
Treatment Day 29 – Visit 3 ..................................................................... 60 
6.3.5. 
Treatment Day 57 – Visit 4 ..................................................................... 61 
6.3.6. 
Treatment Day 85 – Visit 5 ..................................................................... 62 
6.3.7. 
Treatment Day 113 – Visit 6 ................................................................... 63 
6.3.8. 
Treatment Day 127 – Visit 7 ................................................................... 64 
6.3.9. 
Treatment Day 141 – Visit 8 ................................................................... 65 
6.3.10. 
Treatment Day 155 – Visit 9/ Early Termination .................................... 65 
6.3.11. 
Follow-up Day 169 – Visit 10 ................................................................. 66 
6.4. 
Description of Study Procedures ............................................................. 67 
6.4.1. 
Demographic and Baseline Assessments................................................. 67 
6.4.2. 
Tilt-Table Test ......................................................................................... 67 
6.4.3. 
Montreal Cognitive Assessment .............................................................. 68 
6.4.4. 
Valsalva Maneuver .................................................................................. 68 
6.4.5. 
OHQ Subject Training ............................................................................. 68 
6.4.6. 
Efficacy Assessments .............................................................................. 68 
6.4.6.1. 
Orthostatic Hypotension Questionnaire ................................................... 68 
6.4.6.2. 
Patient Global Impression of Severity ..................................................... 68 
6.4.6.3. 
Wearable Device ...................................................................................... 69 
6.4.6.4. 
Unified Parkinson’s Disease Rating Scale .............................................. 69 

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6.4.6.5. 
The Parkinson's Disease Questionnaire-8 ................................................ 69 
6.4.6.6. 
Unified Multiple System Atrophy Rating Scale ...................................... 69 
6.4.6.7. 
Composite Autonomic Symptom Score-31 ............................................. 70 
6.4.6.8. 
Incidence of Falls – Subject Diary ........................................................... 70 
6.4.6.9. 
Orthostatic Standing Test ........................................................................ 70 
6.4.7. 
Pharmacokinetic Assessments ................................................................. 70 
6.4.8. 
Pharmacodynamic Assessments .............................................................. 71 
6.4.9. 
Exploratory Assessments ......................................................................... 71 
6.4.9.1. 
EQ-5D-5L Descriptive System ................................................................ 71 
6.4.9.2. 
Non-Motor Symptom Scale ..................................................................... 71 
6.4.9.3. 
Hospital Anxiety and Depression Scale .................................................. 71 
6.4.9.4. 
Burden Scale for Family Caregivers – Short Version ............................. 72 
6.4.10. 
Safety Assessments .................................................................................. 72 
6.4.10.1. 
Columbia-Suicide Severity Rating Scale ................................................. 72 
6.4.10.2. 
Adverse Events ........................................................................................ 72 
6.4.10.3. 
Medication and Medical History ............................................................. 72 
6.4.10.4. 
Physical Examination .............................................................................. 73 
6.4.10.5. 
Neurological Examination ....................................................................... 73 
6.4.10.6. 
Height and Weight ................................................................................... 73 
6.4.10.7. 
Vital Signs ............................................................................................... 73 
6.4.10.8. 
Electrocardiograms .................................................................................. 74 
6.4.10.9. 
24-hour Ambulatory Blood Pressure Monitoring .................................... 74 
6.4.10.10. Laboratory Tests ...................................................................................... 74 
6.4.10.11. Dosing Diary Dispensation and/or Collection ......................................... 75 
6.4.10.12. Unscheduled Visit .................................................................................... 75 
6.5. 
Concomitant Medications ........................................................................ 75 
6.5.1. 
Impact of Other Medications on TD-9855 .............................................. 76 
6.5.2. 
Impact of TD-9855 on Other Medications .............................................. 76 
6.6. 
Rescue Medications ................................................................................. 76 
6.7. 
Prohibitions and Restrictions ................................................................... 76 
6.8. 
Discontinuation ........................................................................................ 77 
6.8.1. 
Dose Stopping Rules................................................................................ 77 
6.8.2. 
Subject Discontinuation ........................................................................... 77 
6.8.3. 
Subject Replacement ............................................................................... 78 
6.8.4. 
Study Discontinuation ............................................................................. 78 

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6.9. 
Pregnancy ................................................................................................ 78 
7. 
ADVERSE EVENTS............................................................................... 79 
7.1. 
Definitions ............................................................................................... 79 
7.1.1. 
Adverse Event .......................................................................................... 79 
7.1.2. 
Serious Adverse Event ............................................................................. 80 
7.1.3. 
Additional Considerations for Serious Adverse Events .......................... 80 
7.1.4. 
Adverse Event of Special Interest ............................................................ 81 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ............................................. 82 
7.3. 
Assessment of Adverse Events ................................................................ 82 
7.3.1. 
Severity .................................................................................................... 82 
7.3.2. 
Causal Relationship to Study Medication ................................................ 82 
7.4. 
Adverse Event Reporting and Recording ................................................ 83 
7.4.1. 
Adverse Event Reporting ......................................................................... 83 
7.4.2. 
Adverse Event and Serious Adverse Event Recording ............................ 83 
7.4.3. 
Serious Adverse Event and Adverse Event of Special Interest Reporting 
Timeline ................................................................................................... 84 
7.5. 
Adverse Event Follow-up ........................................................................ 85 
8. 
STATISTICAL CONSIDERATIONS .................................................... 86 
8.1. 
General Considerations ............................................................................ 86 
8.2. 
Sample Size and Power ........................................................................... 86 
8.3. 
Analysis Sets ............................................................................................ 86 
8.3.1. 
Examination of Subgroups ...................................................................... 87 
8.3.2. 
Major Protocol Analysis Deviations ........................................................ 87 
8.4. 
General Analyses ..................................................................................... 87 
8.4.1. 
Demographics and Other Baseline Characteristics .................................. 87 
8.4.2. 
Medical History ....................................................................................... 88 
8.5. 
Analysis of Efficacy ................................................................................ 88 
8.5.1. 
Efficacy Endpoints ................................................................................... 88 
8.5.1.1. 
Primary Efficacy Evaluation .................................................................... 89 
8.5.1.2. 
Secondary and Other Efficacy Evaluations ............................................. 89 
8.5.2. 
Multiplicity Adjustment........................................................................... 90 
8.5.3. 
Analysis of Pharmacokinetics .................................................................. 90 
8.5.4. 
Analysis of Pharmacodynamics ............................................................... 90 
8.6. 
Safety Analyses ....................................................................................... 91 

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8.6.1. 
Extent of Exposure .................................................................................. 91 
8.6.2. 
Adverse Event Data ................................................................................. 91 
8.6.3. 
Concomitant Medications ........................................................................ 92 
8.6.4. 
Laboratory Data ....................................................................................... 92 
8.6.5. 
Vital Signs Data ....................................................................................... 92 
8.6.6. 
Electrocardiogram Data ........................................................................... 92 
8.7. 
Missing Data Handling ............................................................................ 94 
8.7.1. 
Mitigation and Analysis Strategies in Response to COVID-19 .............. 94 
8.8. 
Independent Data Monitoring Committee ............................................... 94 
9. 
STUDY ADMINISTRATION ................................................................ 95 
9.1. 
Principal Investigator Responsibilities .................................................... 95 
9.2. 
Institutional Review Board/Independent Ethics Committee ................... 96 
9.3. 
Informed Consent .................................................................................... 97 
9.4. 
Data Recording and Quality Assurance ................................................... 97 
9.5. 
Document Retention ................................................................................ 98 
9.6. 
Confidentiality ......................................................................................... 98 
9.7. 
Access to Data and Documents ............................................................... 99 
9.8. 
Quality Control: Study Monitoring and Auditing ................................... 99 
9.9. 
Publication ............................................................................................. 100 
10. 
REFERENCES ...................................................................................... 101 
APPENDIX 1. PROTOCOL SIGNATURE FORM .............................................. 102 
APPENDIX 2. EXAMPLES OF DISEASE INSTRUMENTS ............................. 103 
APPENDIX 3. INCIDENCE OF FALLS .............................................................. 150 
APPENDIX 4. AMBULATORY BLOOD PRESSURE MONITORING - 
POSITION DIARY ............................................................................... 151 
APPENDIX 5. DOSING DIARY .......................................................................... 152 
APPENDIX 6. MIDODRINE RESCUE MEDICATION DIARY ........................ 153 
APPENDIX 7. PROHIBITED MEDICATIONS ................................................... 154 
APPENDIX 8. SAMPLE SCREENING VISIT FOR DENOVO SUBJECTS ...... 155 
APPENDIX 9. OVERVIEW OF DECENTRALIZATION PLAN ....................... 156 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ................................................................. 19 
Table 2: 
Vital Sign Assessment Outlier Thresholds .............................................. 92 
Table 3: 
Electrocardiogram Test Outlier Thresholds ............................................. 93 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
3-D 
3-dimensional 
5-HT 
Serotonin 
ABPM 
Ambulatory blood pressure monitoring 
ADHD 
Attention-deficit hyperactivity disorder 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase  
ANCOVA 
Analysis of covariance 
ANS 
Autonomic Nervous System 
ASP 
Autonomic Symptom Profile 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
bHCG  
Beta human chorionic gonadotropin 
BP 
Blood pressure 
BSFC-s 
Burden Scale for Family Caregivers - short version 
CFR 
(United States) Code of Federal Regulations 
Cmax 
The maximum concentration recorded 
CNS 
Central Nervous System 
COA 
Clinical Outcome Assessment 
COMPASS 
Composite Autonomic Symptom Score 
COMPASS-31 
Composite Autonomic Symptom Score-31 
CRF 
Case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
DHPG 
Dihydroxyphenylglycol 
DSM-IV-TR  
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessments (eCOA) 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ESC 
Enrollment Steering Committee 

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Abbreviation 
Description 
ET 
Early Termed/ Early Termination 
EQ VAS 
EQ Visual Analogue Scale 
EQ-5D-5L 
EuroQol-5D-5L 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FM 
Fibromyalgia 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HADS 
Hospital Anxiety and Depression Scale 
hERG 
Human ether-a-go-go-related gene 
Hgba1c 
Hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
IB 
Investigator's Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
intra-uterine devices 
MAD 
Multiple ascending dose 
MAO-I 
Monoamine oxidase inhibitor  
MAP 
Mean arterial pressure 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MMRM 
Mixed Model for Repeated Measures 
MoCA 
Montreal Cognitive Assessment 
MSA 
Multiple System Atrophy 
MSA-C 
MSA of the cerebellar subtype 
MSA-P 
MSA of the Parkinsonian subtype 
NE 
Norepinephrine 

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Abbreviation 
Description 
NET 
Norepinephrine transporter 
NMSS 
Non-motor Symptom Scale 
nOH 
Neurogenic Orthostatic Hypotension 
NOAEL 
No-observed-adverse-event level 
NRI 
Norepinephrine reuptake inhibitor 
NYHA 
New York Heart Association 
OATP1B3 
Organic anion transporting polypeptide 1B3 
OH 
Orthostatic Hypotension 
OHDAS 
Orthostatic Hypotension Daily Activity Scale 
OHQ 
Orthostatic Hypotension Questionnaire 
OHSA 
Orthostatic Hypotension Symptom Assessment 
OHSA#1 
Orthostatic Hypotension Symptom Assessment Question 1 
OL 
open label 
PAF 
Pure Autonomic Failure 
PBO 
placebo 
PD 
Parkinson’s disease  
PDQ-39 
Parkinson’s Disease Questionnaire-39 
PDQ-8 
Parkinson’s Disease Questionaire-8 
PGI-S 
Patient Global Impression of Severity 
P-gp 
p-glycoprotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PT  
Preferred term 
QD 
Daily 
QTcF 
Corrected QT interval using the Fridericia’s formula 
REB 
Research Ethics Board 
RR 
Respiratory rate 
RTSM 
Randomization and trial supply management 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SERT 
Serotonin Reuptake Transporter 

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Abbreviation 
Description 
symptomatic nOH 
Symptomatic Neurogenic Orthostatic Hypotension 
SNRI 
Serotonin norepinephrine reuptake inhibitor 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SUSARS 
Suspected unexpected serious adverse reaction 
t1/2 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TD-9855 
Laboratory code for ampreloxetine hydrochloride 
UKPDS 
United Kingdom Parkinson's Disease Society 
ULN 
Upper Limit of Normal 
UMSARS 
Unified Multiple System Atrophy Rating Scale 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US 
United States 
V1, V2, V3, etc. 
Study Visits 
 

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1. 
INTRODUCTION 
1.1. 
Background and Rationale 
In healthy individuals, changes in blood pressure (BP) are highly regulated and well 
controlled with systolic blood pressure (SBP) being transiently and minimally reduced upon 
standing. This is reflective of the normal physiological response in which neuronally 
mediated pathways remain intact, thereby maintaining the appropriate cerebral perfusion. 
Individuals with impaired compensatory mechanisms may develop orthostatic hypotension 
(OH), which reduces cerebral perfusion pressure and may lead to a sensation of 
lightheadedness, dizziness, or syncope, amongst other symptoms. In disorders with primary 
or secondary autonomic impairment, OH is accompanied by the profound reduction in or 
failure of norepinephrine (NE) neurotransmission and is said to be neurogenic in nature1. 
Disorders with prominent autonomic impairment include neurodegenerative diseases, such as 
Parkinson’s disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF). 
Common amongst these conditions are the reported loss of peripheral sympathetic nerves 
containing NE in PD and PAF patients, or the central mechanism controlling NE release 
becoming dysfunctional in patients with MSA. When neurogenic orthostatic hypotension 
(nOH) becomes symptomatic, the experienced sudden drop in BP can cause dizziness, visual 
problems, and fatigue, which greatly interfere with the daily activities of patients. This 
interference is highly debilitating and may cause severe injuries through frequent falling, 
leading to potential increases in disability and morbidity2,3. 
Recent developments in the understanding of the underlying pathophysiology of various 
clinical forms of autonomic failure have revealed that patients with MSA are characterized by 
impairment of central autonomic pathways crucial for autonomic cardiovascular control but 
have intact peripheral postganglionic noradrenergic fibers. This is evidenced by the near 
normal levels of circulating plasma NE in these patients, and by the observation that cardiac 
uptake of labeled catecholamines is intact4. This latter observation implies the presence of 
both intact noradrenergic nerve terminals and catecholamine reuptake mechanisms. Thus, 
patients with MSA have peripheral residual sympathetic tone that is no longer modulated by 
central autonomic centers and is not under baroreflex control, which cannot be harnessed to 
improve orthostatic hypotension. 
It is now recognized that the continual degeneration of dopaminergic neurons in the 
substantia nigra is preceded by the loss of non-dopaminergic neurons including NE neurons 
of the locus coeruleus in patients with PD. These losses ultimately result in the tremor, 
rigidity, akinesia, and postural instability associated with PD5,6. In the early stages of the 
disease, PD and MSA follow similar pathophysiology and may be difficult to distinguish 
clinically.  
Patients with PAF are also characterized by neurodegeneration and loss of peripheral 
noradrenergic fibers, as evidenced by lower levels of plasma NE and absent cardiac uptake of 
labeled catechols. However, the presence of residual sympathetic tone principally means that 
NE reuptake inhibition may serve as a useful treatment in this subset of both PAF and PD 
patients. 
Pharmacological inhibition of NE transporters (NET) may prove beneficial toward the 
treatment of primary autonomic disorders by permitting patients to take advantage of their 
own remaining residual sympathetic tone. Norepinephrine transport inhibition increases 
tonically released synaptic NE by preventing its reuptake, resulting in increased BP and relief 
from the symptomatic effects ensuing from critical falls in BP. This mechanism of action 

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(i.e., inhibition of NE uptake) may also offer an improved safety profile relative to other 
mechanisms of action, such as the addition of exogenous NE or NE prodrug. For example, 
published proof-of-concept studies indicate that the NET inhibitor atomoxetine is an effective 
pressor agent in these patients, and acutely improves standing SBP and symptoms of 
orthostatic intolerance7,8.  
TD-9855 (ampreloxetine hydrochloride), a new chemical entity, is a potent NE reuptake 
inhibitor (NRI) being developed for a range of medical treatments.  It has a high affinity for 
binding to NE and serotonin (5-HT) transporters and is designed to demonstrate selectivity 
for inhibition of NE versus 5-HT uptake. 
TD-9855 is orally bioavailable with pharmacokinetic (PK) properties supportive of once 
daily dosing. The safety and tolerability of TD-9855 have been demonstrated in a single 
ascending dose (SAD) study in healthy subjects at doses ranging from 2 to 50 mg and a 
multiple ascending dose (MAD) study in healthy subjects at daily doses of 4, 10, 20, and 
40 mg for up to 14 days. In healthy subjects, a single dose up to 50 mg and multiple doses up 
to 20 mg daily (QD) of TD-9855 were generally well tolerated. The PK of TD-9855 was 
linear with near dose proportional exposure in terms of Cmax and AUC across the anticipated 
therapeutic range. TD-9855 has an elimination half-life (t1/2) of approximately 30 to 40 hours 
achieving steady state by 6 days. Consistent with the elimination half-life, 3- to 4-fold 
accumulation of TD-9855 was observed at steady state. Based on clinical PK studies in 
healthy subjects, TD-9855 is >90% eliminated through metabolism and CYP1A2 is the 
primary enzyme driving TD-9855 metabolism. Accordingly, drug-drug interactions are 
expected with strong inhibitors and inducers of CYP1A2 impacting TD-9855 exposure. 
The safety, tolerability, and efficacy of TD-9855 were also evaluated in two Phase 2 studies 
including subjects with attention-deficit hyperactivity disorder (ADHD) and Fibromyalgia 
(FM). TD-9855 doses of 5 mg and 20 mg QD were administered for 6 weeks in both studies 
and was generally well tolerated with no clinically significant safety signals.  
Theravance conducted a study in adult subjects with primary autonomic failure (including 
MSA, PD, and PAF) in which TD-9855 was investigated for the treatment of symptomatic 
neurogenic orthostatic hypotension (symptomatic nOH). In the 0145 Study, TD-9855 was 
administered to subjects once daily in doses up to 20 mg for a duration of 20 weeks to 
evaluate the effect on symptoms of symptomatic nOH, pressor response, safety, and 
tolerability. 
1.2. 
Nonclinical Profile 
A review of the nonclinical profile of TD-9855 can be found in the current version of the 
TD-9855 Investigator’s Brochure (IB). The following is a brief summary of the pertinent 
findings. 
1.2.1. 
Nonclinical Pharmacology 
TD-9855 is a potent, dual inhibitor of NET and serotonin reuptake transporter (SERT) with 
higher in vitro potency for inhibition of NE (pIC50 = 8.6, IC50 = 2.5 nM) than 5-HT 
(pIC50 = 8.0, IC50 = 10.0 nM) uptake. TD-9855 exhibits selectivity for binding to NET and 
SERT over the dopamine transporter and various other transporter, receptor, ion channel, and 
enzyme targets tested. 
 
 

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In anesthetized rats, TD-9855 produced dose-dependent increases in mean arterial pressure 
(MAP) and heart rate (HR) in anesthetized rats. At doses that evoked cardiovascular effects, 
TD-9855 also produced dose-dependent and complete inhibition of tyramine-induced pressor 
responses, consistent with NET target engagement. 
1.2.2. 
Safety Pharmacology 
TD-9855 inhibits human ether-a-go-go-related gene (hERG) potassium channels with an IC50 
of 0.95 µM. The no-effect free concentration of TD-9855 in the canine Purkinje fiber assay is 
0.3 µM. Free concentrations ≥1 µM have effects consistent with multiple ion channel effects. 
An oral TD-9855 dose of 10 mg/kg resulted in increased BP, head tremors, and unsteady gait 
in dogs. The no-observed-adverse-event level (NOAEL) for these effects was 3 mg/kg.  
Behavioral effects in rats, characterized by increase in home cage arousal and decreased 
grooming behavior, were noted but were not considered adverse up to the highest dose tested, 
100 mg/kg, although adverse effects on body weight were noted in this study at 30 and 
100 mg/kg, with a NOAEL of 10 mg/kg. 
There were no adverse effects on respiratory function in rats at doses up to 100 mg/kg, the 
highest dose tested. 
1.2.3. 
Nonclinical Pharmacokinetics 
TD-9855 is orally bioavailable in rats (34.6%) and dogs (62.2%) and it penetrates the central 
nervous system (CNS). TD-9855 is not a p-glycoprotein (P-gp) substrate.  
TD-9855 is moderately bound to plasma proteins (69.1% to 96.5%) and exhibits preferential 
partitioning into whole blood. No metabolites unique to humans have been identified from in 
vitro and in vivo studies. TD-9855 is metabolized primarily by CYP1A2 prior to conjugation 
by Phase 2 enzymes. Extensive metabolism of TD-9855 is observed in rats and dogs. 
Excretion in rats and dogs is primarily via biliary excretion. 
TD-9855 exhibits weak or no inhibition of CYP450 enzymes (IC50 ≥6.6 μM). TD-9855 does 
not induce CYP450 enzymes. TD-9855 exhibits weak (IC50 >30 μM for organic anion 
transporting polypeptide 1B3 [OATP1B3]) or no inhibition of P-gp, breast cancer resistance 
protein, or OATP1B1. Accordingly, drug-drug interactions with TD-9855 due to inhibition of 
CYP450 metabolism or transporters are not anticipated in humans. Further information can 
be found in the TD-9855 IB. 
1.2.4. 
Toxicology 
The toxicity and toxicokinetic profile of TD-9855 has been characterized in a series of 
single- and repeated-dose exploratory dose-range studies. Good Laboratory Practice 
(GLP)-compliant studies of TD-9855 included single-dose oral and intravenous studies in rat, 
repeated-dose oral studies of up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in dogs, 
genetic toxicology studies, and assessments of fertility, embryo-fetal toxicity, and pre- and 
postnatal development.  
Findings of toxicological significance that were attributed to TD-9855 in toxicity studies 
included: 
• CNS effects (tremors, agitation, convulsions) with mortality at higher doses 
• Decreases in food consumption, body weight gain, and/or body weight 

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• Increased neonatal mortality and decreased rates of pup growth in the pre- and 
postnatal study in rats 
Further information can be found in the TD-9855 IB. 
1.3. 
Clinical Experience 
A description of the clinical profile of TD-9855 can be found in the TD-9855 IB. The 
following is a brief summary of the pertinent findings. 
To date, eight clinical studies have been completed with ampreloxetine. Five Phase 1 studies 
(0068, 0070, 0072, 0105, and 0172) were completed in healthy subjects. Three Phase 2 
studies (0085, 0092, and 0145) were completed in subjects diagnosed with ADHD, FM, and 
symptomatic nOH, respectively. One Phase 1 study (0179) is ongoing in subjects with 
hepatic impairment and data are not yet available.  
In the single-dose clinical study of healthy subjects (Study 0068), 40 subjects in 5 sequential 
cohorts were enrolled in the study, comprising a total of 10 subjects in the placebo group and 
30 subjects in the TD-9855 groups (6 subjects in each of the 5 dose groups: 2, 4, 8, 20, and 
50 mg). The most frequently reported TD-9855 treatment-related adverse events (AEs) were 
increased HR (3 subjects), dry mouth (2 subjects), and fatigue (2 subjects). Most AEs were 
mild, transient, and resolved spontaneously without sequelae.  
Following multiple dosing (Study 0070), the overall incidence of AEs was comparable 
between the placebo group and the TD-9855 dose groups up to 20 mg. The most common AE 
was dry mouth. The majority of AEs were assessed as mild in severity. Vital signs data at the 
TD-9855 40-mg dose indicate the possibility of drug-related orthostatic effects, including an 
increased frequency of transient asymptomatic OH. Orthostatic tachycardia was observed in 
all treatment groups including the placebo, but no dose-response trend was apparent. 
The single-dose study in healthy male subjects using positron emission tomography to assess 
TD-9855 NET and serotonin transporter (SERT) occupancy (Study 0072) showed greater 
NET occupancy than SERT binding. The NET binding varied in a dose-dependent fashion. 
The NET occupancy by TD-9855 increased in a plasma concentration–dependent manner 
over the tested dose range.  
The results of the two Phase 2 clinical studies indicate that TD-9855 is generally well 
tolerated in subjects with ADHD (Study 0085) or with FM (Study 0092). 
In Study 0085, a multicenter, randomized double-blind, parallel, placebo-controlled, 
proof-of-concept study, both the 5 mg and 20 mg TD-9855 doses taken for up to 6 weeks 
showed no clinically significant safety signals in 196 adult subjects with ADHD treated with 
TD-9855. Adverse events considered common and drug-related (i.e., reported in at least 5% 
of TD-9855 treated subjects at a rate at least twice that in the placebo group) included 
headache, dizziness (including postural dizziness), decreased appetite, and dry mouth. 
In Study 0092, a Phase 2, placebo-controlled, parallel group, 3-group, randomized study 
comparing a lower dose regimen and a higher dose regimen of TD-9855 with placebo for 
6 weeks in 255 adult subjects with FM treated with TD-9855, 2 serious adverse events 
(SAEs) were observed in the TD-9855 treatment groups: 1 SAE of neurological symptoms in 
the 5-mg TD-9855 treatment group was considered possibly treatment related, and 1 SAE of 
supraventricular tachycardia in the 20-mg TD-9855 treatment group was judged not related to 
study treatment. In the 20-mg TD-9855 treatment group, the most common treatment-
emergent adverse events (TEAEs) were headache, nausea and constipation. These safety 

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findings are consistent with those observed following TD-9855 administration in Phase 1 
studies. 
In Study 0145, a multicenter, randomized, 3 parts, single-blind (Part A), double-blind, 
placebo-controlled (Part B), and open-label multiple dose extension (Part C) study of 
TD-9855 in subjects with symptomatic nOH is now completed with 34 subjects in Part A, 
10 subjects in Part B, and 21 subjects in Part C.  
Part A evaluated the dose response of single, ascending doses up to 20 mg. Although no dose 
response was observed, a numerical trend in increased seated and standing SBP was observed 
at the higher doses. An improvement in standing time of approximately 100 seconds was 
observed at 4 hours after dosing at 10 mg.   
Part B Subjects were treated with TD-9855 (up to 15 mg) and demonstrated a sustained 
increase of greater than ~20 mmHg in SBP over baseline following 3 minutes of standing at 
4- and 7-hours post-dose. No such increase in SBP was observed in placebo-treated subjects.  
Part C evaluated durability of response, safety, and tolerability of TD-9855 in a 24-week 
open-label phase 2 multicenter study of subjects with nOH. Subjects were treated with oral 
ampreloxetine (3-20 mg) once-daily for ≤20 weeks with 4-week follow-up after treatment 
withdrawal (week 24). Primary efficacy endpoint OHSA#1 (improvement from baseline in 
the Likert scale [“dizziness, lightheadedness, feeling faint, or feeling like you might black 
out”]) was assessed at week 4; durability at week 20; and follow-up at week 24. A large 
proportion of subjects, 48% of the ITT population and 63% of Day 29 completers, met this 
endpoint. The mean improvement for subjects completing Day 29 was 2.4 points. Greater 
reductions were observed in subjects having a baseline score of > 4 at baseline (mean 
reduction of 3.8 points in 76.9% of responders). Similar trends in improvement were 
observed in OHSA and OHDAS composite scores. Twenty-one subjects enrolled in the 
open-label phase (mean age, 64 years; 57% multiple-system atrophy). Sixteen (76%), 
11 (52%), and 10 (48%) subjects completed assessments at weeks 4, 20, and 24, respectively. 
Mean (SD) improvement from baseline in OHSA#1 was 2.4 (4.5), 1.9 (3.1), and -0.5 (2.7) for 
all subjects, and 3.8 (3.1), 3.1 (3.0), and 0.3 (1.9), for symptomatic subjects (OHSA#1 >4 at 
baseline) at weeks 4, 20, and 24, respectively. Similar trends in improvement were observed 
in OHSA and OHDAS composite scores.  
Ampreloxetine resulted in a mean increase in standing SBP at all visits and all time points 
including post treatment. On Day 29, at 3 minutes standing, the mean increase from baseline 
was ≥7 mm Hg; the mean increase was ≥20 mm Hg at visits after Day 29. At Day 29, a large 
proportion of subjects (64% to 77%) maintained an SBP of ≥ 80 mmHg after standing for 
3 minutes. Consistent responses in both seated and standing SBP increases were observed.  
Ampreloxetine was administered at up to 20-mg doses to 21 subjects with symptomatic nOH 
for up to 20 weeks in Part C of the study. Ampreloxetine was well tolerated in this study with 
no deaths. A total of 6 SAEs (4 preferred terms), unrelated to treatment (23.8%), were 
observed in 5 subjects (all in Part C). These SAEs were urinary tract infection in 3 subjects; 
and jaw fracture, pain in extremity, and meniscus injury in 1 subject each.  
Overall, of the 34 subjects dosed in the study, 3 subjects discontinued study drug due to 
TEAEs: 1 in Part A (TEAE of visual hallucination of moderate severity considered 
possibly/probably related to study drug); and 2 in Part C (SAE of jaw fracture considered 
unrelated to study drug and TEAE of headache of moderate severity considered 
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The most frequently reported drug-related TEAEs were headache in 4 subjects (2 each in 
Part A and Part C) and hypertension in 2 subjects (Part C). 
The most frequently reported TEAEs in the study were urinary tract infection (2 subjects who 
received TD-9855 vs. 1 subject who received placebo in Part A, 1 subject who received 
TD-9855 in Part B, and 5 subjects in Part C); and headache (4 subjects who received 
TD-9855 vs. 2 subjects who received placebo in Part A, and 3 subjects in Part C).  
The study did not reveal any new safety signals of potential concern. 
Overall, ampreloxetine has exhibited an acceptable safety and tolerability profile in the 
Phase 1 and Phase 2 clinical programs to date. Common AEs were typically associated with 
the drug’s noradrenergic mechanism of action and occurred at rates comparable to those of 
other marketed SNRI drugs. 
1.3.1. 
Clinical Pharmacokinetics 
TD-9855 is orally bioavailable with PK properties supportive of once daily dosing. The PK 
profile of TD-9855 has been measured in a SAD study in healthy subjects at doses ranging 
from 2 to 50 mg and a MAD study in healthy subjects at daily doses of 4, 10, 20, and 40 mg 
for up to 14 days. The PK of TD-9855 was linear with near dose proportional exposure in 
terms of Cmax and AUC across the anticipated therapeutic range. TD-9855 has a t1/2 of 
approximately 30 to 40 hours, achieving steady state by 6 days. Consistent with the t1/2, 3- to 
4-fold accumulation of TD-9855 was observed at steady state. Based on clinical PK studies in 
healthy subjects, TD-9855 is >90% eliminated through metabolism, and CYP1A2 is the 
primary enzyme driving TD-9855 metabolism. Accordingly, drug-drug interactions are 
expected with strong inhibitors and inducers of CYP1A2 impacting TD-9855 exposure. 
Further information can be found in the TD-9855 IB. 
1.4. 
Risks and Benefits 
Results from preclinical and clinical studies indicate that TD-9855 is a potent inhibitor of 
NET with modest selectivity for NET over SERT. These studies demonstrated a moderate 
increase in HR and BP, suggesting that TD-9855 has the potential to provide a novel 
treatment option for symptomatic nOH. 
While it is not known whether TD-9855 will provide clinical efficacy, this study will provide 
a number of beneficial services to subjects. These include autonomic evaluations, 
neurohumoral evaluation, and information on new research developments in the field. 
Subjects will have access to routine autonomic follow up that may improve orthostatic 
symptoms. They will have symptom rating testing performed that may assist in educational 
planning. 
During the conduct of the TD-9855 clinical development program, the following have been 
recognized as important potential risks, with none characterized as identified risks associated 
with the administration of TD-9855: 
• Increase in HR 
• Increase in BP 
• Syncope 

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Possible risks to subjects participating in this study include AEs associated with other 
serotonin norepinephrine reuptake inhibitors (SNRIs), such as nausea, dry mouth, headache, 
dizziness, somnolence, fatigue, diarrhea, insomnia, vomiting, syncope, seizures, constipation, 
hyponatremia, hyperhidrosis, urinary retention, and decrease appetite. 
Furthermore, subjects may experience adverse effects as a result of study procedures, such as 
repeated blood sampling and associated procedures. 
To help ensure subject safety, subjects will be closely monitored during this study. Study 
visits except for the Screening visit (S) for De Novo group subjects which must be conducted 
in the clinic, study visits can be conducted in the Investigator’s autonomic disorders clinic or 
appropriately qualified research facility, or remotely using a telemedicine platform, under the 
supervision of qualified site personnel with help from a home health care provider.  
The schedule of procedures requires subjects to be closely monitored on a regular basis 
during the dosing and follow-up periods. If any subject should incur any unexpected and 
untoward event during the testing procedure, the Investigator is instructed to provide the 
subject immediate and appropriate care as needed including unscheduled in clinic or remote 
visits.  
A summary of known and potential risks to human subjects is provided in the IB in the 
Summary of Data and Guidance for the Investigators. 

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2. 
OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is: 
• To evaluate the durability of effect of TD-9855 in subjects with symptomatic 
neurogenic orthostatic hypotension (symptomatic nOH) due to multiple system 
atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) 
compared with placebo (PBO) over a double-blind, randomized withdrawal period 
of 6 weeks following an open label (OL) treatment of 16 weeks.  
• To evaluate the safety and tolerability of TD-9855 when taken for up to 22 weeks. 
2.2. 
Secondary and Other Objectives 
The secondary objective(s) of the study (during the 6-week randomized withdrawal period) 
are as follows: 
Key secondary objectives: 
• To evaluate the durability of effect of TD-9855 by symptom and activity 
assessments using Orthostatic Hypotension Symptom Assessment (OHSA) and 
Orthostatic Hypotension Daily Activity Scale (OHDAS). 
• To evaluate subject’s symptomatic improvement as measured by a wearable 
device. 
The exploratory objectives of the study are: 
• To evaluate the effect of TD-9855 using disease-specific instruments and generic 
quality of life assessment. 
• To evaluate the effect of TD-9855 using standing blood pressure during 
orthostatic standing test. 
• To evaluate the effect of TD-9855 using generic quality of life assessment 
EuroQol-5D-5L (EQ-5D-5L), Non-Motor Symptom Scale (NMSS), and Hospital 
Anxiety and Depression Scale (HADS). 
• To evaluate pharmacodynamic markers (NE and dihydroxyphenylglycol 
[DHPG]).  
• To inform population PK modeling through collection of sparse PK samples. 
• To assess caregiver burden in caring for subjects with primary autonomic failure 
using Burden Scale for Family Caregivers - short version (BSFC-s). 

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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a Phase 3, multi-center, randomized withdrawal study to evaluate the sustained benefit 
in efficacy and safety of TD-9855 in subjects with primary autonomic failures (MSA, PD, or 
PAF) and symptomatic nOH after 22 weeks of treatment.  Given the challenges presented by 
the COVID-19 pandemic the trial utilizes an operational design featuring the ability to 
conduct protocol required visits as either in clinic or remote visits. Investigators, in 
discussion with each individual subject at their site, will be required to elect to conduct visits 
either in the clinic or remotely. Sites must conduct the randomization withdrawal visits 
6 through 9 (V6/D113 - V9/D155) for a given subject in a consistent manner to reduce the 
possibility of variability in data collection and reporting. Tools and systems are available to 
sites and subjects to support remote visits (e.g., direct to subject shipping of study medication 
and other study supplies, standardized HIPAA/GDPR compliant telemedicine platform, 
in-home health nurses).  
 
Due to the potential for resurgence of COVID-19 and its impact on both sites and subjects, 
the Sponsor will allow Investigators to request exceptions to the selected type of study visit 
modality for V6/D113 through V9/D155 due to COVID-19 or COVID-19 related 
circumstances. Approved exceptions will be recorded as COVID-19 related protocol 
deviations. 
All sites are allowed at Investigator discretion to conduct either in clinic or remote 
unscheduled visit(s) for subject safety or unexpected subject medical needs outside of the 
regular visit schedule.  In this case, unscheduled visits are not considered protocol deviations 
and the Investigator is not required to obtain pre-approval from the Sponsor. Data collected 
during these visits may include any protocol-specified assessments which will be captured in 
the clinical database. 
For De Novo subjects that have previously completed the Screening visit at the time 
regulatory and ethics approval for Amendment 4 is received, sites must reconsent the subject 
using the most recently approved version of the Informed Consent Form to obtain subject 
consent for remote study visits, if that modality is selected by the Investigator and 

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subject. For those subjects who are already randomized into the randomized withdrawal 
portion of Study 0170 and active in the study at the time regulatory and ethics approval for 
Amendment 4 is received, the Investigator and subject should continue the remaining study 
visits in the same visit modality as the Randomization Visit (V6/D113). 
Refer to Appendix 9 and the Study Reference Manual for detailed instructions for conducting 
subject assessments in clinic and remotely. These instructions have been provided to ensure 
the method and conduct of each assessment is consistent across sites and subjects for both in 
clinic and remote visits. 
Eligible subjects are either (i) completers of Study 0169 (0169 Completers Group), or 
(ii) symptomatic nOH subjects meeting all applicable study inclusion criteria and none of the 
applicable exclusion criteria (De Novo Group). 
Symptomatic neurogenic orthostatic hypotension is defined as: 
• A sustained reduction of BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) 
within 3 minutes of standing or tilted-up to ≥60o elevation from a supine position. 
• A score of at least a 4 on the Orthostatic Hypotension Symptom Assessment 
Question #1 
The study consists of 3 periods: (i) 16-week open-label (OL) treatment with TD-9855, 
(ii) 6-week randomized placebo-controlled treatment, and (iii) 2-week follow-up (only for 
patients who do not enroll in Study 0171). A 4-week screening period will apply to the 
De Novo Group only and the Screening visit must be conducted in clinic for ALL De Novo 
group subjects. The schematic representation is as shown below: 
 
 
 
 

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Subjects entering from Study 0169 (0169 Completers Group) 
Following signing of the informed consent, subjects will enter Study 0170 Visit 1 (V1), 
which will be conducted on the same day as V6 / D29 of Study 0169 of Study 0169. The visit 
modality for 0170, either in-clinic or remote for each subject, for a given subject should be 
consistent with the modality selected by the subject for study 0169.  
Study 0169 procedures conducted at V6 will serve as the baseline assessments for V1 of 
Study 0170. 
Beginning on Day 2, subjects will receive a single dose of 10-mg TD-9855 once daily (QD) 
and continue thereafter for the 16-week duration of the OL treatment period. Following this 
16-week OL treatment period, subjects will be randomized to either continue on the active 
treatment or PBO for a period of 6 weeks. 
Subjects not participating in Study 0169 (De Novo Group)  
Following signing informed consent, subjects will enter a screening period of up to 4 weeks 
to confirm eligibility. At the Screening visit (Visit S), which must be performed in the clinic, 
subjects will provide a comprehensive medical history of their disease and treatments. The 
subjects’ disease will be characterized and documented by the principal Investigator (PI) or 
sub-Investigator. 
Subjects will receive an assessment of their physical condition, including safety and 
laboratory evaluations and related aspects of their disease states according to the Schedule of 
Study Procedures. The presence of symptomatic nOH must be confirmed using a tilt-table 
test. 
Eligible subjects will undergo training of accurate scoring of their sensation of dizziness, 
lightheadedness, feeling faint, or feeling like blacking out, as outlined by Orthostatic 
Hypotension Symptom Assessment Question 1 (OHSA#1). 
Following the screening period, subjects will proceed to V1 to further confirm the additional 
eligibility criteria prior to proceeding. This includes the completion of the Orthostatic 
Hypotension Questionnaire (OHQ) in which a minimum score of 4 points in OHSA#1 is 
required.  
Subjects meeting all inclusion criteria, none of the exclusion criteria, and whose disease 
characterization is confirmed by the independent Enrollment Steering Committee (ESC) 
(see Section 3.5.3, also separate charter will be available), will receive TD-9855 in the OL 
period. 
Beginning on Day 2, subjects will receive a single dose of 10-mg TD-9855 once daily (QD) 
and continue thereafter for the 16-week duration of the OL treatment period. Following this 
16-week OL treatment period, subjects will be randomized to either continue on the active 
treatment or PBO for a period of 6 weeks. 
Open Label Period (Weeks 1 to 16) 
Subjects enrolled into the OL period of the study will have visits scheduled for Day 15, 
Day 29, and every 4 weeks thereafter for assessments as outlined in the Schedule of Study 
Procedures. At V3 (Week 4), following the initial 4-week OL treatment, subjects must 
demonstrate a reduction in OHSA#1 of at least 2 points compared to the baseline value, as 
determined in Study 0169 for subjects entering from Study 0169 and from V1 for de novo 
subjects, in order to continue in Study 0170. Those subjects not meeting this continuation 

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criterion must be discontinued and undergo an end of study visit. The end of study visit must 
be completed within 2 weeks from the date of the last dose. 
All subjects completing the initial 4-week OL treatment period and meeting the continuation 
criterion will continue receiving open label TD-9855 tablets for 12 additional weeks 
(16 weeks total). 
Double-blind Period (Weeks 17 to 22) 
Following the completion of a total of 16 weeks OL treatment with TD-9855 (V6) subjects 
will be assessed for randomization in a 1:1 manner. Eligible subjects will receive 6 weeks of 
double-blind treatment of TD-9855 or PBO once daily. Only subjects with OHSA#1 score of 
≤7 will be eligible for randomization for the double-blind treatment period.  
Treatment period (Weeks 1 to 22): 
No dose reduction is permitted during the treatment period.  
Subjects unable to tolerate 10-mg TD-9855 will be discontinued from the study. 
At any time during the study, if a subject meets at least one of the following stopping rules, 
they should be discontinued and undergo an end of study visit: 
• A determination from the PI that further administration of the investigational 
product may pose a safety concern to the subject 
• Sustained (at least 4 hours) SBP ≥180 mmHg or diastolic BP (DBP) ≥110 mmHg 
after 3 min of standing or after 5 mins in the sitting position, or a sustained (at 
least 4 hours) SBP ≥180 mmHg or DBP ≥110 mmHg measured in the supine state 
(head/torso elevated at approximately 30o from horizontal position).  
• Intolerable AE, as determined by the PI 
• Subject becomes pregnant 
Safety assessments will include a physical examination, neurological examination, vital signs 
(body temperature, HR, respiratory rate [RR], and BP), body weight, 12-lead 
electrocardiograms (ECGs, laboratory tests (hematology, chemistry, and urinalysis), 
Columbia Suicide Severity Rating Scale (C-SSRS) and monitoring of AEs.  
Safety will be periodically reviewed by an Independent Data Monitoring Committee (IDMC); 
see separate charter. 
Subjects will be requested to refrain from making any significant dietary changes throughout 
the duration of the study. During their scheduled visits, subjects should be reminded to 
maintain an adequate fluid intake.  
Subjects completing the 6-week double-blind treatment period will be eligible to continue 
into the OL, long term safety study (Study 0171). Those subjects who do not complete the 
6-week double-blind treatment period or who choose not to continue into Study 0171 will 
complete the Early Termination Visit (V9) or Follow-up visit (V10), respectively. The 
Follow-Up Visit must be completed 2 weeks from the date of the last dose. 

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3.2. 
Rationale for Study Design 
Utilizing a randomized withdrawal following a predefined open label period, this study is 
designed to evaluate worsening from baseline in the OHSA#1 score of 1.0 point and a 
worsening of disease severity as assessed by a 1-point change in Patient Global Impression of 
Severity (PGI-S), in subjects with symptomatic nOH with a primary diagnosis of MSA, PD, 
or PAF following 6 weeks of daily treatment with TD-9855 at a dose of 10-mg compared to 
placebo. OHSA#1 is the validated primary efficacy endpoint in this patient population. The 
inclusion of PGI-S with OHSA#1 further exemplifies the patient-centric assessments thereby 
refining the treatment failure criteria. Prior to the randomized withdrawal phase of the study, 
all eligible subjects will receive OL TD-9855 for a period of 16 weeks. The OL period is 
designed to capture durability of effect following long-term TD-9855 administration. This 
durability of effect is confirmed through the subsequent randomized withdrawal period. 
The eligibility criteria are designed to adequately characterize these subjects and will include 
confirmation from an ESC (committee of independent neurologists) to determine the 
appropriateness of each subject for study inclusion. Prespecified population and PK and 
pharmacodynamic sampling will be used to further profile TD-9855 and the relationship 
between plasma exposure and TD-9855 efficacy. A dedicated charter outlining the procedure 
will include the details needed on the ESC form, a timeline for review, and the decision 
conveyed. In addition, an IDMC comprised of independent key opinion leaders, potentially 
from the field of neurology, cardiology, dysautonomia, and biostatistics, will evaluate the 
safety of TD-9855, with a dedicated charter outlining Study 0170 assessments at planned 
time points. Prespecified safety endpoints and measurements have been selected based upon 
their known relevance to a patient population that has been diagnosed with MSA, PD or PAF. 
Subjects that complete Study 0170 will be eligible to participate in Study 0171, which is 
designed to evaluate the long-term safety of TD-9855 in a 6-month OL design. 
3.3. 
Selection of Dose and Duration of Treatment 
TD-9855 has been previously investigated in FM and ADHD at doses up to 20 mg QD. 
TD-9855 was also investigated in a study in patients with nOH. Study 0145 was conducted in 
three parts including Part A (exploratory), Part B (proof-of-concept), and Part C (ongoing OL 
extension) to determine if TD-9855 improves the acute pressor response and OHSA#1, 
respectively. OHSA#1 is a measure of dizziness, lightheadedness, feeling faint, or the 
sensation of being about to black out. 
Part A evaluated the dose response of single, ascending doses up to 20 mg. Although no dose 
response was observed, a numerical trend in increased seated and standing SBP was observed 
at the higher doses. An improvement in standing time of approximately 100 seconds was 
observed at 4 hours after dosing at 10 mg.  
In Part B, subjects treated with TD-9855 (single dose up to 15 mg) demonstrated a sustained 
increase of approximately 20 mmHg in SBP over baseline following 3 minutes of standing at 
4, 7, and 9 hours post-dose. No such increase in SBP was observed in placebo-treated 
subjects.  
Part C evaluated durability of response, safety, and tolerability of TD-9855 over 20 weeks in 
an open label extension design. Top line results of interim data available for the first 4 weeks 
of the study (through Day 29) demonstrate durable improvements in subjects' disease 
symptom severity after treatment with TD-9855, as measured by OHSA #1.  

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Subjects demonstrated a mean symptom improvement of 2.4 points from baseline at four 
weeks. Importantly, mean symptom improvement from baseline was greatest (3.8 points) in 
nOH subjects who reported dizziness symptoms (OHSA#1 > 4) at baseline. Additionally, 
TD-9855 consistently increased systolic blood pressure (SBP), including clinically 
meaningful increases in standing SBP at the 3-minute assessment at all time points up to 
Day 29. There were no drug-related SAEs reported, and TD-9855 was generally well 
tolerated in the study. Per interim data from the first 4 weeks of Part C of Study 0145, the 
majority of subjects received TD-9855 10-mg QD.  
Based on the results of the human positron-emission tomography study in healthy volunteers, 
the estimated IC50 of TD-9855 for NET inhibition is 1.21 ng/mL. Accordingly, based on the 
population PK-pharmacodynamic model for TD-9855 in healthy and diseased subjects, 
10-mg dose of TD-9855 is expected to achieve >80% NET inhibition in a majority of 
subjects. Thus, 10-mg dose of TD-9855 is considered adequate to achieve the desired 
pharmacological and clinical effect while minimizing the risk for safety concerns in subjects 
with symptomatic nOH. 
3.4. 
Study Endpoints 
3.4.1. 
Primary Endpoint 
The primary study endpoint is the proportion of treatment failure at Week 6 during the 
double-blind randomized withdrawal phase. Treatment failure is defined as subjects who 
meet the following criteria at Week 6 following randomization (V9, D155): 
Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening 
of disease severity as assessed by a 1-point change in PGI-S. 
The assessments done at the Week 16 (V6, D113) visit in the OL phase prior to 
randomization are considered baseline for the double-blind randomized withdrawal phase of 
the study.  Subjects who withdraw for any reason prior to V9 (D155) or subjects who fail to 
provide assessment at V9 (D155) will be considered as treatment failures. 
3.4.2. 
Secondary Endpoints 
The secondary endpoints include: 
• Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155) 
• Change from baseline in OHSA composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHDAS composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in PGI-S at Week 6 post randomization (V9, D155) 
• Change from baseline in percent of time spent in standing position as measured by 
a wearable device at Week 6 post randomization (V9, D155) 
• Change from baseline in average number of steps taken as measured by a 
wearable device at Week 6 post randomization (V9, D155) 

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3.4.3. 
Safety and Tolerability Endpoint 
The safety and tolerability endpoints include: 
• Physical examination 
• Neurological examination 
• Vital signs including ambulatory BP 
• Resting ECGs 
• Clinical laboratory tests, including biochemistry, hematology, urinalysis 
• Concomitant medication  
• AEs 
• C-SSRS 
3.4.4. 
Exploratory Endpoints 
Exploratory endpoints include: 
• Standing SBP during orthostatic standing test at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHQ overall composite score at Week 6 post 
randomization (V9, D155) 
• Change from baseline in EQ-5D-5L at Week 6 post randomization (V9, D155) 
• NMSS at Week 6 post randomization (V9, D155) 
• HADS at Week 6 post randomization (V9, D155) 
• BSFC-s at Week 6 post randomization (V9, D155)  
• PK and pharmacodynamic parameters 
For subjects with PD 
• Change from baseline in UPDRS at Week 6 post randomization (V9, D155) 
• Change from baseline in PDQ-8 at Week 6 post randomization (V9, D155) 
For subjects with MSA 
• Change from baseline in UMSARS at Week 6 post randomization (V9, D155) 
• Change from baseline in COMPASS-31 at Week 6 post randomization (V9, 
D155) 
3.5. 
Minimization of Bias 
This is a randomized withdrawal study, including an OL and a placebo controlled 
double-blind randomized withdrawal phases. Treatments will be assigned centrally using a 
randomization and trial supply management (RTSM) system. 
All persons involved in this study (i.e., physicians, nurses, participants, and site monitors) 
will remain blinded to study treatment during the randomized withdrawal period, except in 
the event of a medical emergency as outlined in Section 3.5.1. 

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3.5.1. 
Blinding 
This section is only applicable to the randomized withdrawal part of the study. 
TD-9855 and placebo tablets will be of the same shape, size, and color to ensure that the 
blind is maintained. Also, subjects who are randomized to receive placebo will receive the 
equivalent number of tablets as those randomized to receive TD-9855.  
A subject’s treatment assignment will only be unblinded when knowledge of the treatment is 
essential for the further clinical management of the subject on this study. Unblinding at the 
study site for any other reason will be considered a protocol deviation. In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
subject’s treatment assignment is warranted. Subject safety must always be the first 
consideration in making such a determination. Any Investigator unblinding will be 
documented within the appropriate case report form (CRF) and will be captured in the RTSM 
system. 
Sponsor Drug Safety personnel may independently unblind cases for expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs). With these exceptions, sponsor 
personnel involved in the conduct of the study, data cleaning, or data analysis will remain 
blinded to subject treatment assignments until the database has been locked for final analysis.  
3.5.2. 
Treatment Assignment 
Once the subject has been determined to be eligible to receive study treatment in the OL part 
of the study, the PI or their delegate will use the RTSM system to provide TD-9855 to the 
subject and dispense study medication accordingly.  
Once the subject has been determined to be eligible to receive study treatment in the 
randomized withdrawal part of the study, the PI or their delegate will use the RTSM system 
to randomize the subject and dispense study medication accordingly. Except for cases of 
emergency unblinding as described above, investigational site staff will remain blinded to 
treatment assignments until all subjects have completed the study and the database has been 
locked.  
Further details regarding the randomization procedure and dose assignment will be outlined 
in the RTSM system manual. 

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3.5.3. 
Enrollment Steering Committee (for De Novo Group only) 
The Investigator must obtain approval from the ESC prior to randomizing the subject in the 
study.  The ESC is a committee of independent neurologists that will make a 
predetermination of the subject’s appropriateness for study inclusion by reviewing medical 
information provided by the site. The ESC will review both the medical history to support the 
diagnosis (MSA, PD, or PAF), and confirm the presence of symptomatic nOH based on the 
results of the tilt-table test. Review of the tilt-table test results may include confirmation that 
the subject maintains a sustained fall in blood pressure to a level that is consistent with 
cerebral hypoperfusion. The ESC will consult with the Investigator to address any 
outstanding questions. The ESC review is recommended to be completed within 48 hours and 
the Investigator will be informed in writing (e.g., by e-mail) of the decision. Following ESC 
approval of the subject, the Investigator will determine eligibility based upon the protocol 
Inclusion and Exclusion criteria for randomization. In cases where the ESC determines 
subject ineligibility based on tilt-table test findings that are not consistent with symptomatic 
neurogenic orthostatic hypotension, the decision will be accompanied by rationale. A 
dedicated charter has been implemented to address the mode of operations of the ESC to 
ensure the protection of the study integrity. The communication from the ESC, documenting 
review and approval of the subject, will serve as ESC documentation for inclusion into the 
study. 

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4. 
STUDY POPULATION 
This study will enroll adult subjects with confirmed symptomatic nOH due to MSA, PD, or 
PAF and who meet all of the applicable inclusion criteria and none of the applicable 
exclusion criteria defined below. 
4.1. Inclusion Criteria 
A subject who meets the following applicable criteria will be eligible for study enrollment: 
Inclusion Criteria (For 0169 Completers Group): 
101. 
Completion of 4 weeks of double-blind treatment in Study 0169 (V6) and, in the 
opinion of the Investigator, could benefit from continued treatment with TD-9855. 
No minimum score of OHSA#1 is required to enter V1 of Study 0170. 
102. 
The subject has a minimum of 80% study medication compliance in Study 0169. 
103. 
The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study procedures (including an 
understanding that entry to Study 0170 may result in changes occurring in the 
subject’s current therapeutic regimen). 
104. 
The subject must be willing to continue on treatment regardless of the possibility of 
randomization to either TD-9855 or PBO during the randomized withdrawal phase 
and must continue to meet the inclusion criteria for the preceding study (Study 0169) 
with the exception that tilt-table test, ESC review and approval of eligibility are not 
required for entry into Study 0170. 
Inclusion Criteria (For De Novo Group): 
1. Subject is male or female and at least 30 years old. 
2. If subject is female, the subject must be non-pregnant and non-lactating. A woman of 
childbearing potential must have a documented negative pregnancy test at screening. 
NOTE: A woman is considered to be of childbearing potential unless she is 
postmenopausal (amenorrheic for at least 2 years) or documented to be surgically 
sterile (bilateral tubal ligation or total hysterectomy). A female subject may be 
admitted to the study on the basis of a negative urine pregnancy test. If the urine beta 
human chorionic gonadotropin (bHCG) test is positive, a serum bHCG test must be 
performed. The pregnancy test must be confirmed negative for a subject to be eligible 
for this study. 
3. During the study and for 30 days after receiving the last dose of the study drug, 
females of childbearing potential or males capable of fathering children must agree to 
use highly effective birth control measures (failure rate <1% when used consistently 
and correctly) or agree to abstain from sexual intercourse. (Refer to Section 4.3). 
4. Subject must meet the diagnostic criteria of nOH, as demonstrated by a sustained 
reduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) within 3 min of 
being tilted-up ≥60o from a supine position as determined by a tilt-table test. 
5. Subject must score at least a 4 on the OHSA#1 at V1. 
6. For subjects with PD only: Subject has a diagnosis of PD according to the United 
Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria (1992). 

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7. For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of 
the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The 
Gilman Criteria (2008). 
8. For subjects with PAF only: Subject has documented impaired autonomic reflexes, 
including the Valsalva maneuver performed within 24 months from the date of 
randomization. 
9. Subject has plasma NE levels ≥ 100 pg/mL after being in seated position for 
30 minutes. 
10. Subject is willing and able to provide signed and dated written informed consent to 
participate prior to initiation of any study related procedures. 
11. Subject is able to communicate well with the Investigator and understand clinic staff, 
understands the expectations of the study and is able to comply with the study 
procedures, requirements, and restrictions. 
4.2. 
Exclusion Criteria 
A subject who meets any of the following applicable criteria is not eligible for study 
enrollment: 
Exclusion Criteria (For 0169 Completers Group): 
101. Subject may not be enrolled in another clinical trial (other than exiting Study 0169). 
102. Subject has psychiatric, neurological, or behavioral disorders that may interfere with 
the ability of subjects to give informed consent or interfere with the conduct of the 
study. 
103. Medical, laboratory, or surgical issues deemed by the Investigator to be clinically 
significant. 
104. Uncooperative attitude or reasonable likelihood of non-compliance with the protocol. 
105. Subject has a concurrent disease or condition that, in the opinion of the Investigator, 
would confound or interfere with study participation or evaluation of safety, 
tolerability, or pharmacokinetics of the study drug. 
Exclusion Criteria (For De Novo Group): 
1. Subject has a known systemic illness known to produce autonomic neuropathy, 
including, but not limited to, amyloidosis and autoimmune neuropathies.  Subject has 
diabetes mellitus and diagnosis of PAF. Subject with diabetes mellitus and either 
MSA or PD, will be evaluated on a case by case basis by the medical monitor and 
considered ineligible unless they meet all of the following criteria: 
a. Well controlled type-2 DM in treatment with only oral medications and diet  
b. HgbA1C of ≤7.5% performed during screening or up to 12 weeks before 
screening 
c. No clinically evident peripheral neuropathy (e.g., normal sensory examination on 
peripheral extremities) 
d. No known retinopathy (e.g., annual ophthalmic exam is sufficient)  
e. No nephropathy (e.g., absence of albuminuria and GFR >60) 

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2. Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake 
inhibitors (SNRIs). 
3. Subject currently uses concomitant antihypertensive medication for the treatment of 
essential hypertension. 
4. Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, 
whichever is longer, prior to V1 or requires concomitant use until the follow-up visit. 
5. Subject has changed dose, frequency, or type of prescribed medication for orthostatic 
hypotension within 7 days prior to V1.  
• Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior 
to V1. 
6. Subject has known or suspected alcohol or substance abuse within the past 12 months 
(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision [DSM-IV-TR®] definition of alcohol or substance abuse). 
7. Subject has a clinically unstable coronary artery disease or has had a major 
cardiovascular or neurological event in the past 6 months. 
8. Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to 
V1. 
9. Subject has a history of untreated closed angle glaucoma, or treated closed angle 
glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk 
to the subject. 
10. Subject has any significant uncontrolled cardiac arrhythmia. 
11. Subject has a Montreal Cognitive Assessment (MoCA) ≤23. 
12. Subject is unable or unwilling to complete all protocol specified procedures including 
questionnaires. 
13. Subject had a myocardial infarction in the past 6 months or has current unstable 
angina. 
14. Subject has known congestive heart failure (New York Heart Association [NYHA] 
Class 3 or 4). 
15. Subject has had any malignant disease, other than carcinoma in situ of the cervix or 
basal cell carcinoma, within the past 2 years prior to screening. 
16. Subject has a known gastrointestinal (GI) condition, which in the Investigator’s 
judgment, may affect the absorption of study medication (e.g., ulcerative colitis, 
gastric bypass). 
17. Subject has psychiatric, neurological, or behavioral disorders that may interfere with 
the ability of the subject to give informed consent or interfere with the conduct of the 
study. 
18. Subject is currently receiving any investigational drug or has received an 
investigational drug within 30 days of dosing. An investigational drug is defined as 
drug that is not approved by a regulatory agency (e.g., Food and Drug Administration 
[FDA]). 

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19. Subject has a clinically significant abnormal laboratory finding (e.g., alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST] >3.0 x upper limit of 
normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration rate 
(eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could interfere 
with safety of the subject). 
20. Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal 
behavior, as outlined by the C-SSRS (Baseline/Screening Version). Subject should be 
assessed by the rater for risk of suicide and the subject’s appropriateness for inclusion 
in the study.  
21. Subject has a concurrent disease or condition that, in the opinion of the Investigator, 
would confound or interfere with study participation or evaluation of safety, 
tolerability, or pharmacokinetics of the study drug. 
22. Subject has known hypersensitivity to TD-9855 (ampreloxetine hydrochloride), or 
any excipients in the formulation. 
23. Subject has (i) confirmed severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) documented with coronavirus disease 2019 [COVID-19] positive test result, 
OR (ii) is suspected of SARS-CoV-2 infection (clinical features without documented 
test results two weeks after resolution of symptoms and remains asymptomatic until 
Day 1), OR (iii) has been in close contact with a person with known (or suspected) 
SARS-CoV-2 infection and remains asymptomatic until Day 1. 
 
4.3. 
Pregnancy and Contraception 
4.3.1. 
Females of Childbearing Potential  
Females of childbearing potential must have documentation of a negative pregnancy test at 
screening and prior to dosing.  
Females are considered to be not of childbearing potential if they have had a total 
hysterectomy and/or bilateral tubal ligation or hysteroscopic sterilization (documentation for 
surgeries must be provided before randomization) or are in a postmenopausal state 
(i.e., females who have had cessation of prior occurring menses for ≥24 months without 
alternative causes or females with premature ovarian failure). 
4.3.2. 
Contraception for Male and Female Subjects  
All female subjects of childbearing potential and males who are able to father children must 
agree to abstain from sexual intercourse or to use a highly effective method of birth control 
during the study and for at least 30 days after the completion of study drug dosing.  A highly 
effective method of birth control is defined as one that results in a low failure rate 
(i.e., <1% per year) when used consistently and correctly. Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 

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• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomized partner provided that partner is the sole sexual partner of the female 
trial participant of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success  
• sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. 
NOTE:  Birth control methods which may not be considered highly effective: 
• progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
• male or female condom with or without spermicide 
• cap, diaphragm or sponge with spermicide 
4.4. 
Continuation Criteria 
• At V3 (Week 4), following the initial 4-week OL treatment, subjects must 
demonstrate a reduction in OHSA#1 of at least 2 points compared to the baseline 
value, as determined in Study 0169 for subjects entering from Study 0169 and from 
V1 for de novo subjects, in order to continue in Study 0170. 
4.5. 
Randomization Criteria for Double-Blind Period  
A subject who meets the following criteria will be eligible for randomized withdrawal period 
201. Subject has OHSA#1 score of ≤7.  
202. Subject’s unused OL study medications (10 mg TD-9855 tablets) are returned to site. 
203. The subject has a minimum of 80% study medication compliance in OL treatment 
period. 
204. Subjects without excessive deterioration of disease or symptoms during the OL phase 
and in the opinion of the Investigator, would benefit from continued participation in 
the study. 

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5. 
STUDY MEDICATION 
All study medication supplied by the sponsor must be stored in a secure location accessible 
only to designated study personnel. 
5.1. 
Description of Study Medications 
For OL treatment period: 
All subjects will receive TD-9855 once daily through the end of the treatment period. 
For randomized treatment period: 
Subjects will be randomized in a 1:1 ratio to receive either TD-9855 (test product) or PBO 
(reference product) once daily through the end of the treatment period.  
Further details regarding study medication handling, storage, and destruction are found in a 
separate pharmacy manual.  
5.1.1. 
TD-9855 Test Product 
For OL treatment period: 
All subjects will receive TD-9855 and continue to take the study medication once daily 
starting on Day 2 through the end of the treatment period. The test product will be TD-9855 
supplied as a 10-mg tablet in 35-count high-density polyethylene bottles. 
For randomized treatment period: 
Subjects randomized to TD-9855 will receive TD-9855 tablets and continue to take the study 
medication once daily starting in the morning post randomization (Day 2) through the end of 
the treatment period. The test product will be TD-9855 supplied as a 10-mg tablet in 35-count 
or 5-count high-density polyethylene bottles labeled in a blinded fashion (i.e., bottle label for 
test product will be indistinguishable from reference product except for a coded, unique bottle 
number).  
5.1.2. 
Placebo Reference Product 
For OL treatment period: 
No subjects will receive the reference product. 
For randomized treatment period: 
Subjects randomized to PBO will receive PBO tablets that are supplied to match TD-9855 
tablets in excipient content (except for the absence of TD-9855), appearance, tablet count, 
and in packaging (i.e., bottle label for reference product will be indistinguishable from test 
product except for a coded, unique bottle number). 
5.2. 
Dosage and Administration 
All study medications will be administered orally without regard to food at approximately the 
same time each morning and taken with approximately 8 ounces of water. 

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5.3. 
Treatment Compliance 
Subjects will be instructed to provide all used and unused study medication containers at each 
visit. Compliance with the dosing regimen will be assessed by reconciliation of used and 
unused study medication.  
The subjects’ dosing diary entries will also be reviewed at applicable study visits to assess 
compliance with study medication administration per documentation of the daily dosing 
times.  
Subjects with poor dosing compliance (i.e., < 80% or > 120%), as assessed by reconciliation 
of used and unused study medication and/or missing entries on the study medication 
administration diary, should receive counseling, assistance, and re-training as appropriate. 
5.4. 
Drug Accountability and Reconciliation 
The Investigator or designee is responsible for maintaining accountability records for all 
study medication(s) received from the sponsor, in accordance with applicable government 
regulations and study procedures. The accountability record will include entries for receipt, 
distribution or dispensing, and destruction of the material(s). Unused and expired study 
medications will be disposed of in accordance with written instructions in the pharmacy 
manual. 

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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1. Refer to the footnotes in 
Schedule of Study Procedures (Table 1) for a description of all assessments.  Refer to 
Appendix 9 and the Study Reference Manual for detailed instructions for conducting subject 
assessments in clinic and remotely.  These instructions have been provided to ensure the 
method and conduct of each assessment is consistent across sites and subjects for both in 
clinic and remote visits. 
6.2. 
Total Blood Volume 
The total volume of blood to be drawn from each subject for safety, PK, and 
pharmacodynamic laboratory tests is approximately 114 mL. Additional safety laboratory 
tests may be drawn as needed to manage any emergent health needs as directed by the 
Investigator. 
6.3. 
Procedures by Visit (Recommended Order) 
6.3.1. 
Screening – Visit S (De Novo Group Only) 
Screening visit assessments will be performed in clinic between 28 and 7 days prior to Day 1.  
The following procedures must be completed first, and in the order below: 
• Written informed consent (signed and dated) after the nature of the study has been 
explained and before any study procedure is performed 
• Review of protocol inclusion and exclusion criteria prior to beginning subject 
evaluations 
• Medical history, including smoking history 
• Review concomitant medications and smoking usage 
• MoCA 
• OHQ subject training 
• C-SSRS 
• Tilt-table test 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• Orthostatic standing test 
• Vital signs 
• HR, systolic BP (SBP), and diastolic BP (DBP) 
• Respiratory rate (RR) and body temperature 
• Height (in cm) and weight (in kg) 
• Physical examination  
• Neurological examination 

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• 12-lead ECG (in triplicate separated by at least 1 minute for each replicate, after the 
subject has been resting for at least 5 minutes) 
• Pregnancy test (in women of childbearing potential only) 
• Blood collection 
• Hematology 
• Chemistry 
• NE sample collection (after being seated for approximately 30 minutes) 
• Urine collection 
• Urinalysis 
• ESC (for confirmation of diagnosis)  
• 24-hour ambulatory BP device provision (device collection prior or on Visit 2) 
• Wearable device provision  
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, adverse event of special interest [AESIs]) 
• Valsalva maneuver (only for subjects with PAF) 
A sample screening visit with approximate duration required for subject is provided in 
Appendix 8. 
6.3.2. 
Treatment Day 1 – Visit 1 
De Novo Group subjects meeting all applicable eligibility criteria, including ESC 
confirmation of diagnosis, following completion of the screening assessments, will continue 
towards enrollment assessments on Day 1. Prior to dosing, the results of the clinical and 
laboratory evaluations from screening (as described in Table 1) must be reviewed by the 
Investigator to confirm the continued eligibility of each subject to participate in the study. 
The following assessments or procedures will be performed within 24-hours prior to the 
subject taking the study medication as part of study 0170 (pre-dose).  
For 0169 Completers Group subjects, Study 0169 procedures conducted at V6 will serve as 
the baseline assessments for V1 of Study 0170.  
Beginning on Day 2, subjects will receive a single dose of 10-mg TD-9855 once daily (QD) 
and continue thereafter for the 16-week duration of the OL treatment period. Following this 
16-week OL treatment period, subjects will be randomized to either continue on the active 
treatment or PBO for a period of 6 weeks. 
The following procedures must be completed first, and in the order below: 
• Written informed consent (signed and dated) after the nature of the study has been 
explained and before any study procedure is performed (0169 Completers only) 
• Review of protocol inclusion and exclusion criteria prior to beginning subject 
evaluations 
• Review concomitant medications and smoking usage 

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• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• NMSS 
• HADS 
• PD subject assessments  
• UPDRS 
• PDQ-8 
• MSA subject assessments  
• UMSARS 
• COMPASS-31 
• EQ-5D-5L 
• BSFC-s 
• Orthostatic standing test 
• Vital signs 
• HR, SBP, and DBP 
• RR and body temperature 
• Weight (in kg) 
• Physical examination 
• Neurological examination 
• 12-lead ECG (in triplicate separated by at least 1 minute for each replicate, after 
the subject has been resting for at least 5 minutes) 
• Pregnancy test (in women of childbearing potential only) 
• Blood collection 
• Hematology 
• Chemistry 
• Urine collection 
• Urinalysis 
• Pharmacodynamic sampling (after being seated for approximately 30 minutes) 
• 24-hour ambulatory BP device collection and re-provision 
• Wearable device collection and re-provision  

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• Incidence of Falls and ABPM position diaries 
• Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Dispense study medication 
6.3.3. 
Treatment Day 15 – Visit 2 
The following procedures will be performed on the Day 15 visit (+/- 3 days) after the daily 
dose of TD-9855: 
• Review concomitant medications and smoking usage 
• Vital signs 
• HR, SBP, and DBP 
• RR and body temperature 
• Physical examination 
• Blood collection 
• Hematology  
• Chemistry 
• Urine collection 
• Urinalysis  
• 24-hour ambulatory BP device collection  
• Incidence of Falls and ABPM position diaries 
• Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
• AE assessment (AEs, SAEs, AESIs) 
6.3.4. 
Treatment Day 29 – Visit 3 
At V3 (Day 29), following the initial 4-week OL treatment, subjects must demonstrate a 
reduction in OHSA#1 of at least 2 points compared to the baseline value, as determined in 
Study 0169 for subjects entering from Study 0169 and from V1 for de novo subjects, in order 
to continue in Study 0170. 
The following procedures will be performed on the Day 29 visit (+/- 3 days) after the daily 
dose of TD-9855: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 

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• C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• BSFC-s 
• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• 12-lead ECG (in triplicate separated by at least 1 minute for each replicate, after 
the subject has been resting for at least 5 minutes) 
• 24-hour ambulatory BP device and position diary provision for all subjects 
• Wearable device collection and re-provision 
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 
• Dosing and Rescue medication diary dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Collect, review, and dispense study medication 
6.3.5. 
Treatment Day 57 – Visit 4 
The following procedures will be performed on the Day 57 visit (+/- 3 days) after the daily 
dose of TD-9855: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• NMSS 
• HADS 
• UPDRS (only for patients with PD) 
• PDQ-8 (only for patients with PD) 
• UMSARS (only for patients with MSA) 
• COMPASS-31 (only for patients with MSA) 
• EQ-5D-5L 
• BSFC-s 

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• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• Blood collection  
• Hematology 
• Chemistry 
• Urine collection 
• Urinalysis 
• Pharmacokinetic sampling 
• Pharmacodynamic sampling (after being seated for approximately 30 minutes) 
• 24-hour ambulatory BP device collection  
• Wearable device collection and re-provision 
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 
• Dosing and Rescue medication diary dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Collect, review, and dispense study medication 
6.3.6. 
Treatment Day 85 – Visit 5 
The following procedures will be performed on the Day 85 visit (+/- 3 days) after the daily 
dose of TD-9855: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• BSFC-s 
• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• Wearable device collection and re-provision 
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 

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• Dosing and Rescue medication diary dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Collect, review, and dispense study medication 
6.3.7. 
Treatment Day 113 – Visit 6 
At V6 (Day 113), following the OL treatment, only subjects with OHSA#1 score of ≤7 will 
be eligible for randomization for the double-blind treatment period. Ensure “Randomization 
Criteria” is met prior to continuation. First dose date of the randomized treatment should be 
used to determine the subsequent visits during the randomized treatment period (first dose 
date + 13 days for Day 127 [Visit 7], first dose date + 27 days for Day 141 [Visit 8], first 
dose date + 41 days for Day 155 [Visit 8]). 
The following procedures will be performed on the Day 113 visit (+/- 3 days) after the daily 
dose of TD-9855: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 
• Randomization via a RTSM system (after all procedures have been completed and 
subject is confirmed eligible to be randomized per randomization criteria 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• NMSS 
• HADS 
• UPDRS (only for patients with PD) 
• PDQ-8 (only for patients with PD) 
• UMSARS (only for patients with MSA) 
• COMPASS-31 (only for patients with MSA) 
• EQ-5D-5L 
• BSFC-s 
• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• Weight (kg) 
• Physical examination 
• Neurological examination 

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• 12-lead ECG (in triplicate separated by at least 1 minute for each replicate, after 
the subject has been resting for at least 5 minutes) 
• Pregnancy test (in women of childbearing potential only) 
• Blood collection 
− Hematology 
− Chemistry  
• Urine collection 
− Urinalysis 
• PK sampling 
• Wearable Device collection and re-provision 
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 
• Dosing and Rescue medication diary dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Collect, review, and dispense study medication 
6.3.8. 
Treatment Day 127 – Visit 7 
The following procedures will be performed on the Day 127 visit (+/- 3 days) after the daily 
dose of TD-9855: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• BSFC-s 
• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• PK sampling 
• Wearable Device collection and re-provision 
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 

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• Dosing and Rescue medication diary dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Collect, review, and dispense study medication, if applicable 
6.3.9. 
Treatment Day 141 – Visit 8 
The following procedures will be performed on the Day 141 visit (+/- 3 days) after the daily 
dose of TD-9855: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• BSFC-s 
• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• Wearable device collection and re-provision 
• Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 
• Dosing and Rescue medication diary dispensation and review of diary completion 
instructions 
• AE assessment (AEs, SAEs, AESIs) 
• Collect, review, and dispense study medication 
6.3.10. 
Treatment Day 155 – Visit 9/ Early Termination 
Subjects completing Day 155 (V9) can proceed to Study 0171 following this visit. The 
following procedures will be performed on the Day 155 visit (+/- 3 days) after the daily dose 
of TD-9855/Early Termination: 
The following procedures must be completed first, and in the order below: 
• Review concomitant medications and smoking usage 
• OHQ subject training 
• OHQ (OHSA and OHDAS) 
• PGI-S 
• C-SSRS 

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The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
• NMSS 
• HADS 
• UPDRS (only for patients with PD) 
• PDQ-8 (only for patients with PD) 
• UMSARS (only for patients with MSA) 
• COMPASS-31 (only for patients with MSA) 
• EQ-5D-5L 
• BSFC-s 
• Orthostatic standing test 
• Vital signs: HR, SBP, and DBP; RR and body temperature 
• Weight (kg) 
• Physical examination 
• Neurological examination 
• 12-lead ECG (in triplicate separated by at least 1 minute for each replicate, after 
the subject has been resting for at least 5 minutes) 
• Pregnancy test (in women of childbearing potential only) 
• Blood collection 
− Hematology 
− Chemistry 
• Urine collection 
− Urinalysis  
• Wearable device collection 
• Incidence of falls – subject diary review for completion 
• Dosing and Rescue medication diary review for completion 
• AE assessment (AEs, SAEs, AESIs) 
• Collect and review study medication 
6.3.11. 
Follow-up Day 169 – Visit 10 
The follow-up visit is applicable only for those subjects that will not proceed to Study 0171 
and will be completed two weeks from the date of the last dose. 
The following procedures will be performed on the Day 169 visit (+/- 3 days): 
• Review concomitant medications and smoking usage 
• C-SSRS 

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• Vital signs: HR, SBP, and DBP; RR and body temperature 
• Weight (kg) 
• AE assessment (AEs, SAEs, AESIs) 
 
6.4. 
Description of Study Procedures 
Written informed consent must be obtained prior to performing any protocol specific 
procedures. After providing full informed consent, subjects will undergo a medical screen to 
determine their eligibility for participation based on the criteria outlined in this protocol.  
The site should make every effort to perform procedures at the scheduled times, and 
information should be recorded in the source documents and on the CRFs. All patient 
reported outcomes for subjects with PD should be completed in an ON state, and within 
1-4 hours of taking the PD medications. 
Additional safety tests, such as vital signs (BP, HR, RR, and body temperature), physical 
examinations, ECGs, and laboratory safety assessments, may be obtained during the course 
of the study on the basis of newly available data to ensure appropriate safety monitoring.  
6.4.1. 
Demographic and Baseline Assessments 
Demographic information to be collected will include: year of birth, sex, race, and ethnicity. 
For De Novo Group subjects, inclusion and exclusion criteria will be assessed at screening 
and on Day 1 prior to OL treatment. Subjects will only be eligible for enrollment into the 
study if they meet all the applicable inclusion and none of the applicable exclusion criteria. 
Each subject will be asked to provide relevant medical history (including medication history; 
see Section 6.4.10.3). 
For 0169 Completers Group subjects, the data would be confirmed with information captured 
in Study 0169. 
6.4.2. 
Tilt-Table Test 
A tilt-table test is used to evaluate the cause of unexplained fainting (syncope). A tilt-table 
attempts to trigger signs and symptoms, like lightheadedness, dizziness, feeling faint, or 
feeling like blacking out, while HR and BP are being monitored.  If the subject has symptoms 
while in the upright position on the tilt-table, the part of the nervous system that controls BP 
and HR suddenly lowers for a short time, less blood flows to the brain, and could possibly 
cause the subject to faint. The endpoint of tilt-table testing is the reproduction of symptoms 
along with the characteristic circulatory pattern of the indication mentioned above, namely 
the induction of reflex hypotension/bradycardia, orthostatic hypotension, postural orthostatic 
tachycardia syndrome, or psychogenic pseudosyncope. The tilt-table test will be applied until 
a sustained reduction of BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) is observed in 
≤3 minutes of being tilted-up to ≥60o from a supine position, ideally between 60o to 65o. The 
tilt-table test should be performed following at least 12-hours of withdrawal from vasoactive 
medications. The tilt-table test should be performed at least 2 hours after meals and with an 
empty bladder. A single tilt-table retest may be performed providing the Investigator has 
concluded a technical problem or operational issue during the initial test impacted the results. 
Under these circumstances, a follow-up tilt-table test may be performed in order to 
appropriately evaluate the subject’s orthostasis.  The follow-up tilt-table test should be 

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performed at a minimum of one hour after the initial test, and at least 7 days prior to 
enrollment. Tilt-table test is only applicable for De Novo group. Assessments will be 
performed as specified in Schedule of Study Procedures (Table 1).  
6.4.3. 
Montreal Cognitive Assessment  
The MoCA is a global cognitive screening test with favorable psychometric properties that 
has been shown to be more sensitive to executive impairment than the Mini-Mental State 
Examination. It screens 8 domains including: visuospatial/executive, naming, memory, 
attention, language, abstraction, delayed recall, and orientation. Assessments will be 
performed as specified in the Schedule of Study Procedures (). An example of the instrument 
is provided in Appendix 2. 
6.4.4. 
Valsalva Maneuver 
The Valsalva maneuver is a breathing technique that can be used to help diagnose a problem 
with the autonomic nervous system (ANS). Changes in intrathoracic pressure produce 
autonomically modulated transient changes in HR and BP. The Valsalva maneuver will be 
performed as specified in the Schedule of Study Procedures (Table 1) only for subjects with 
PAF to confirm diagnosis. 
6.4.5. 
OHQ Subject Training 
Empirical evidence exists that the OHQ can accurately evaluate the severity of symptoms and 
the functional impact of symptomatic nOH as well as assess the efficacy of treatment9. To 
ensure that subjects are able to complete the OHQ questionnaires successfully with a 
complete understanding of the individual point differences on the scale as associated with 
their symptoms and to standardize the manner of completion of the 11-point scale from 0 to 
10, the subjects will undergo OHQ training. Subjects should be rested prior to beginning the 
training.  Assessments will be performed as specified in the Schedule of Study Procedures 
(Table 1). 
6.4.6. 
Efficacy Assessments 
6.4.6.1. 
Orthostatic Hypotension Questionnaire 
The OHQ is a 2-component scale made up of a 6-item symptom assessment scale referred to 
as OHSA and a 4-item daily activity scale referred to as the OHDAS9. The items are scored 
on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 
10 indicating the worst possible symptoms/complete interference, and the option of selecting 
“cannot do for other reasons.” Assessments will be performed as specified in the Schedule of 
Study Procedures (Table 1). An example of the instrument is provided in Appendix 2. 
6.4.6.2. 
Patient Global Impression of Severity 
Patient Global Impression of Severity is a 1-item patient rated questionnaire designed to 
assess the patient’s impression of symptom severity. The PGI-S item asks the respondent to 
best describe the current severity of symptoms of his/her neurogenic orthostatic hypotension 
on a 5-category scale, where a higher score is associated with greater symptom severity. 
Assessments will be performed as specified in the Schedule of Study Procedures (Table 1). 
An example of the instrument is provided in Appendix 2.  

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6.4.6.3. 
Wearable Device  
A wearable device, such as an activity monitor, that provides date- and time-stamped activity 
information will be used to collect raw motion data to measure the time spent in supine, 
sitting, and standing positions. 
In countries where the wearable devices are available, 2 consecutive days of device use will 
be required on the days shown in Table 1. The 2 consecutive days of device use should be 
within 5 days before the subsequent visit. Site coordinators will monitor subject compliance. 
If the site coordinator becomes aware that a subject has not used the device for the required 
time, they will contact the subject and remind them to use the device. Subjects will be 
identified by subject ID and no personally identifiable information is collected or stored.  
In countries where the devices are available, assessments will be performed as specified in 
the Schedule of Study Procedures (Table 1). 
6.4.6.4. 
Unified Parkinson’s Disease Rating Scale 
Unified Parkinson’s disease Rating Scale, a clinical rating scale for PD, has nearly 
comprehensive coverage of motor symptoms and its clinimetric properties, including 
reliability and validity. The UPDRS is only for subjects with PD. It is made up of 6 parts, 
namely, 1: evaluation of mentation, behavior, and mood; 2: self-evaluation of the activities of 
daily living (ADLs), including speech, salivation, swallowing, handwriting, cutting 
food/handling utensils, dressing, hygiene, turning in bed/adjusting bedclothes, falling, 
freezing when walking, tremor, and sensory complaints; 3: clinician-scored monitored motor 
evaluation; 4: complications of therapy; 5: modified Hoehn and Yahr staging of severity of 
PD; and 6: modified Schwab and England ADL scale. Assessments will be performed as 
specified in the Schedule of Study Procedures (Table 1). The UPDRS scale should be 
completed in an ON state, and within 2-4 hours of taking the PD medications. All UPDRS 
Parts will be completed on Day 1 for De Novo Group subjects, while only Parts 2 and 3 of 
the questionnaire would be completed for 0169 Completers Group, and for subsequent visits. 
An example of the instrument is provided in Appendix 2. 
6.4.6.5. 
The Parkinson's Disease Questionnaire-8 
The PDQ-8 is derived from the Parkinson’s Disease Questionnaire-39 (PDQ-39) and is only 
for subjects with PD. The short-form 8-item PDQ-8 was developed to reflect scores on the 
PDQ-39 single index, but with a smaller number of items, placing less burden upon 
respondents. In the original formulation, 1 item was selected from each of the 8 dimensions 
of the PDQ-39. The item selected being the one that correlated most strongly with the 
dimension total to which it contributes. These 8 items constitute the PDQ-8 and are then 
summed to produce a single figure. Assessments will be performed as specified in the 
Schedule of Study Procedures (Table 1). 
An example of the instrument is provided in Appendix 2. 
6.4.6.6. 
Unified Multiple System Atrophy Rating Scale 
The UMSARS is only for subjects with MSA and comprises the following components: 
Part 1, historical review, 12 items; Part 2, motor examination, 14 items; Part 3, autonomic 
examination; and Part 4, global disability scale. Assessments will be performed as specified 
in the Schedule of Study Procedures (Table 1). An example of the instrument is provided in 
Appendix 2. 

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6.4.6.7. 
Composite Autonomic Symptom Score-31  
The COMPASS-31 is a refined, internally consistent, and markedly abbreviated quantitative 
measure of autonomic symptoms. It is based on the original Autonomic Symptom Profile 
(ASP) and Composite Autonomic Symptom Score (COMPASS), applies a more simplified 
scoring algorithm, and is suitable for widespread use in autonomic research and practice. It is 
only used for subjects with MSA. Assessments will be performed as specified in the Schedule 
of Study Procedures (Table 1). An example of the instrument is provided in Appendix 2. 
6.4.6.8. 
Incidence of Falls – Subject Diary 
Falls in subjects with symptomatic nOH are common and potentially catastrophic. They can 
lead to serious injuries including hip fractures or head trauma; furthermore, fear of falling can 
limit mobility and physical activity. Thus, incidence of subject-reported falls is being 
captured in a diary. Assessments will be performed as specified in the Schedule of Study 
Procedures (Table 1). An example of the instrument is provided in Appendix 3. 
6.4.6.9. 
Orthostatic Standing Test  
The orthostatic standing test (including SBPs) will be performed at the time points described 
in the Schedule of Study Procedures (Table 1). 
At each time point, BP and HR measurements will be recorded with automated (or manual) 
sphygmomanometer while resting supine (with the torso and head elevated 30 degrees from 
horizontal), for a total of 10 minutes, with measurements taken at 5 and 10 minutes. Followed 
by, seated for a total of 10 minutes, with measurements taken at 5 and 10 minutes. Lastly, 
standing for up to a total of 10 minutes, with measurements taken at 1, 3, 5, and 10 minutes 
while standing. The standing time will be measured with a chronometer and the duration of 
standing will be recorded. The total duration of standing may occur in between the time 
points (i.e., 1, 3, 5, and 10 minutes) for the standing test. In either case, the total duration 
should be recorded. The BP and HR collected after 10 minutes supine and seated from the 
orthostatic standing test can be used for safety vital sign assessment. The assessments should 
be performed at approximately (±2 hour) the same time of day on Day 1 (except Screening). 
Subjects should abstain from eating for at least 90 minutes prior to this assessment.   
Assessments will be performed as specified in the Schedule of Study Procedures (Table 1). 
6.4.7. 
Pharmacokinetic Assessments 
A sparse PK sampling strategy is being employed in this study. At the time points described 
in the Schedule of Study Procedures (Table 1), blood samples for PK assay of TD-9855 will 
be collected, centrifuged, and split into aliquots. Detailed instructions and collection kits for 
sample collection, handling, and shipping will be provided in the laboratory manual. 
All PK sampling times will be accurately recorded by collection date, hour, and minute. 
Study medication dosing time on the day before each PK collection and on the day of each 
PK collection will be accurately recorded by dosing date, hour, and minute by the study staff 
using time recorded in Dosing Diary by Subjects. 
Assessments will be performed as specified in the Schedule of Study Procedures (Table 1). 

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6.4.8. 
Pharmacodynamic Assessments 
At the time points described in the Schedule of Study Procedures (Table 1), blood samples 
for pharmacodynamic markers may be measured. Detailed instructions and collection kits for 
sample collection, handling, and shipping will be provided in the laboratory manual.  
Blood samples for pharmacodynamic markers (DHPG and NE) will be collected at select 
study visits as defined in the Schedule of Study Procedures after the subject has been seated 
for 30 minutes. Note that all pharmacodynamic marker samples should be collected at 
approximately (±1 hour) the same time of day. Time-matched sampling will enable 
time-matched analysis, which is critical for biomarkers of the NE pathway owing to diurnal 
variations.NE alone will also be collected at Screening Visit as part of the eligibility criteria 
evaluations. 
Assessments will be performed as specified in the Schedule of Study Procedures (Table 1). 
6.4.9. 
Exploratory Assessments 
6.4.9.1. 
EQ-5D-5L Descriptive System 
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. The 
EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual 
analogue scale (EQ VAS). 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The subject is asked 
to indicate his/her health state by ticking the box next to the most appropriate statement in 
each of the 5 dimensions.  
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, where 
the endpoints are labelled, “The best health you can imagine” and “The worst health you can 
imagine.” The EQ VAS can be used as a quantitative measure of health outcome that reflect 
the subject’s own judgment. Assessments will be performed as specified in the Schedule of 
Study Procedures (Table 1). An example of the instrument is provided in Appendix 2. 
6.4.9.2. 
Non-Motor Symptom Scale 
The NMSS is a 30-item scale for the assessment of non-motor symptoms. The NMSS 
contains 9 domains: cardiovascular including falls, sleep/fatigue, mood/cognition, perceptual 
problems/hallucinations, attention/memory, GI tract, urinary, sexual function, and 
miscellaneous. The NMSS can be used to assess the frequency and severity of non-motor 
symptoms in patients across all stages in conjunction with the validated non-motor 
questionnaire. Assessments will be performed as specified in the Schedule of Study 
Procedures (Table 1). An example of the instrument is provided in Appendix 2. 
6.4.9.3. 
Hospital Anxiety and Depression Scale 
The HADS is a brief questionnaire comprised of 2 domains including anxiety (7-items) and 
depression (7-items). It has been validated for in-clinic and out-patient settings. Assessments 
will be performed as specified in the Schedule of Study Procedures (Table 1). An example of 
the instrument is provided in Appendix 2. 

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6.4.9.4. 
Burden Scale for Family Caregivers – Short Version 
The burden experienced by family caregivers is the most important caregiver-related variable 
in care at home of a chronically-ill person. The extent of subjective burden has significant 
impact on the emotional and physical health of the family caregiver, and even influences the 
mortality of spouse caregivers. It affects the way the family caregiver deals with the 
care-receiver and determines the time of institutionalization. The shorter version consists of 
the 10 statements of the BSFC-s and are rated on a 4-point scale ranging from 0 (strongly 
disagree) to 3 (strongly agree). Assessments will be performed as specified in the Schedule of 
Study Procedures (Table 1).  An example of the instrument is provided in Appendix 2. 
6.4.10. 
Safety Assessments 
6.4.10.1. Columbia-Suicide Severity Rating Scale  
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal 
behavior and suicidal ideation). The strength of this suicide classification system is in its 
ability to comprehensively identify suicidal events while limiting the over-identification of 
suicidal behavior. The C-SSRS Baseline/Screening Version will be used at V1 and the 
C-SSRS Since Last Visit Version will be used for subsequent visits. Assessments will be 
performed as specified in the Schedule of Study Procedures (Table 1). An example of the 
instrument is provided in Appendix 2. 
6.4.10.2. Adverse Events 
Adverse events will be reviewed and recorded from signing of the informed consent through 
the end of follow-up. Adverse events may be observed by the study personnel or 
spontaneously reported by the subject. 
Subjects entering from Study 0169 (0169 Completers Group): Adverse events that start 
after signing of Study 0170 informed consent, but before the first dose of study drug is taken 
on Day 2, are to be captured in Study 0169 database. Adverse events started in Study 0169 
but which worsen in severity or seriousness during Study 0170 should be reported as a new 
adverse event. 
All AEs must be recorded in the subject’s CRF and, if applicable, reported as described in 
Section 7. 
The Investigator must take all therapeutic measures necessary for resolution of AEs. Any 
medications necessary for the treatment of an AE must be recorded in the subject’s CRF. 
Refer to Section 7. 
Except where described above, the Investigator may prescribe medications to provide 
adequate supportive care. However, the Investigator should use judgment to avoid 
medications that may confound the interpretation of this study. 
6.4.10.3. Medication and Medical History 
A complete medical history will be taken during the screening visit (for De Novo subjects 
only) and will include evaluation of past and present cardiovascular, respiratory, GI, renal, 
hepatic, neurological, endocrine, lymphatic, hematologic, immunologic, dermatologic, 
psychiatric, genitourinary, substance abuse, surgical history, or any other diseases or 
disorders. Medical conditions will be recorded for 2 years prior to screening visit, along with 
the date of diagnosis, and any other relevant medical history that has an impact to the subject. 

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Medical events or conditions that arise or worsen in severity or frequency after the signing of 
the informed consent will be recorded as an AE.  
All medications used during the 60 days prior to screening will be recorded in the source 
records. The only exception is drugs that were used to treat previous orthostatic hypotension; 
these will be recorded since the time of primary diagnosis. 
6.4.10.4. Physical Examination 
A full physical examination at the screening visit will be performed by an appropriately 
qualified individual (e.g., physician, nurse practitioner, physician’s assistant, or equivalent, 
under the supervision of a physician) and will include examination of the following: general 
appearance; skin; head, ears, eyes, nose, and throat; neck; cardiovascular system; respiratory 
system; abdomen/ GI system; extremities; lymphatic system [lymph nodes]; and nervous 
system). 
Subsequent physical examinations, after the screening visit, per discretion of the Investigator, 
can be abbreviated and symptomatic, largely focused on evaluation of AEs, if any, and any 
abnormalities identified on the screening visit examination. 
6.4.10.5. Neurological Examination 
Any abnormalities identified at the screening visit will be recorded as neurological medical 
history. Any abnormalities or symptoms reported during treatment that arise or worsen in 
severity or frequency will be reported as AEs. 
The PI should perform a neurological exam in clinic or via telemedicine platform for remote 
visits (assisted as necessary by the home health nurse) as required to assess the subject’s 
current condition and include the following exams per the PI’s medical discretion. 
The examination will assess the following: 
• Cranial nerves (cranial nerves II-XII, excluding funduscopic examination) 
• Motor system (tone, strength, and abnormal movements) 
• Sensory system (light touch, pinprick, joint position, and vibration) 
• Reflexes (deep tendon reflexes and plantar responses) 
• Coordination (upper and lower extremities) 
• Gait (base and tandem gait) 
• Station (posture and stability) 
6.4.10.6. Height and Weight  
Height (in cm) and weight (in kg) will be recorded as outlined in the Schedule of Study 
Procedures (Table 1). Reasonable efforts will be taken to ensure the measurements for weight 
occur at approximately the same time each visit using the same scale and with similar 
clothing. 
6.4.10.7. Vital Signs 
The HR, SBP and DBP, RR, and body temperature will be recorded according to the 
Schedule of Study Procedures (Table 1). The vital sign measurements (BP and HR) should be 
performed after the subject has rested sufficiently as determined by the appropriate staff. 

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Subject position, measurement device, and arm (left vs. right) should be kept consistent 
throughout the study. Blood pressure will be measured using a calibrated manual or 
automatic BP device.  
Heart rate will be recorded by palpation of the radial pulse over at least a 30-second period or 
by the automated BP device. 
The BP and HR collected at 10 minutes supine and seated from the orthostatic standing test 
can be used for safety vital sign assessment. 
Body temperature will be measured and reported in degrees Celsius. The method used to 
collect temperature can be either oral or tympanic but should be consistent throughout the 
subject’s participation. 
Any vital sign outside the normal range may be repeated at the discretion of the Investigator. 
Collection of additional vital sign measurements for routine safety monitoring at additional 
time points or study days may be performed at the discretion of the Investigator, or upon 
request by the sponsor.  
6.4.10.8. Electrocardiograms  
The 12-lead ECGs will be recorded in triplicate and separated by at least 1 minute for each 
replicate, according to the Schedule of Study Procedures (Table 1), after the subject has been 
resting at least 5 minutes in the seated or supine position before the first reading. The total 
time to conduct ECGs ideally would not exceed 15 minutes. Actual time of the assessment 
must be recorded for each iteration. The corrected QT interval using the Fridericia’s formula 
(QTcF) will be used. The ECGs should be reviewed on the visit day to allow for any 
appropriate action, if required.  
6.4.10.9. 24-hour Ambulatory Blood Pressure Monitoring 
Ambulatory blood pressure monitoring (ABPM) equipment will be provided to the subject 
during the screening visit for De Novo Group subjects, and on V1 for 0169 Completers 
Group subjects. Beginning approximately 72 to 24-hours before a subject returns to the 
scheduled clinic visits that require the procedure, subjects will put on the 24-hour blood 
pressure monitoring equipment and initiate the recording. Once the 24-hour session is 
complete, subjects will remove and return the equipment to the research center during the 
next visit. During each 24-hour session, the BP monitoring device will be programmed to 
automatically measure BP every 2 hours beginning at the top of the hour. During each 
24-hour session, subjects will log their posture at the time of each BP measurement in the 
provided ABPM Position Diary (Appendix 4). More details regarding the ambulatory 
monitoring will be provided in a separate manual. ABPM will be performed as specified in 
the Schedule of Study Procedures (Table 1). 
6.4.10.10. Laboratory Tests 
Laboratory tests will be performed as specified in the Schedule of Study Procedures 
(Table 1). Additional and repeat laboratory safety testing for the evaluation of abnormal 
results and/or AEs during the study may be performed at the discretion of the Investigator or 
upon request of the sponsor. 
Detailed instructions and collection kits for sample collection, handling, and shipping will be 
provided in the laboratory manual. 

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6.4.10.10.1. 
Hematology 
Hematology samples will be analyzed for the following: hematocrit and hemoglobin; red 
blood cell count; mean corpuscular volume; mean corpuscular hemoglobin; white blood cell 
count, including differential count (percent and absolute) of neutrophils, eosinophils, 
basophils, monocytes, lymphocytes; platelet count and HgbA1C (if applicable).  
6.4.10.10.2. 
Chemistry 
Chemistry samples will be analyzed for the following: sodium, potassium, calcium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, eGFR, total protein, albumin, alkaline 
phosphatase, ALT, AST, bilirubin, lactate dehydrogenase, and creatine phosphokinase. 
6.4.10.10.3. 
Urinalysis 
Urinalysis includes determination of specific gravity; presence of blood, protein, and 
leukocytes; and microscopic examination of sediment, if clinically indicated. 
6.4.10.11. Dosing Diary Dispensation and/or Collection 
On a daily basis, the subjects will record the time of study medication administration in the 
diary provided on V1. Dosing diary with completion instructions, including study medication 
dosing details, will be provided to each subject. Subjects will be instructed to record daily 
dosing through the end of the treatment period (Appendix 5). Diary completion will be 
monitored for completeness at each return study visit after the diary is dispensed. Subjects 
will be counseled on missed study medication doses and missed diary entries. Compliance 
with the dosing regimen will be assessed by reconciliation of used and unused study 
medication. 
6.4.10.12. Unscheduled Visit 
All sites are allowed at Investigator discretion to conduct either in clinic or remote 
unscheduled visit(s) for subject safety or unexpected subject medical needs outside of the 
regular visit schedule. In this case, unscheduled visits are not considered protocol deviations 
and the Investigator is not required to obtain pre-approval from the Sponsor. Data collected 
during these visits may include any protocol-specified assessments which will be captured in 
the clinical database. 
6.5. 
Concomitant Medications 
For the De Novo Group, subjects should not have changed dose, frequency, or type of 
prescribed medication for orthostatic hypotension within 7 days prior to V1/D1.  
Concomitant use of antihypertensive medication for the treatment of essential hypertension is 
not allowed.  
Subjects can continue on a stable dosing regimen of fludrocortisone if the regimen was 
initiated at least 7 days prior to V1/D1.  
Cannabinoids usage for medical reasons is permissible at a stable dosing regimen established 
at least 7 days prior to V1/D1 in countries where cannabinoids are permissible. 
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Subjects who are smokers will be recommended to either stop smoking (cigarettes or 
cannabinoids in countries where cannabinoids are permissible) at least 7 days before first 
dose or maintain a constant smoking habit during the entire course of the study. 
6.5.1. 
Impact of Other Medications on TD-9855 
Preliminary results from the clinical drug-drug interaction study suggest that concomitant 
administration of itraconazole (CYP3A4 inhibitor) resulted in minimal impact on the 
exposure of TD-9855 while concomitant administration of fluvoxamine (CYP1A2 inhibitor) 
resulted in significant increase in TD-9855 exposure. Additionally, TD-9855 exposure was 
lower in subjects who are smokers as compared to nonsmokers. Accordingly, it is expected 
that TD-9855 metabolism is primarily driven by the CYP1A2 enzyme. Restrictions on the 
concomitant use of strong CYP1A2 inhibitors and inducers are described in Section 6.7. 
6.5.2. 
Impact of TD-9855 on Other Medications 
In vitro evaluation indicates that clinical drug-drug interactions due to CYP450 metabolism 
or transporters with TD-9855 as the perpetrator are not anticipated in humans. Thus, no 
clinical studies have been conducted and no impact on exposure of concomitant medications 
is expected. 
6.6. 
Rescue Medications 
Usage of any rescue medications is discouraged during the course of the study. However, 
under exceptional circumstances, based on the discretion of the Investigator and to ensure 
subject’s safety, midodrine is permitted as follows: 
• A maximum of 10mg (increments of 2.5mg are available) may be administered, one 
day per week 
• Cannot be used on the assessment days 
Dosing instructions will be provided by the Investigator as dosing for this medication will 
differ between subjects. Subjects will record their use of midodrine in the Midodrine Rescue 
Medication Diary. Midodrine use will be captured in the database. Refer to Appendix 6.  
6.7. 
Prohibitions and Restrictions 
The following are prohibited or restricted during study participation as specified: 
• For the De Novo Group, subjects must stop the concomitant use of strong 
CYP1A2 inhibitors and inducers 7 days or 5 half-lives, whichever is longer, prior 
to V1. This restriction applies to concomitant medications, herbal supplements 
(e.g., St. John’s Wort), and ordinary dietary intake. Refer to Appendix 7 for a list 
of prohibited medications.  
• Prescribed medications for OH other than fludrocortisone are prohibited  
• Alpha blockers are prohibited (e.g., Prazosin, Terazosin, Doxazosin, Silodosin, 
Alfuzosin, Tamsulosin) 
• Norepinephrine reuptake inhibitors (NRIs) and serotonin and norepinephrine 
reuptake inhibitors (SNRIs) are prohibited 
− NRIs (e.g. atomoxetine and reboxetine) and SNRIs (e.g. duloxetine, 
milnacipran, levomilnacipran, venlafaxine, desvenlafaxine) 

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• Psychostimulants (e.g. amphetamine, dextroamphetamine, methylphenidate, 
pemoline) are prohibited 
• Subjects will be requested to refrain from making any significant dietary changes 
throughout the duration of the study. During their scheduled visits, subjects should 
be reminded to maintain an adequate fluid intake. 
6.8. 
Discontinuation 
6.8.1. 
Dose Stopping Rules 
Any subject meeting 1 or more of the following stopping criteria will be required to 
immediately discontinue dosing with study medication and subsequently subject will be 
discontinued from participation in the study:  
• A determination from the Investigator that further administration of the study 
medication may pose a safety concern to the subject 
• Sustained (at least 4 hours) SBP ≥180 mmHg or diastolic BP (DBP) ≥110 mmHg 
after 3 min of standing or after 5 min in the sitting position, or a sustained (at least 
4 hours) SBP ≥180 mmHg or DBP ≥110 mmHg measured in the supine state 
(head/torso elevated at approximately 30o from horizontal position).  
• Intolerable AE as determined by the Investigator 
• Subject becomes pregnant 
6.8.2. 
Subject Discontinuation 
Any subject (or his or her legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The Investigator must withdraw from 
the study any subject who requests to be withdrawn. A subject’s participation in the study 
may be discontinued at any time at the discretion of the Investigator and in accordance with 
his or her clinical judgment. When possible, the tests and evaluations listed for the 
termination visit should be completed. If a subject withdraws before completing the study, 
the reason for withdrawal is to be documented on the CRF. 
The sponsor will be notified of all subject withdrawals. 
Reasons for which the Investigator may withdraw a subject from the study or a subject may 
choose to terminate participation before completion of the study include, but are not limited 
to, the following: 
• Adverse Event 
• Physician Decision 
• Pregnancy 
• Protocol Violation 
• Withdrawal by Subject 
• Other  
The subject may also discontinue from the study if the study is discontinued by the Sponsor  

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Subjects who discontinue study medication early because of an adverse reaction should be 
encouraged to continue their participation in the follow-up safety assessments. If a subject 
fails to return for scheduled visits, a documented effort must be made to determine the 
reason. 
6.8.3. 
Subject Replacement 
Subjects will not be replaced. 
6.8.4. 
Study Discontinuation 
The sponsor reserves the right to discontinue this study at any time for any reason.  
Periodic review of unblinded safety data by an external IDMC (Section 8.8) may lead to the 
board’s recommendation of pausing dosing or terminating the study. In the event of 
premature study termination, best efforts to guarantee appropriate safety follow-up of 
subjects who have already been enrolled will be made and institutional review boards (IRBs) 
and the regulatory authorities will be informed. 
6.9. 
Pregnancy 
TD-9855 has been shown to be non-genotoxic in a standard battery of genotoxicity assays 
(in vitro Ames and chromosomal aberration assays and in vivo micronucleus assay in rat). 
TD-9855 demonstrated effects on neonatal mortality and decreased rates of pup growth in the 
pre- and postnatal study in rats. Based on the NOAEL in reproductive-toxicology studies in 
preclinical species, there exists a greater than 100x margin between exposure in preclinical 
species at NOAEL vs. exposure in male and female subjects at 4 weeks post stopping 
administration of 10-mg TD-9855 dose. Thus, application of pregnancy prevention measures 
for 30 days post last dose of TD-9855 is sufficient to address the risk of substantial drug 
exposure in semen or maternal circulation. 
To confirm the absence of pregnancy in female subjects of childbearing potential, urine 
bHCG testing will be performed during specified visits, as listed in the Schedule of Study 
Procedures (Table 1). If the urine bHCG test is positive, a serum bHCG test must be 
performed. The pregnancy test must be confirmed negative for a subject to be eligible for this 
study unless the PI deems the test is falsely positive.  
If a subject becomes pregnant while taking TD-9855, or during the 30 days after the last dose 
of treatment, the pregnancy must be reported to the sponsor’s medical monitor (or designee) 
immediately (within 24-hours) by following the procedures for SAE reporting as outlined in 
Section 7.4.3. Study drug must be discontinued for any pregnant subject still on study drug 
treatment. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.   

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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
The definitions below are based on International Council for Harmonization (ICH) guideline 
E2A, “Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting.” 
7.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a clinical trial subject administered a 
pharmaceutical product that does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product.  
• AEs may be new events. 
• AEs may be preexisting events that increase in frequency, severity, or change in 
nature or seriousness during or as a consequence of participation in clinical 
studies. 
• AEs may be pre- or posttreatment complications that occur as a result of a 
protocol-mandated procedure (such as a biopsy). 
• AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigation (e.g., laboratory results, x-ray 
findings). 
• AEs may result from an overdose of the study medication.  
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) should 
be recorded as the AE term. 
An AE does not include the following: 
• Medical or surgical procedures (such as surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an AE 
• Pre-existing diseases or conditions present or detected before signing an informed 
consent form (ICF) that do not worsen 
• Situations where an untoward medical occurrence has not occurred (such as 
hospitalization for elective surgery or social and/or convenience admissions) 
• Overdose of either study medication or concomitant medication without any signs 
or symptoms, unless the subject is hospitalized for observation 
Any medical condition or clinically significant laboratory abnormality with an onset date 
prior to the time the subject signed the ICF is considered to be preexisting and should be 
documented in the medical history CRF. 
 
 

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Pregnancy is not an AE; however, if a female subject becomes pregnant during the conduct of 
the study, the sponsor will be notified according to the procedures for SAE reporting as 
outlined in Section 7.4.3. Follow-up information regarding the outcome of the pregnancy and 
any fetal or neonatal sequelae will be obtained and documented. 
7.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence occurring at 
any dose that results in any of the following outcomes: 
• Death 
• Life-threatening situation. “Life threatening” refers to a situation in which the 
subject was at risk of death at the time of the event; it does not refer to an event 
which might have caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization 
Note: “Inpatient hospitalization” means the subject has been formally admitted to 
a hospital for medical reasons, for any length of time. This may or may not be 
overnight. It does not include presentation and care within an emergency 
department. A scheduled hospitalization for a preexisting condition that has not 
worsened during participation in the study does not meet this criterion. Preplanned 
hospitalizations for an elective medical/surgical procedure, scheduled treatments, 
or routine check-ups do not meet this criterion. Complications that occur during 
hospitalizations are AEs. If a complication prolongs hospitalization, it is an SAE. 
• Disability- A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Congenital anomaly/birth defect in the offspring of a subject who received study 
medication 
• Important medical events that may not result in death, be immediately life 
threatening, or require hospitalization, may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such events are as follows: 
− Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
− Blood dyscrasias or convulsions that do not result in hospitalization 
− Development of drug dependency or drug abuse 
7.1.3. 
Additional Considerations for Serious Adverse Events 
• Death is an outcome of an AE and not an AE in itself. Deaths of unknown cause 
for which the Investigator cannot identify a cause of death will be captured as 
death of unknown cause or death not otherwise specified. 
• All deaths, regardless of cause, must be reported for subjects if the death occurs 
while the subject is participating in the study. 
 
 

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• “Occurring at any dose” does not imply that the subject is receiving study 
medication at the time of the event; dosing may have been given as treatment 
cycles or interrupted temporarily before the onset of the SAE but may have 
contributed to the event. 
7.1.4. 
Adverse Event of Special Interest 
• At each study visit, the Investigator (or designee) will specifically query for any 
AESIs. The following events are considered AESIs for this study: 
− Supine hypertension 
− Cardiovascular events (myocardial infarction, cerebrovascular accident, 
cardiac arrhythmia, congestive heart failure) 
− Convulsion 
• All AESIs must be reported to Sponsor Clinical Safety and Pharmacovigilance 
within 24-hours of awareness by the Investigator or his/her designee. 
The SAE/AESI Report Form must be completed in accordance with the SAE/AESI Report 
Form Completion Guidelines. If all information on the SAE/AESI Report Form is not 
available at the time of the initial report, follow-up AESI reports will be completed and 
submitted.  
To report an AESI, complete and send the SAE/AESI Report Form to the following: 
Theravance Biopharma Clinical Safety 
Fax: 
(650) 808-3786 
Email: 
0170_Safety@theravance.com 
For medical questions regarding an AESI, contact the medical monitor by telephone as 
follows: 
Medical Monitor Contact Information:  
Telephone: 
+1 (650) 449-8840 (US) /  
353-1-566-8682 (Ireland) 
Email: 
0170_Medical@theravance.com 
For sites located in Mexico, Peru, Chile or Argentina:  
Email: 
0170_Medical_LATAM@theravance.com 

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7.2. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as ECGs, x-rays, or vital signs) that are associated with signs 
and/or symptoms or are considered clinically significant in the judgment of the Investigator 
must be recorded as AEs or SAEs if they meet the definition of an AE (or SAE), as described 
in Section 7.1.1 (Adverse Event) and Section 7.1.2 (Serious Adverse Event). 
If there are any AE questions, the Investigator is encouraged to contact the sponsor to 
discuss. 
7.3. 
Assessment of Adverse Events 
All AEs will be assessed by the Investigator and recorded in the CRF, including the dates of 
onset and resolution, severity, relationship to study medication, outcome, and action taken 
with study medication. 
7.3.1. 
Severity 
The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe nausea). This is not the same as 
“serious,” which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. The severity of AEs will be 
assessed according to the following definitions:  
• Mild: The AE is noticeable to the subject and/or the Investigator but does not 
interfere with routine activity. 
• Moderate: The AE interferes with routine activity but responds to symptomatic 
therapy or rest. 
• Severe: The AE significantly limits the subject’s ability to perform routine 
activities despite symptomatic therapy. 
7.3.2. 
Causal Relationship to Study Medication 
The Investigator’s assessment of causality is based on clinical judgment regarding the 
reasonable possibility that the study medication caused the event and may include 
consideration of some or all of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, 
comorbid conditions, other medications, and environmental factors. 
• The temporal association between drug exposure and onset of the AE.  
• Whether the clinical or laboratory manifestations of the AE are consistent with 
known actions or toxicity of the study medication. 
• Whether the AE resolved or improved with decreasing the dose or stopping the 
study medication (“de-challenge”) or recurred or worsened upon re-exposure to 
the study medication (“re-challenge”).  
 
 

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The causal relationship between the study medication and the AE will be described using one 
of the following categories: 
• Not Related: Evidence exists that the AE has an etiology other than the study 
medication (such as a preexisting condition, underlying disease, intercurrent 
illness, or concomitant medication). 
• Related: A temporal relationship exists between the event onset and 
administration of the study medication. It cannot be readily explained by the 
subject’s clinical state or concomitant therapies and appears with some degree of 
certainty to be related based on the known therapeutic and pharmacologic actions 
of the drug. In case of cessation or reduction of the dose, the event abates or 
resolves and reappears upon re-challenge. It should be emphasized that ineffective 
treatment should not be considered as causally related in the context of AE 
reporting. 
7.4. 
Adverse Event Reporting and Recording 
7.4.1. 
Adverse Event Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
trials is crucial for the protection of subjects and is mandated by regulatory agencies. The 
sponsor has established standard operating procedures (SOPs) in compliance with regulatory 
requirements worldwide to ensure appropriate reporting of safety information. All clinical 
trials sponsored by Theravance Biopharma will be conducted in accordance with these 
procedures. 
7.4.2. 
Adverse Event and Serious Adverse Event Recording 
All AEs, regardless of seriousness, severity, or causal relationship to study medication, will 
be recorded from signing informed consent through the last study visit (or last subject contact 
in the case of a follow-up telephone call). The AEs will be recorded on the AE page of the 
CRF. The SAEs, regardless of relationship to study medication will be recorded from signing 
informed consent through the last study visit (or last subject contact in the case of a follow-up 
telephone call). *Exception for Subjects entering from Study 0169 (0169 Completers 
Group): Adverse Events, including Serious Adverse Events, that start after the Study 0170 
ICF is signed, but before the first dose on Study 0170 is taken, are considered events 
originating in Study 0169. Additionally, Investigators may report SAEs assessed as related to 
study medication through 30 days following the last study visit (or last subject contact in the 
case of a follow-up telephone call). All SAEs will be recorded on both the SAE/AESI Report 
Form and the AE page of the CRF and should include the following:  
 
 

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Description of event:  
• Signs and symptoms due to a common etiology should be reported as a single 
diagnosis; for example, cough, runny nose, sneezing, sore throat, and head 
congestion would be reported as “upper respiratory infection.”  
• A diagnosis or description must be as specific and as complete as possible 
(e.g., “lower extremity edema” instead of “edema”).  
• Hospitalization or surgical procedures should not be used as AE terms (e.g., if a 
subject was hospitalized for cholecystectomy due to cholecystitis, the AE term 
should be recorded as cholecystitis, and not as the procedure, cholecystectomy).  
• “Death” should not be used as an AE term unless the cause of death is unknown. 
For events with a fatal outcome, the cause of death should be the AE term (e.g., if 
a subject died of an acute myocardial infarction, the AE term should be recorded 
as “Myocardial Infarction” and the event outcome as fatal).   
Relationship to study medication: The Investigator will make an assessment of the causal 
relationship of the study medication to the AE using the guidelines in Section 7.3.2.  
Severity: The severity of the AE will be assessed using the guidelines in Section 7.3.1. 
Outcome: The outcome of AEs will be recorded.  
Therapeutic measures: Measures taken for the treatment or management of the AEs will be 
recorded. 
7.4.3. 
Serious Adverse Event and Adverse Event of Special Interest Reporting 
Timeline 
All SAEs and AESIs must be reported to Clinical Safety and Pharmacovigilance within 
24-hours of the time the Investigator or his/her designee becomes aware that an SAE or AESI 
has occurred, whether or not the event is considered to be related to study medication. If the 
initial SAE or AESI is reported by telephone, a written report signed by the Investigator must 
be submitted within 24-hours.  
The SAE/AESI Report Form must be completed in accordance with the SAE/AESI Report 
Form Completion Guidelines. If all information on the SAE/AESI Report Form is not 
available at the time of the initial report, follow-up SAE or AESI reports will be completed 
and submitted.  
To report an SAE or AESI, complete and send the SAE/AESI Report Form to the following: 
Theravance Biopharma Clinical Safety 
Fax: 
(650) 808-3786 
Email: 
0170_Safety@theravance.com 
 
 
 

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For medical questions regarding an SAE or AESI, contact the medical monitor by telephone 
as follows: 
Medical Monitor Contact Information:  
Telephone: +1 (650) 449-8840 (US) /  
 
353-1-566-8682 (Ireland) 
Email: 
0170_Medical@theravance.com 
For sites located in Mexico, Peru, Chile or Argentina: 
Email:          0170_Medical_LATAM@theravance.com 
For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, 
and other documents when requested. Additional information may be requested from the 
Investigator to ensure the timely completion of accurate safety reports. 
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable 
to the study medication and is unexpected/unlisted based on the current TD-9855 IB. In this 
case, all Investigators will receive notification of the event. The Investigator is responsible 
for notifying the Institutional Review Board or Ethics Committee and documenting the 
notification, as required by local regulatory authorities and in accordance with the local 
institutional policy. 
7.5. 
Adverse Event Follow-up 
A subject experiencing an AE, AESI, or SAE will be followed by the Investigator or his/her 
trained delegate(s) through the follow-up visit or until the Investigator and/or the sponsor has 
determined that the AE, AESI, or SAE has resolved or a stable clinical endpoint is reached, 
whichever is longer. The sponsor may request follow-up of certain AEs until resolution and 
documentation of assessments made during this period. 
The Investigator must take all therapeutic measures necessary for resolution of an AE. Any 
medications necessary for treatment of the AE must be recorded in the concomitant 
medication section of the CRF. 

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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
All data for each subject will be listed as collected. All statistical summaries and analyses 
will be performed using SAS software (SAS Institute, Cary, North Carolina, US). 
Continuous data will be summarized using an 8-point descriptive summary (n, mean, 
standard deviation, median, interquartile range [25% quartile, 75% quartile], minimum, and 
maximum) unless otherwise specified in the statistical analysis plan (SAP) or table shell. 
Categorical data will be summarized using counts and percentages. 
For analysis, Day 1 is defined as the day of the first study medication dose. The preceding 
day is Day –1. 
Baseline is the last assessment (scheduled or unscheduled) obtained before start of study 
medication dosing for each phase of the study (OL or double-blind randomized withdrawal 
phase), unless otherwise specified in the SAP. Baseline for endpoints that have more than one 
component is calculated from the individual component baselines, whether or not they were 
assessed during the same visit. 
Any changes to the data summaries and analyses outlined in this section will be described in 
the applicable SAP. Any changes to the definition of the endpoints will also be included in a 
protocol amendment. 
8.2. 
Sample Size and Power 
Assuming that 60% are eligible for randomization at the end of the 16-week OL period, 
approximately 258 subjects will be enrolled such that 154 subjects are expected to continue 
into the randomized treatment period. For the De Novo Group, the goal is to enroll at least 
40% of MSA subjects. 
The primary analysis will occur when all subjects in the Full analysis set (FAS) 
(Section 8.3.2) of double-blinded randomized withdrawal phase of the study have either 
completed the primary endpoint assessment (OHSA#1 and PGI-S at Week 6 post 
randomization) (V9, D155)) or discontinued earlier and the database has been cleaned and 
locked. A sample size of 154 at randomization will provide an overall power of 90% to detect 
a difference of 25% (25% TD-9855 vs. 50% PBO) in the primary endpoint of proportion of 
subjects that meet the criteria of treatment failure at Week 6 (V9, D155) during the 
double-blind randomized withdrawal phase at two-sided alpha level of 0.05. 
8.3. 
Analysis Sets 
All efficacy analyses in the double-blind randomized withdrawal phase will be performed 
based on the FAS using the assigned randomized treatments. The FAS of the double-blind 
randomized withdrawal phase is defined as all randomized subjects who have received at 
least 1 dose of study medication post randomization. 
The per-protocol (PP) analysis set of the double-blind randomized withdrawal phase 
comprises all subjects in the FAS with no major analysis protocol deviations (Section 8.3.2). 
If the number of FAS subjects excluded from the PP analysis set is <5% per treatment group, 
PP analyses will not be performed. Otherwise, both the FAS and the PP analysis set will be 
used for selected efficacy summaries and analyses. 

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The safety analysis set (Safety set) of the double-blind randomized withdrawal phase is 
comprised of all randomized subjects who receive at least 1 dose of study medication. The 
safety analysis set will be the analysis set for both general (baseline, exposure, and 
compliance) and safety analyses in the double-blind randomized withdrawal phase. Subjects 
in the safety analysis set will be grouped according to the actual study treatments they 
receive.  
The FAS and Safety set for OL phase will be identical and is defined as all enrolled subjects 
who have received at least one dose of TD-9855.  
8.3.1. 
Examination of Subgroups 
Predefined subgroups will include, stratification stratum (i.e., disease type), gender, and 
smoking status. Additional subgroups may be predefined in the SAP. 
8.3.2. 
Major Protocol Analysis Deviations 
Protocol deviations will be identified separately for each phase of the study. The following 
protocol deviations are defined as major and would be considered to have an impact on the 
interpretation of efficacy results: 
• Poor study medication compliance (as calculated from drug accountability data), 
defined as compliance <80% over the interval from first to last dose in each phase 
of the study 
• Not meeting efficacy-related inclusion criteria or meeting efficacy-related 
exclusion criteria (criteria to be listed in the applicable SAP) 
• Using efficacy-related prohibited concomitant medications (to be listed in the 
applicable SAP) 
Additional criteria may be specified in the SAP. Subjects with major analysis protocol 
deviations will be identified before the database lock and provided in a listing. In addition, a 
listing of all protocol deviations will be provided. 
8.4. 
General Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in the SAP. Additional statistical analyses other than those described in 
this section may be performed and described in the SAP if deemed appropriate. 
The demographics, baseline characteristics, medical history and safety will be summarized 
separately for OL phase and double-blind randomized withdrawal phase. In the OL phase, 
data will be summarized for all subjects and by enrollment group (De Novo Group or 0169 
Completers Group). In the double-blind randomized withdrawal phase, data will be 
summarized by treatment group. 
All data as collected will be listed by subject. 
8.4.1. 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics including age, sex, race, ethnicity, height, weight, 
body mass index, and other medical history will be descriptively summarized. 

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8.4.2. 
Medical History 
Descriptive summary of medical history will be provided. 
8.5. 
Analysis of Efficacy 
8.5.1. 
Efficacy Endpoints 
The primary study endpoint is the proportion of treatment failure at Week 6 during the 
double-blind randomized withdrawal phase. Treatment failure is defined as subjects who 
meet the following criteria at Week 6 following randomization (V9, D155): 
Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening 
of disease severity as assessed by a 1-point change in PGI-S. 
The assessments done at the Week 16 (V6, D113) visit in the OL phase prior to 
randomization are considered baseline for the double-blind randomized withdrawal phase of 
the study.  Subjects who withdraw for any reason prior to V9 (D155) or subjects who fail to 
provide assessment at V9 (D155) will be considered as treatment failures. 
The secondary endpoints are: 
• Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155) 
Change from baseline in OHSA composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHDAS composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in PGI-S at Week 6 post randomization (V9, D155) 
• Change from baseline in percent of time spent in standing position as measured by 
a wearable device at Week 6 post randomization (V9, D155) 
• Change from baseline in average number of steps taken as measured by a 
wearable device at Week 6 post randomization (V9, D155) 
The exploratory endpoints are: 
• Standing systolic blood pressure during orthostatic standing test at Week 6 post 
randomization (V9, D155) 
• Change from baseline in OHQ overall composite score at Week 6 post 
randomization (V9, D155) 
• Change from baseline in EQ-5D-5L at Week 6 post randomization (V9, D155) 
• Non-Motor Symptom Scale (NMSS) at Week 6 post randomization (V9, D155) 
• Hospital Anxiety and Depression Scale (HADS) at Week 6 post randomization 
(V9, D155) 
• Burden Scale for Family Caregivers – short version (BSFC-s) at Week 6 post 
randomization (V9, D155) 
For subjects with PD 
• Change from baseline in UPDRS at Week 6 post randomization (V9, D155) 
• Change from baseline in PDQ-8 at Week 6 post randomization (V9, D155) 

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For subjects with MSA 
• Change from baseline in UMSARS at Week 6 post randomization (V9, D155) 
• Change from baseline in COMPASS-31 at Week 6 post randomization 
(V9, D155) 
8.5.1.1. 
Primary Efficacy Evaluation 
The primary study endpoint is the proportion of treatment failure at Week 6 during the 
double-blind randomized withdrawal phase. Treatment failure is defined as subjects who 
meet the following criteria at Week 6 following randomization: 
Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening 
of disease severity as assessed by a 1-point change in PGI-S. 
The assessments done at the Week 16 (V6, D113) visit in the OL phase prior to 
randomization are considered baseline for the double-blind randomized withdrawal phase of 
the study.  Subjects who withdraw for any reason prior to V9 (D155) or subjects who fail to 
provide assessment at V9 (D155) will be considered as treatment failures. 
Logistic regression model will be used to compare treatment differences based on the FAS. 
The model will include fixed effect class terms of treatment, baseline disease type 
(MSA, PAF, PD), and continuous covariate of baseline OHSA#1 score, and baseline PGI-S 
score. Odds Ratio with 95% confidence intervals will be calculated and presented, 
least-square proportion and 95% confidence intervals on the differences between TD-9855 
and placebo groups will be calculated and presented. In addition, the proportion of subject 
with treatment failure along with proportion of subjects failing separately due to worsening of 
OHSA#1 and PGI-S will be reported. 
Sensitivity analyses on the primary endpoint will be carried out (1) using per-protocol set 
which excludes subjects with major protocol deviations, (2) using multiple imputation for 
subject missing OHSA#1 and/or PGI-S score at Week 6 post randomization (V9, D155) and 
(3) by excluding subjects with missing data on primary endpoint. Additional sensitivity 
analyses may be defined in the SAP.  
The primary analysis will be repeated on a set of pre-specified subgroups (e.g., disease type) 
and presented in graphical format. Details will be specified in the Statistical Analysis Plan 
(SAP). 
8.5.1.2. 
Secondary and Other Efficacy Evaluations 
Secondary efficacy endpoints involving assessment of change from baseline at multiple time 
points such as OHSA#1, OHSA composite score, OHDAS composite score, and percent of 
time spent in supine, sitting and standing position as measured by a wearable device, will be 
analyzed using mixed model for repeated measures (MMRM) to compare treatment 
differences based on the FAS. The model will include fixed effect class terms of treatment, 
baseline disease type (MSA, PD, PAF), week, and continuous covariate of baseline score of 
the respective measure, a random subject effect, with an unstructured covariance structure. 
If the model doesn’t converge, compound symmetry or other covariance structures will be 
used as alternative covariance structure. Least-square means and 95% confidence intervals on 
the differences between TD-9855 and PBO will be calculated and presented. 

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Exploratory endpoints involving assessment of change from baseline at multiple time points 
such as standing SBP during orthostatic standing test will be analyzed using mixed model for 
repeated measures (MMRM) to compare treatment differences based on the FAS. 
Exploratory endpoints involving assessment of change from baseline but only at Week 6 such 
as PDQ-8, UPDRS, UMSARS, and COMPASS-31 an analysis of covariance (ANCOVA) 
will be used to compare treatment differences based on the FAS. The model will include 
fixed effect of treatment, baseline disease type (MSA, PD, PAF) and continuous covariate of 
baseline score of the respective scales.   
All other efficacy endpoints will be analyzed descriptively as supportive analysis. 
In addition, descriptive analysis of efficacy data collected during OL phase will be carried out 
for all subjects and summarized by enrollment group (De Novo Group or 0169 Completers 
Group). 
8.5.2. 
Multiplicity Adjustment 
If the treatment effect of the primary efficacy endpoint has been demonstrated, secondary 
efficacy endpoints (Section 8.5.1) will be tested via a statistical testing procedure, to be 
described in the SAP, that will protect the family-wise Type I error rate at 2-sided 
significance level of 5%. No statistical significance will be claimed after a failure to reject the 
null hypothesis has occurred. 
• Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155) 
• Change from baseline in OHSA composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in OHDAS composite score at Week 6 post randomization 
(V9, D155) 
• Change from baseline in PGI-S at Week 6 post randomization (V9, D155) 
• Change from baseline in percent of time spent in standing position as measured by 
a wearable device at Week 6 post randomization (V9, D155) 
• Change from baseline in average number of steps taken as measured by a 
wearable device at Week 6 post randomization (V9, D155) 
For all supportive analyses including other efficacy endpoints and sensitivity analyses of the 
primary efficacy endpoint, p-values and confidence intervals will be evaluated descriptively 
at 2-sided 5% significance level with no adjustment for multiplicity. 
8.5.3. 
Analysis of Pharmacokinetics 
All PK data collected in the study will be listed. PK analyses will follow the PK SAP and be 
reported in a separate Population-PK report.  
8.5.4. 
Analysis of Pharmacodynamics 
All pharmacodynamic data collected will be listed. Pharmacodynamic analyses will be detailed 
as appropriate in a separate report. 

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8.6. 
Safety Analyses  
Safety data, including C-SSRS, will be descriptively summarized separately for OL phase 
and double-blind randomized withdrawal phase.  
The OL phase data will be summarized for all subjects and by enrollment group (De Novo 
Group or 0169 Completers Group), and the double-blind randomized withdrawal phase data 
will be summarized by treatment group according to treatment subjects received. Quantitative 
data collected at unscheduled times will be listed but will not be included in summaries. 
Categorical data collected at unscheduled times (e.g., ECG finding categories) will not be 
included in summaries by time point but will be included in summaries of findings during the 
entire treatment period. 
Safety analyses will be performed using the safety analysis set.  Unless specified otherwise, 
there will be no imputation of missing data in safety summaries. Subjects without post 
baseline measurement (e.g. ECG or vital signs) for a given time point will be excluded from 
the summary statistic (e.g., denominator of the summary statistic) for that time point.  
8.6.1. 
Extent of Exposure 
Extent of exposure will be calculated from the study medication administration page of the 
CRF and summarized. Dosing information for individual subjects will be listed. Reasons for 
study medication discontinuation will be summarized. For each subject, treatment compliance 
over the interval from first to last dose will be calculated from the study medication 
administration and drug accountability pages of the CRF. Treatment compliance will be 
summarized for all subjects and by enrollment group in OL phase and by treatment group in 
the double-blinded randomized withdrawal phase. 
8.6.2. 
Adverse Event Data 
The AEs will be coded to the preferred terms (PTs) of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will be presented by system organ class (SOC), PT, and 
severity (mild, moderate, severe), along with the number and percentage of subjects for 
whom events were reported. 
For subjects continuing from OL phase to the double-blinded randomized withdrawal phase, 
an AE that begins on or after the date of the first dose of TD-9855 up to the date of last dose 
of TD-9855 in OL phase will be considered TEAE for OL phase. For subjects discontinuing 
the study during the OL phase, an AE that begins on or after the date of the first dose of 
TD-9855 and up to the date of last dose of TD-9855 plus 14 days follow-up period will be 
considered TEAE for OL phase. 
In the double-blinded randomized withdrawal phase, a TEAE is defined as any AE that 
begins on or after the date of the first dose of study medication post randomization and up to 
the date of last dose of study medication plus 14 days follow-up period. 
The number and percentage of subjects who experience TEAEs will be summarized. 
Summaries of TEAEs will include the following: 
• All AEs, by SOC and PT and also by PT (by descending overall frequency) 
• All AEs, by SOC, PT, and severity 
• All study medication-related AEs, by SOC and PT 
• All study medication-related AEs, by SOC, PT, and severity 

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• All AEs leading to premature discontinuation of study medication, by SOC and 
PT 
• All AEs leading to temporary interruption of study medication, by SOC and PT 
• All SAEs, by SOC and PT 
• All study medication-related SAEs, by SOC and PT 
All AEs reported will be listed by subject. A separate listing will be provided for all subjects 
who experience an SAE. Separate listings will also be provided for subjects who discontinued 
study treatment prematurely because of AEs and subjects who temporarily interrupted study 
treatment because of AEs. The AESIs, as described in Section 7.1.4, will be listed and 
summarized. 
8.6.3. 
Concomitant Medications 
All medications used during the 60 days prior to screening will be recorded in the source 
records. The only exception is drugs that were used to treat previous orthostatic hypotension; 
these will be recorded since the time of primary diagnosis. 
Medication names will be mapped according to the World Health Organization Drug 
Dictionary. Both prior and concomitant medications summaries will be provided, by drug 
class and preferred name.  
8.6.4. 
Laboratory Data 
Laboratory values, changes from baseline, values relative to normal ranges, and values and 
changes meeting specified criteria, will be summarized by nominal visit. 
Reference ranges provided by the laboratory for each test will be used to evaluate the clinical 
significance of laboratory test results. Values falling outside the relevant reference range will 
be flagged, as appropriate, in the data listings. Abnormalities in clinical laboratory test results 
will be listed in a separate listing. 
8.6.5. 
Vital Signs Data 
The HR, SBP and DBP, RR, and body temperature values at each visit and time point and 
changes from baseline at each visit and time point after the first dose will be summarized and 
counts and percentages will be shown for the categories. 
Table 2: Vital Sign Assessment Outlier Thresholds 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
8.6.6. 
Electrocardiogram Data 
The QTcF, PR interval, QT interval, QRS duration, and HR from standard digital ECGs will 
be summarized in terms of observed values, changes from baseline, and counts and 
percentages within appropriately defined categories. 

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Table 3: 
Electrocardiogram Test Outlier Thresholds 
Heart 
Rate 
(bpm) 
Heart Rate 
Change From 
Baseline 
(bpm) 
PR 
 Interval 
(msec) 
PR Percentage 
Change From 
Baseline (%) 
QRS 
 Interval 
(msec) 
QTcF 
(msec) 
QTcF 
Change 
From 
Baseline 
(msec) 
>120 
≥20 
≥ 200 
≥ 15 
≥ 120 
Males: 
≤ 30 
>130 
≥30 
≥ 220 
≥ 25 
  
< 430 
>30, ≤ 60 
  
  
 
  
  
≥ 430 
> 60 
  
  
 
  
  
≥ 450 
  
  
  
 
  
  
≥ 470 
  
  
  
 
  
  
≥ 480 
  
  
  
 
  
  
≥ 500 
  
  
  
  
  
  
Females: 
  
  
  
  
  
  
< 450 
  
  
  
  
  
  
≥ 450 
  
  
  
  
  
  
≥ 470 
  
  
  
  
  
  
≥ 480 
  
  
  
  
  
  
≥ 500 
  
In addition, QTcF (msec) will also be summarized by the following categories: Normal 
(males <430, females <450), Borderline (males [≥430, <450], females [≥450, <470]), and 
Prolonged (males ≥450, females ≥470). 
All recorded ECG interval values and ECG assessments will be presented in a by-subject 
listing. A separate listing of subjects with extreme values or changes, as specified in the SAP 
(e.g., values of QTcF ≥450 msec if male or ≥470 msec if female, QTcF increases from 
baseline >60 msec) will be provided. 
Treatment-emergent ECG abnormalities are defined as those not present at baseline, or those 
that worsened after treatment, e.g., borderline at baseline but were prolonged after treatment.  
When multiple values exist for the same nominal time point (e.g., triplicate reading), the 
average of the readings taken for ECG parameters will be used in the data analysis, including 
the outlier analysis stated below. 
Cumulative distribution plots will be provided for maximum change in QTcF by day. 

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8.7. 
Missing Data Handling 
Missing data in the MMRM analysis is assumed as missing at random (MAR) and will not be 
imputed for the analysis of the primary endpoint. Sensitivity analyses on the primary 
endpoint will be conducted using multiple imputation and excluding subjects with missing 
data on primary endpoint. 
Rules for imputation of missing safety data (e.g., missing or partial AE start dates) will be 
specified in the SAP. General principles are to count AEs as treatment emergent if they might 
have been, given the data obtained, and likewise to count medications as concomitant if they 
might have been, given the data obtained. There will be no imputation of missing safety 
assessments (e.g., laboratory test results). 
8.7.1. 
Mitigation and Analysis Strategies in Response to COVID-19 
Subject-level data will be collected to capture details around any deviations resulting from 
COVID-19.  Data may include discontinuation of treatment, withdrawal from the trial, use of 
alternative or rescue treatments, missed endpoint ascertainment, and visit modality (e.g., in 
clinic vs remote visit). This information will be incorporated into the planned primary 
analysis and sensitivity analyses to assess potential impact associated with COVID-19. 
Further details will be provided in SAP. 
8.8. 
Independent Data Monitoring Committee 
There will be an external IDMC comprising 2 clinicians and a biostatistician. The sponsor 
will also perform ongoing blinded review of the safety data. 
The IDMC will act in an advisory capacity to the sponsor. The IDMC responsibilities will be 
detailed in a charter and will include but not be limited to the following: 
• Review the following documents before commencing activities as an IDMC: draft 
IDMC charter, Investigator brochure, study protocols, template informed consent 
form, blank case report forms, and data monitoring plans 
• Evaluate the progress of the study; timeliness and quality of the data; subject 
recruitment, accrual, and retention; risk versus benefit to subjects; and other 
factors that might affect the outcome of the study 
• Consider relevant information that may have an impact on subject safety or the 
ethics of the study 
• Make recommendations to the sponsor concerning continuation, termination, or 
other modifications to the study based on their observations of the study and its 
data.   
• Conduct routine review of efficacy and safety data according to a preplanned 
schedule.  
The Sponsor has enlisted an Independent Statistical Supporting Group (ISRG) to prepare and 
present reports to the IDMC to facilitate their data reviews. 

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9. 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1. 
Principal Investigator Responsibilities 
Before beginning the study, the PI at each site must provide to the sponsor or its designee 
either a fully executed and signed Form FDA 1572 (for US sites) or the equivalent 
information on the study-specific form. If applicable, a “Disclosure: Financial Interests and 
Arrangements of Clinical Investigators” form (Form FDA 3455; Financial Disclosure Form) 
should also be provided. For applicable studies, Financial Disclosure Forms must also be 
completed for all sub-Investigators who will be directly involved in the treatment or 
evaluation of research subjects in this study. (A sub-Investigator is defined in ICH E6 as any 
individual member of the clinical study team designated and supervised by the Investigator at 
a study site to perform critical study-related procedures and/or to make important 
study-related decisions [e.g., associates, residents, research fellows, research staff designated 
as Clinical Outcome Assessment (COA) raters].) 
The PI will ensure the following: 
• He or she will conduct the study in accordance with the relevant, current protocol 
and will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
• He or she will personally conduct or supervise the study, including oversight of 
the home health provider. 
• He or she will inform any potential subjects, or any persons used as controls, that 
the drugs are being used for investigational purposes and he or she will ensure that 
the applicable local and international regulatory requirements relating to obtaining 
informed consent at that site are met, for example in the US, compliance with 
Chapter 21 US Code of Federal Regulations (CFR) Part 50 and IRB review and 
approval in 21 CFR 56 is required and outside of the US, compliance with ICH E6 
and/or local regulatory requirements is required.  
• He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with applicable local and international harmonized 
regulatory requirements, for example in the US, 21 CFR 312.64 is required and 
outside of the US, compliance with ICH E6 and/or local regulatory requirements 
is required. 
• He or she has read and understands the information in the TD-9855 IB, including 
potential risks and side effects of the drug. 
• His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments. 
• He or she will ensure that adequate and accurate records in accordance with local 
and international regulatory requirements, and to make those records available for 
inspection, for example in the US, in accordance with 21 CFR 312.62 and 
21 CFR 312.68 and outside of the US, compliance with ICH E6 and/or local 
regulatory requirements is required. 
 
 

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• He or she will ensure that the IRB/ Independent Ethics Committee (IEC) complies 
with the local and international regulatory requirements (for example in the US, 
compliance with 21 CFR 56 is required and outside of the US, compliance with 
ICH E6 and/or local regulatory requirements is required), and other applicable 
regulations, and conducts initial and ongoing reviews and approvals of the study. 
He or she will also ensure that any change in research activity and all problems 
involving risks to human subjects or others are reported to the IRB/IEC. 
Additionally, he or she will not make any changes in the research without 
IRB/IEC approval, except where necessary to eliminate apparent immediate 
hazards to human subjects. 
• He or she agrees to comply with all other local and international regulatory 
requirements regarding the obligations of clinical Investigators and all other 
pertinent requirements, for example, in the US, 21 CFR 312, and outside of the 
US, ICH E6 and/or local regulatory requirements. 
9.2. 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the Investigator will obtain written confirmation 
that the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant 
with ICH and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to the 
sponsor or its designee. The protocol, ICF, IB, and any other appropriate written information 
provided to the subjects that the IRB/IEC/REB may require to fulfill its responsibilities will 
be submitted to the IRB/IEC/REB in advance of the study. The sponsor or its designee must 
approve the ICF and all subject recruitment materials before they are submitted to the 
IRB/IEC/REB. The study will not proceed until the Investigator has been notified by the 
sponsor that regulatory agency approval of the clinical trial (or acknowledgement of the 
notification if applicable) has been received and appropriate documents from the 
IRB/IEC/REB confirming unconditional approval of the protocol and the ICF are obtained by 
the Investigator and copies are received by the sponsor or its designee. If possible, the 
approval document should refer to the study by study protocol title and the sponsor study 
number, identify the documents reviewed, and include the date of the review and approval. 
The written approval of the IRB/IEC/REB will be retained as part of the study file. The study 
may proceed before approval of consent forms and other study documents translated to a 
language other than the native language of the clinical site, provided that written 
IRB/IEC/REB approval of the translated documents is obtained before they are used. Any 
amendments to the protocol should be reviewed promptly. 
The Investigator must provide the appropriate periodic reports on the progress of the study to 
the IRB/IEC/REB and the sponsor in accordance with local IRB/IEC/REB requirements and 
applicable governmental regulations, whichever is strictest. 

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9.3. 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (GCP Guideline, 
Section 4.8), 21 CFR 50, and other applicable local regulations, will be obtained for each 
subject before enrollment of the subject into the study. The Investigator will prepare the ICF 
or revise the template ICF and provide the documents to the sponsor (or designee) for 
approval before submission to the IRB/IEC/REB. The sponsor and the IRB/IEC/REB must 
approve the documents before they are implemented. 
The Investigator will provide copies of the signed ICF to each subject (or the subject’s legally 
authorized representative) and will maintain the original in the subject’s record file. 
9.4. 
Data Recording and Quality Assurance 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used. 
A CRF (approved by the sponsor) is required and should be completed (in English) for each 
randomized subject. The Investigator has ultimate responsibility for the accuracy, 
authenticity, completeness, and timely collection and reporting of all clinical, safety, and 
laboratory data entered on the CRFs and any other data collection forms. The Investigator 
must review and sign the CRFs to attest that the data contained on the CRFs are correct. 
Electronic data capture (EDC) technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the electronic CRFs approved by the sponsor, 
or via other data collection methods, e.g., electronic clinical outcome assessments (eCOA), 
electronic laboratory data transfer. Study site personnel will enter (in English) study data into 
the CRFs for each subject that is screened. Training on systems used by site personnel 
(e.g. EDC, eCOA) or study subjects (e.g. eCOA) will be completed and documented before 
access to the EDC system is given. 
In the event of a CRF data change (e.g., correction of an error or addition of new 
information), corrections will be made to the CRF. Corrections to the CRFs, including the 
reason for change, will be automatically documented through the EDC system’s audit trail. 
The Investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The Investigator is designated as the signatory 
coordinating Investigator. 
An electronic copy of the CRF casebooks and eCOAs will be sent to the site for retention 
with other study documents after full completion of the study, i.e., after database lock. 
The Investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The Investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, 
computer discs, tapes, and worksheets). In most cases the source is the subject’s medical 
record. Data collected on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the Investigator’s site and clearly identify those data that will be 
recorded in the CRF and for which the CRF will stand as the source document. 

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9.5. 
Document Retention 
Until otherwise notified by the sponsor, an investigative site must retain in a controlled 
manner all study documents required by the sponsor and by the applicable regulations. The 
investigative site must take measures to prevent accidental or premature destruction of 
essential documents, that is, documents that individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, including paper copies of study 
records (e.g., subject charts) and any original source documents that are electronic, as 
required by applicable regulations. 
The Investigator must consult the sponsor representative before disposal of any study records 
and must notify the sponsor of any change in the location or disposition of the study files. 
If an Investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study documents, custody must be transferred to a person who will accept the 
responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian and must approve this transfer of responsibility. 
9.6. 
Confidentiality 
The Investigator or designee must explain to each subject, before enrollment into the study, 
that, for evaluation of study results, the subject’s confidential medical information obtained 
during the study may be shared with the study sponsor, the study sponsor’s affiliated 
companies, the study sponsor’s designated service providers, regulatory agencies, and the 
IRB or IEC. The Investigator (or designee) is responsible for obtaining written permission to 
use confidential medical information in accordance with country-specific regulations (such as 
the Health Insurance Portability and Accountability Act in the US) from each subject or, if 
appropriate, the subject’s legally authorized representative. If permission to use confidential 
medical information is withdrawn, the Investigator is responsible for documenting that no 
further data from the subject will be collected. 
Subject medical information obtained during this study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by 
the subject identification number, year of birth, and study number, and not by the subject’s 
full name, except the subject consent form, which is archived at the study center only. The 
subject’s name will not be used in any public report of the study. 
During the course of the study, a confidential subject identification list will be maintained by 
the Investigator and archived at the investigative site. 
Before and during the conduct of the study, no study-related details may be disclosed, 
i.e., placed on the internet, published, or otherwise publicized, or provided to a third party 
without prior written permission from the sponsor. The policy for publication of data after 
completion of the study is described in Section 9.9 (Publication). 

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9.7. 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original 
recordings, laboratory reports, and subject records generated by this study must be available 
to the sponsor, representatives of the sponsor, the IRB/IEC/REB, and applicable regulatory 
authorities, and they may be used for submission to regulatory authorities. In addition, all 
source data should be attributable (signed and dated), consistent with local medical practice. 
The Investigator must therefore agree to allow direct access to all source data. Subjects 
(or their legally authorized representatives) must also allow access to their medical records, 
and subjects will be informed of this and will confirm their agreement when giving informed 
consent. 
9.8. 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the sponsor will monitor all aspects of the study 
according to GCP and SOPs for compliance with applicable government regulations. The 
Investigator agrees to allow these monitors direct access to the clinical data and supplies, 
dispensing, and storage areas and, if requested, agrees to assist the monitors. The Investigator 
and staff are responsible for being present or available for consultation during routinely 
scheduled site visits conducted by the sponsor or its designees. 
Members of the sponsor’s GCP Quality Assurance Department or designees may conduct an 
audit of a clinical site at any time during or after completion of the study. The Investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Inspections and audits are typically carried out during the clinical and reporting phases of this 
study to ensure that the study is conducted and data are generated, documented, and reported 
in compliance with the protocol, GCP, written SOPs, and applicable laws, rules, and 
regulations. 
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives 
may also conduct an audit of the study. If informed of such an inspection, the Investigator 
should notify the sponsor immediately. The Investigator will ensure that the auditors have 
access to the clinical supplies, study site facilities, laboratory, and all data (including original 
source documentation), and all study files are available, if requested. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
Investigator, institution, institution staff, or representatives of the sponsor will lead to prompt 
action by the sponsor to secure compliance. Continued noncompliance may result in 
termination of the Investigator’s involvement in the study. The IRB/IEC/REB and relevant 
regulatory authority will be informed. 

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9.9. 
Publication 
The sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and presentation at seminars or 
conferences. The sponsor will retain the ownership of the data collected in this study. The 
Investigator will provide any proposed manuscript or abstract to the sponsor before 
submission for publication or presentation of any results or data obtained in this study. 
Additional details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Study 
Agreement between the sponsor and the Investigator. 

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10. 
REFERENCES 
1. Metzler M, Duerr S, Granata R, Krismer F, Robertson D, Wenning GK. Neurogenic 
orthostatic hypotension: pathophysiology, evaluation, and management. J Neurol. 
2013 Sept;260(9):2212-9. doi: 10.1007/s00415-012-6736-7. Epub 2012 Nov 20. 
2. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological 
approach. Circulation. 2009 Jan 6;119(1):139-46. doi: 
10.1161/CIRCULATIONAHA.108.805887. 
3. Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W, Tassinari M. EFNS 
guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neurol. 
2006 Sep;13(9):930-6. 
4. Goldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ. Sympathetic 
cardioneuropathy in dysautonomias. N Eng J Med. 1997 Mar 6;336(10):696-702. 
5. Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine 
(3-hydroxytyramine) in the human brain and their behavior in diseases of the 
extrapyramidal system. Parkinsonism Relat Disord. 1998 Aug;4(2):53-7. 
6. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the 
development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004 
Oct;318(1):121-34. Epub 2004 Aug 24. 
7. Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, et al. Norepinephrine 
transporter blockade with atomoxetine induces hypertension in patients with impaired 
autonomic function. Hypertension. 2007 Jul;50(1):47-53. Epub 2007 May 21. 
8. Ramirez CE, Okamoto LE, Arnold AC, Gamboa A, Diedrich A, Choi L, et al. 
Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension 
in autonomic failure. Hypertension. 2014 Dec;64(6):1235-40. doi: 
10.1161/HYPERTENSIONAHA.114.04225. Epub 2014 Sep 2. 
9. Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The 
Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom 
assessment scale. Clin Auton Res. 2012 Apr;22(2):79-90. doi: 10.1007/s10286-011-
0146-2. Epub 2011 Nov 2. 
 

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APPENDIX 1. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:   
0170 
Protocol Title:  
A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of 
TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension 
in Subjects with Primary Autonomic Failure 
Version: 
1.0 (Amendment 4) 
Version Date: 
05 August 2020 
 
 
I have read the protocol described above and agree to conduct this study in accordance with 
the procedures described therein. I also agree to conduct the study in compliance with all 
applicable regulations. 
 
 
 
Investigator’s Name (print) 
 
 
 
Investigator’s Signature 
 
Date 

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APPENDIX 2. EXAMPLES OF DISEASE INSTRUMENTS 
Appendix 2-1 
 

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Appendix 2-2 
 
 
 
 
 

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Appendix 2-3 
 

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Appendix 2-4 
 
 
 
 
 
 

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Appendix 2-5 
 

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Appendix 2-6 
 

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Appendix 2-7 
 

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Appendix 2-8 
 
 

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Appendix 2-9 
 
 
 
 
 
 

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Appendix 2-10 
 

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Appendix 2-11 
 
 
 
 

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Appendix 2-12 
 
 

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Appendix 2-13 
 
 
 

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APPENDIX 3. INCIDENCE OF FALLS 
  

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APPENDIX 4. AMBULATORY BLOOD PRESSURE MONITORING - 
POSITION DIARY 
 

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APPENDIX 5. DOSING DIARY 
 

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APPENDIX 6. MIDODRINE RESCUE MEDICATION DIARY 
 

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APPENDIX 7. PROHIBITED MEDICATIONS 
The following are restricted during study participation as specified: 
• Strong CYP1A2 inhibitors and inducers. This restriction applies to concomitant 
medications, herbal supplements, and ordinary dietary intake and include, but are 
not limited to the following:   
− Angelica root, St John’s Wort, ciprofloxacin, clinafloxacin, enoxacin, 
fluvoxamine, oltipraz, rofecoxib, zafirlukast 
• Prescribed medications (e.g. droxidopa, etc.) for OH other than fludrocortisone are 
prohibited  
• Alpha blockers are prohibited (e.g., Prazosin, Terazosin, Doxazosin, Silodosin, 
Alfuzosin, Tamsulosin) 
• Norepinephrine reuptake inhibitors (NRIs) and serotonin and norepinephrine 
reuptake inhibitors (SNRIs) are prohibited 
− NRIs (e.g. atomoxetine and reboxetine) and SNRIs (e.g. duloxetine, 
milnacipran, levomilnacipran, venlafaxine, desvenlafaxine) 
• Psychostimulants (e.g. amphetamine, dextroamphetamine, methylphenidate, 
pemoline) are prohibited 
 

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APPENDIX 8. SAMPLE SCREENING VISIT FOR DENOVO 
SUBJECTS 
Study Period: 
Screening 
Study Day (Visit): 
Day -28 to -7 (Visit 1) 
Procedure 
Start Time 
Approximate 
Time for 
Subject 
Breakfast @ home and then travel 
8:00 AM 
1:00 
Hospital Visit 
9:00 AM 
0:30 
Informed consent (prior review) 
9:30 AM 
0:25 
Inclusion /exclusion criteria 
9:55 AM 
0:15 
Medical history (including smoking history) 
10:10 AM 
0:05 
Concomitant medications (and smoking usage) 
10:15 AM 
0:05 
MoCA 
10:20 AM 
0:10 
C-SSRS 
10:30 AM 
0:10 
OHQ subject training 
10:40 AM 
0:15 
Tilt-table test 
10:55 AM 
0:30 
Orthostatic standing test 
11:25 AM 
0:30 
Vital Signs (Body Temperature, Heart Rate, 
Respiration Rate, Blood Pressure) 
11:55 AM 
0:05 
Height (cm) 
12:00 PM 
0:02 
Weight (kg) 
12:02 PM 
0:03 
Physical examination 
12:05 PM 
0:05 
Neurological examination 
12:10 PM 
0:05 
12-lead electrocardiogram 
12:15 PM 
0:10 
Pregnancy test 
12:25 PM 
0:05 
Norepinephrine (NE) 
12:30 PM 
0:35 
Safety laboratory test (chemistry, hematology, and 
urinalysis) 
1:05 PM 
0:10 
Adverse events 
1:15 PM 
0:10 
ESC (for confirmation of diagnosis) 
1:25 PM 
0:10 
24-hour ambulatory BP device provision 
1:35 PM 
0:05 
Wearables 
1:40 PM 
0:15 
Incidence of Falls and ABPM position Diaries 
1:55 PM 
0:05 
Total Time (at 
Hospital): 
5:00 

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APPENDIX 9. OVERVIEW OF DECENTRALIZATION PLAN  
This appendix provides information for those sites who choose to conduct remote study visits 
for at least one of their subjects.  Detailed instructions for the conduct of both in clinic and 
remote study visits can be found in the Study Procedures Manual, which must be used in 
conjunction with the protocol. 
The Principal Investigator retains accountability for all data collected and processed for each 
study subject either via in clinic or remote visits.  Procedures to protect subject safety, subject 
privacy, and data integrity will be followed by all personnel (clinic and home health 
personnel) involved in study conduct.  
Rationale for Decentralized Platform:  
Considering the frailty of the symptomatic nOH subject population, the risk of future 
exposure to COVID-19 via in clinic visits, the unpredictable duration of the pandemic, 
and the potential for additional waves of the COVID-19 pandemic, the study will utilize an 
operational design featuring the ability for sites to conduct protocol required visits as either in 
clinic or remote visits.    
Selection of Visit Modality:  
The Screening visit for all De Novo subjects must be conducted in clinic, regardless of 
which visit modality is selected.    
Investigators, in discussion with each individual subject at their site, will be required to elect 
to conduct study visits either in the clinic or remotely. Sites must conduct the randomization 
withdrawal visits 6 through 9 (V6/D113 - V9/D155) for a given subject in a consistent 
manner to reduce the possibility of variability in data collection and reporting.  
Tools and systems are available to sites and subjects to support remote visits (e.g., direct to 
subject shipping of study medication and other study supplies, standardized HIPAA/GDPR 
compliant telemedicine platform, in-home health nurses).   
For those sites who opt to use remote visits (the decentralized platform) for study conduct, all 
required regulatory and ethics committee or IRB approvals will be obtained before utilization 
of remote study visits under the decentralized platform.    
Sites will use the most recent approved version of the Informed Consent Form to obtain 
subject consent for remote study visits. 
Due to the potential for resurgence of the COVID-19 pandemic and its impact on both sites 
and subjects, the Sponsor will allow Investigators to request exceptions to the selected type of 
study visit modality for V6/D113 through V9/D155 due to COVID-19 or COVID-19 related 
circumstances. Approved exceptions will be recorded as COVID-19 related protocol 
deviations. 

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Before a change in visit type from in clinic to remote is made, the Investigator will 
submit a request to the Sponsor via the established process. Theravance (or their designee) 
will review and respond to these requests as per established processes and 
timelines.  Requests for and approval of changes in visit type will be documented and 
retained in study records at the Investigator site.  
For De Novo subjects that have previously completed the Screening visit at the time 
regulatory and ethics approval for Amendment 4 is received, sites must reconsent the subject 
using the most recently approved version of the Informed Consent Form to obtain subject 
consent for remote study visits. For those subjects who are already randomized into the 
randomized withdrawal portion of Study 0170 and active in the study at the time regulatory 
and ethics approval for Amendment 4 is received, the Investigator and subject should 
continue the remaining study visits in the same visit modality as the Randomization Visit 
(V6/D113). 
Conduct of the Study and the Decentralized Platform:  
All sites will follow the protocol Schedule of Procedures (see Table 1 of the protocol) for 
study visit scheduling and protocol required procedures (either in clinic or remote).   Refer to 
the Study Procedures Manual for detailed instructions for conducting subject assessments in 
clinic and remotely. These instructions have been provided to ensure the method and conduct 
of each assessment is consistent across sites and subjects for both in clinic and remote 
visits.     
Training and mechanisms will be available to sites and subjects to support remote visits.  
Sites will continue to follow their established processes and procedures for the conduct of in- 
clinic study visits.  
 
 

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Study operations support for remote visits:  
Tools and systems are provided by the Sponsor and are available to sites and subjects to 
support remote visits: 
• A courier service has been engaged to ship investigational study drug and other 
study supplies to the subject (or designee).  
• A standardized HIPAA/GDPR compliant telemedicine platform will be provided 
so that site personnel can participate in remote visits that are conducted in the 
subject’s home (or designated location), utilizing Home Health Providers.  
• A Home Health Provider (HHP) service has been employed.    
• Medically qualified and trained HHP staff employed will visit the subject’s home 
(or designated location) and will work with Site Staff (SS) to conduct each remote 
study visit from the privacy of the subject’s home or designated location (such as 
a caregiver’s home).   
• During these remote visits, in coordination with Site Staff, the HHPs will use the 
Rater Station to facilitate collection of patient reported outcomes, will collect 
blood samples for safety labs and PK testing, will collect ECGs, and will measure 
the subject’s vital signs.  
• All data collected during the remote visits will be transferred to the Investigator 
and the study site via established processes (either electronically or on paper). 
Data signifying where the visit was conducted (in clinic or remote), how the data were 
collected, and who collected data remotely will be recorded in subject source documents and 
in the clinical study database. 
A Home Health Provider Delegation Log will be used to record the names of HHP 
professionals who assist Site Staff with the conduct of the remote visits.  This separate 
delegation log will distinguish between those individuals who are part of the site staff 
(recorded on Site Delegation Log) and those who are employed by the HH Provider.   
Logistics Arrangements for Remote Visits: 
For remote study visits, the home health personnel conducting the visit will be notified by the 
clinic-based study staff of each upcoming scheduled visit for the study subject(s).  The clinic-
based staff will coordinate with the home health personnel to ensure access to all necessary 
subject source documents, required equipment, and procedural instructions to complete the 
remote assessment.  
Clinic-based staff will participate in the remote study visit(s) via the established telemedicine 
platform available for the study.   
Home health personnel will transfer the source documents completed during the remote visit 
to the Investigator’s site via established processes.  Home health personnel will transfer via 
established secure means the data collected in electronic format to the appropriate data 
repository for inclusion in the clinical database. 
Data collected in paper format (subject diaries and any handwritten source notes) will be 
retrieved by HHP during the remote visit and will be returned to the Investigator’s site.  
Appropriate technical support and training will be provided to facilitate remote conduct of 
required study assessments.   

Protocol 0170, Amendment 4 
Version 1.0, 05AUG2020 
TD-9855 (ampreloxetine) 
Page 159 of 159 
 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
Laboratory samples collected by home health personnel during the remote visit will be 
prepared for shipment to designated laboratories following established collection and 
shipping procedures. 
Summary:  
In closing, the tools, mechanisms, and processes put into place as part of the Decentralized 
Platform support sites and subjects who choose remote visits.  Further, they protect subject 
safety, privacy, and consistency in data collection and reporting.  In the event of future 
resurgences of the COVID-19 pandemic, these tools, mechanisms, and processes will be 
available to sites and subjects who have selected the in clinic visit modality