Clinical trial NCT03750552
Conditions: Symptomatic Neurogenic Orthostatic Hypotension
Keywords: Symptomatic Neurogenic Orthostatic Hypotension symptomatic nOH multiple system atrophy MSA Parkinson's disease PD pure autonomic failure PAF primary autonomic failure SEQUOIA ampreloxetine low blood pressure dizziness fainting blacking out lightheadedness norepinephrine hypotension Parkinsonism TD-9855 Neurogenic Orthostatic Hypotension nOH 0145 145 169 0169 TD9855
Sponsor: Theravance Biopharma
Start date: 2019-01-24; Completion date: 2021-07-21
Enrollment: 195 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH with up to 4 weeks of treatment.

Detailed description:
A Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and symptomatic nOH. The study consists of 3 periods: (i) 4-week screening, (ii) 4-week randomized treatment, and (iii) 2-week follow up. The trial utilizes an operational design featuring the ability to conduct protocol required visits as either in clinic or remote visits (except Screening visit).

Arms: arm 1: Participants randomized to ampreloxetine will receive a single, oral, daily dose of active drug for 4 weeks. arm 2: Participants randomized to Placebo will receive a single, oral, daily dose of placebo for 4 weeks.
Interventions: intervention 1: ampreloxetine intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet, QD intervention 2: Oral tablet, QD

Protocol documents:
Prot_000.pdf: 
Protocol Number: 0169 
Official Title: A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in 
Subjects With Primary Autonomic Failure 
NCT Number: NCT03750552 
Document Date: 05 August 2020


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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, 4-week, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study of TD-9855 in 
Treating Symptomatic Neurogenic Orthostatic Hypotension in 
Subjects With Primary Autonomic Failure 
Study Short Title: 
Phase 3 Clinical Effect of TD-9855 for Treating symptomatic 
nOH in Subjects With Primary Autonomic Failure (Sequoia 
Study) 
Sponsor Study No.: 
0169 
Date: 
05 August 2020 
 
  
 
 
Test Product: 
TD-9855 (ampreloxetine hydrochloride) tablets 
US IND: 
129797 
EudraCT No.: 
2018-003289-15 
Sponsor: 
Theravance Biopharma Ireland Limited  
Connaught House 
1 Burlington Road 
Dublin 4  
D04 C5Y6 
Ireland 
Clinical Study Director: 
 
 
Theravance Biopharma Ireland Limited 
 
 
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, Inc. (Unpublished Work). All rights reserved. 


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PROTOCOL SYNOPSIS 
Study Number and Title: Study 0169: A Phase 3, 4-week, Multicenter, Randomized, 
Double-blind, Placebo-controlled, Parallel-group Study of TD-9855 in Treating 
Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic 
Failure. 
Study Short Title: Phase 3 Clinical Effect of TD-9855 for Treating symptomatic nOH in 
Subjects with Primary Autonomic Failure (Sequoia Study). 
Estimated Number of Study Centers and Countries or Regions: 
 
 
Background and Rationale:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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PROTOCOL SYNOPSIS (CONTINUED) 
 
 
Confidential – Property of Theravance Biopharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 


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Objectives: 
The primary objective of the study is: 
• To evaluate the efficacy of TD-9855 in subjects with multiple system atrophy 
(MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) experiencing 
symptomatic neurogenic orthostatic hypotension (symptomatic nOH) compared 
with placebo at Week 4, as measured by the change from baseline of the 
Orthostatic Hypotension Symptom Assessment (OHSA) Question 1 (OHSA#1) 
score. 
The secondary objectives of the study are as follows: 
• To evaluate the efficacy of TD-9855 by symptom and activity assessments using 
OHSA and the Orthostatic Hypotension Daily Activity Scale (OHDAS). 
• To evaluate the efficacy of TD-9855 using the Patient Global Impression of 
Change (PGI-C). 
• To evaluate the efficacy of TD-9855 in preventing incidence of falls. 
• To evaluate the safety and tolerability of TD-9855, including adverse events 
(AEs) and changes in blood pressure (BP), heart rate (HR), electrocardiogram 
(ECG), Columbia Suicide Severity Rating Scale (C-SSRS) and laboratory tests. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design:  
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study to evaluate efficacy, safety, and tolerability of TD-9855 in subjects with primary 
autonomic failures (MSA, PD, or PAF) and symptomatic nOH after 4 weeks of treatment.  


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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 must conduct all study visits for Study 0169 for a given subject in a 
consistent manner to reduce the possibility of variability in data collection and reporting. 
Therefore, Investigators, in discussion with each individual subject at their site, will be 
required to elect to conduct all visits either in the clinic or remotely.  Regardless of which 
election an Investigator and subject make, the Screening visit (V1) must be conducted in 
clinic for all subjects. 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 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 subjects that have previously completed the Screening visit at the time regulatory and 
ethics approval for 
 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 visit modality is selected by the Investigator and the subject. For 
those subjects who are already randomized to study treatment and active in the study at the 
time regulatory and ethics approval for 
 is received, the Investigator and 
subject should continue the remaining study visits in the same visit modality as the 
Randomization Visit. 
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. 


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• A score of at least a 4 on the Orthostatic Hypotension Symptom Assessment 
Question #1 
The study consists of 3 periods: (i) 4-week screening, (ii) 4-week randomized treatment, 
and (iii) 2-week follow up. The schematic representation is as shown below: 
  
After signing the informed consent, the subject will enter a screening period of up to 
4 weeks to confirm eligibility. At the Screening visit, which must be performed in the clinic 
for all subjects, the subject will provide a comprehensive medical history of their disease 
and treatments. The subject’s disease will be characterized and documented by the 
Investigator. 
The subject 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 (Table 1). The presence of symptomatic nOH symptoms and reported 
sensation of dizziness, lightheadedness, feeling faint, or feeling like blacking out 
(OHSA#1) must be confirmed by the application of a tilt-table test. This tilt-table test 
serves 2 purposes: (i) determination of the systolic/diastolic BP (DBP) changes, and 
(ii) training the subjects to recognize the sensations associated with OHSA#1. 
Eligible subjects will undergo training of accurate scoring of their sensation of dizziness, 
lightheadedness, feeling faint, or feeling like blacking out as outlined by the OHSA#1. 
Following the screening period, the subject will proceed to Visit 2 to further confirm the 
additional eligibility criteria prior to randomization. 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 applicable inclusion criteria and none of the 
applicable exclusion criteria, including confirmation of relevant criteria by the independent 
Enrollment Steering Committee (ESC), will be randomized to receive either TD-9855 or 
matching placebo for the next 4 weeks. 


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Following randomization and completion of study assessments, the subject will receive a 
 dose of TD-9855 (or matching placebo) once daily (QD) for the remaining 
double-blind treatment period. 
Weekly assessments will be conducted as outlined in the Schedule of Study Procedures 
(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.  
Discontinuation of subjects may occur at any time. Dose stopping criteria include meeting 
at least 1 of the following rules: 
 
 
 
 
 
 
 
 
  
 
 
 
 
No dose reduction is permitted at any time. 
Safety assessments will include a physical examination, neurological examination, vital 
signs (body temperature, HR and BP), body weight, ECGs, safety laboratory tests 
(hematology, chemistry, and urinalysis), C-SSRS, and AEs. 
Safety will be periodically reviewed by an independent data monitoring committee, see 
separate charter. 
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. 
Subjects completing the 4-week double-blind treatment period will be eligible to enroll and 
continue receiving study medication in Study 0170. The final study visit for those subjects 
who do not complete the 4-week double-blind treatment period or who choose not to 
continue into Study 0170 will be the follow-up visit (V7). This visit must be completed two 
weeks from the date of the last dose. 
Enrollment Steering Committee (ESC) 
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 


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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. 
Duration of Study Participation: 
Approximately 10 weeks 
Number of Subjects:  
 
 
 
Study Population:  
This study will enroll adult subjects with confirmed symptomatic nOH due to MSA, PD, or 
PAF and who meet all of the inclusion criteria and none of the exclusion criteria defined 
below. 
Inclusion Criteria: 
A subject who meets the following criteria will be eligible for study enrollment: 
1. Subject is male or female and at least 30 years old. 
2. Subject is female and must be nonpregnant and nonlactating. 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 
bHCG (beta human chorionic gonadotropin) 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 


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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 to ≥60o from a supine position as determined by a tilt-table test. 
5. Subject must score at least a 4 on the Orthostatic Hypotension Symptom 
Assessment Question #1 at randomization visit. 
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 clinic staff, 
understands the expectations of the study and is able to comply with the study 
procedures, requirements, and restrictions. 
Exclusion Criteria: 
A subject who meets any of the following criteria is not eligible for study enrollment: 
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) 
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. 


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4. Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, 
whichever is longer, prior to randomization 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 randomization visit.  
• Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior 
to randomization. 
6. Subject has a known or suspected alcohol or substance abuse within the past 
12 months (DSM-IV-TR® definition of alcohol or substance abuse). 
7. Subject has a clinically unstable coronary artery disease, or 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 
randomization. 
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 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 
nonregulatory agency approved drug (e.g., Food and Drug Administration). 
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 


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rate (eGFR) <30 mL/min/1.73m2, 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. 
Prohibitions and Restrictions: 
The following are prohibited or restricted during study participation as specified: 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
Subjects will be randomized 
 to receive either TD-9855 (test product) or 
placebo (reference product) once daily through the end of the treatment period. 
The test product will be TD-9855 supplied as
 
 
TD-9855 will be administered orally without regard to food at approximately the same time 
each morning and taken with approximately 8 ounces of water. 
Subjects randomized to receive TD-9855 will begin taking study medication on Day 2 in 
the morning at a 
 and will continue to take this dose once daily through the 
end of the treatment period. 
Reference Product, Dose, and Route of Administration; Regimen; Duration of 
Treatment:  
The reference product will be placebo tablets that are supplied to match TD-9855 in 
excipient content (except for TD-9855), appearance, tablet count, and in packaging 
(e.g., bottle label for reference product will be indistinguishable from test product except 
for a coded, unique bottle number). 
Placebo will be administered orally without regard to food at approximately the same time 
each morning and taken with approximately 8 ounces of water.  
Subjects randomized to receive placebo will begin taking study medication on Day 2 in the 
morning and will continue to take placebo once daily through the end of the treatment 
period. 
Study Evaluations  
Efficacy Assessments: 
• OHQ 
• PGI-C 
• Incidence of falls 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety and Tolerability Assessments: 
• Physical examination 
• Neurological examination 
• Vital signs, including ambulatory BP 
• Resting ECGs 
• Safety laboratory tests, including chemistry, hematology, and urinalysis 
• Concomitant medication 
• AEs 
• Subject compliance to study treatment 
• C-SSRS 
 
 
 
 
 
 
 
Statistical Methods  
 
 
 
 
 
 


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Study Endpoints: 
The primary study endpoint is the change from baseline in OHSA#1 (dizziness, 
lightheadedness, feeling faint, or feeling like blacking out) at Week 4. 
The secondary endpoints are: 
• Change from baseline in OHSA composite score in Weeks 1 to 4 
• Change from baseline in OHDAS composite score in Weeks 1 to 4 
• PGI-C at Week 4 
• Incidence of falls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
• Subject compliance to study treatment 
• C-SSRS 
Analysis: 
Analyses conducted based on the FAS will be based on the assigned randomized 
treatments. 
The safety analysis set will be defined as all randomized subjects who have received at least 
1 dose of study medication and subjects will be analyzed according to the actual study 
treatments they receive. 
Unless specified otherwise, all data will be summarized by treatment 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 efficacy evaluation is the change from baseline of OHSA#1 at Week 4. 
Baseline is defined as Day 1 pre-dose measurement. Mixed model for repeated measures 
(MMRM) will be used to compare treatment differences. The model will include fixed 
effect class terms of treatment, baseline disease type (MSA, PD, PAF), week, and 
continuous covariate of baseline OHSA#1 score, a random subject effect, with an 
unstructured covariance structure using the FAS. 
Least-square means and 95% confidence intervals on the differences between TD-9855 and 
placebo will be calculated and presented. 
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. The primary analysis will be 
repeated on a set of pre-specified subgroups and presented in graphical format. 
If the treatment effect of the primary efficacy endpoint has been demonstrated, the 
following secondary efficacy endpoints will be tested via 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% until a failure to reject the null hypothesis 
occurs.  No statistical significance will be claimed after a failure to reject the null 
hypothesis has occurred. 


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• Change from baseline in OHSA composite score at Week 4 
• Change from baseline in OHDAS composite score at Week 4 
• PGI-C at Week 4 
• Incidence of falls at Week 4 
Secondary efficacy endpoints involving assessment of change from baseline, such as OHSA 
composite score and OHDAS composite score, will be analyzed in a similar fashion as the 
primary efficacy endpoint of change from baseline in OHSA#1. 
The PGI-C will be summarized as number and percentage for subjects with ‘no change or 
better’ and ‘worse than no change’ at Week 4. Incidence of falls will be summarized as 
number and percentage of subjects with at least 1 fall at Week 4. These endpoints will be 
tested using Cochran-Mantel Haenzel chi-square test, stratified by disease type at baseline. 
For all supportive analyses including sensitivity analyses of the primary efficacy endpoint 
and exploratory endpoints, nominal p-values and 95% confidence intervals with no 
adjustment for multiplicity will be presented. 
Safety data will be listed by subject and summarized using the frequency of event or 
descriptive statistical summaries, as appropriate. Summary tables will be provided for 
physical examination, neurological examination, vital signs (body temperature, HR and 
BP), body weight, ECGs, safety laboratory tests (hematology, chemistry, and urinalysis), 
C-SSRS, AEs and concomitant medications. 
 


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Table 1: 
Schedule of Study Procedures 
Study Period: 
Screening a 
(in clinic) 
Treatment  
(All visits for each subject either in clinic or remote) 
Follow-up  
Study Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
Mandated Order of Procedures (when applicable) 
Informed consent 
X 
  
  
  
  
  
  
Inclusion /exclusion criteria 
X 
X 
  
  
  
  
  
Medical history (including smoking 
history)  
Xb 
  
  
  
  
  
  
Concomitant medications (and smoking 
usage) 
Xb 
X 
X 
X 
X 
X 
X 
MoCA 
X 
  
  
  
  
  
  
OHQ subject trainingc 
Xc 
X 
X 
X 
X 
X 
 
OHQ (OHSA and OHDAS) 
  
Xm 
X 
X 
X 
X 
 
PGI-C 
  
  
  
  
  
X 
  
C-SSRS 
X 
Xm,n 
Xn 
Xn 
Xn 
Xn 
X 
Tilt-table test 
Xd 
 
  
  
  
  
  
Randomization 
  
Xa 
  
  
  
  
  
Recommended Order of Procedures (when applicable) 
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  


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Table 1: 
Schedule of Study Procedures 
Study Period: 
Screening a 
(in clinic) 
Treatment  
(All visits for each subject either in clinic or remote) 
Follow-up  
Study Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Vital Signs (Body Temperature, Heart 
Rate, Respiration Rate, Blood Pressure)f 
X 
Xm 
X 
X 
X 
X 
X 
Height (cm) 
X 
  
  
  
  
  
  
Weight (kg) 
X 
Xm 
X 
X 
X 
X 
X 
Physical examination 
X 
Xm 
  
  
  
X 
  
Neurological examination 
X 
Xm 
  
  
  
X 
  
12-lead electrocardiogramg 
X 
  
  
  
  
X 
  
Pregnancy testh 
X 
Xm 
  
  
  
X 
  
Norepinephrine (NE) 
X 
  
  
  
  
  
  


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Table 1: 
Schedule of Study Procedures 
Study Period: 
Screening a 
(in clinic) 
Treatment  
(All visits for each subject either in clinic or remote) 
Follow-up  
Study Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
Safety laboratory test (chemistry, 
hematology, and urinalysis) 
X 
Xm 
  
X 
  
X 
  
 
  
 
 
 
  
 
 
 
  
 
  
  
  
 
  
ESC (for confirmation of diagnosis)a 
X 
  
  
  
  
  
  
24-hour ambulatory BP device 
provisionk 
X 
X  
  
X  
  
  
  
24-hour ambulatory BP device 
collectionk 
  
X 
X 
  
X 
  
  
Incidence of Falls and ABPM position 
Diaries 
X 
Xm 
X 
X 
X 
X 
  
Dosing and Midodrine rescue 
medication Diaries 
  
Xm 
X 
X 
X 
X 
  
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication 
  
Xm 
  
  
  
  
  
Study medication dosingl 
  
X  
  
Collect, review, and re-dispense study 
medication 
  
  
X 
X 
X 
  
  
Collect and review study medication 
  
  
  
  
  
X 
  


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Table 1: 
Schedule of Study Procedures 
Study Period: 
Screening a 
(in clinic) 
Treatment  
(All visits for each subject either in clinic or remote) 
Follow-up  
Study Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
Valsalva maneuver 
Xq 
 
 
 
 
 
 
 
Abbreviations: 
; BP: Blood Pressure; 
; C-SSRS: 
Columbia Suicide Severity Rating Scale; ESC: Enrollment Steering Committee; ET: Early Terminated; 
 
; HR: Heart Rate; MoCA: Montreal Cognitive Assessment; 
; OHDAS: Orthostatic Hypotension Daily Activity Scale; 
OHSA: Orthostatic Hypotension Symptom Assessment; OHQ: Orthostatic Hypotension Questionnaire; 
 PGI-C: Patient Global 
Impression of Change; Randomization and trial supply management (RTSM); RR: Respiratory Rate; 
 
. 
a. 
 in clinic for ALL subjects. Subject eligibility will be assessed by the Investigator during Screening and primary diagnosis will be 
verified by the ESC prior to randomization; subjects meeting OHSA#1 criterion on Visit 2 (Day 1) and who otherwise meet eligibility criteria may be randomized via 
RTSM. 
b. A complete medical and medication history evaluation will be performed during screening. 
c. 
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 study visit (Visit 2 to 6). Subjects should be rested prior to beginning the training.  
d. During Screening, 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.   
e. 
 
f. 
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. 
g. 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. 
h. 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. 


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i. 
 
 
 
 
k. Ambulatory blood pressure monitoring equipment will be provided to the subject during the screening visit. Beginning approximately 72 to 24-hours before a subject 
conducts the Day 1 (Visit 2), and before the Day 8 and Day 22 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 should also maintain a log of their posture at the time of each blood pressure measurement. Details regarding the ambulatory monitoring will be provided in a 
separate manual.  
l. 
Study medication will be ingested in the morning at approximately the same time of day with 8 ounces of water. The exact time and day of dosing will be recorded on 
the mornings of study visits. Subjects should be reminded to maintain an adequate fluid intake during their scheduled visits. 
m. The assessments or procedures will be performed within 24-hours prior to subject taking the study medication (pre-dose). Following randomization and completion of 
study assessments, the subject will begin taking study medication on Day 2 in the morning.   
n. C-SSRS is to be completed following OHQ questionnaire from Visit 2 to Visit 6. 
o. Follow-up visit is only applicable for those subjects that do not proceed to Study 0170 and will be completed two weeks from the date of the last dose. 
p. 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.   
q. 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 ............................... 27 
1. 
INTRODUCTION ................................................................................... 30 
1.1. 
Background and Rationale ....................................................................... 30 
1.2. 
Nonclinical Profile ................................................................................... 31 
1.2.1. 
Nonclinical Pharmacology ....................................................................... 31 
1.2.2. 
Safety Pharmacology ............................................................................... 32 
1.2.3. 
Nonclinical Pharmacokinetics ................................................................. 32 
1.2.4. 
Toxicology ............................................................................................... 32 
1.3. 
Clinical Experience .................................................................................. 33 
1.3.1. 
Clinical Pharmacokinetics ....................................................................... 35 
1.4. 
Risks and Benefits ................................................................................... 35 
2. 
OBJECTIVES .......................................................................................... 37 
2.1. 
Primary Objective .................................................................................... 37 
2.2. 
Secondary and Exploratory Objectives ................................................... 37 
3. 
STUDY DESIGN .................................................................................... 38 
3.1. 
Overview .................................................................................................. 38 
3.2. 
Rationale for Study Design ...................................................................... 40 
3.3. 
Selection of Dose and Duration of Treatment ......................................... 41 
3.4. 
Study Endpoints ....................................................................................... 42 
3.4.1. 
Primary Endpoint ..................................................................................... 42 
3.4.2. 
Secondary Endpoints ............................................................................... 42 
3.4.3. 
Exploratory Endpoints ............................................................................. 42 
3.4.4. 
Safety and Tolerability Endpoint ............................................................. 43 
3.5. 
Minimization of Bias ............................................................................... 43 
3.5.1. 
Blinding ................................................................................................... 43 
3.5.2. 
Treatment Assignment ............................................................................. 44 
3.5.3. 
Enrollment Steering Committee .............................................................. 44 
4. 
STUDY POPULATION .......................................................................... 45 
4.1. 
Inclusion Criteria ..................................................................................... 45 
4.2. 
Exclusion Criteria .................................................................................... 46 
4.3. 
Pregnancy and Contraception .................................................................. 47 
4.3.1. 
Females of Childbearing Potential........................................................... 47 
4.3.2. 
Contraception for Male and Female Subjects .......................................... 48 


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5. 
STUDY MEDICATION .......................................................................... 49 
5.1. 
Description of Study Medications ........................................................... 49 
5.1.1. 
TD-9855 Test Product ............................................................................. 49 
5.1.2. 
Placebo Reference Product ...................................................................... 49 
5.2. 
Dosage and Administration ..................................................................... 49 
5.3. 
Treatment Compliance ............................................................................. 49 
5.4. 
Drug Accountability and Reconciliation ................................................. 50 
6. 
STUDY PROCEDURES ......................................................................... 51 
6.1. 
Schedule of Study Procedures ................................................................. 51 
6.2. 
Total Blood Volume ................................................................................ 51 
6.3. 
Procedures by Visit (Recommended Order) ............................................ 51 
6.3.1. 
Screening – Visit 1 ................................................................................... 51 
6.3.2. 
Treatment Day 1 – Visit 2 ....................................................................... 52 
6.3.3. 
Treatment Day 8 – Visit 3 ....................................................................... 53 
6.3.4. 
Treatment Day 15 – Visit 4 ..................................................................... 54 
6.3.5. 
Treatment Day 22 – Visit 5 ..................................................................... 55 
6.3.6. 
Treatment Day 29 – Visit 6 / Early Termination ..................................... 55 
6.3.7. 
Follow-up Day 43 – Visit 7 ..................................................................... 57 
6.4. 
Description of Study Procedures ............................................................. 57 
6.4.1. 
Demographic and Baseline Assessments................................................. 57 
6.4.2. 
Tilt-Table Test ......................................................................................... 57 
6.4.3. 
Montreal Cognitive Assessment .............................................................. 58 
6.4.4. 
Valsalva Maneuver .................................................................................. 58 
6.4.5. 
OHQ Subject Training ............................................................................. 58 
6.4.6. 
Efficacy Assessments .............................................................................. 58 
6.4.6.1. 
Orthostatic Hypotension Questionnaire ................................................... 58 
6.4.6.2. 
Patient Global Impression of Change ...................................................... 59 
 
 
 
 
 
 
 
 
6.4.6.7. 
Incidence of Falls – Subject Diary ........................................................... 60 
 
 
 
 
 
 


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6.4.10. 
Safety Assessments .................................................................................. 62 
6.4.10.1. 
Columbia-Suicide Severity Rating Scale ................................................. 62 
6.4.10.2. 
Adverse Events ........................................................................................ 62 
6.4.10.3. 
Medication and Medical History ............................................................. 62 
6.4.10.4. 
Physical Examination .............................................................................. 62 
6.4.10.5. 
Height and Weight ................................................................................... 63 
6.4.10.6. 
Vital Signs ............................................................................................... 63 
6.4.10.7. 
Electrocardiograms .................................................................................. 63 
6.4.10.8. 
24-hour Ambulatory Blood Pressure Monitoring .................................... 63 
6.4.10.9. 
Laboratory Tests ...................................................................................... 64 
6.4.10.10. Neurological Examination ....................................................................... 64 
6.4.10.11. Dosing Diary Dispensation and/or Collection ......................................... 65 
6.4.10.12. Unscheduled Visit .................................................................................... 65 
6.5. 
Concomitant Medications ........................................................................ 65 
6.5.1. 
Impact of Other Medications on TD-9855 .............................................. 65 
6.5.2. 
Impact of TD-9855 on Other Medications .............................................. 66 
6.6. 
Rescue Medications ................................................................................. 66 
6.7. 
Prohibitions and Restrictions ................................................................... 66 
6.8. 
Discontinuation ........................................................................................ 67 
6.8.1. 
Dose Stopping Rules................................................................................ 67 
6.8.2. 
Subject Discontinuation ........................................................................... 67 
6.8.3. 
Subject Replacement ............................................................................... 67 
6.8.4. 
Study Discontinuation ............................................................................. 68 
6.9. 
Pregnancy ................................................................................................ 68 
7. 
ADVERSE EVENTS............................................................................... 69 
7.1. 
Definitions ............................................................................................... 69 
7.1.1. 
Adverse Event .......................................................................................... 69 
7.1.2. 
Serious Adverse Event ............................................................................. 70 
7.1.3. 
Additional Considerations for Serious Adverse Events .......................... 70 
7.1.4. 
Adverse Event of Special Interest ............................................................ 71 


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7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ............................................. 71 
7.3. 
Assessment of Adverse Events ................................................................ 71 
7.3.1. 
Severity .................................................................................................... 72 
7.3.2. 
Causal Relationship to Study Medication ................................................ 72 
7.4. 
Adverse Event Reporting and Recording ................................................ 73 
7.4.1. 
Adverse Event Reporting ......................................................................... 73 
7.4.2. 
Adverse Event and Serious Adverse Event Recording ............................ 73 
7.4.3. 
Serious Adverse Event and Adverse Event of Special Interest Reporting 
Timeline ................................................................................................... 74 
7.5. 
Adverse Event Follow-up ........................................................................ 74 
8. 
STATISTICAL CONSIDERATIONS .................................................... 75 
8.1. 
General Considerations ............................................................................ 75 
8.2. 
Sample Size and Power ........................................................................... 75 
8.3. 
Analysis Sets ............................................................................................ 75 
8.3.1. 
Examination of Subgroups ...................................................................... 76 
8.3.2. 
Major Protocol Analysis Deviations ........................................................ 76 
8.4. 
General Analyses ..................................................................................... 76 
8.4.1. 
Demographics and Other Baseline Characteristics .................................. 76 
8.4.2. 
Medical History ....................................................................................... 76 
8.5. 
Analysis of Efficacy ................................................................................ 76 
8.5.1. 
Efficacy Endpoints ................................................................................... 76 
8.5.1.1. 
Primary Efficacy Evaluation .................................................................... 77 
8.5.1.2. 
Secondary and Exploratory Efficacy Evaluations ................................... 78 
8.5.2. 
Multiplicity Adjustment........................................................................... 78 
8.5.3. 
Analysis of Pharmacokinetics .................................................................. 78 
8.5.4. 
Analysis of Pharmacodynamics ............................................................... 78 
8.6. 
Safety Analyses ....................................................................................... 78 
8.6.1. 
Extent of Exposure .................................................................................. 79 
8.6.2. 
Adverse Event Data ................................................................................. 79 
8.6.3. 
Concomitant Medications ........................................................................ 79 
8.6.4. 
Laboratory Data ....................................................................................... 80 
8.6.5. 
Vital Signs Data ....................................................................................... 80 
8.6.6. 
Electrocardiogram Data ........................................................................... 80 
8.7. 
Missing Data Handling ............................................................................ 81 


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8.7.1. 
Mitigation and Analysis Strategies in Response to COVID-19 .............. 81 
8.8. 
Independent Data Monitoring Committee ............................................... 81 
9. 
STUDY ADMINISTRATION ................................................................ 83 
9.1. 
Principal Investigator Responsibilities .................................................... 83 
9.2. 
Institutional Review Board/Independent Ethics Committee ................... 84 
9.3. 
Informed Consent .................................................................................... 84 
9.4. 
Data Recording and Quality Assurance ................................................... 85 
9.5. 
Document Retention ................................................................................ 85 
9.6. 
Confidentiality ......................................................................................... 86 
9.7. 
Access to Data and Documents ............................................................... 86 
9.8. 
Quality Control: Study Monitoring and Auditing ................................... 87 
9.9. 
Publication ............................................................................................... 87 
10. 
REFERENCES ........................................................................................ 88 
11. 
APPENDICES ......................................................................................... 89 
APPENDIX 1. PROTOCOL SIGNATURE FORM ................................................ 90 
APPENDIX 2. EXAMPLES OF DISEASE INSTRUMENTS ............................... 91 
APPENDIX 3. INCIDENCE OF FALLS .............................................................. 134 
APPENDIX 4. AMBULATORY BLOOD PRESSURE MONITORING - 
POSITION DIARY ............................................................................... 135 
APPENDIX 5. DOSING DIARY .......................................................................... 136 
 
 
 
APPENDIX 9. OVERVIEW OF DECENTRALIZATION PLAN ....................... 140 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ................................................................. 17 
Table 2: 
Vital Sign Assessment Outlier Thresholds .............................................. 80 
Table 3: 
Electrocardiogram Test Outlier Thresholds ............................................. 80 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
5-HT 
Serotonin 
ADHD 
Attention-deficit hyperactivity disorder 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase  
ANS 
Autonomic Nervous System 
ASP 
Autonomic Symptom Profile 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
bHCG  
Beta human chorionic gonadotropin 
BP 
Blood pressure 
 
 
CFR 
(United States) Code of Federal Regulations 
Cmax 
Maximum concentration recorded 
CNS 
Central Nervous System 
COA 
Clinical Outcome Assessment 
 
 
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 
ET 
Early Termed 
EQ VAS 
EQ Visual Analogue Scale 
 
 
FAS 
Full analysis set 
FM 
Fibromyalgia 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GI 
Gastrointestinal 


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Abbreviation 
Description 
GLP 
Good Laboratory Practice 
 
 
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 
NET 
Norepinephrine transporter 
 
 
nOH 
Neurogenic Orthostatic Hypotension 
NOAEL 
No observed adverse event level 
NRI 
Norepinephrine reuptake inhibitor 
NYHA 
New York Heart Association 
OH 
Orthostatic Hypotension 
OHQ 
Orthostatic Hypotension Questionnaire 
OHDAS 
Orthostatic Hypotension Daily Activity Scale 
OHSA 
Orthostatic Hypotension Symptom Assessment 
OHSA#1 
Orthostatic Hypotension Symptom Assessment Question 1 
PAF 
Pure Autonomic Failure 
PD 
Parkinson’s disease  


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Abbreviation 
Description 
 
 
PGI-C 
Patient Global Impression of Change 
P-gp 
p-glycoprotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
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 
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 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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mechanisms of action, including the addition of exogenous NE or NE prodrug. For example, 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
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 
 
 
 
 
 


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1.2.2. 
Safety Pharmacology 
 
 
 
 
 
  
 
 
 
 
 
 
1.2.3. 
Nonclinical Pharmacokinetics 
 
  
 
 
 
 
 
 
 
 
 
 
 
1.2.4. 
Toxicology 
 
 
 
 
 
  
 
 
 
 
 
 


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1.3. 
Clinical Experience 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1. 
Clinical Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
1.4. 
Risks and Benefits 
Results from preclinical and clinical studies indicate that TD-9855 is a 
 
 
 
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. 
 
 
 
 
 
 
 
 
 


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To help ensure subject safety, subjects will be closely monitored during this study. Except for 
the Screening visit (V1) 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 efficacy of TD-9855 in subjects with multiple system atrophy 
(MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) experiencing 
symptomatic neurogenic orthostatic hypotension (symptomatic nOH) compared 
with placebo at Week 4, as measured by the change from baseline of the 
Orthostatic Hypotension Symptom Assessment (OHSA) Question 1 (OHSA#1) 
score. 
2.2. 
Secondary and Exploratory Objectives 
The secondary objectives of the study are as follows: 
• To evaluate the efficacy of TD-9855 by symptom and activity assessments using 
OHSA and the Orthostatic Hypotension Daily Activity Scale (OHDAS). 
• To evaluate the efficacy of TD-9855 using the Patient Global Impression of 
Change (PGI-C). 
• To evaluate the efficacy of TD-9855 on incidence of falls. 
• To evaluate the safety and tolerability of TD-9855, including adverse events 
(AEs) and changes in blood pressure (BP), heart rate (HR), electrocardiogram 
(ECG), Columbia Suicide Severity Rating Scale (C-SSRS), and laboratory tests. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study to evaluate efficacy, safety, and tolerability of TD-9855 in subjects with primary 
autonomic failures (MSA, PD, or PAF) and symptomatic nOH after 4 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 must conduct all study visits for Study 0169 for a given subject in a 
consistent manner for each subject to reduce the possibility of variability in data collection 
and reporting. Therefore, Investigators, in discussion with each individual subject at their site, 
will be required to elect to conduct all visits either in the clinic or remotely for each 
individual subject at their site.  Regardless of which election an Investigator and subject 
make, the Screening visit (V1) must be conducted in clinic for all subjects. 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 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 subjects that have previously completed the Screening visit at the time regulatory and 
ethics approval for 
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 visit modality is selected by the Investigator and the subject. For those 
subjects who are already randomized to study treatment and active in the study at the time 
regulatory and ethics approval for 
 is received, the Investigator and subject 
should continue the remaining study visits in the same visit modality as the Randomization 
Visit. 


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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) 4-week screening, (ii) 4-week randomized treatment, and 
(iii) 2-week follow up. The schematic representation is as shown below: 
  
After signing the informed consent, the subject will enter a screening period of up to 4 weeks 
to confirm eligibility. At the screening visit, which must be performed in the clinic for all 
subjects, the subject will provide a comprehensive medical history of their disease and 
treatments. The subject’s disease will be characterized and documented by the Investigator. 
The subject 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 (Table 1). The presence of symptomatic nOH symptoms and reported 
sensation of dizziness, lightheadedness, feeling faint, or feeling like blacking out (OHSA#1) 
must be confirmed by the application of a tilt-table test. This tilt-table test serves 2 purposes: 
(i) determination of the systolic/diastolic BP (DBP) changes, and (ii) training the subjects to 
recognize the sensations associated with OHSA#1. 
Eligible subjects will undergo training of accurate scoring of their sensation of dizziness, 
lightheadedness, feeling faint, or feeling like blacking out as outlined by the OHSA#1. 
Following the screening period, the subject will proceed to Visit 2 to further confirm the 
additional eligibility criteria prior to randomization. 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 applicable inclusion criteria and none of the 
applicable exclusion criteria, including confirmation of relevant criteria by the independent 
Enrollment Steering Committee (ESC), will be randomized to receive either TD-9855 or 
matching placebo for the next 4 weeks. 


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Following randomization and completion of study assessments, the subject will receive a 
se of TD-9855 (or matching placebo) once daily (QD) for the remaining 
double -blind treatment period. 
Weekly assessments will be conducted as outlined in the Schedule of Study Procedures 
(Table 1). Refer to the footnotes in Schedule of Study Procedures 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.  
Discontinuation of subjects may occur at any time. Dose stopping criteria include meeting at 
least 1 of the following rules: 
 
 
 
 
 
 
 
  
 
 
 
 
No dose reduction is permitted at any time. 
Safety assessments will include a physical examination, neurological examination, vital signs 
(body temperature, HR and BP), body weight, ECGs, safety laboratory tests (hematology, 
chemistry, and urinalysis), C-SSRS, and AEs. 
Safety will be periodically reviewed by an independent data monitoring committee, see 
separate charter. 
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. 
Subjects completing the 4-week double-blind treatment period will be eligible to enroll and 
continue receiving study medication in Study 0170. The final study visit for those subjects 
who do not complete the 4-week double-blind treatment period or who choose not to continue 
into Study 0170 will be the follow-up visit (V7). This visit must be completed two weeks 
from the date of the last dose. 
3.2. 
Rationale for Study Design 
 
 
 
 
 
 


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3.3. 
Selection of Dose and Duration of Treatment 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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3.4. 
Study Endpoints 
3.4.1. 
Primary Endpoint 
The primary study endpoint is the change from baseline in OHSA#1 (dizziness, 
lightheadedness, feeling faint, or feeling like blacking out) at Week 4. 
3.4.2. 
Secondary Endpoints 
The secondary endpoints include: 
• Change from baseline in OHSA composite score in Weeks 1 to 4 
• Change from baseline in OHDAS composite score in Weeks 1 to 4 
• PGI-C at Week 4 
• Incidence of falls 
3.4.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4.4. 
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 
• Subject compliance to study treatment 
• C-SSRS 
3.5. 
Minimization of Bias 
This is a double-blind, placebo-controlled, randomized study. 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 at all times, except in the event of a medical emergency as outlined in 
Section 3.5.1. 
3.5.1. 
Blinding 
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.  


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3.5.2. 
Treatment Assignment 
Once the subject has been determined to be eligible to receive study treatment, 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. 
3.5.3. 
Enrollment Steering Committee 
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 drop 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., 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 inclusion criteria and none of the exclusion criteria defined 
below. 
4.1. 
Inclusion Criteria 
A subject who meets the following criteria will be eligible for study enrollment: 
1. Subject is male or female and at least 30 years old. 
2. Subject is female and must be nonpregnant and nonlactating. 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 
bHCG (beta human chorionic gonadotropin) 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 to ≥60o from a supine position as determined by a tilt-table test. 
5. Subject must score at least a 4 on the Orthostatic Hypotension Symptom Assessment 
Question #1 at randomization visit. 
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 clinic staff, understands 
the expectations of the study and is able to comply with the study procedures, 
requirements, and restrictions. 


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4.2. 
Exclusion Criteria 
A subject who meets any of the following criteria is not eligible for study enrollment: 
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) 
2. Subject has a known intolerance to other NRIs or 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 randomization 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 randomization visit.  
• Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior 
to randomization. 
6. Subject has a known or suspected alcohol or substance abuse within the past 
12 months (DSM-IV-TR® definition of alcohol or substance abuse). 
7. Subject has a clinically unstable coronary artery disease, or 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 
randomization. 
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). 


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15. Subject has 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 
nonregulatory agency approved drug (e.g., Food and Drug Administration). 
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/1.73m2, 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). 


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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 
• 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 


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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 
 
 
5.1.1. 
TD-9855 Test Product 
 
 
 
 
5.1.2. 
Placebo Reference Product 
 
 
   
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. 
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’ 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 (e.g., < 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. 


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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 
. 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 1 
Screening visit assessments will be performed in clinic and the following procedures must be 
completed first, and in the order below: 
1. Written informed consent (signed and dated) after the nature of the study has been 
explained and before any study procedure is performed 
2. Review of protocol inclusion and exclusion criteria prior to beginning subject 
evaluations 
3. Medical history, including smoking history 
4. Review concomitant medications and smoking usage 
5. MoCA 
6. OHQ subject training 
7. C-SSRS 
8. Tilt-table test 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
9. 
 
10. Vital signs 
a. HR, systolic BP (SBP), and diastolic BP (DBP) 
b. Respiratory rate (RR) and body temperature 
11. Height (in cm) and weight (in kg) 
12. Physical examination  
13. Neurological examination 


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14. 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) 
15. Pregnancy test (in women of childbearing potential only) 
16. Blood collection 
a. Hematology 
b. Chemistry 
c. NE sample collection (after being seated for approximately 30 minutes) 
17. Urine collection 
a. Urinalysis 
18. AE assessment (AEs, SAEs, adverse event of special interest [AESIs]) 
19. Incidence of falls – subject diary, dispensation and review of diary completion 
instructions 
20. 24-hour ambulatory BP device provision (device collection prior or on Visit 2) 
21. ESC (for confirmation of diagnosis)  
22. 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 2 
Subjects meeting all applicable eligibility criteria, including ESC confirmation of diagnosis, 
following completion of the screening assessments will complete enrollment assessments on 
Day 1.  
Prior to randomization, 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 assessments will be performed within 24-hours prior to the subject taking the study 
medication. 
The following procedures must be completed first, and in the order below: 
1. Review of protocol inclusion and exclusion criteria prior to beginning subject 
evaluations 
2. Review concomitant medications and smoking usage 
3. OHQ subject training 
4. OHQ (OHSA and OHDAS) 
5. C-SSRS 
6. Randomization via a RTSM system (after all pre-dose procedures have been 
completed and subject is confirmed to be eligible for the study) 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 


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14. Vital signs 
a. HR, SBP, and DBP 
b. RR and body temperature 
15. Weight (in kg) 
16. Physical examination 
17. Neurological examination 
18. Pregnancy test (in women of childbearing potential only) 
19. Blood collection 
a. Hematology 
b. Chemistry 
20. Urine collection 
a. Urinalysis 
 
22. Incidence of Falls and ABPM position diaries 
23. 24-hour ambulatory BP device collection and re-provision 
24. Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
25. AE assessment (AEs, SAEs, AESIs) 
26. Dispense study medication 
6.3.3. 
Treatment Day 8 – Visit 3 
The following procedures will be performed on the Day 8 visit (+/- 3 days) and the following 
procedures must be completed first, and in the order below: 
1. Review concomitant medications and smoking usage 
2. OHQ subject training 


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3. OHQ (OHSA and OHDAS)  
4. C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
5.
 
 
7. Vital signs 
a. HR, SBP, and DBP 
b. RR and body temperature 
8. Weight (in kg) 
 
10. Incidence of Falls and ABPM position diaries 
11. 24-hour ambulatory BP device collection  
12. Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
13. AE assessment (AEs, SAEs, AESIs) 
14. Collect, review, then re-dispense study medication 
6.3.4. 
Treatment Day 15 – Visit 4 
The following procedures will be performed on the Day 15 visit (+/- 3 days and the following 
procedures must be completed first, and in the order below: 
1. Review concomitant medications and smoking usage 
2. OHQ subject training 
3. OHQ (OHSA and OHDAS) 
4. C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
 
 
7. Vital signs 
a. HR, SBP, and DBP 
b. RR and body temperature 
8. Weight (in kg) 
9. Blood collection 
a. Hematology 
b. Chemistry 


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10. Urine collection 
a. Urinalysis 
 
12. Incidence of Falls and ABPM position diaries 
13. Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
14. AE assessment (AEs, SAEs, AESIs) 
15. Collect, review, then re-dispense study medication 
6.3.5. 
Treatment Day 22 – Visit 5 
The following procedures will be performed on the Day 22 visit (+/- 3 days) and the 
following procedures must be completed first, and in the order below: 
1. Review concomitant medications and smoking usage 
2. OHQ subject training 
3. OHQ (OHSA and OHDAS) 
4. C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
 
 
7. Vital signs 
− HR, SBP, and DBP 
− RR and body temperature 
8. Weight (in kg) 
9. Incidence of Falls and ABPM position diaries 
10. 24-hour ambulatory BP device collection  
11. Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
12. AE assessment (AEs, SAEs, AESIs) 
13. Collect, review, then re-dispense study medication  
6.3.6. 
Treatment Day 29 – Visit 6 / Early Termination 
The following procedures will be performed on the Day 29 visit (+/- 3 days) and the 
following procedures must be completed first, and in the order below: 
1. Review concomitant medications and smoking usage 
2. OHQ subject training 
3. OHQ (OHSA and OHDAS) 


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4. PGI-C 
5. C-SSRS 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
 
 
  
 
 
  
 
 
 
 
 
13. Vital signs 
a. HR, SBP, and DBP 
b. RR and body temperature 
14. Weight (in kg) 
15. Physical examination 
16. Neurological examination 
17. 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) 
18. Pregnancy test (in women of childbearing potential only) 
19. Blood collection 
a. Hematology 
b. Chemistry 
20. Urine collection 
a. Urinalysis 
 
 
23. Incidence of Falls and ABPM position diaries 
24. Dosing and Midodrine rescue medication diaries dispensation and review of diary 
completion instructions 
25. AE assessment (AEs, SAEs, AESIs) 


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26. Collect and review study medication 
6.3.7. 
Follow-up Day 43 – Visit 7  
The follow-up visit is applicable only for those subjects that will not proceed to Study 0170 
and will be completed two weeks from the date of the last dose. 
The following procedures will be performed on the Day 43 visit (+/- 3 days): 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
1. Review concomitant medications and smoking usage 
2. C-SSRS 
3. Vital signs 
a. HR, SBP, and DBP 
b. RR and body temperature 
4. Weight (in kg) 
5. 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 subject 
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. 
Inclusion and exclusion criteria will be assessed at screening and on Day 1 prior to 
randomization. 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). 
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 


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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 
performed at a minimum of one hour after the initial test, and at least 7 days prior to 
randomization. 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 (Table 1). 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. 
 
 
 
 
 
 
 
 
6.4.6. 
Efficacy Assessments 
6.4.6.1. 
Orthostatic Hypotension Questionnaire 
The Orthostatic Hypotension Questionnaire (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 Orthostatic Hypotension Daily Activities Scale (OHDAS). The items are 
scored on an 11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 


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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 Change 
In the PGI-C scale, subject is asked to compare their current symptoms to their symptoms at 
study baseline (i.e., prior to randomization) on a 5-category scale ranging from 1 (much 
better) to 5 (much worse). 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. 
Incidence of Falls – Subject Diary 
Falls in subjects with symptomatic neurogenic orthostatic hypotension 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. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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6.4.9. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 Visit 1 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. 
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 adverse event must be recorded in the subjects 
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 and will include 
evaluation visit for 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 two years prior to screening visit, along with the date of 
diagnosis, and any other relevant medical history that has an impact to the subject. 
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/gastrointestinal (GI) system; extremities; lymphatic system [lymph nodes]; 
and nervous system).  


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Subsequent physical examinations, after the screening visit on Visit 2 and Visit 6, 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. 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. 
6.4.10.6. 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. 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 
 
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.  
6.4.10.7. 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 at the site to allow for 
any appropriate action, if required.  
6.4.10.8. 24-hour Ambulatory Blood Pressure Monitoring 
Ambulatory blood pressure monitoring equipment will be provided to the subject during the 
screening visit. Beginning approximately 72 to 24-hours before a subject conducts Day 1 
(Visit 2), and before the Day 8 and Day 22 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 BP monitoring device will be programmed to 


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automatically measure BP every 2 hours beginning at the top of the hour. During each 
24-hour session, subjects should also maintain a log of their posture at the time of each BP 
measurement (Appendix 4). More details regarding the ambulatory monitoring will be 
provided in a separate manual. 
6.4.10.9. Laboratory Tests 
Laboratory tests will be performed as specified in 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. 
6.4.10.9.1. 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).  
6.4.10.9.2. 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. 
6.4.10.9.3. Urinalysis 
Urinalysis includes determination of specific gravity; presence of blood, protein, and 
leukocytes; and microscopic examination of sediment, if clinically indicated. 
6.4.10.10. 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) 


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• Station (posture and stability) 
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 Visit 2. 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 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 visits 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 
Subjects should not have changed dose, frequency or type of prescribed medication for 
orthostatic hypotension within 7 days prior to the randomization visit.  
 
  
 
  
 
Stable dosing regimen is defined as the same dosage and frequency on any given day. 
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 
 
 
 
 
 


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6.5.2. 
Impact of TD-9855 on Other Medications 
 
 
 
6.6. 
Rescue Medications 
 
 
 
 
 
 
 
 
 
  
6.7. 
Prohibitions and Restrictions 
The following are prohibited or restricted during study participation as specified: 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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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:  
 
 
 
 
 
 
 
  
 
 
 
 
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. 
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. 


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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 independent data monitoring 
committee (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 10mg TD-9855 dose. Thus, application of pregnancy prevention measures 
for 1 month 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 beta 
human chorionic gonadotropin (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 1 month 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 subject or 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 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 informed consent form is considered to be preexisting 
and should be documented in the medical history CRF. 
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. 


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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. 
• “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. 


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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 AESI Report Form must be completed in accordance with the AESI Report Form 
Completion Guidelines. If all information on the 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 AESI Report Form to the following: 
Theravance Biopharma Clinical Safety 
 
 
 
For medical questions regarding an AESI, contact the medical monitor by telephone as 
follows: 
Medical Monitor Contact Information:  
  
 
 
 
 
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. 


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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”).  
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. 


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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). 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:  
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. 


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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 questionnaires 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 
 
 
 
 
For medical questions regarding an SAE or AESI, contact the medical monitor by telephone 
as follows: 
Medical Monitor Contact Information:  
  
 
 
 
 
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 
 
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, 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 
A total of approximately 
 will be randomized in a 
 
 
   
The primary analysis will occur when all subjects in the Full analysis set (FAS) have 
completed the primary endpoint assessment (OHSA#1 at Week 4) and the database has been 
cleaned and locked. A total sample size of
 will have an overall power of 90% to 
detect a treatment difference of 1.5 in the primary endpoint of change from baseline in 
OHSA#1, assuming a common standard deviation of 3.0 for both treatment groups at a 
2-sided alpha level of 0.05. 
Assuming a 10% dropout rate by Week 4, it is anticipated that the study will randomize 
approximately 
 in order to achieve 
 in the FAS. 
8.3. 
Analysis Sets 
 
 
 
 
 
 
 
 
 


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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 
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data: 
 
 
 
 
 
 
 
Additional criteria may be specified in the SAP. 
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 if deemed appropriate. 
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 summarized. 
8.4.2. 
Medical History 
Summary of medical history will be provided. 
8.5. 
Analysis of Efficacy 
8.5.1. 
Efficacy Endpoints 
The primary study endpoint is: 
• Change from baseline in OHSA#1 (dizziness, lightheadedness, feeling faint, or 
feeling like blacking out) at Week 4 
The secondary endpoints are: 
• Change from baseline in OHSA composite score in Weeks 1 to 4 
• Change from baseline in OHDAS composite score in Weeks 1 to 4 
• PGI-C at Week 4 
• Incidence of falls 
 
 


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8.5.1.1. 
Primary Efficacy Evaluation 
The primary efficacy evaluation is the change from baseline of OHSA#1 at Week 4. Baseline 
is defined as Day 1 pre-dose measurement. Mixed model for repeated measures (MMRM) 
will be used to compare treatment differences. The model will include fixed effect class terms 
of treatment, baseline disease type (MSA, PD, PAF), week, and continuous covariate of 
baseline OHSA#1 score, a random subject effect, with an unstructured covariance structure 
using the FAS. 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 
placebo will be calculated and presented.  
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 of the primary endpoint 
will be conducted using multiple imputation. 
The primary analysis will be repeated on a set of prespecified subgroups and presented in 
graphical format.  


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8.5.1.2. 
Secondary and Exploratory Efficacy Evaluations 
The secondary efficacy endpoints involving assessment of change from baseline, such as 
OHSA composite score and OHDAS composite score, will be analyzed in a similar fashion 
as the primary efficacy endpoint of change from baseline in OHSA#1.   
The PGI-C will be summarized as number and percentage for subjects with ‘no change or 
better’ and ‘worse than no change’ at Week 4. Incidence of falls will be summarized as 
number and percentage of subjects with at least 1 fall in Week 4. The PGI-C and incidence of 
falls will be tested using Cochran-Mantel Haenzel chi-square test stratified by disease type at 
baseline. 
8.5.2. 
Multiplicity Adjustment 
If the treatment effect of the primary efficacy endpoint has been demonstrated at a 2-sided 
statistical significance level of 5%, secondary efficacy endpoints (Section 8.5.1) will be tested 
using the same statistical significance level.  The secondary endpoints will be tested 
sequentially via a prospectively defined order to be described in the SAP, until a failure to 
reject the null hypothesis occurs.  No statistical significance will be claimed after a failure to 
reject the null hypothesis has occurred. 
For all supportive analyses including sensitivity analyses of the primary efficacy endpoint 
and exploratory endpoints, nominal p-values and 95% confidence intervals with no 
adjustment for multiplicity will be presented. 
8.5.3. 
 
 
  
8.5.4. 
 
 
8.6. 
Safety Analyses  
Safety data, including C-SSRS, will be summarized by treatment received. Summaries will 
be provided by nominal visit and time point or for the entire treatment period, as appropriate 
for the type of data. 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.  


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8.6.1. 
Extent of Exposure 
 
 
 
 
 
 
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 present by system organ class (SOC), preferred term, 
and severity (mild, moderate, severe), the number and percentage of subjects for whom 
events were reported. 
In general, a treatment-emergent adverse event (TEAE) will be defined as any AE that begins 
on or after the date and time of the first dose of study medication and up to the date of last 
dose of study medication plus the number of days in the follow-up period.  
The number and percentage of subjects who experience TEAEs will be summarized. 
Summaries of TEAEs will include the following: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs reported will be listed by subject. A listing will be provided for all subjects who 
experience an SAE. 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. 


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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. 
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, systolic and diastolic BP, 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. 
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 
 


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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. 
8.7. 
Missing Data Handling 
 
 
 
 
 
 
 
 
8.7.1. 
Mitigation and Analysis Strategies in Response to COVID-19 
 
  
 
 
 
. 
8.8. 
Independent Data Monitoring Committee 
 
 
 
 
 
 
 
 
 
 
 
 


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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 designed 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 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, informed consent form (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. 
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. 


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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. 
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. 
 
 


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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, subject initials, date 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). 
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. 


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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. 
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;260(9):2212–9. 
2. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological 
approach. Circulation. 2009;119(1):139-46. 
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;13(9):930-6. 
4. Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G, Kopin IJ. Sympathetic 
cardioneuropathy in dysautonomias. N Eng J Med. 1997;50(1):47-53. 
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;4(2):53-7. 
6. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the 
development of Parkinson’s disease-related pathology. Cell Tissue Res. 
2004;318(1):121-34. 
7. Shibao C, Raj SR, Gamboa A, et al. Norepinephrine transporter blockade with 
atomoxetine induces hypertension in patients with impaired autonomic function. 
Hypertension. 2007;50(1):47-53. 
8. Ramirez CE, Okamoto LE, Arnold AC, et al. Efficacy of atomoxetine versus 
midodrine for the treatment of orthostatic hypotension in autonomic failure. 
Hypertension. 2014;64(6):1235-40. 
9. Kaufmann H1, 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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11. 
APPENDICES 


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APPENDIX 1. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:   
0169 
Protocol Title:  
A Phase 3, 4-week, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study of TD-9855 in Treating 
Symptomatic Neurogenic Orthostatic Hypotension in Subjects With 
Primary Autonomic Failure 
Version: 
1.0 
 
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 2-3 
 


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Appendix 2-4 


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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 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 subjects must be conducted in clinic, regardless of which visit 
modality selection an Investigator and subject make.    
All sites must conduct all study visits for Study 0169 for a given subject in a consistent 
manner to reduce the possibility of variability in data collection and reporting. Therefore,  
Investigators, in discussion with each individual subject at their site, will be required to elect  
to conduct all visits either in the clinic, or remotely.   
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 COVID-19 and its impact on both sites and subjects, 
the Sponsor will allow Investigators to request exceptions to the selected typed of study visit 
modality 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 an 
exemption request to the Sponsor via the established process. Theravance (or their designee) 
will review and respond to these exemption requests as per established processes and 
timelines.  Requests for and approval of exemptions in visit modality will be documented and 
retained in study records at the Investigator site.  
Once an Investigator and subject have elected a visit type (in clinic or remote) the expectation 
is for all post-Screening visits for that subject to be conducted via the same modality, except 
as described above.   
For subjects that have previously completed the Screening visit at the time regulatory and 
ethics approval for 
 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 visit modality is selected by the Investigator and the subject. For those 
subjects who are already randomized to study treatment and active in the study at the time 
regulatory and ethics approval for 
 is received, the Investigator and subject 
should continue the remaining study visits in the same visit modality as the Randomization 
Visit. 
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.  
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).  


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• 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.   
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. 
 
 
 


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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.  

SAP_001.pdf: 
Protocol Number: 0169 
 
Official Title: A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in 
Subjects With Primary Autonomic Failure 
 
NCT Number: NCT03750552 
 
Document Date: 19 July 2021 


 
 
TD-9855 
Theravance Biopharma R&D, Inc. 
 
19JULY2021 
Statistical Analysis Plan - Protocol 0169 
 
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TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
PHASE 3 
 
VERSION: 1.0 
DATE OF PLAN: 
July 19, 2021 
 
BASED ON: 
Protocol 
 05 August 2020 
 
STUDY DRUG: 
TD-9855 
 
PROTOCOL NUMBER: 
0169 
 
STUDY TITLE: 
A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects 
With Primary Autonomic Failure 
 
SPONSOR: 
Theravance Biopharma R&D, Inc. 
c/o Theravance Biopharma US, Inc. 
901 Gateway Boulevard 
South San Francisco, CA 94080 
 
This study is being conducted in compliance with good clinical practice, including 
the archiving of essential documents. 


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SIGNATURE PAGE 
TD-9855 (ampreloxetine), Study 0169 Statistical Analysis Plan 
A Phase 3, 4-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects 
With Primary Autonomic Failure 
Plan Version: 
19JULY2021 
Author: 
c. 
Reviewer: 
Theravance Biopharma US, Inc. 
Reviewer: 
Theravance Biopharma US, Inc. 
         


 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
LIST OF ABBREVIATIONS .......................................................................................7 
2. 
INTRODUCTION ........................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
3.1. 
Study Objectives ...........................................................................................................9 
3.1.1. 
Primary Objective .........................................................................................................9 
3.1.2. 
Secondary Objectives ...................................................................................................9 
3.1.3. 
Exploratory Objectives .................................................................................................9 
3.2. 
Study Endpoints ..........................................................................................................10 
3.2.1. 
Primary Study Endpoint .............................................................................................10 
3.2.2. 
Secondary Study Endpoints ........................................................................................10 
3.2.3. 
Exploratory Study Endpoints ......................................................................................10 
3.2.4. 
Safety and Tolerability Endpoints ..............................................................................11 
4. 
STUDY DESIGN .......................................................................................................11 
4.1. 
Summary of Study Design ..........................................................................................11 
4.2. 
Definition of Study Drugs ..........................................................................................14 
4.3. 
Sample Size Considerations .......................................................................................14 
4.4. 
Randomization ............................................................................................................14 
4.5. 
Clinical Assessments ..................................................................................................15 
5. 
TIMING OF PLANNED ANALYSES ......................................................................19 
6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING .......................19 
6.1. 
Analysis Sets ...............................................................................................................19 
6.1.1. 
Screen Failures ............................................................................................................19 
6.1.2. 
Randomized Analysis Set ...........................................................................................19 
6.1.3. 
Safety Analysis Set .....................................................................................................19 
6.1.4. 
Full Analysis Set (FAS) ..............................................................................................19 
6.1.5. 
Per-Protocol (PP) Analysis Set ...................................................................................19 
6.1.6. 
Examination of Subgroups .........................................................................................20 
6.2. 
Baseline Definition .....................................................................................................20 
6.3. 
Derived and Transformed Data ..................................................................................20 


 
 
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6.3.1. 
Study Day ...................................................................................................................20 
6.3.2. 
Change from Baseline .................................................................................................21 
6.3.3. 
Body Mass Index (BMI) .............................................................................................21 
6.3.4. 
Analysis Visit Windows .............................................................................................21 
6.3.5. 
Multiple Assessments .................................................................................................22 
7. 
STUDY POPULATION .............................................................................................22 
7.1. 
Enrollment by Investigator .........................................................................................22 
7.2. 
Subject Disposition and Completion Status ...............................................................22 
7.3. 
Protocol Deviations ....................................................................................................23 
7.4. 
Medical History and Medical Conditions Present at Entry ........................................23 
7.5. 
Demographic and Baseline Clinical Characteristics ...................................................23 
8. 
EFFICACY .................................................................................................................23 
8.1. 
General Considerations ...............................................................................................23 
8.2. 
Statement of the Null and Alternative Hypotheses for the Primary Endpoint ...........24 
8.3. 
Analysis of the Primary Efficacy Endpoint ................................................................24 
8.3.1. 
Primary Efficacy Analysis ..........................................................................................24 
8.3.2. 
Sensitivity and Supplementary Analyses for Primary Efficacy Endpoint ..................24 
8.3.2.1. 
Per Protocol Analysis .................................................................................................25 
8.3.2.2. 
Tipping Point Analysis ...............................................................................................25 
8.3.2.3. 
Analysis Accounting for Visit Modality Change .......................................................25 
8.3.2.4. 
Subgroup Analyses .....................................................................................................25 
8.3.2.5. 
OHSA#1 Completeness and Visit Modality ...............................................................26 
8.4. 
Analysis of Secondary Efficacy Endpoints ................................................................26 
8.4.1. 
Analysis of Change From Baseline in OHSA and OHDAS Composite Score ..........26 
8.4.2. 
Analysis of PGI-C and Incidence of Falls ..................................................................26 
8.4.3. 
Multiplicity Adjustment ..............................................................................................28 
8.5. 
Analysis of Exploratory Efficacy Endpoints ..............................................................28 
8.5.1. 
Analysis of Change From Baseline for Endpoints With Multiple 
Assessments ................................................................................................................28 
8.5.2. 
Analysis of Change From Baseline for Endpoints With Assessments Only at 
Week 4 ........................................................................................................................29 
8.6. 
Scoring and Analysis of Clinical Outcome Assessments ...........................................29 


 
 
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8.6.1. 
OHQ ............................................................................................................................29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 
SAFETY AND TOLERABILITY ..............................................................................37 
9.1. 
Adverse Events ...........................................................................................................37 
9.1.1. 
Adverse Events of Special Interest .............................................................................37 
9.2. 
Extent of Exposure and Treatment Compliance .........................................................38 
9.3. 
Concomitant and Other Medications ..........................................................................38 
9.4. 
Laboratory Data ..........................................................................................................39 
9.5. 
Vital Signs and Weight ...............................................................................................39 
9.5.1. 
Ambulatory Blood Pressure ........................................................................................40 
9.6. 
ECGs ...........................................................................................................................40 
9.7. 
C-SSRS .......................................................................................................................41 
10. 
POTENTIAL IMPACT OF COVID-19 .....................................................................42 
11. 
REFERENCES ...........................................................................................................43 
12. 
SUPPORTING DOCUMENTATION........................................................................44 
12.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................44 
12.2. 
Appendix 2: Handling of Missing Data ......................................................................44 
12.2.1. 
Adverse Events Severity .............................................................................................44 
12.2.2. 
Missing Start and Stop Dates for Adverse Events ......................................................44 
12.2.3. 
Missing Start and Stop Dates for Medications ...........................................................46 
12.2.4. 
Laboratory Data ..........................................................................................................46 
 
 


 
 
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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Schedule of Study Procedures ....................................................................................15 
Table 3: 
Analysis Visit Windows .............................................................................................21 
Table 4: 
Mapping of PGI-C From 7-Point Scale to 5-Point Scale ...........................................27 
Table 5: 
Item Scoring for COMPASS-31 .................................................................................33 
Table 6: 
Weight and Total Score for COMPASS-31 ................................................................34 
Table 7: 
Health State Parameter Estimates ...............................................................................36 
 
 
 
 
 
 


 
 
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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSR 
clinical study report 
DOB 
date of birth 
dy 
days 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
LLN 
lower limit of normal 
LS 
least squares 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model repeated measures 
mo 
months 
MSA 
multiple system atrophy 
NE 
norepinephrine level 
OTC 
over-the-counter medication 
PAF 
pure autonomic failure 
PD 
Parkinson’s disease 
PP 
per protocol 
QTcF 
corrected QT interval, Fridericia correction 
RR 
respiratory rate 
SAE 
serious adverse event 


 
 
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Abbreviation 
Term 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
systolic blood pressure 
SD 
standard deviation 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WBC 
white blood cell count 
WHO 
World Health Organization 
yr 
years 
 


 
 
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2. 
INTRODUCTION 
This document describes the plan for the summarization and analysis of clinical data collected in 
Study 0169 for ampreloxetine (TD-9855). It serves as the final authority regarding data analyses. 
 
  
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of the study is: 
• To evaluate the efficacy of ampreloxetine (TD-9855) in subjects with multiple system 
atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) 
experiencing symptomatic neurogenic orthostatic hypotension (nOH) compared with 
placebo at Week 4, as measured by the change from baseline of the Orthostatic 
Hypotension Symptom Assessment (OHSA) Question 1 (OHSA#1) score. 
3.1.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To evaluate the efficacy of ampreloxetine (TD-9855) by symptom and activity 
assessments using OHSA and the Orthostatic Hypotension Daily Activities Scale 
(OHDAS). 
• To evaluate the efficacy of ampreloxetine (TD-9855) using the Patient Global 
Impression of Change (PGI-C). 
• To evaluate the efficacy of ampreloxetine (TD-9855) in preventing incidence of falls. 
• To evaluate the safety and tolerability of ampreloxetine (TD-9855), including adverse 
events (AEs) and changes in blood pressure (BP), heart rate (HR), electrocardiogram 
(ECG), Columbia Suicide Severity Rating Scale (C-SSRS) and laboratory tests. 
3.1.3. 
Exploratory Objectives 
 
 
 
 
 


 
 
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3.2. 
Study Endpoints 
3.2.1. 
Primary Study Endpoint 
The primary study endpoint is: 
• Change from baseline in OHSA#1 (dizziness, lightheadedness, feeling faint, or 
feeling like blacking out) at Week 4 
3.2.2. 
Secondary Study Endpoints 
• Change from baseline in OHSA composite score in Weeks 1 to 4 
• Change from baseline in OHDAS composite score in Weeks 1 to 4 
• PGI-C at Week 4 
• Incidence of falls 
3.2.3. 
Exploratory Study Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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3.2.4. 
Safety and Tolerability Endpoints 
• Physical examination 
• Neurological examination 
• Vital signs including ambulatory BP 
• Resting ECGs 
• Clinical laboratory tests, including biochemistry, hematology, urinalysis 
• Concomitant medication 
• AEs 
• Subject compliance to study treatment 
• C-SSRS 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter 
study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with 
primary autonomic failures (MSA, PD, or PAF) and symptomatic neurogenic orthostatic 
hypotension (nOH) after 4 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 must conduct all study visits for Study 
0169 for a given subject in a consistent manner for each subject to reduce the possibility of 
variability in data collection and reporting. Therefore, Investigators, in discussion with each 
individual subject at their site, will be required to elect to conduct all visits either in the clinic or 
remotely for each individual subject at their site. Regardless of which election an Investigator 
and subject make, the Screening visit (V1) must be conducted in clinic for all subjects. 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). 


 
 
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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 
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 preapproval from the Sponsor. Data collected during these 
visits may include any protocol-specified assessments which will be captured in the clinical 
database. 
For subjects that have previously completed the Screening visit at the time regulatory and ethics 
approval for 
 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 visit modality is selected by the Investigator and the subject. For those subjects who 
are already randomized to study treatment and active in the study at the time regulatory and 
ethics approval for 
 is received, the Investigator and subject should continue the 
remaining study visits in the same visit modality as the Randomization Visit. 
Symptomatic neurogenic orthostatic hypotension is defined as: 
• A sustained reduction of BP of ≥20 mm Hg (systolic) or ≥10 mm Hg (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 
 
 


 
 
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The study consists of 3 periods: (i) 4-week screening, (ii) 4-week randomized treatment, and (iii) 
2-week follow up. The schematic representation is as shown below: 
 
After signing the informed consent, the subject will enter a screening period of up to 4 weeks to 
confirm eligibility. At the screening visit, which must be performed in the clinic for all subjects, 
the subject will provide a comprehensive medical history of their disease and treatments. The 
subject’s disease will be characterized and documented by the investigator. 
The subject 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 (Table 2). The presence of nOH symptoms and reported sensation of dizziness, 
lightheadedness, feeling faint, or feeling like blacking out (OHSA#1) must be confirmed by the 
application of a tilt-table test. This tilt-table test serves 2 purposes: (i) determination of the 
systolic/diastolic BP changes, and (ii) training the subjects to recognize the sensations associated 
with OHSA#1. 
Eligible subjects will undergo training of accurate scoring of their sensation of dizziness, 
lightheadedness, feeling faint, or feeling like blacking out as outlined by the OHSA#1. 
Following the screening period, the subject will proceed to Visit 2 to further confirm the 
additional eligibility criteria prior to randomization. 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 applicable inclusion criteria and none of the applicable 
exclusion criteria, including confirmation of relevant criteria by the independent Enrollment 
Steering Committee (ESC), will be randomized to receive either ampreloxetine (TD-9855) or 
matching placebo for the next 4 weeks. 
Following randomization and completion of study assessments, the subject will receive a 
 
of ampreloxetine (TD-9855) (or matching placebo) 
 for the 
remaining double-blind treatment period. 


 
 
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Subjects completing the 4-week double-blind treatment period will be eligible to enroll and 
continue receiving study medication in Study 0170. The final visit for those subjects who do not 
complete the 4-week double-blind treatment period or who choose not to continue into Study 
0170 will be the follow-up visit (V7). This visit must be completed two weeks from the date of 
the last dose. 
The subject will return for weekly assessments as outlined in the Schedule of Study Procedures 
(Table 2). 
4.2. 
Definition of Study Drugs 
Study drug includes the following (placebo and ampreloxetine [TD-9855]): 
• Ampreloxetine (TD-9855) 
: Taken orally for 4 weeks without regard 
to food at approximately the same time each morning with approximately 8 ounces of 
water 
• Placebo once daily: Taken orally for 4 weeks without regard to food at approximately 
the same time each morning with approximately 8 ounces of water 
 
 
 
 
 
 
 
 
 
4.3. 
Sample Size Considerations 
 
 
 
 
 
 
 
4.4. 
Randomization 
Central randomization for treatment allocation will be implemented. A computer-generated 
randomization schedule will be prepared for this study under the supervision of the sponsor. 
Subjects will be randomized at Visit 2 in a 1:1 ratio to ampreloxetine (TD-9855) or placebo 
using a randomization schedule stratified by disease type (MSA, PD, or PAF). 
At least 40% of the subjects enrolled will have MSA (at least 76 subjects). 


 
 
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4.5. 
Clinical Assessments 
Table 2: 
Schedule of Study Procedures 
Study Period: 
Screening  
Treatment  
Follow-up  
Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
Mandated Order of Procedures (when applicable) 
Informed consent 
X 
  
  
  
  
  
  
Inclusion /exclusion criteria 
X 
X 
  
  
  
  
  
Medical history (including smoking 
history)  
Xb 
  
  
  
  
  
  
Concomitant medications (and 
smoking usage) 
Xb 
X 
X 
X 
X 
X 
X 
MoCA 
X 
  
  
  
  
  
  
OHQ subject trainingc 
Xc 
X 
X 
X 
X 
X 
 
OHQ (OHSA and OHDAS) 
  
Xm 
X 
X 
X 
X 
 
PGI-C 
  
  
  
  
  
X 
  
C-SSRS 
X 
Xm,n 
Xn 
Xn 
Xn 
Xn 
X 
Tilt-table test 
Xd 
 
  
  
  
  
  
Randomization 
  
Xa 
  
  
  
  
  
Recommended Order of Procedures (when applicable) 
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  


 
 
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Study Period: 
Screening  
Treatment  
Follow-up  
Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Vital Signs (Body Temperature, 
Heart Rate, Respiration Rate, Blood 
Pressure)f 
X 
Xm 
X 
X 
X 
X 
X 
Height (cm) 
X 
  
  
  
  
  
  
Weight (kg) 
X 
Xm 
X 
X 
X 
X 
X 
Physical examination 
X 
Xm 
  
  
  
X 
  
Neurological examination 
X 
Xm 
  
  
  
X 
  
12-lead electrocardiogramg 
X 
  
  
  
  
X 
  
Pregnancy testh 
X 
Xm 
  
  
  
X 
  
Norepinephrine (NE) 
X 
  
  
  
  
  
  
Safety laboratory test (chemistry, 
hematology, and urinalysis) 
X 
Xm 
  
X 
  
X 
  
 
  
 
 
 
  
 
 


 
 
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Study Period: 
Screening  
Treatment  
Follow-up  
Day (Visit):  
Day -28 to -7 
(Visit 1) 
Day 1 
(Visit 2) 
Day 8 
(Visit 3) 
+/- 3 days 
Day 15 
(Visit 4) 
+/- 3 days 
Day 22 
(Visit 5) 
+/- 3 days 
Day 29 
(Visit 6) / ET 
+/- 3 days 
Day 43o 
(Visit 7) 
+/- 3 days 
 
  
 
  
  
  
 
  
ESC (for confirmation of diagnosis)a 
X 
  
  
  
  
  
  
24-hour ambulatory BP device 
provisionk 
X 
X  
  
X  
  
  
  
24-hour ambulatory BP device 
collectionk 
  
X 
X 
  
X 
  
  
Incidence of Falls and ABPM 
position Diaries 
X 
Xm 
X 
X 
X 
X 
  
Dosing and Midodrine rescue 
medication Diaries 
  
Xm 
X 
X 
X 
X 
  
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication 
  
Xm 
  
  
  
  
  
Study medication dosingl 
  
X  
  
Collect, review, and re-dispense 
study medication 
  
  
X 
X 
X 
  
  
Collect and review study medication 
  
  
  
  
  
X 
  
Valsalva maneuver 
Xq 
 
 
 
 
 
 
Abbreviations: 
; BP: Blood Pressure; 
 
C-SSRS: Columbia Suicide Severity Rating Scale; ESC: Enrollment Steering Committee; ET: Early Terminated; 
 
 HR: Heart Rate; MoCA: Montreal Cognitive Assessment; 
; OHDAS: Orthostatic Hypotension 
Daily Activity Scale; OHSA: Orthostatic Hypotension Symptom Assessment; OHQ: Orthostatic Hypotension Questionnaire; 
 
 PGI-C: Patient Global Impression of Change; Randomization and trial supply management (RTSM); RR: Respiratory Rate; 
 
 


 
 
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a. 
d in clinic for ALL subjects. Subject eligibility will be assessed by the Investigator during Screening and primary 
diagnosis will be verified by the ESC prior to randomization; subjects meeting OHSA#1 criterion on Visit 2 (Day 1) and who otherwise meet eligibility 
criteria may be randomized via RTSM. 
b. A complete medical and medication history evaluation will be performed during screening. 
c. 
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 study visit (Visit 2 to 6). Subjects should be rested prior to beginning the training. 
d. During Screening, 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. 
e. 
The UPDRS scale should be completed in an ON state, and within 1-4 hours of taking the PD medications. All 6 parts would be completed on Day 1, while 
only Parts 2 and 3 of the questionnaire would be completed on Day 29. 
f. 
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. 
g. 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. 
h. 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. 
i. 
 
 
 
 
k. Ambulatory blood pressure monitoring equipment will be provided to the subject during the screening visit. Beginning approximately 72 to 24-hours before 
a subject conducts the Day 1 (Visit 2), and before the Day 8 and Day 22 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 should also maintain a log of their posture at the time of each blood pressure measurement. Details 
regarding the ambulatory monitoring will be provided in a separate manual. 
l. 
Study medication will be ingested in the morning at approximately the same time of day with 8 ounces of water. The exact time and day of dosing will be 
recorded on the mornings of study visits. Subjects should be reminded to maintain an adequate fluid intake during their scheduled visits. 
m. The assessments or procedures will be performed within 24-hours prior to subject taking the study medication (pre-dose). Following randomization and 
completion of study assessments, the subject will begin taking study medication on Day 2 in the morning. 
n. C-SSRS is to be completed following OHQ questionnaire from Visit 2 to Visit 6. 
o. Follow-up visit is only applicable for those subjects that do not proceed to Study 0170 and will be completed two weeks from the date of the last dose. 
p. 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. 
q. 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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5. 
TIMING OF PLANNED ANALYSES 
The analyses will occur when all subjects have completed or terminated early from the study and 
the database has been cleaned and locked. 
6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING 
Analyses and tabulations will generally be prepared using 
 
Summary tables and listings will be prepared according to ICH Guideline E3 and include a 
“footer” providing explanatory notes. 
6.1. 
Analysis Sets 
 
 
6.1.1. 
Screen Failures 
Subjects who give written informed consent but are not randomized are considered screen 
failures. Screen failure subjects and the reason for screen failure are captured in the EDC. 
6.1.2. 
Randomized Analysis Set 
The randomized analysis set comprises all subjects who are randomized. 
6.1.3. 
Safety Analysis Set 
The safety analysis set comprises 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. Subjects in the safety analysis set will be grouped 
according to the study treatments they receive. 
6.1.4. 
Full Analysis Set (FAS) 
The Full analysis set (FAS) is defined as all randomized subjects who have received at least 
1 dose of study medication and have baseline and at least 1 post baseline measurement of 
OHSA#1.  The FAS is the primary analysis set for efficacy endpoints. FAS analyses will use the 
randomized treatments. 
6.1.5. 
Per-Protocol (PP) Analysis Set 
The per-protocol (PP) analysis set comprises all subjects in the FAS who have an OHSA#1 
assessment at Week 4 obtained no earlier than study day 25 and no later than study day 42, did 
not use a prohibited medication during the treatment period, and did not meet any of the 
following criteria: 
1. Poor study drug compliance, defined as compliance < 80% or ≥ 120% over the interval 
from first to last dose during the treatment period 


 
 
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2. Did not meet efficacy-related inclusion criteria (criterion 5, OHSA#1 score ≥ 4) 
3. Took a prohibited medication prior to randomization (exclusion criterion 4, subject has 
used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives before 
randomization or requires concomitant use until the follow-up visit; exclusion criterion 5, 
subject has changed dose, frequency, or type of prescribed medication for orthostatic 
hypotension within 7 days prior to randomization, or failed to taper off midodrine and 
droxidopa (if applicable) at least 7 days prior to randomization) 
4. Received a treatment other than the randomized treatment 
Subjects who used midodrine not per protocol will be excluded from the PP analysis set. 
Subjects who used midodrine as rescue therapy per the instructions in the protocol will be 
included in the PP analysis set, and OHSA#1 collected on the visits when rescue therapy was 
used (if any) will be censored. 
A listing of FAS subjects excluded from the PP set will be provided, with reasons for exclusion.  
6.1.6. 
Examination of Subgroups 
To assess consistency of treatment effect across subgroups, the primary analysis of OHSA#1 will 
be repeated for each of the following subgroups: 
1. Disease Type: MSA, PD, and PAF 
2. Gender: Male and Female 
3. Timing of Primary Endpoint Visit Relative to COVID-19 Pandemic Onset: 
Before 18MAR2020, On or After 18MAR2020 
6.2. 
Baseline Definition 
Unless stated otherwise, baseline is the last assessment (scheduled or unscheduled) obtained 
before the first dose of randomized study medication. 
6.3. 
Derived and Transformed Data 
6.3.1. 
Study Day 
If the date of interest occurs on or after the date of the first dose, study day will be calculated as 
date of interest – date of first dose + 1. 
If the date of interest occurs prior to the date of the first dose, study day will be calculated as date 
of interest – date of first dose. There is no study day 0. 
In this study, subject will receive the first dose of study medication in the morning of the day 
following randomization and completion of baseline study assessments. Study day 1 for a subject 
in the analysis will be defined as the first day the subject receives study drug, which is different 
from the protocol definition of study day 1 as the day of randomization. To make it clear which 
definition is being used, in this document “Day x” (e.g., Day 1 [Visit 2]) refers to the protocol 
definition and “study day x” refers to study day relative to the date of the first dose. 


 
 
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6.3.2. 
Change from Baseline 
Change from baseline is calculated as postbaseline result – baseline result. 
If either the baseline or the postbaseline result is missing, the change from baseline is set to 
missing. 
6.3.3. 
Body Mass Index (BMI) 
BMI will be calculated as follows: 
𝐵𝐵𝐵𝐵𝐵𝐵(𝑘𝑘𝑘𝑘/𝑚𝑚2) = 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡(𝑘𝑘𝑘𝑘)
ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡(𝑚𝑚)2 
 
6.3.4. 
Analysis Visit Windows 
Assessments that are summarized by visit will be assigned to analysis visits using the following 
analysis visit windows, without regard to the visit label associated with the assessment in the 
clinical database. 
Table 3: 
Analysis Visit Windows 
 
Analysis Visit Window 
Analysis Visit 
Start (study day) 
Stop (study day) 
For endpoints collected at Weeks 1, 2, 3, and 4, including C-SSRS, BSFC-s, OHSA, OHDAS, and vital 
signs 
Week 1 (study day 7) 
2 
10 
Week 2 (study day 14) 
11 
17 
Week 3 (study day 21) 
18 
24 
Week 4 (study day 28) 
25 
42 
For endpoints collected at Weeks 1 and 3, including ABPM position 
Week 1 (study day 7) 
2 
14 
Week 3 (study day 21) 
15 
42 
For endpoints collected at Weeks 2 and 4, including safety laboratory tests 
Week 2 (study day 14) 
2 
21 
Week 4 (study day 28) 
22 
42 
For endpoints other than PGI-C collected at Week 4, including EQ-5D, NMSS, HADS, UPDRS, PDQ-8, 
COMPASS-31, UMSARS, and ECG 
Week 4 (study day 28) 
15 
42 
For PGI-C* (collected at Week 4) 
Week 4 (study day 28) 
2 
42 
*All endpoints except PGI-C are also collected on or prior to study day -1. PGI-C, being a change assessment, is 
collected only at the Week 4 visit or early termination visit. 


 
 
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6.3.5. 
Multiple Assessments 
In general, if multiple valid observations exist in the window of an analysis visit, the record to be 
included in the summary and analyses will be chosen on the following basis, unless otherwise 
specified: 
• The record closest to the nominal visit 
If records are equidistant or distance cannot be determined: 
• The latest record 
If records have the same date/time: 
• The average 
7. 
STUDY POPULATION 
7.1. 
Enrollment by Investigator 
Enrollment by geographic region (North America, Europe, Asia/Pacific, and Other), country, and 
investigator will be summarized overall and by treatment group for all randomized subjects. 
7.2. 
Subject Disposition and Completion Status 
Subject disposition will be summarized for all randomized subjects by treatment group. The 
summary will include the counts and percentages of subjects in each analysis set as well as of 
subjects who: 
• Were randomized and treated with study drug 
• Were randomized and not treated with study drug 
• Completed the 4-week treatment period 
• Didn’t complete the 4-week treatment period and the reason for not completing it 
(adverse event, loss of follow-up, noncompliance with study drug, physician decision, 
pregnancy, protocol violation, study terminated by Sponsor, and other) 
• Completed the study 
• Didn’t complete the study and the reason (adverse event, loss of follow-up, 
noncompliance with study drug, physician decision, pregnancy, protocol violation, 
study terminated by Sponsor, and other) 
• Continued to Study 0170 
• Didn’t continue to Study 0170 and the reason (did not complete study, chose not to 
continue, and other) 
 


 
 
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A listing of subject disposition will include the FAS status, the date of informed consent signed, 
the date of first dose and last dose of study drug, the primary reason for discontinuation of study 
treatment, the date of last visit, the study completion status, the primary reason for study 
termination, and the date of last contact. 
7.3. 
Protocol Deviations 
FAS subjects reporting major protocol deviations will be summarized overall and by treatment 
group. The summary will include counts and percentages of subjects who have any major PDs 
and counts and percentages of subjects who have major PDs in each category. A separate 
summary table will be provided for COVID-19 related PDs. 
A subject listing with all protocol deviations identified prior to database lock will be provided. 
All subject listings will be based on the randomized analysis set. 
7.4. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized by system organ class and preferred term, overall and by 
treatment group, for the safety analysis set. No statistical comparisons will be performed. 
Medical history will be mapped according to 
. 
7.5. 
Demographic and Baseline Clinical Characteristics 
A summary of demographic and baseline characteristics will include the following items: age 
(years), age category (<65 years, ≥65 years), sex, race, ethnicity, weight (kg), height (cm), 
BMI (kg/m2), smoking status (Never, Current, Former, Missing), Diagnosis of Primary 
Autonomic Failure (Multiple System Atrophy, Parkinson’s Disease, Pure Autonomic Failure), 
OHSA#1 score, OHSA composite score, OHDAS composite score, OHQ overall composite 
score, Supine SBP (mmHg, an average of 5 min and 10 min measurements), 3 min Standing SBP 
(mmHg), and norepinephrine (NE) (pg/mL). 
This summary will be presented for the safety analysis set, FAS, and PP analysis set. 
8. 
EFFICACY 
8.1. 
General Considerations 
For all efficacy data analyses, the FAS will be used unless otherwise specified. 
Nominal p-values (i.e., unadjusted for multiple testing) will be provided as appropriate. 
If a statistically significant treatment effect on the primary efficacy endpoint has been 
demonstrated, secondary efficacy endpoints will be tested in a hierarchical fashion using 2-sided 
tests at the 5% level of significance until a failure to reject the null hypothesis occurs. 


 
 
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8.2. 
Statement of the Null and Alternative Hypotheses for the Primary 
Endpoint 
The primary endpoint, the change from baseline in OHSA#1 (dizziness, lightheadedness, feeling 
faint or feeling like blacking out) at Week 4, is used to evaluate the effectiveness of TD-9855 
(ampreloxetine) therapy relative to the placebo. 
The null hypothesis for the treatment comparison is that there is no difference between 
ampreloxetine (TD-9855) (active) group and the placebo group in the mean change in OHSA#1 
from baseline at Week 4. The alternative hypothesis is that there is a difference. The hypothesis 
testing schema is expressed as follows: 
 
0
placebo
1
placebo
:
:
µ
µ
µ
µ
=
≠
Active
Active
H
H
 
 
where 𝜇𝜇 stands for the mean change from baseline at Week 4. 
8.3. 
Analysis of the Primary Efficacy Endpoint 
8.3.1. 
Primary Efficacy Analysis 
A mixed effects model for repeated measures (MMRM) incorporating the change from baseline 
in OHSA#1 as the dependent variable will be used to assess the primary endpoint hypothesis. 
The model will include fixed class terms for treatment group and baseline disease type (MSA, 
PD, PAF), a covariate for baseline OHSA#1 score, and a time effect (week) and its interaction 
terms with treatment and baseline OHSA#1 score. An unstructured covariance structure 
(type=UN) to account for the repeated measures within a subject will be fitted. If the model 
doesn’t converge, the data will be reanalyzed fitting a compound symmetric covariance structure 
(type=CS) and a compound symmetric with heterogenous variance covariance structure 
(type=CSH) and the structure with a lower AIC value will be selected. 
Least squares (LS) mean change in OHSA#1 in each treatment group and the difference in 
LS mean change between treatment groups will be estimated. Point estimates, 95% confidence 
intervals (CIs), and p-values will be provided. 
Figures 
A plot will present the LS mean change from baseline in OHSA#1 at each postbaseline time 
point by treatment group with 95% CIs.  
8.3.2. 
Sensitivity and Supplementary Analyses for Primary Efficacy Endpoint 
A sensitivity analysis is planned to evaluate the sensitivity of the primary efficacy analysis 
results to the assumption that missing data are missing at random (MAR). A supplementary per 
protocol analysis will be performed. 


 
 
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8.3.2.1. 
Per Protocol Analysis 
The per protocol analysis follows the same MMRM method described in Section 8.3.1 and is 
restricted to subjects in the PP analysis set. 
8.3.2.2. 
Tipping Point Analysis 
The tipping-point analysis will be conducted for the primary efficacy endpoint, change in 
OHSA#1 at Week 4, to evaluate the robustness against deviation from the missing at random 
(MAR) assumption using MMRM.  The tipping-point analysis refers to imputing the missing 
data with a range of scenarios to identify the tipping point at which the imputation overturns the 
significance of the treatment effect under MAR assumption. The tipping point is determined as 
the minimum shift value to overturn the significant results of the multiple imputation (MI) when 
the shift value is added to the Week 4 imputed values for active group subjects. If the tipping 
point is implausibly large, it is concluded that the study results are not sensitive to the MAR 
assumption. 
For the tipping point analysis, the MMRM model as specified for the primary efficacy analysis 
will be fitted. The initial results obtained when no shift is applied to active group Week 4 
imputed values will be provided, along with the minimum shift that overturns the significant 
result.  
8.3.2.3. 
Analysis Accounting for Visit Modality Change 
There could be systematic differences between OHSA#1 scores collected during remote visits 
and OHSA#1 scores collected during in-clinic visits. Hence, a sensitivity analysis to assess the 
effect of visit modality on the primary efficacy analysis will be performed by adding a post 
baseline visit modality class variable with values “In-clinic” and “Remote” to the primary 
analysis model. The analysis will include all subjects in FAS. Week 4 LS mean and LS mean 
difference estimates and p-values will be provided. 
8.3.2.4. 
Subgroup Analyses 
To characterize the consistency of the treatment effect for the primary endpoint, the primary 
endpoint analysis will be repeated for the subgroups specified in Section 6.1.6. 
The subgroup analyses will use the same analysis model and reporting structure as in 
Section 8.3.1. For the disease type subgroup analyses, the disease type stratum terms are 
redundant and will be omitted from the model. Subgroup analysis will not be performed when 
n < 10 or n > N – 10, where n is the number of FAS subjects in the subgroup and N is the 
number in the FAS. 
For each subgroup, a plot of LS mean change from baseline in OHSA#1 at each postbaseline 
time point will be presented by treatment group with 95% CIs. 
In addition, a forest plot of the difference between the treatment groups in LS mean change from 
baseline in OHSA#1 at Week 4 with 95% CI will be plotted. The x-axis will be difference in LS 
mean change from baseline and the y-axis will be the subgroups. 


 
 
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8.3.2.5. 
 
 
 
 
 
 
 
 
 
 
8.4. 
Analysis of Secondary Efficacy Endpoints 
8.4.1. 
Analysis of Change From Baseline in OHSA and OHDAS Composite Score 
The following two secondary efficacy endpoints will be analyzed in the same way as the primary 
efficacy endpoint, as described in Section 8.3.1, using the baseline value of the endpoint as the 
covariate: 
• Change from baseline in OHSA composite score in Weeks 1 to 4 
• Change from baseline in OHDAS composite score in Weeks 1 to 4 
The hypothesis testing schema is similar to the primary efficacy endpoint for the treatment 
comparison, i.e., no difference between ampreloxetine (TD-9855) (active) group and the 
placebo. 
Figures 
Plots will present the LS mean change from baseline at each postbaseline time point by treatment 
group with 95% CIs for OHSA and OHDAS composite scores.  
8.4.2. 
Analysis of PGI-C and Incidence of Falls 
There are two binary secondary efficacy endpoints and their analyses are described below. 
Patient Global Impression of Change (PGI-C)  
PGI-C is a 5-point scale depicting the overall change in a patient’s neurogenic orthostatic 
hypotension symptoms since the initiation of study medication. Patients rate their change as 
“Much better,” “A little better,” “No change,” “A little worse,” or “Much worse.” Early versions 
of the protocol (original and Amendment 1) used the PGI-C on a 7-point scale. For analysis 
purposes, the 7-point scale will be mapped to the 5-point scale (Table 4). However, the data will 
be listed as collected. 
The PGI-C will be summarized as number and percentage of subjects with “better” and “no 
change or worse” at Week 4 (see Appendix 1).  


 
 
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The proportion of subjects with PGI-C responses indicating improvement and the proportion 
with at least one fall will be compared between treatment groups using a Cochran-Mantel-
Haenszel chi-squared test stratified by disease type at baseline. 
Table 4: 
Mapping of PGI-C From 7-Point Scale to 5-Point Scale 
7-Point Scale 
5-Point Scale 
Very Much Improved 
Much Better 
Much Improved 
Minimally Improved 
A Little Better 
No Change 
No Change 
Minimally Worse 
A Little Worse 
Much Worse 
Much Worse 
Very Much Worse 
 
In case the treatment groups differ substantially with respect to timing of assessment, the PGI-C 
analysis will be supplemented by a sensitivity analysis restricted to subjects with PGI-C 
collected within the narrowed window study day 25 to 42. 
A plot will be presented to show the CMH-weighted average proportion of subjects with PGI-C 
responses indicating improvement by treatment group at Week 4. 
Incidence of falls 
Incidence of falls will be summarized as number and percentage of subjects with at least one fall 
during the interval from the date of the first dose to the date of the last dose. 
The falls analysis will be supplemented by corresponding analyses of the incidence of at least 
one near-fall and of the incidence of at least one fall or near-fall, and by generalized linear 
model-based analyses of the reported number of falls, near-falls, and falls or near-falls during the 
treatment period. For these count analyses, the null and alternative hypotheses will be 
H0: θ = 1 
H1: θ ≠ 1 
where θ is the TD-9855:placebo weekly incidence density ratio of falls (or near-falls, or either) 
during the evaluation period. The analyses will be performed by fitting a generalized linear 
model with a negative binomial error distribution, log link, and log time at risk in weeks as the 
offset, including disease type stratum and the pre-treatment weekly incidence rate of falls (or 
near-falls, or either) as covariates. For purposes of this analysis, the pretreatment period will be 
defined as beginning on the date of the screening visit and ending on the day before the first dose 
date. 
 
 


 
 
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Analysis results provided will include the model-based estimates of weekly incidence rate for 
each treatment group and point and interval estimates of their ratio, and descriptive statistics for 
the number of events per patient week during the pretreatment period and during the evaluation 
period. For falls, this will be calculated as: 
7 × (total number of falls reported)/(evaluation end date - first dose date + 1) 
The incidence rate will be calculated likewise for near-falls and for falls and near-falls combined. 
A plot will be presented to show the CMH-weighted average proportion of subjects with at least 
one fall during the treatment period by treatment group. 
8.4.3. 
Multiplicity Adjustment 
If a statistically significant treatment effect has been demonstrated for the primary efficacy 
endpoint, the following secondary efficacy endpoints will be tested in a hierarchical fashion in 
the order below using 2-sided tests at the 5% level of significance until a failure to reject the null 
hypothesis occurs: 
• Change from baseline in OHSA composite score at Week 4 
• Change from baseline in OHDAS composite score at Week 4 
• PGI-C at Week 4 
• Incidence of falls during treatment 
For all other analyses, including additional analyses of the primary efficacy endpoint, analyses of 
the other secondary efficacy endpoints change from baseline in OHSA composite score in Weeks 
1 to 3 and change from baseline in OHDAS composite score in Weeks 1 to 3, and analyses of 
exploratory endpoints, unadjusted p-values and nominal 95% CI intervals will be provided. 
8.5. 
Analysis of Exploratory Efficacy Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8.5.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6. 
Scoring and Analysis of Clinical Outcome Assessments 
This section discusses the scoring of clinical outcome assessments and provides additional 
details on their analyses. 
8.6.1. 
OHQ 
The Orthostatic Hypotension Questionnaire (OHQ) includes two parts, the Orthostatic 
Hypotension Symptom Assessment (OHSA) to measure the presence and severity of symptoms 
and the Orthostatic Hypotension Daily Activity Scale (OHDAS) to measure the impact of 
orthostatic symptoms on daily activities. Recall period is “over the past week.” 
OHSA consists of six questions, each rating the intensity of one characteristic symptom of NOH: 
1. Dizziness, lightheadedness, feeling faint, or feeling like you might black out 
2. Problems with vision (blurring, seeing spots, tunnel vision, etc.) 
3. Generalized weakness 
4. Fatigue 
5. Trouble concentrating 
6. Head/neck discomfort 


 
 
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OHDAS consists of four questions that assess the impact of NOH symptoms on daily activities. 
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. OHDAS has 
an option of selecting “cannot be done for other reasons,” which will not be included in scoring. 
OHSA and OHDAS composite scores are an unweighted average of the scores of their 
nonmissing constituent items. The OHQ overall composite score will be calculated as 
(Sum of nonmissing OHSA item scores / Number of nonmissing OHSA items + 
Sum of nonmissing OHDAS item scores / Number of nonmissing OHDAS items)/2 
The calculated OHSA and OHDAS composite scores and the OHQ overall composite score will 
will be rounded to the nearest 0.1. 
OHSA#1 is assessed as the primary efficacy endpoint and its analysis is described in 
Section 8.4.1. Additionally, composite scores of OHSA and OHDAS, OHQ overall composite 
score, and individual item scores for OHSA items 2-6 and OHDAS items 1-4 will be analyzed 
similarly. 
8.6.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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𝑠𝑠 
𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒
𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑚𝑚𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
𝑝𝑝𝑝𝑝 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑥𝑥𝑡𝑡𝑡𝑡
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛
𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞
 
 
 
 
 
 
 
 
 
 
 
 
8.6.5. 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 6: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6.7. 
 
 
 
 
 
 
 


 
 
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8.6.8. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 7: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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9. 
Safety and Tolerability 
The analysis of safety and tolerability data includes an overall summary of adverse events, drug 
exposure (duration of treatment), dosing information/compliance, concomitant medications, 
clinical laboratory results, vital signs, ECGs, and C-SSRS. 
In general, inferential statistical tests are not performed for the analyses of safety and tolerability 
data. 
For all safety analyses, the safety analysis set will be used. The listing of TEAE and vitals signs 
will be provided using the randomized analysis set to include the subjects from site 27045. 
9.1. 
Adverse Events 
Adverse events are collected from signing of the informed consent through the end of follow-up. 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®, version 24.0). 
A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after 
the date of first dose of study drug up to 14 days after the date of last dose of study drug. 
However, for patients who continued into Study 0170, any AE occurs after Study 0170 Visit 1 
(Study 0169 Visit 6) will be considered as a TEAE for Study 0170 and will not be included in 
the AE summary for Study 0169 to avoid double counting.     
AEs observed during the period from obtaining informed consent to the start of administration of 
study drug will not be considered as TEAEs and will be listed only. 
AEs and TEAEs will be listed by subject. In addition, subjects with AEs leading to permanent or 
temporary discontinuation of treatment will be listed separately. 
TEAEs will be summarized overall with counts and percentages of subjects with the events, by 
treatment group, system organ class, and preferred term. TEAEs leading to permanent or 
temporary discontinuation of treatment, related to study treatment (i.e., any reported as related), 
serious TEAEs, frequent TEAEs (defined as >3% in the study population), TEAEs by severity, 
TEAEs of special interest, deaths, and TEAEs by maximum severity and causality will be 
summarized. 
If no adverse events meeting a specific table criterion are observed, the summary table will 
indicate that there were no occurrences. 
9.1.1. 
 
 
 
 
 
 
 
 


 
 
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9.2. 
Extent of Exposure and Treatment Compliance 
Duration of study drug exposure (days) will be summarized. Duration of exposure to study drug 
is calculated as (date of last dose – date of first dose + 1). 
Subjects will receive their assigned dose (10-mg dose of ampreloxetine (TD-9855) or matching 
placebo) once daily. Treatment compliance as a percentage of the expected total dose will be 
calculated as follows, using the information captured on the CRF page for “Study Drug 
Dispensing / Return”: 
• 100 × (number of tablets dispensed – number of tablets returned)/ 
(date of last dose – date of first dose + 1) 
Treatment compliance as a percentage of expected total dose will be summarized by treatment 
group for the safety analysis set as a continuous variable and using the following categories, after 
rounding to the nearest 0.1%: 
• ≥120% 
• ≥80% - <120% 
• <80% 
Study drug administration (date/time and study day) and drug accountability data will be listed. 
9.3. 
Concomitant and Other Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODD, 3Q 
2020 C3). Medications entered on the case report form will be mapped to Anatomic Therapeutic 
Chemical (ATC) drug class and generic drug name. Each verbatim name will be classified by 
anatomical main group (ATC level 1), therapeutic subgroup (ATC level 2), pharmacological 
subgroup (ATC level 3), chemical subgroup (ATC level 4), and preferred name (ATC level 5, 
chemical substance). 
Prior medications are medications used before initiation of study drug. Concomitant medications 
are medications used after initiation of study drug, including ongoing prior medications and 
medications beginning up to 14 days after the last dose of study drug. 
The number and percentage of subjects receiving prior and concomitant medications will be 
summarized by treatment group, medication class and standardized medication name (preferred 
name) for the safety analysis set. ATC level 4 is generally used to determine the medication class 
for a medication. If ATC level 4 is not available, the next available level of ATC code (i.e., level 
3, level 2, or level 1) will be used. Subjects reporting use of more than one medication at each 
level of summarization (any medication received, ATC class, and preferred name) will be 
counted only once. 


 
 
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Summaries of prohibited prior medications will be provided. 
On-treatment midodrine usage will be summarized for days of midodrine usage and daily dosage 
(mg) of midodrine. For days of midodrine usage, counts and percentages will be provided for the 
following categories: 
• 0 
• 1 
• 2 
• 3 
• 4 
• ≥ 5 
Numbers and percentages of subjects who took midodrine on assessment days will be provided. 
Listings of prior medications, concomitant medications, and midodrine usage will be provided. 
9.4. 
Laboratory Data 
Quantitative hematology, serum chemistry and urinalysis test results will be summarized in 
terms of observed values and changes from baseline for each visit. In addition, changes from 
baseline for each visit relative to normal ranges (e.g., shifts from normal to abnormal high/low) 
will be summarized in shift tables for hematology and serum chemistry. 
Listings will flag laboratory values that are outside the normal range, and listings of all abnormal 
laboratory values will be provided. 
9.5. 
Vital Signs and Weight 
The weight and vital sign (HR, systolic and diastolic BP, RR, and body temperature) values and 
their changes from baseline at each visit will be summarized. At visits when both vital signs and 
orthostatic standing test are performed, the vital signs (BP and HR) collected after 10 minutes 
supine and seated from the orthostatic standing test will be used for safety vital signs assessment. 
Therefore, the summaries will also include body position (supine and seated) as appropriate. The 
counts and percentages of subjects with vital signs in the following categories will be presented 
in a vital sign outlier summary. The outliers will be flagged in the listing. 
Table 8: 
Vital Signs Outlier Thresholds 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
>120 
<85 
>160 
<45 
>100 


 
 
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9.5.1. 
Ambulatory Blood Pressure 
Ambulatory blood pressure monitoring equipment will be provided to the subjects during the 
screening visit. Beginning approximately 72 to 24 hours before subjects return to the clinic on 
Visit 2, and before the Week 1 and Week 3 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 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 should also 
maintain a log of their posture at the time of each BP measurement. 
The ABPM time point and body position time point will be matched using a +/- 10 minutes 
window. Values outside the window will be excluded from analysis by position. If there are 
multiple position time points within the ABPM time point window, the position closest to the 
ABPM time will be used. If more than one entry is closest, the earlier entry will be used. 
The SBP, DBP, and HR in the supine position from ABPM will be summarized for 24 hour, 
daytime (8am-4pm), and nighttime (11pm-5am) average by treatment and visit. Assessments in 
other positions will be listed. 
9.6. 
ECGs 
A summary of ECG parameters, including QTcF, PR interval, QT interval, QRS duration, RR, 
and HR, will be summarized in terms of observed values and change from baseline. The ECG are 
planned to be collected as triplicates and the average of the measures will be used for the 
summary. 
Outlier Analysis 
The number of subjects with absolute ECG values and change from baseline in the ranges shown 
in Table 9 will be presented in electrocardiogram outlier summary by visit. 
In addition, in the same summary, QTcF 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). 
Individual ECG data collected during the study will be presented in a listing. A separate listing 
of subjects with values of QTcF ≥ 450 msec if male or ≥ 470 msec if female or an increase > 60 
msec will be provided, as necessary. 
Investigator Assessment of ECG Readings 
The investigator’s assessment of ECGs as normal, abnormal and clinically significant, or 
abnormal but not clinically significant will be summarized for baseline and for each visit. 


 
 
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Table 9: 
ECG 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 
 
9.7. 
C-SSRS 
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 Visit 1 and the C-SSRS Since 
Last Visit Version will be used at subsequent visits. 
Although the Since Last Visit Version of C-SSRS is collected at Visit 2 prior to the 1st dose of 
the study medication on the following day, it cannot be used as the baseline for C-SSRS 
assessment. The Baseline/Screening Version of C-SSRS collected at Visit 1 will be used as the 
baseline. If the Since Last Visit Version of C-SSRS is collected on the same day as the 
Baseline/Screening Version of C-SSRS, the Since Last Visit Version of C-SSRS doesn’t have a 
valid reference and hence will be excluded from summaries and analyses. But it will be 
presented in the listing. 
The following eleven C-SSRS categories, accepted by FDA as their standard, include five 
subtypes of suicidal ideation (1-5), five subtypes of suicidal behavior (6-10), and self-injurious 
behavior without suicidal intent (11). They all have binary responses (yes/no). 
1. Wish to be Dead 
2. Non-specific Active Suicidal Thoughts 


 
 
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3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
5. Active Suicidal Ideation with Specific Plan and Intent 
6. Preparatory Acts or Behavior 
7. Aborted Attempt 
8. Interrupted Attempt 
9. Actual Attempt (non-fatal) 
10. Completed Suicide 
11. Self-injurious behavior without suicidal intent 
Frequency counts and percentages will be presented for subjects in each C-SSRS category, as 
well as subjects with any suicidal ideation (1-5), subjects with any suicidal behavior (6-10), and 
subjects with any suicidal ideation or behavior (1-10), by treatment group at each visit where the 
items were collected. The summary of the Baseline/Screening Version of C-SSRS will present 
separately the assessment over the subject’s lifetime and during the last 12 months. 
10. 
POTENTIAL IMPACT OF COVID-19 
The following additional analyses will be performed to assess the potential impact of COVID-19 
on the data collection, extent of missing data, patient population, treatment and/or study 
discontinuation: 
• Subject visits before or after COVID-19 pandemic onset by visit modality 
• Separate summaries of demographic and baseline characteristics for subjects randomized 
before and after COVID-19 pandemic onset 
• Separate subject disposition tables for subjects who completed or discontinued treatment 
before and after COVID-19 pandemic onset 
• Subgroup analyses of OHSA#1 using MMRM for subgroups defined by timing of 
primary endpoint visit relative to COVID-19 pandemic onset (before, on or after) 


 
 
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11. 
REFERENCES 
 
 


 
 
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12. 
SUPPORTING DOCUMENTATION 
12.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Laboratory data that are continuous in nature but are less than the lower limit of