Conditions: Symptomatic Neurogenic Orthostatic Hypotension
Keywords: Symptomatic Neurogenic Orthostatic Hypotension sympomatic nOH multiple symptom atrophy MSA Parkinson's disease PD pure autonomic failure PAF orthostatic hypotension OH ampreloxetine 171 low blood pressure dizziness fainting blacking out lightheadedness norepinephrine hypotension OAK
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 110
Healthy volunteers: no

Brief summary:
A Phase 3, multi-center, open-label study to evaluate the safety and tolerability of ampreloxetine in subjects with primary autonomic failures (MSA, PD, and PAF) and symptomatic nOH over 182 weeks.

Detailed description:
This is a Phase 3, multi-center, open-label study to evaluate the safety and tolerability of ampreloxetine in subjects with primary autonomic failures (MSA, PD, and PAF) and symptomatic nOH. The study consists of 3 periods: (i) 26-week treatment, (ii) 156-week treatment extension, and (iii) 2-week follow-up.

Arms:
arm 1: Participants will receive a single, oral, daily dose of active drug (TD-9855) for 182 weeks.

Interventions: intervention 1: ampreloxetine
Intervention descriptions: intervention 1: Oral tablet, QD

Protocol document:
Prot_000.pdf: 
Protocol Number: 0171 
 
Official Title: A Phase 3, 182-week, Open-Label Extension Study to Investigate the Safety and 
Tolerability of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension 
(symptomatic nOH) in Subjects with Primary Autonomic Failure 
 
NCT Number: NCT04095793 
 
Document Date: 05 August 2020 


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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, 182-week, Open-Label Extension Study to 
Investigate the Safety and Tolerability of TD-9855 in Treating 
Symptomatic Neurogenic Orthostatic Hypotension 
(symptomatic nOH) in Subjects with Primary Autonomic 
Failure 
Study Short Title: 
Phase 3 Open-Label Extension Study of TD-9855 for Treating 
symptomatic nOH in Subjects with Primary Autonomic 
Failure 
Sponsor Study No.: 
0171 
Date: 
05 August 2020 
  
 
Test Product: 
TD-9855 (ampreloxetine hydrochloride) tablets 
US IND: 
129797 
EudraCT No.: 
2019-002425-30 
Sponsor: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
Clinical Study Director: 
 
 
Theravance Biopharma US, Inc. 
 
This study will be conducted according to the principles of Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma, Inc. It may not be 
copied or provided to any other party without the express written consent of 
Theravance Biopharma, Inc. 
© Theravance Biopharma (Unpublished Work). All rights reserved. 


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PROTOCOL SYNOPSIS 
Study Number and Title:  Study 0171: A Phase 3, 182-week, Open-Label Extension 
Study to Investigate the Safety and Tolerability Study of TD-9855 in Treating 
Symptomatic Neurogenic Orthostatic Hypotension (symptomatic nOH) in Subjects with 
Primary Autonomic Failure 
Study Short Title:  Phase 3 Open-Label Extension Study of TD-9855 for Treating 
symptomatic nOH in Subjects with Primary Autonomic Failure 
Estimated Number of Study Centers and Countries or Regions:  
 
 
Background and Rationale:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Objectives:   
The primary objective of the study is to evaluate the long-term safety of TD-9855 over a 
182-week period. 


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The exploratory objective of the study is to assess the patient reported outcome using 
EuroQoL Five-Dimensional Questionnaire (EQ-5D-5L). 
Study Design:   
This is a Phase 3, multi-center, open-label study to evaluate the safety and tolerability of 
TD-9855 in subjects with primary autonomic failures (MSA, PD, and PAF) and 
symptomatic nOH over 182 weeks. 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.  Based upon discussion with the subject, 
the Investigator may conduct each study visit for a given subject either in clinic or 
remotely. The Investigator is recommended to conduct in clinic study visits consistent 
either with the standard of care for a subject outside of a clinical trial or at a minimum 
once per year for each subject. 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, 
these tools, mechanisms, and processes will be made available to sites and subjects who 
have selected the in clinic visit modality.  
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. Data collected during these visits may include any protocol-
specified assessments which will be captured in the clinical database. 
Refer to Appendix 6 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. 
Subjects who complete Study 0170 will be eligible for this study.  Following signing of the 
informed consent, subjects will enter Study 0171 Visit 1, which will be conducted on the 
same day as Visit 9 of Study 0170. 
Eligible subjects will receive a single dose of 
 TD-9855 
) for 
182 weeks.  
Subjects will complete study visits as outlined below: 
• Visit 2 (Week 2) 
• Visit 3 (Week 6) 
• Visit 4 (Week 10) 
• Visit 5 (Week 18) 
• Visit 6 (Week 26) 
• Visit 7 (Week 38) 


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• Visit 8 (Week 50) 
• Visit 9 (Week 74) 
• Visit 10 (Week 98) 
• Visit 11 (Week 122) 
• Visit 12 (Week 146) 
• Visit 13 (Week 170)  
• Visit 14 (Week 182) 
Telephone contact will be made to assess patient safety at Weeks 14, 22, 62, 86, 110, 134, 
158, and 184. 
The schematic representation is as shown below: 
Visits 1 to 6 
 
Visits 7 to Telephone 8 
 
Assessments will be conducted as outlined in the Schedule of Study Procedures (Table 1). 
Refer to Appendix 6 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. The stopping criteria include meeting 
at least one of the following rules: 
• A determination from the Investigator that further administration of the 
investigational product may pose a safety concern to the subject. 


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• Sustained (at least 4 hours) SBP >180 mmHg or diastolic BP (DBP) 
>110 mmHg after 3 min of standing or after 5 min in the sitting position, or a 
sustained (at least 4 hours) SBP >180 mmHg or DBP >110 mmHg measured in 
the supine state (head/torso elevated at approximately 30o from horizontal 
position).  
• Intolerable AE as determined by the Investigator. 
• Subject becomes pregnant.  
No dose reduction is permitted at any time.  
Safety assessments for the first 26 weeks will include a physical examination, neurological 
examination, vital signs (HR, BP, RR and body temperature), ECGs, safety laboratory 
tests (hematology, chemistry, and urinalysis), C-SSRS, and AEs.  Safety assessments for 
the remaining 158 weeks will include evaluation of adverse events and concomitant 
medications.  
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 must be reminded to maintain an adequate 
fluid intake during their scheduled visits. 
Duration of Study Participation: Subjects will participate in this study for approximately 
182 weeks of treatment and 2 weeks of follow up. 
Number of Subjects: 
 
   
Study Population: 
This study will enroll adult subjects with confirmed symptomatic nOH due to MSA, PD or 
PAF and who meet the inclusion and none of the exclusion criteria defined below. Eligible 
subjects will be subjects who complete Study 0170. 
Inclusion Criteria: 
1. Completion of Study 0170 and, in the opinion of the Investigator, would benefit 
from long-term treatment with TD-9855.  
2. The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study procedures (including 
any changes occurring in the subject’s current therapeutic regimen). 
3. The subject must be willing to continue on treatment and must continue to meet all 
the inclusion criteria for the preceding study (Study 0170) except, a score of >4 in 
OHSA#1. 
Exclusion Criteria: 
1. Subjects may not be enrolled in another clinical trial, with the exception of purely 
observational studies, which are allowed. 


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2. Psychiatric, neurological, or behavioral disorders that may interfere with the ability 
of subjects to give informed consent or interfere with the conduct of the study. 
3. Medical, laboratory, or surgical issues deemed by the Investigator to be clinically 
significant. 
4. Hypersensitivity to TD-9855 or the formulation excipients. 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
 
  
 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:  
 
 
Study Evaluations 
Safety Assessments: 
• Physical examination 
• Neurological examination 
• Vital signs 
• Resting ECGs 
• Clinical laboratory tests including biochemistry, hematology, and urinalysis. 
• Concomitant medication 
• AEs 
• Subject compliance to study treatment 
• Incidence of falls 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Statistical Methods 
 
 
 
 
 
 
 
 
 


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Study Endpoints: 
Primary safety and tolerability endpoints include: 
• Physical examination 
• Neurological examination 
• Vital signs 
• Resting ECGs 
• Clinical laboratory tests including biochemistry, hematology, and urinalysis. 
• Concomitant medication 
• AEs 
• Subject compliance to study treatment 
• Incidence of falls 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 
 
Analysis: 
The FAS (Full Analysis Set) and Safety analysis set will be identical and is defined as all 
enrolled subjects who have received at least one dose of TD-9855 in this study. 
Descriptive summaries will be provided for demographics and baseline characteristics. 
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 
adverse events, hematology, biochemistry and urinalysis laboratory evaluations, vital 
signs, 12 lead ECG findings, and concomitant medications. 
Incidence of falls will be descriptively summarized using number of falls per subject, 
number and percentage of subjects with at least 1 fall since the previous study visit. 
 
   
 


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SCHEDULE OF STUDY PROCEDURES 
Table 1: 
Schedule of Study Procedures (Visits 1 – 6) 
Each study visit for each subject may be conducted either in clinic or remotely 
Study Week (Visit/Telephone):  
Week 0 
Visit 1 
(0170 
Visit 9) 
Week 2 
Visit 2 
+/- 3 days 
Week 6 
Visit 3 
+/- 3 days 
Week 10 
Visit 4 
+/- 7 days 
Week 14 
Telephone 1 
+/- 3 days 
Week 18 
Visit 5 
+/- 7 days 
Week 22 
Telephone 2 
+/- 3 days 
Week 26 
 Visit 6 
+/- 7 days 
Early 
Termination 
up to Week 26 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
Medical history, including 
smoking history 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
 Xa 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
Xa 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (heart rate, blood 
pressure, respiratory rate and 
body temperature) 
Xa, b 
Xb 
Xb 
Xb 
 
Xb 
 
Xb 
Xb 
Physical examination  
Xa 
 
 
X 
 
 
 
X 
X 
Neurological examination 
Xa 
 
 
X 
 
 
 
X 
X 
12-lead electrocardiograme 
Xa 
 
 
X 
 
 
 
X 
X 
Pregnancy Test 
Xa,c 
 
 
Xc 
 
 
 
Xc 
Xc 
Safety Labs (chemistry, 
hematology, urinalysis) 
Xa 
 
 
X 
 
 
 
X 
X 
Dosing, Incidence of Falls, and 
Midodrine Diaries  
Xa 
X 
X 
X 
 
X 
 
X 
X 
Adverse Events 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
Xd 
Xd 
Xd 
Xd 
 
Xd 
 
Xd 
 
Study Drug Dosing 
Xd 
 
Collect Study Drug 
 
X 
X 
X 
 
X 
 
X 
X 
a. Study 0170 procedures conducted at Visit 9 will serve as the baseline assessment for Visit 1 of Study 0171.  
b. Vital signs will be assessed after the subject has been resting for at least 5 minutes in the seated or supine position. 


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c. In women of childbearing potential only, urine beta human chorionic gonadotropin (βhCG) test will be performed and if positive, confirmation with serum βhCG 
test is required. The pregnancy test must be confirmed negative for a subject to be eligible for this study. 
d. Study drug 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 must be reminded to maintain an adequate fluid intake during their scheduled visits. Subjects will start taking study drug on 
the day after Visit 1.  
e. 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. 
 
 


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Table 2: 
Schedule of Study Procedures (Visits 7 – 14 Extension) 
Study Week 
(Visit/Telephone):  
Wk 38 
Visit 7 
+/-7 days 
Wk 50  
Visit 8 
+/-7 days 
Wk 62 
Telephone 3 
+/-7 days 
Wk 74 
Visit 9 
+/-7 day 
Wk 86 
Telephone 4 
+/-7 days 
Wk 98  
Visit 10 
+/-7 days 
Wk 110 
Telephone 5 
+/-7 days 
Wk 122  
Visit 11 
+/-7 days 
Wk 134 
Telephone 6 
+/-7 days 
Wk 146  
Visit 12 
+/-7 days 
Wk 158 
Telephone 7 
+/-7 days 
Wk 170  
Visit 13 
+/-7 days 
Wk 182  
Visit 14 
End of 
Treatment 
Early Termination 
after Week 26 
+/-7 days 
Wk 184 
Telephone 8 
Follow-up 
+/-7 days 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testa 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Dispense Study Drug 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Study Drug Dosing 
 
Xb 
 
 
Collect Study Drug 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
a. In women of childbearing potential only, urine beta human chorionic gonadotropin (βhCG) test will be performed.  
b. Study drug will be ingested in the morning at approximately the same time of day with 8 ounces of water. 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 17 
1. 
INTRODUCTION ................................................................................... 19 
1.1. 
Background and Rationale ....................................................................... 19 
1.2. 
Nonclinical Profile ................................................................................... 20 
1.2.1. 
Nonclinical Pharmacology ....................................................................... 20 
1.2.2. 
Safety Pharmacology ............................................................................... 21 
1.2.3. 
Nonclinical Pharmacokinetics ................................................................. 21 
1.2.4. 
Toxicology ............................................................................................... 21 
1.3. 
Clinical Experience .................................................................................. 22 
1.4. 
Risks and Benefits ................................................................................... 24 
2. 
OBJECTIVE ............................................................................................ 26 
3. 
STUDY DESIGN .................................................................................... 27 
3.1. 
Overview .................................................................................................. 27 
3.2. 
Rationale for Study Design ...................................................................... 29 
3.3. 
Selection of Dose and Duration of Treatment ......................................... 30 
3.4. 
Study Endpoints ....................................................................................... 31 
4. 
STUDY POPULATION .......................................................................... 32 
4.1. 
Inclusion Criteria ..................................................................................... 32 
4.2. 
Exclusion Criteria .................................................................................... 32 
4.3. 
Pregnancy and Contraception .................................................................. 32 
4.3.1. 
Females of Childbearing Potential........................................................... 32 
4.3.2. 
Contraception for Male and Female Subjects .......................................... 33 
5. 
STUDY DRUG ........................................................................................ 34 
5.1. 
Description of Study drug ........................................................................ 34 
5.1.1. 
TD-9855 Test Product ............................................................................. 34 
5.2. 
Dosage and Administration ..................................................................... 34 
5.3. 
Treatment Compliance ............................................................................. 34 
5.4. 
Drug Accountability and Reconciliation ................................................. 34 
6. 
STUDY PROCEDURES ......................................................................... 35 
6.1. 
Schedule of Study Procedures ................................................................. 35 
6.2. 
Total Blood Volume ................................................................................ 35 
6.3. 
Procedures by Visit .................................................................................. 35 
6.3.1. 
Screening ................................................................................................. 35 


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6.3.2. 
Visit 1 – Week 0 ...................................................................................... 35 
6.3.3. 
Visit 2 – Week 2 ...................................................................................... 36 
6.3.4. 
Visit 3 – Week 6 ...................................................................................... 36 
6.3.5. 
Visit 4 – Week 10 .................................................................................... 37 
6.3.6. 
Telephone Contact 1 – Week 14 .............................................................. 37 
6.3.7. 
Visit 5 – Week 18 .................................................................................... 37 
6.3.8. 
Telephone Contact 2 – Week 22 .............................................................. 38 
6.3.9. 
Visit 6 – Week 26 .................................................................................... 38 
6.3.10. 
Early Termination Up to Week 26 ........................................................... 39 
6.3.11. 
Visit 7 – Week 38 .................................................................................... 39 
6.3.12. 
Visit 8 – Week 50 .................................................................................... 39 
6.3.13. 
Telephone Contact 3 – Week 62 .............................................................. 40 
6.3.14. 
Visit 9 – Week 74 .................................................................................... 40 
6.3.16. 
Visit 10 – Week 98 .................................................................................. 40 
6.3.17. 
Telephone Contact 5 – Week 110 ............................................................ 40 
6.3.18. 
Visit 11 – Week 122 ................................................................................ 40 
6.3.19. 
Telephone Contact 6 – Week 134 ............................................................ 41 
6.3.20. 
Visit 12 – Week 146 ................................................................................ 41 
6.3.21. 
Telephone Contact 7 – Week 158 ............................................................ 41 
6.3.22. 
Visit 13 – Week 170 ................................................................................ 41 
6.3.23. 
Visit 14 – Week 182/End of Treatment/Early Termination after 
Week 26 through Week 182 .................................................................... 41 
6.3.24. 
Telephone Contact 8 – Week 184/Follow-up .......................................... 41 
6.4. 
Description of Study Assessments ........................................................... 42 
6.4.1. 
Demographic and Baseline Assessments................................................. 42 
 
 
 
 
6.4.3. 
Safety Assessments .................................................................................. 42 
6.4.3.1. 
Columbia-Suicide Severity Rating Scale ................................................. 42 
6.4.3.2. 
Adverse Events ........................................................................................ 43 
6.4.3.3. 
Medication and Medical History ............................................................. 43 
6.4.3.4. 
Physical Examination .............................................................................. 43 
6.4.3.5. 
Neurological Examination ....................................................................... 43 
6.4.3.6. 
Vital Signs ............................................................................................... 44 
6.4.3.7. 
Electrocardiograms .................................................................................. 44 


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6.4.3.8. 
Incidence of Falls Diary ........................................................................... 44 
6.4.3.9. 
Laboratory Tests ...................................................................................... 44 
6.5. 
Concomitant Medications ........................................................................ 45 
 
 
6.6. 
Rescue Medications ................................................................................. 45 
 
 
 
 
6.8.1. 
Subject Discontinuation ........................................................................... 46 
6.8.2. 
Subject Replacement ............................................................................... 47 
6.8.3. 
Study Discontinuation ............................................................................. 47 
6.8.4. 
Dose Stopping Rules................................................................................ 47 
6.9. 
Pregnancy ................................................................................................ 47 
7. 
ADVERSE EVENTS............................................................................... 49 
7.1. 
Definitions ............................................................................................... 49 
7.1.1. 
Adverse Events (AE) ............................................................................... 49 
7.1.2. 
Serious Adverse Event (SAE) ................................................................. 50 
7.1.3. 
Additional Considerations for Serious Adverse Events .......................... 50 
7.1.4. 
Adverse Event of Special Interest (AESI) ............................................... 51 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ........................................ 51 
7.3. 
Assessment of Adverse Events ................................................................ 52 
7.3.1. 
Severity .................................................................................................... 52 
7.3.2. 
Causal Relationship to Study drug .......................................................... 52 
7.4. 
Adverse Event Reporting and Recording ................................................ 53 
7.4.1. 
Adverse Event Reporting ......................................................................... 53 
7.4.2. 
Adverse Event and Serious Adverse Event Recording ............................ 53 
7.4.3. 
Serious Adverse Event and Adverse Event of Special Interest Reporting 
Timeline ................................................................................................... 54 
7.5. 
Adverse Event Follow-up ........................................................................ 55 
8. 
STATISTICAL CONSIDERATIONS .................................................... 56 
8.1. 
General Considerations ............................................................................ 56 
 
 
8.3. 
Analysis Sets ............................................................................................ 56 
8.3.1. 
Examination of Subgroups ...................................................................... 56 
8.3.2. 
Major Protocol Analysis Deviations ........................................................ 56 


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8.4. 
General Analyses ..................................................................................... 57 
8.4.1. 
Demographics Characteristics and Other Baseline Characteristics ......... 57 
 
 
8.5. 
Safety Analyses ....................................................................................... 57 
8.5.1. 
Extent of Exposure .................................................................................. 57 
8.5.2. 
Adverse Event Data ................................................................................. 57 
8.5.3. 
Concomitant Medications ........................................................................ 58 
8.5.4. 
Laboratory Data ....................................................................................... 58 
8.5.5. 
Vital Signs Data ....................................................................................... 58 
8.5.6. 
ECG Data ................................................................................................. 58 
8.5.7. 
Analysis of Falls ...................................................................................... 59 
8.6. 
Missing Data Handling ............................................................................ 60 
 
 
9. 
STUDY ADMINISTRATION ................................................................ 61 
9.1. 
Principal Investigator Responsibilities .................................................... 61 
9.2. 
Institutional Review Board/Independent Ethics Committee ................... 62 
9.3. 
Informed Consent .................................................................................... 62 
9.4. 
Data Recording and Quality Assurance ................................................... 62 
9.5. 
Document Retention ................................................................................ 63 
9.6. 
Confidentiality ......................................................................................... 64 
9.7. 
Access to Data and Documents ............................................................... 64 
9.8. 
Quality Control: Study Monitoring and Auditing ................................... 65 
9.9. 
Publication ............................................................................................... 65 
10. 
REFERENCES ........................................................................................ 66 
APPENDIX 1. EXAMPLES OF DISEASE INSTRUMENTS ............................... 67 
APPENDIX 2. INCIDENCE OF FALLS DIARY................................................... 73 
APPENDIX 3. DOSING DIARY ............................................................................ 74 
 
 
APPENDIX 7. PROTOCOL SIGNATURE FORM ................................................ 80 
 


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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures (Visits 1 – 6) ............................................. 9 
Table 2: 
Schedule of Study Procedures (Visits 7 – 14 Extension) ........................ 11 
Table 3: 
Outlier Threshold for Vital Signs ............................................................ 58 
Table 4: 
Electrocardiogram Test Outlier Thresholds ............................................. 59 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ...................................................................................... 28 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
5-HT 
Serotonin 
ADHD 
Attention-deficit hyperactivity disorder 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
βhCG  
Beta human chorionic gonadotropin 
BP 
Blood pressure 
CFR 
(United States) Code of Federal Regulations 
Cmax 
Maximum concentration recorded 
CNS 
Central Nervous System 
eCOA 
Electronic Clinical Outcome Assessment 
CRF 
Case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Early Termed 
 
 
FAS 
Full analysis set 
FM 
Fibromyalgia 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
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 
MAP 
Mean arterial pressure 
MAR 
Missing at random 


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Abbreviation 
Description 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MMRM 
Mixed Model for Repeated Measures 
MSA 
Multiple System Atrophy 
NE 
Norepinephrine 
NET 
Norepinephrine transporter 
nOH 
Neurogenic Orthostatic Hypotension 
NOAEL 
No observed adverse event level 
NRI 
Norepinephrine reuptake inhibitor 
OH 
Orthostatic Hypotension 
OHSA#1 
Orthostatic Hypotension Symptom Assessment Question 1 
PAF 
Pure Autonomic Failure 
PD 
Parkinson’s disease  
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 
t1/2 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TD-9855 
Laboratory code for ampreloxetine hydrochloride 
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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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. 
 
 
 


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SERT over DAT and various other transporter, receptor, ion channel, and enzyme targets 
 
 
 
 
1.2.2. 
 
 
 
 
 
  
 
 
 
 
 
 
1.2.3. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
1.2.4. 
 
 
 
 
 
 
 
 


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1.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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Overall, of the 34 subjects dosed in the study, 3 subjects discontinued study drug due to 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.1. 
 
 
 
 
 
 
 
 
 
 
 
 
1.4. 
Risks and Benefits 
Results from preclinical and clinical studies indicate that TD-9855 is
 
 
 
 Efficacy of 
TD-9855 is being further evaluated in confirmatory studies (Studies 0169 and 0170). 
Study 0171 provides access to drug for subjects who participated in Study 0170 and for 
whom Investigators believe could benefit from longer term treatment with TD-9855.   
 
 
 
 
 
 
 


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To help ensure subject safety, subjects will be closely monitored during this study. Study 
visits will 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 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 
procedures, 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. 
OBJECTIVE 
The primary objective of the study is to evaluate the long-term safety of TD-9855 over a 
182-week period. 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a Phase 3, multi-center, open-label study to evaluate the safety and tolerability of 
TD9855 in subjects with primary autonomic failures (MSA, PD, and PAF) and symptomatic 
nOH over 182 weeks. 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.  Based upon discussion with the subject, the Investigator may 
conduct each study visit for a given subject either in clinic or remotely. The Investigator is 
recommended to conduct in clinic study visits consistent either with the standard of care for a 
subject outside of a clinical trial or at a minimum once per year for each subject. 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, 
these tools, mechanisms, and processes will be made available to sites and subjects who have 
selected the in clinic visit modality. 
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. Data collected during these visits may include any protocol-specified 
assessments which will be captured in the clinical database. 
Subjects who complete Study 0170 will be eligible for this study.  Following signing of the 
informed consent, subjects will enter Study 0171 Visit 1, which will be conducted on the 
same day as Visit 9 of Study 0170. Study 0170 procedures conducted at Visit 9 will serve as 
the baseline assessments for Visit 1 of Study 0171. 
Beginning on the day after Visit 1, subjects will receive a single dose of 
 TD-9855 
 
and continue thereafter for the 182-week duration of the treatment period. 
Subjects will complete study visits as outlined below: 
• Visit 2 (Week 2) 
• Visit 3 (Week 6) 
• Visit 4 (Week 10) 
• Visit 5 (Week 18) 
• Visit 6 (Week 26) 
• Visit 7 (Week 38) 
• Visit 8 (Week 50) 
• Visit 9 (Week 74) 
• Visit 10 (Week 98) 


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• Visit 11 (Week 122) 
• Visit 12 (Week 146) 
• Visit 13 (Week 170) 
• Visit 14 (Week 182)  
Telephone contact will be made to assess patient safety on Weeks 14, 22, 62, 86, 110, 134, 
158, and 184. 
The study consists of 3 periods: (i) 26-week treatment, (ii) 156-week treatment extension and 
(iii) 2-week follow-up. The schematic representation is as shown below: 
Figure 1: 
Study Schematic 
Visits 1 to 6 
 
Visits 7 to Telephone 8 
 
No dose reduction is permitted during the treatment periods.  
Subjects unable to tolerate 
 TD-9855 will be discontinued from the study.  
Assessments will be conducted as outlined in the Schedule of Study Procedures (Table 1).  
Refer to Appendix 6 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.  
At any time during the study, if a subject meets at least one of the following stopping rules, 
they must be discontinued and undergo an end of study visit:  
• A determination from the PI (in discussion with the Sponsor’s medical monitor) 
that further administration of the investigational product may pose a safety 
concern to the subject.  


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• Sustained (at least 4 hours) SBP >180 mmHg or diastolic BP (DBP) >110 mmHg 
after 3 min of standing or after 5 mins in the sitting position, or a sustained 
(at least 4 hours) SBP >180 mmHg or DBP >110 mmHg measured in the supine 
state (head/torso elevated at approximately 30° from horizontal position).  
• Intolerable AE, as determined by the PI.  
• Subject becomes pregnant.  
During the first 26 weeks, safety assessments will include a physical examination, 
neurological examination, vital signs (HR, BP, respiratory rate [RR] and body temperature), 
12-lead electrocardiograms (ECGs), laboratory tests (hematology, chemistry, and urinalysis), 
Columbia Suicide Severity Rating Scale (C-SSRS), and monitoring of AEs.  Safety 
assessments after Week 26 will include assessments of AEs and Concomitant Medications. 
  
Subjects will be requested to refrain from making any significant dietary changes throughout 
the duration of the study. During their scheduled visits, subjects should be reminded to 
maintain an adequate fluid intake.  
Subjects will complete the Early Termination Visit if they terminate from the study prior to 
Week 26.  All subjects will complete the End of Treatment Visit (Visit 14) upon completion 
of the 182-week treatment period or if terminating early after Week 26.  The Follow-up visit 
must be completed within 2 weeks (+/- 7 days) from the date of the last dose for all subjects 
who complete the 182-week treatment period or who terminate the study early at any point.  
3.2. 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 


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3.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 


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Based on the results of the human positron-emission tomography study in healthy volunteers, 
 
 
 
 
 
  
   
3.4. 
Study Endpoints 
Study Endpoints: 
Primary safety and tolerability endpoints include: 
• Physical examination 
• Neurological examination 
• Vital signs 
• Resting ECGs 
• Clinical laboratory tests including biochemistry, hematology, and urinalysis. 
• Concomitant medication 
• AEs 
• Subject compliance to study treatment 
• Incidence of falls 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 
 
 
 


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4. 
STUDY POPULATION 
This study will enroll adult subjects with confirmed symptomatic nOH due to MSA, PD, or 
PAF and who meet all of the applicable inclusion criteria and none of the applicable 
exclusion criteria defined below. 
4.1. 
Inclusion Criteria 
Subjects who meet the following criteria will be eligible for study enrollment: 
1. Completion of Study 0170 and, in the opinion of the Investigator, would benefit from 
long-term treatment with TD-9855.  
2. The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study procedures (including any 
changes occurring in the subject’s current therapeutic regimen). 
3. The subject must be willing to continue on treatment and must continue to meet all 
the inclusion criteria for the preceding study (Study 0170) except, a score of >4 in 
OHSA#1. 
4.2. 
Exclusion Criteria 
Subjects who satisfy any of the following criteria are not eligible for study enrollment: 
1. Subjects may not be enrolled in another clinical trial, with the exception of purely 
observational studies, which are allowed. 
2. Psychiatric, neurological, or behavioral disorders that may interfere with the ability of 
subjects to give informed consent or interfere with the conduct of the study. 
3. Medical, laboratory, or surgical issues deemed by the Investigator to be clinically 
significant. 
4. Hypersensitivity to TD-9855 or the formulation excipients. 
4.3. 
Pregnancy and Contraception 
4.3.1. 
Females of Childbearing Potential 
Females of childbearing potential must have documentation of a negative pregnancy test prior 
to dosing.  
Females are not considered to be 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 enrollment) 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 
(Section 6.9).  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 are not 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 DRUG 
All study drug supplied by the Sponsor must be stored in a secure location accessible only to 
designated study personnel. 
5.1. 
 
 
 
.  
5.1.1. 
 
 
 
 
5.2. 
Dosage and Administration 
All study drug 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 drug containers at each visit. 
Compliance with the dosing regimen will be assessed by reconciliation of used and unused 
study drug.  
The subjects’ dosing diary entries will also be reviewed at applicable study visits to assess 
compliance with study drug administration per documentation of the daily dosing times. 
An example of the diary is provided in Appendix 3.  
Subjects with poor dosing compliance (i.e., < 80% or > 120%), as assessed by reconciliation 
of used and unused study drug and/or missing entries on the study drug administration diary, 
should receive counseling, assistance, and re-training as appropriate. 
5.4. 
Drug Accountability and Reconciliation 
The Investigator or designee is responsible for maintaining accountability records for all 
study drug(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 drug 
will be disposed of in accordance with written instructions from the Sponsor. 


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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1 and Table 2. Assessments will be 
conducted as outlined in the Schedule of Study Procedures.  Refer to Appendix 6 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 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 
The Enrollment date for the Study is defined as Week 0/Visit 1. 
6.3.1. 
Screening 
All subjects enrolled into Study 0171 will roll over from Study 0170, therefore there is no 
screening visit. Study 0170 procedures conducted at Visit 9 will serve as the baseline 
assessments for Visit 1 of Study 0171.  
6.3.2. 
Visit 1 – Week 0 
Study 0170 procedures conducted at Visit 9 will serve as the baseline assessments for Visit 1 
of Study 0171.  
Beginning on the day after Visit 1, subjects will receive a single dose of 
 TD-9855 
 
 and continue thereafter for the 182-week duration of the treatment period.  
The following procedures must be completed first, and in the order below at the Week 0 
Visit:  
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 
The following procedures are listed in the recommended order, however flexibility for 
scheduling is permitted: 
5. C-SSRS 
6. 
 
7. Vital signs 
a. HR, systolic BP (SBP), and diastolic BP (DBP) 
b. Respiratory rate (RR) and body temperature 


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8. Physical examination 
9. Neurological examination 
10. 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) 
11. Pregnancy test (in women of childbearing potential only) 
12. Blood collection:  
a. Hematology 
b. Chemistry  
13. Urine collection: Urinalysis 
14. Dosing Diary dispensation 
15. Incidence of Falls Diary, dispensation and review of diary completion instructions 
16. Midodrine Diary dispensation 
17. AE assessment (AEs, SAEs, adverse event of special interest [AESIs]) 
18. Dispense study drug  
6.3.3. 
Visit 2 – Week 2 
The following procedures will be performed at the Week 2 visit: 
1. Review concomitant medications  
2. C-SSRS 
3. 
 
4. Vital signs  
a. HR, SBP, and DBP 
b. RR and body temperature 
5. Dosing Diary collection and review 
6. Incidence of Falls Diary collection and review  
7. Midodrine Diary collection and review 
8. AE assessment (AEs, SAEs, AESIs) 
9. Collect, review, and dispense study drug 
6.3.4. 
Visit 3 – Week 6 
The following procedures will be performed at the Week 6 visit: 
1. Review concomitant medications 
2. C-SSRS 
3. EQ-5D-5L 
4. Vital signs:  
a. HR, SBP, and DBP 


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b. RR and body temperature 
5. Dosing Diary collection and review  
6. Incidence of Falls Diary collection and review  
7. Midodrine Diary collection and review 
8. AE assessment (AEs, SAEs, AESIs) 
9. Collect, review, and dispense study drug 
6.3.5. 
Visit 4 – Week 10 
The following procedures will be performed at the Week 10 visit: 
1. Review concomitant medications  
2. C-SSRS 
3.
 
4. Vital signs 
a. HR, SBP, DBP 
b. RR and body temperature 
5. Physical examination 
6. Neurological examination 
7. 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) 
8. Pregnancy test (in women of childbearing potential only) 
9. Blood collection: Hematology, Chemistry  
10. Urine collection: Urinalysis 
11. Dosing Diary collection and review  
12. Incidence of Falls Diary collection and review  
13. Midodrine Diary collection and review 
14. AE assessment (AEs, SAEs, AESIs) 
15. Collect, review, and dispense study drug 
6.3.6. 
Telephone Contact 1 – Week 14 
The following procedures will be performed at Week 14: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.7. 
Visit 5 – Week 18 
The following procedures will be performed at the Week 18 visit: 
1. Review concomitant medications 
2. C-SSRS 


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3. 
 
4. Vital signs 
a. HR, SBP, DBP 
b. RR and body temperature 
5. Dosing Diary collection and review  
6. Incidence of Falls Diary collection and review 
7. Midodrine Diary collection and review 
8. AE assessment (AEs, SAEs, AESIs) 
9. Collect, review, and dispense study drug 
6.3.8. 
Telephone Contact 2 – Week 22 
The following procedures will be performed at Week 22: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.9. 
Visit 6 – Week 26  
The following procedures will be performed at the Week 26 visit. 
1. Review concomitant medications 
2. C-SSRS 
3. 
 
4. Vital signs 
a. HR, SBP, DBP 
b. RR and body temperature 
5. Physical examination 
6. Neurological examination 
7. 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) 
8. Pregnancy test (in women of childbearing potential only) 
9. Blood collection: Hematology, Chemistry  
10. Urine collection: Urinalysis 
11. Dosing Diary collection and review  
12. Incidence of Falls Diary collection and review 
13. Midodrine Diary collection and review 
14. AE assessment (AEs, SAEs, AESIs) 
15. Collect, review, and dispense study drug  


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6.3.10. 
Early Termination Up to Week 26 
Subjects terminating the study prior to Week 26 will complete all of the following 
procedures. 
1. Review concomitant medications  
2. C-SSRS 
3. 
 
4. Vital signs 
a. HR, SBP, DBP 
b. RR and body temperature 
5. Physical examination 
6. Neurological examination 
7. 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) 
8. Pregnancy test (in women of childbearing potential only) 
9. Blood collection: Hematology, Chemistry  
10. Urine collection: Urinalysis 
11. Dosing Diary collection and review  
12. Incidence of Falls Diary collection and review 
13. Midodrine Diary collection and review 
14. AE assessment (AEs, SAEs, AESIs) 
15. Collect and review study drug 
6.3.11. 
Visit 7 – Week 38 
The following procedures will be performed at the Week 38 visit: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
3. Collect, review, and dispense study drug 
6.3.12. 
Visit 8 – Week 50 
The following procedures will be performed at the Week 50 visit: 
1. Review concomitant medications 
2. Pregnancy test (in women of childbearing potential only) 
3. AE assessment (AEs, SAEs, AESIs) 
4. Collect, review, and dispense study drug 


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6.3.13. 
Telephone Contact 3 – Week 62 
The following procedures will be performed at Week 62: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.14. 
Visit 9 – Week 74 
The following procedures will be performed at the Week 74 visit: 
1. Review concomitant medications 
2. Pregnancy test (in women of childbearing potential only) 
3. AE assessment (AEs, SAEs, AESIs) 
4. Collect, review, and dispense study drug 
6.3.15. 
Telephone Contact 4 – Week 86 
The following procedures will be performed at Week 86: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.16. 
Visit 10 – Week 98 
The following procedures will be performed at the Week 98 visit: 
1. Review concomitant medications  
2. Pregnancy test (in women of childbearing potential only) 
3. AE assessment (AEs, SAEs, AESIs) 
4. Collect, review, and dispense study drug 
6.3.17. 
Telephone Contact 5 – Week 110 
The following procedures will be performed at Week 110: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.18. 
Visit 11 – Week 122 
The following procedures will be performed at the Week 122 visit: 
1. Review concomitant medications 
2. Pregnancy test (in women of childbearing potential only) 
3. AE assessment (AEs, SAEs, AESIs) 
4. Collect, review, and dispense study drug 


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6.3.19. 
Telephone Contact 6 – Week 134 
The following procedures will be performed at Week 134: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.20. 
Visit 12 – Week 146 
The following procedures will be performed at the Week 146 visit: 
1. Review concomitant medications 
2. Pregnancy test (in women of childbearing potential only)  
3. AE assessment (AEs, SAEs, AESIs) 
4. Collect, review, and dispense study drug 
6.3.21. 
Telephone Contact 7 – Week 158 
The following procedures will be performed at Week 158: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
6.3.22. 
Visit 13 – Week 170 
The following procedures will be performed at the Week 170 visit: 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 
3. Collect, review, and dispense study drug 
6.3.23. 
Visit 14 – Week 182/End of Treatment/Early Termination after 
Week 26 through Week 182 
Subjects who complete the 182-week treatment period, or terminate the study early after 
Week 26 will complete all End of Treatment visit procedures. 
1. Review concomitant medications 
2. Pregnancy test (in women of childbearing potential only) 
3. AE assessment (AEs, SAEs, AESIs) 
4. Collect and review study drug 
6.3.24. 
Telephone Contact 8 – Week 184/Follow-up 
The Follow-up visit must be completed within 2 weeks (+/- 7 days) from the date of the last 
dose for all subjects who complete the 182-week treatment period or terminate the study early 
at any point during the study. The following procedures will be performed at the Follow-up 
visit. 
1. Review concomitant medications  
2. AE assessment (AEs, SAEs, AESIs) 


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6.4. 
Description of Study Assessments 
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. 
The data will be confirmed with information captured in Study 0170. 
6.4.2. 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
6.4.3. 
Safety Assessments 
6.4.3.1. 
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 Since Last Visit Version will be used for all visits. 
Assessments will be performed as specified in the Schedule of Study Procedures (Table 1). 
An example of the instrument is provided in Appendix 1.  


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6.4.3.2. 
Adverse Events 
Study 0171 AEs will be reviewed and recorded from date of first dose of study drug through 
the end of follow-up. Adverse events may be observed by the site study personnel or 
spontaneously reported by the subject or subject’s caregiver. In addition, ongoing AEs from 
preceding Study 0170 will be followed in this study.  
Adverse events that start after signing of Study 0171 informed consent, but before the first 
dose of study drug is taken on Day 2, are to be captured in Study 0170 database. Adverse 
events started in Study 0170 but which worsen in severity or seriousness during Study 0171 
should be reported as a new adverse event.  
All AEs must be recorded in the subject’s CRF and, if applicable, reported as described in 
Section 7.   
6.4.3.3. 
Medication and Medical History 
A complete medical history will be taken during Study 0170 and will include evaluation of 
past and present cardiovascular, respiratory, GI, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatologic, psychiatric, genitourinary, substance 
abuse, surgical history, or any other diseases or disorders. Medical conditions will be 
recorded for 2 years prior to screening visit, along with the date of diagnosis, and any other 
relevant medical history that has an impact to the subject. 
Medical events or conditions that arise or worsen in severity or frequency after date of first 
dose of study drug will be recorded as an AE in Study 0171.  
6.4.3.4. 
Physical Examination 
An abbreviated physical examination will be performed by an appropriately qualified 
individual (e.g., physician, nurse practitioner, physician’s assistant, or equivalent, under the 
supervision of a physician) and will include examination of the following: general 
appearance; skin; head, ears, eyes, nose, and throat; neck; cardiovascular system; respiratory 
system; abdomen/ GI system; extremities; lymphatic system (lymph nodes); and nervous 
system. Physical examinations, at the discretion of the Investigator, can be abbreviated and 
symptomatic, largely focused on evaluation of AEs, if any, and any abnormalities identified. 
6.4.3.5. 
Neurological Examination 
Any abnormalities identified at Visit 1 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 examination will assess the following: 
• Cranial nerves (cranial nerves II-XII, excluding funduscopic examination) 
• Motor system (tone, strength, and abnormal movements) 
• Sensory system (light touch, pinprick, joint position, and vibration) 
• Reflexes (deep tendon reflexes and plantar responses) 
• Coordination (upper and lower extremities) 
• Gait (base and tandem gait) 
• Station (posture and stability) 


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6.4.3.6. 
Vital Signs 
The HR, BP, 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. 
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.  
6.4.3.7. 
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. 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.  
6.4.3.8. 
Incidence of Falls Diary 
Falls in subjects with symptomatic nOH are common and potentially catastrophic. They can 
lead to serious injuries including hip fractures or head trauma; furthermore, fear of falling can 
limit mobility and physical activity. Thus, incidence of patient-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 diary is provided in Appendix 2. 
6.4.3.9. 
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. 
6.4.3.9.1. 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; and platelet count. 


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6.4.3.9.2. Serum Chemistry 
Chemistry samples will be analyzed for the following: sodium, potassium, calcium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, total protein, albumin, alkaline 
phosphatase, ALT, AST, bilirubin, lactate dehydrogenase, and creatine phosphokinase. 
6.4.3.9.3. Urinalysis 
Urinalysis includes determination of specific gravity; presence of blood, protein, and 
leukocytes; and microscopic examination of sediment, if clinically indicated. 
6.4.3.9.4. Unscheduled Visit 
All sites are allowed, at Investigator discretion, to conduct either in clinic or remote 
unscheduled visit(s) for subject safety or unexpected subject medical needs outside of the 
regular visit schedule. In this case, unscheduled visits are not considered protocol deviations 
and the Investigator is not required to obtain pre-approval from the Sponsor. Data collected 
during these visits may include any protocol-specified assessments which will be captured in 
the clinical database. 
6.5. 
Concomitant Medications 
Subjects should not have changed dose, frequency, or type of prescribed medication for 
orthostatic hypotension within 7 days prior to Week 0.  
  
 
  
 
6.5.1. 
 
 
 
 
 
 
6.6. 
 
 
 
 
 
 
 
 
 


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6.7. 
 
 
 
 
 
 
    
 
  
 
 
 
 
 
 
 
 
 
 
6.8. 
Discontinuation 
6.8.1. 
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 carried out. 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 or the Sponsor 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: 
• AE 
• Subject choice 
• Major violation of the protocol 
• Termination of the study by the Sponsor 
• Other 
 
 


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Subjects who discontinue study drug 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. 
6.8.2. 
Subject Replacement 
Subjects will not be replaced. 
6.8.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
Periodic review of unblinded data by an external IDMC (Section 8.7) 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. 
6.8.4. 
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 will subsequently be discontinued 
from participation in the study:  
 
 
 
 
 
 
 
  
 
 
 
 
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 patients at 4 weeks post stopping 
administration of 
 TD-9855 dose. Thus, application of pregnancy prevention measures 
for 30 days post last dose of TD-9855 is sufficient to address the risk of substantial drug 
exposure in semen or maternal circulation. 
To confirm the absence of pregnancy in female subjects of childbearing potential, urine 
βhCG testing will be performed during specified visits, as listed in the Schedule of Study 
Procedures (Table 1). If the urine βhCG test is positive, a serum βhCG 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.  


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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 7.4.2. 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 Conference on Harmonization (ICH) 
guideline E2A, “Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting”. 
7.1.1. 
Adverse Events (AE) 
An AE is any untoward medical occurrence in a patient 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. 
• Pre-existing events that increase in frequency, severity or change in nature or 
seriousness during or as a consequence of participation in clinical studies. 
• Pre- or post-treatment 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 drug.  
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 adverse event. 
• Preexisting 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 drug 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 date of first dose in Study 0171, 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, Theravance Biopharma, Inc. (TBPH) 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 (SAE) 
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 
patient 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 pre-existing condition that has not 
worsened during participation in the study does not meet this criterion. 
Pre-planned 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. 
• A persistent or significant disability/incapacity. “Disability” is defined as a 
substantial disruption of a person's ability to conduct normal life functions. 
• Congenital anomaly/birth defect in the offspring of a subject who received study 
drug. 
• 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 adverse event and not an adverse event 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 drug 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 (AESI) 
• At each study visit, the Investigator (or designee) will specifically query for any 
AESIs. The following events are considered AESIs for this study: 
− Supine hypertension 
− Cardiovascular events (myocardial infarction, cerebrovascular accident, 
cardiac arrhythmia, congestive heart failure) 
− Convulsion 
• All AESIs must be reported to Sponsor Clinical Safety and Pharmacovigilance 
within 24-hours of awareness by the Investigator or his/her designee. 
The SAE/AESI Report Form must be completed in accordance with the SAE/AESI Report 
Form Completion Guidelines. If all information on the SAE/AESI Report Form is not 
available at the time of the initial report, follow-up AESI reports will be completed and 
submitted.  
To report an AESI, complete and send the SAE/AESI Report Form to the following: 
Theravance Biopharma Clinical Safety 
 
 
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 clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as electrocardiograms [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 adverse event (or serious adverse event), as described in Sections 7.1.1 (Adverse Event) 
and 7.1.2 (Serious Adverse Event). 
If there are any AE questions, the Investigator is encouraged to contact the Sponsor to 
discuss. 


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7.3. 
Assessment of Adverse Events 
All AEs will be assessed by the Investigator and recorded in the case report form, including 
the dates of onset and resolution, severity, relationship to study drug, outcome, and action 
taken with study drug. 
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 patient/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 patient 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 patient’s ability to perform routine 
activities despite symptomatic therapy. 
7.3.2. 
Causal Relationship to Study drug 
The Investigator’s assessment of causality is based on clinical judgment regarding the 
reasonable possibility that the study drug 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, 
co-morbid conditions, other drugs, 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 drug. 
• Whether the AE resolved or improved with decreasing the dose or stopping the 
study drug (“de-challenge”) or recurred or worsened upon re-exposure to the 
study drug (“re-challenge”).  
The causal relationship between the study drug and the AE will be described using one of the 
following categories: 
• Not Related:  Evidence exists that the adverse event has an etiology other than 
the study drug (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 drug. 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 


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should not be considered as causally related in the context of adverse event 
reporting. 
7.4. 
Adverse Event Reporting and Recording 
7.4.1. 
Adverse Event Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
trials is crucial for the protection of patients and is mandated by regulatory agencies.  Sponsor 
has established standard operating procedures in compliance with regulatory requirements 
worldwide to ensure appropriate reporting of safety information.  All clinical trials sponsored 
by TBPH 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 drug, will be 
recorded from date of first dose of study drug through the last study visit (or last subject 
contact in the case of a follow-up telephone call).  AEs will be recorded on the AE page of 
the CRF.  SAEs, regardless of relationship to study drug will be recorded from date of first 
dose of study drug 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 drug 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 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 adverse event terms 
(e.g., if a subject was hospitalized for cholecystectomy due to cholecystitis, the 
adverse event term should be recorded as cholecystitis, and not as the procedure, 
cholecystectomy).   
• “Death” should not be used as an adverse event term unless the cause of death is 
unknown.  For events with a fatal outcome, the cause of death should be the 
adverse event term (e.g., if a subject died of an acute myocardial infarction, the 
adverse event term should be recorded as “Myocardial Infarction” and the event 
outcome as fatal).     
Relationship to study drug: The Investigator will make an assessment of the causal 
relationship of the study drug 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 drug. If the initial 
SAE or AESI is reported by telephone, a written report signed by the Investigator must be 
submitted within 24-hours.  
The SAE/AESI Report Form must be completed in accordance with the SAE/AESI Report 
Form Completion Guidelines. If all information on the SAE/AESI Report Form is not 
available at the time of the initial report, follow-up SAE or AESI reports will be completed 
and submitted.  
To report an SAE or AESI, complete and send the SAE/AESI Report Form to the following: 
Theravance Biopharma Clinical Safety 
 
 
 
 
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 drug 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. 


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7.5. 
Adverse Event Follow-up 
A subject experiencing an AE 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 or SAE has resolved or a stable clinical endpoint is reached, 
whichever is longer. The Sponsor may request follow-up of certain adverse events until 
resolution and documentation of assessments made during this period. 
The Investigator must take all therapeutic measures necessary for resolution of an SAE. Any 
medications necessary for treatment of the SAE must be recorded in the concomitant 
medication section of the case report form. 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
All individual data 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 (IQR) [25% quartile, 75% quartile]), 
minimum, and maximum value unless otherwise stated.   
Categorical data will be summarized using the counts and percentages. 
For analysis, Day 1 is defined as the day of the first study drug dose. The preceding day is 
Day -1.  
Baseline is the last assessment (scheduled or unscheduled) obtained before start of study drug 
dosing, unless otherwise specified in the SAP. 
Any changes to the protocol-specified analyses will be pre-specified in the Statistical 
Analysis Plan prior to data lock. 
8.2. 
 
 
 
 
 
 
 
 
 
 
 
   
8.3. 
 
 
. 
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 
Not applicable. 


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8.4. 
General Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in the SAP. Additional statistical analyses other than those described in this 
section may be performed and described in the SAP if deemed appropriate. 
8.4.1. 
Demographics Characteristics and Other Baseline Characteristics 
The demographics, baseline characteristics, medical history and safety will be summarized 
for all subject in the Safety set. 
8.4.2. 
  
 
 
 
8.5. 
Safety Analyses  
For all safety analyses, the safety set will be used. 
Safety variables to be summarized include vital signs, adverse events, clinical laboratory 
results (hematology, chemistry, and urinalysis), corrected QT interval (QTcF) from standard 
safety digital ECGs and C-SSRS. Vital signs, ECGs and laboratory results will be 
summarized in terms of observed values and changes from baseline. 
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. 
8.5.1. 
 
 
 
 
8.5.2. 
Adverse Event Data 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will present by system organ class (SOC), preferred term 
(PT) and severity, the frequency and percentage of subjects reporting each observed event. 
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 the date of last dose of study drug 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: 
 
 
 
 
 
 


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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. 
8.5.3. 
Concomitant Medications 
Medication names will be mapped according to the World Health Organization Drug 
Dictionary. Concomitant medications summaries will be provided, by drug class and 
preferred name. The summary of concomitant medications will comprise all medications 
taken during the treatment period, including ongoing medications at entry.  
8.5.4. 
Laboratory Data 
Laboratory data, changes from baseline, values relative to normal ranges, and changes from 
baseline relative to normal ranges will be summarized. Listings will flag laboratory values 
that are outside of normal range. 
Clinical laboratory test results will be listed by subject. Reference ranges provided by the 
laboratory for each parameter will be used to evaluate the clinical significance of laboratory 
test results.  Values falling outside of 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.   
8.5.5. 
Vital Signs Data 
Vital Signs data will be summarized in terms of observed values (by time point), changes 
from baseline (by time point), and counts and percentages within appropriately defined 
categories (Table 3). 
Table 3: 
Outlier Threshold for Vital Signs 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
 
8.5.6. 
ECG 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 4). 


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Table 4: 
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 
 
 
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. 
QTcF {and QTcB} 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). 
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. 
Subjects without post-baseline measurement for a given treatment period will be excluded 
from the summary statistic (e.g., denominator of the summary statistic) for that time point.   
All recorded values for the ECG parameters will be presented in a by-subject listing. 
A separate listing of subjects with values of QTcF > 500 msec or an increase > 60 msec will 
be provided, as necessary. 
Cumulative distribution plots will be provided for maximum change in QTcF by day. 
8.5.7. 
Analysis of Falls 
Incidence of falls will be descriptively summarized using number of falls per subject, number and 
percentage of subjects with at least 1 fall since the previous study visit. 


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8.6. 
Missing Data Handling 
 
8.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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


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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 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 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. 
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 
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. 
 
 


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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 outcomes assessments (eCOA), 
electronic laboratory data transfer. Study site personnel will enter (in English) study data into 
the CRFs for each subject. Training on the 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. 
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. 
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 


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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 
institutional review board (IRB) or independent ethics committee (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 United States) 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 standard operating procedures (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 et al (2013). Neurogenic orthostatic hypotension: 
pathophysiology, evaluation, and management. J Neurol;260(9): 2212-2219 
2. Goldstein DS & Sharabi Y (2009). Neurogenic orthostatic hypotension: a 
pathophysiological approach. Circulation;119(1): 139-146 
3. Lahrmann H, Cortelli P et al (2006). EFNS guidelines on the diagnosis and 
management of orthostatic hypotension. Eur J Neurol;13(9): 930-936 
4. Goldstein DS et al (1997). Sympathetic cardioneuropathy in dysautonomias. N Eng J 
Med;336(10:696-702 
5. Ehringer H & Hornykiewicz O (1998). Distribution of noradrenaline and dopamine 
(3-hydroxytyramine) in the human brain and their behavior in diseases of the 
extrapyramidal system. Parkinsonism Related Disorders;4(2): 53-57 
6. Braak H, Ghebremedhin E et al (2004). Stages in the development of Parkinson’s 
disease-related pathology. Cell Tissue Res;318(1): 121-134 
7. Shibao C et al (2007). Norepinephrine transporter blockade with atomoxetine induces 
hypertension in patients with impaired autonomic function. Hypertension;50(1):47-53 
8. Ramirez CE et al (2014). Efficacy of atomoxetine versus midodrine for the treatment 
of orthostatic hypotension in autonomic failure. Hypertension;64(6):1235-40 
 
 


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APPENDIX 1. EXAMPLES OF DISEASE INSTRUMENTS 
 


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APPENDIX 2. INCIDENCE OF FALLS DIARY 
 
 


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APPENDIX 3. DOSING DIARY 
 


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APPENDIX 5. 
 
 
 
 
 
 
     
 
  
 
 
 
 
 
 
 
 
 


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APPENDIX 6. 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:  
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.  Based upon discussion with the subject, the Investigator may conduct each study visit 
for a given subject either in clinic or remotely. The Investigator is recommended to conduct 
in clinic study visits consistent either with the standard of care for a subject outside of a 
clinical trial or at a minimum once per year for each subject.   
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. 
 
 
Conduct of the Study and the Decentralized Platform:  
All sites will follow the protocol Schedule of Procedures (see Table 1 and Table 2 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.  


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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. A courier service has been engaged to ship investigational study drug and other study 
supplies to the subject (or designee).  
B. 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.  
C. A Home Health Provider (HHP) service has been employed.    
D. 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).   
E. 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.  
F. 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.   
 
 


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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. 
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.  
 


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APPENDIX 7. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:  
0171 
Protocol Title:   
A Phase 3, 182-week, Open-Label, Safety and Tolerability Study of 
TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension 
(symptomatic nOH) 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 
procedures described therein.  I also agree to conduct the study in compliance with all 
applicable regulations. 
 
 
 
Investigator’s Name (print) 
 
 
 
Investigator’s Signature 
 
Date 
 
 

SAP_001.pdf: 
Protocol Number: 0171 
Official Title: A Phase 3, 182-week, Open-Label Extension Study to Investigate the Safety and 
Tolerability of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension 
(symptomatic nOH) in Subjects with Primary Autonomic Failure 
NCT Number: NCT04095793 
Document Date: 13 January 2022 


 
 
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Theravance Biopharma US, Inc. 
 
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Statistical Analysis Plan - Protocol 0171 
 
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STATISTICAL ANALYSIS PLAN 
PHASE 3 
VERSION: 
 
DATE OF PLAN: 
13 January 2022 
BASED ON: 
Protocol 
 05 August 2020 
 
STUDY DRUG: 
TD-9855 
PROTOCOL NUMBER: 
0171 
STUDY TITLE: 
A Phase 3, 182-week, Open-Label Extension Study to Investigate the Safety and Tolerability of 
TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension (symptomatic nOH) in 
Subjects with Primary Autonomic Failure 
SPONSOR: 
Theravance Biopharma Ireland Limited 
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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Theravance Biopharma US, Inc. 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................6 
2. 
INTRODUCTION ........................................................................................................7 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................8 
3.1. 
Objectives .....................................................................................................................8 
3.1.1. 
Primary Objective .........................................................................................................8 
3.1.2. 
Exploratory Objective ...................................................................................................8 
3.2. 
Endpoints ......................................................................................................................8 
3.2.1. 
Primary Study Endpoints ..............................................................................................8 
3.2.2. 
 
4. 
STUDY DESIGN .........................................................................................................9 
4.1. 
Summary of Study Design ............................................................................................9 
4.2. 
Study Drugs ................................................................................................................10 
4.3. 
Sample Size Considerations .......................................................................................10 
4.4. 
Randomization ............................................................................................................10 
4.5. 
Clinical Assessments ..................................................................................................11 
5. 
TIMING OF PLANNED ANALYSES ......................................................................14 
6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING .......................15 
6.1. 
Analysis Sets ...............................................................................................................15 
6.1.1. 
Enrolled Analysis Set .................................................................................................15 
6.1.2. 
Safety Analysis Set .....................................................................................................15 
6.1.3. 
Examination of Subgroups .........................................................................................15 
6.2. 
Baseline Definition .....................................................................................................15 
6.3. 
Derived and Transformed Data ..................................................................................15 
6.3.1. 
Study Day ...................................................................................................................15 
6.3.2. 
Age ..............................................................................................................................16 
6.3.3. 
Change from Baseline .................................................................................................16 
6.3.4. 
BMI (Body Mass Index) .............................................................................................16 
6.3.5. 
Visit Windows ............................................................................................................16 
6.3.6. 
Multiple Assessments .................................................................................................17 
7. 
STUDY POPULATION .............................................................................................18 


 
 
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7.1. 
Enrollment by Investigator .........................................................................................18 
7.2. 
Subject Disposition and Completion Status ...............................................................18 
7.3. 
Protocol Deviations ....................................................................................................18 
7.4. 
Medical History and Medical Conditions Present at Entry ........................................18 
7.5. 
Demographic and Baseline Clinical Characteristics ...................................................18 
8. 
SAFETY AND TOLERABILITY ..............................................................................19 
8.1. 
Adverse Events ...........................................................................................................19 
8.1.1. 
Adverse Events of Special Interest .............................................................................20 
8.2. 
Extent of Exposure and Treatment Compliance .........................................................20 
8.3. 
Concomitant and Other Medications ..........................................................................21 
8.4. 
Laboratory Data ..........................................................................................................22 
8.5. 
Vital Signs ..................................................................................................................22 
8.6. 
12-Lead Safety ECGs .................................................................................................23 
8.7. 
Incidence of Falls ........................................................................................................24 
8.8. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................24 
 
 
9. 
REFERENCES ...........................................................................................................26 
10. 
APPENDICES ............................................................................................................27 
 
 
10.2. 
Handling of Missing Data ...........................................................................................28 
10.2.1. 
Adverse Events Severity and Relationship to Study Drug .........................................28 
10.2.2. 
Missing Start and Stop Dates for Adverse Events ......................................................28 
10.2.3. 
Missing Start and Stop Dates for Medications ...........................................................30 
10.2.4. 
Laboratory Data ..........................................................................................................30 
 


 
 
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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................6 
Table 2: 
Schedule of Study Procedures (Visits 1 – 6) ..............................................................11 
Table 3: 
Schedule of Study Procedures (Visits 7 – 14 Extension) ...........................................13 
Table 4: 
Analysis Windows ......................................................................................................17 
 
 
 
 
Table 7: 
Health State Parameter Estimates ...............................................................................27 
 


 
 
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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
term 
AE 
adverse event 
ATC 
Anatomic Therapeutic Chemical 
BP 
blood pressure 
BMI 
body mass index 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
diastolic blood pressure 
HR 
heart rate 
MedDRA 
Medical Dictionary for Regulatory Activities 
SD 
standard deviation 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
VAS 
visual analogue scale 
WHODD 
World Health Organization Drug Dictionary 
 


 
 
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2. 
INTRODUCTION 
This document describes the plan for the summarization and analysis of clinical data collected in 
Study 0171 for TD-9855, which was terminated early by the sponsor with 110 subjects enrolled. 


 
 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety of TD-9855 over a 
182-week period. 
 
 
 
 
3.2. 
Endpoints 
3.2.1. 
Primary Study Endpoints 
Primary safety and tolerability endpoints include: 
• Physical examination 
• Neurological examination 
• Vital signs 
• Resting ECGs 
• Clinical laboratory tests including biochemistry, hematology, and urinalysis 
• Concomitant medications 
• AEs 
• Subject compliance to study treatment 
• Incidence of falls 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
 


 
 
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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a phase 3, multicenter, open-label study to evaluate the safety and tolerability of TD-9855 
in subjects with primary autonomic failures (MSA, PD, and PAF) and symptomatic neurogenic 
orthostatic hypotension (snOH) over 182 weeks. 
Subjects who complete Study 0170 will be eligible for this study. Following signing of the 
informed consent form, subjects will enter Study 0171 Visit 1, which will be conducted on the 
same day as Visit 9 of Study 0170. 
Eligible subjects will receive a single dose of 
 TD-9855 
 for 182 weeks. 
A schematic representation of study visits is shown below: 
Visits 1 to 6 
 
Visits 7 to Telephone 8 
 


 
 
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Subjects may discontinue at any time. The stopping criteria include meeting at least one of the 
following conditions: 
• A determination from the investigator that further administration of the 
investigational product may pose a safety concern to the subject 
• Sustained (at least 4 hours) SBP > 180 mmHg or diastolic BP (DBP) > 110 mmHg 
after 3 min of standing or after 5 min in the sitting position, or a sustained (at least 4 
hours) SBP > 180 mmHg or DBP > 110 mmHg measured in the supine state 
(head/torso elevated at approximately 30° from horizontal position) 
• Intolerable AE as determined by the investigator 
• Subject becomes pregnant 
No dose reduction is permitted at any time. 
Safety assessments for the first 26 weeks will include a physical examination, neurological 
examination, vital signs (HR, BP, respiratory rate, and body temperature), ECGs, safety 
laboratory tests (hematology, chemistry, and urinalysis), C-SSRS, and AEs. Safety assessments 
for the remaining 158 weeks will include evaluation of adverse events and concomitant 
medications. 
The clinical assessments to be conducted are outlined in Section 4.5. 
4.2. 
Study Drugs 
The study drug will be TD-9855 supplied as a 
 tablet in 35-count high-density 
polyethylene bottles. 
TD-9855 will be administered orally without regard to food at approximately the same time each 
morning and be taken with approximately 8 ounces of water. 
Use of rescue medication during the study was discouraged, but midodrine was nonetheless 
provided as rescue medication, with the following restrictions: 
• A maximum of 10 mg (increments of 2.5 mg are available) may be administered one 
day per week 
• Cannot be used on assessment days 
4.3. 
Sample Size Considerations 
 
4.4. 
Randomization 
Not applicable. 


 
 
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4.5. 
Clinical Assessments 
Table 2: 
Schedule of Study Procedures (Visits 1 – 6) 
Each study visit for each subject may be conducted either in clinic or remotely 
Study Week (Visit/Telephone):  Week 0 
Visit 1 
(0170 
Visit 9) 
Week 2 
Visit 2 
+/- 3 day
s 
Week 6 
Visit 3 
+/- 3 day
s 
Week 10 
Visit 4 
+/- 7 days 
Week 14 
Telephone 
1 +/- 3 days 
Week 18 
Visit 5 
+/- 7 days 
Week 22 
Telephone 
2 
+/- 3 days 
Week 26 
 Visit 6 
+/- 7 days 
Early 
Termination 
up to Week 26 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
Medical history, including 
smoking history 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
 Xa 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
Xa 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (heart rate, blood 
pressure, respiratory rate, and 
body temperature) 
Xa, b 
Xb 
Xb 
Xb 
 
Xb 
 
Xb 
Xb 
Physical examination  
Xa 
 
 
X 
 
 
 
X 
X 
Neurological examination 
Xa 
 
 
X 
 
 
 
X 
X 
12-lead electrocardiograme 
Xa 
 
 
X 
 
 
 
X 
X 
Pregnancy Test 
Xa,c 
 
 
Xc 
 
 
 
Xc 
Xc 
Safety Labs (chemistry, 
hematology, urinalysis) 
Xa 
 
 
X 
 
 
 
X 
X 
Dosing, Incidence of Falls, and 
Midodrine Diaries  
Xa 
X 
X 
X 
 
X 
 
X 
X 
Adverse Events 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
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Each study visit for each subject may be conducted either in clinic or remotely 
Study Week (Visit/Telephone):  Week 0 
Visit 1 
(0170 
Visit 9) 
Week 2 
Visit 2 
+/- 3 day
s 
Week 6 
Visit 3 
+/- 3 day
s 
Week 10 
Visit 4 
+/- 7 days 
Week 14 
Telephone 
1 +/- 3 days 
Week 18 
Visit 5 
+/- 7 days 
Week 22 
Telephone 
2 
+/- 3 days 
Week 26 
 Visit 6 
+/- 7 days 
Early 
Termination 
up to Week 26 
Dispense Study Drug 
Xd 
Xd 
Xd 
Xd 
 
Xd 
 
Xd 
 
Study Drug Dosing 
Xd 
 
Collect Study Drug 
 
X 
X 
X 
 
X 
 
X 
X 
a. Study 0170 procedures conducted at Visit 9 will serve as the baseline assessment for Visit 1 of Study 0171. 
b. Vital signs will be assessed after the subject has been resting for at least 5 minutes in the seated or supine position. 
c. In women of childbearing potential only, urine beta human chorionic gonadotropin (βhCG) test will be performed and if positive, confirmation with serum 
βhCG test is required. The pregnancy test must be confirmed negative for a subject to be eligible for this study. 
d. Study drug 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 must be reminded to maintain an adequate fluid intake during their scheduled visits. Subjects will start taking study 
drug on the day after Visit 1. 
e. 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. 


 
 
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Table 3: 
Schedule of Study Procedures (Visits 7 – 14 Extension) 
Study Week 
(Visit/Telephone):  
Wk 38 
Visit 7 
+/-7 days 
Wk 50 
Visit 8 
+/-7 days 
Wk 62 
Telephone 
3 
+/-7 days 
Wk 74 
Visit 9 
+/-7 day 
Wk 86 
Telephone 
4 
+/-7 days 
Wk 98 
Visit 10 
+/-7 days 
Wk 110 
Telephone 
5 
+/-7 days 
Wk 122 
Visit 11 
+/-7 days 
Wk 134 
Telephone 
6 
+/-7 days 
Wk 146 
Visit 12 
+/-7 days 
Wk 158 
Telephone 
7 
+/-7 days 
Wk 170 
Visit 13 
+/-7 days 
Wk 182 
Visit 14 
End of 
Treatment 
Early 
Termination 
after Week 
26 
+/-7 days 
Wk 184 
Telephone 
8 
Follow-up 
+/-7 days 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testa 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Dispense Study 
Drug 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Study Drug 
Dosing 
Xb 
 
Collect Study 
Drug 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
a. In women of childbearing potential only, urine beta human chorionic gonadotropin (βhCG) test will be performed. 
b. Study drug will be ingested in the morning at approximately the same time of day with 8 ounces of water. 


 
 
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5. 
TIMING OF PLANNED ANALYSES 
The primary analysis was to occur when all subjects had completed the 
 and the 
database had been cleaned and locked. A final analysis was to be conducted when all subjects 
had completed the study through Week 184. 
The study was terminated early by the sponsor and a single analysis of all data obtained is to be 
conducted instead, after the database has been cleaned to the extent possible and locked. 


 
 
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6. 
CONSIDERATIONS FOR DATA ANALYSES AND HANDLING 
All data from scheduled and unscheduled visits will be presented in the subject listings. 
However, unless noted otherwise, only data from visits (scheduled or unscheduled) that fall 
within the analysis windows will be included in summaries, statistical analyses, and calculation 
of derived variables. 
 
Analyses and tabulations will be prepared using 
 
Summary tables and listings will be prepared according to ICH Guideline E3 and will include a 
“footer” providing explanatory notes. 
6.1. 
Analysis Sets 
6.1.1. 
Enrolled Analysis Set 
The enrolled analysis set comprises all subjects who were enrolled into this study. 
6.1.2. 
Safety Analysis Set 
The safety analysis set comprises all enrolled subjects who received at least 1 dose of TD-9855 
in this study. 
6.1.3. 
Examination of Subgroups 
The following subgroups were to be examined: 
1. Disease type: MSA, PD, and PAF 
2. Sex: Male and Female 
3. Age category: < 65 years and ≥ 65 years 
4. Smoking status: Never, Former, Current 
But because the feeder study (Study 0170) was terminated early by the sponsor, the overall 
sample size is too small to warrant safety summaries by subgroup. 
6.2. 
Baseline Definition 
In general, assessments obtained at Study 0170 Visit 9, which coincides with Study 0171 Visit 1, 
will serve as the baseline assessment for Study 0171. Subjects will start taking Study 0171 study 
drug on the day after Visit 1. If the start of Study 0171 dosing is delayed, however, the latest 
assessment obtained before the first Study 0171 dose will be used, even if obtained after Visit 1. 
6.3. 
Derived and Transformed Data 
6.3.1. 
Study Day 
If the date of interest occurs on or after the date of first dose, Study Day will be calculated as 
(date of interest – date of first dose) + 1. 


 
 
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If the date of interest occurs before the date of first dose, Study Day will be calculated as 
(date of interest – date of first dose). 
There is no Study Day 0. For analysis, Day 1 is defined as the day of the first study drug dose. 
The preceding day is Day -1. 
6.3.2. 
Age 
Only year of birth is captured in the clinical database. Hence, for analysis purposes, each 
subject’s age at enrollment into Study 0171 is not derived but set to their age in integer years as 
reported by the site. 
6.3.3. 
Change from Baseline 
Change from baseline is calculated as postbaseline result – baseline result. If either the baseline 
or the postbaseline result is missing, change values are treated as missing. 
6.3.4. 
BMI (Body Mass Index) 
BMI is calculated as: 
(
)
(
)
( )
2
2
/
.
weight kg
BMI kg m
height m
=
 
BMI will be calculated using height as collected in Study 0169 or Study 0170 and weight as 
collected at Study 0170 Visit 9 (Day 154)/Study 0171 Visit 1 (Day -1). 
6.3.5. 
Visit Windows 
All assessments will be summarized using analysis windows. The term “out of window” will be 
applied to assessments that are outside the analysis windows, regardless of the visit label 
associated with the assessment in the EDC system. 


 
 
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The following visit windows will be used in the summarization of clinical data: 
Table 4: 
Analysis Windows 
 
Analysis Window 
Nominal Visit 
Start (days) 
Stop (days) 
Baseline 
See Section 6.2. 
Week 2 (Day 14) 
7 
21 
Week 6 (Day 42) 
35 
49 
Week 10 (Day 70) 
63 
77 
Week 14 (Day 98) 
91 
105 
Week 18 (Day 126) 
119 
133 
Week 22 (Day 154) 
147 
161 
Week 26 (Day 182) 
175 
189 
6.3.6. 
Multiple Assessments 
In general, if multiple valid observations exist at a visit or collection time point, the record(s) to 
be included in the summary and analyses will be chosen based on the following: 
• The record closest to the nominal time 
If 2 records are equidistant or distance cannot be determined: 
• The later record 
If there are 2 or more records with the same date/time: 
• The average (generally applies to assessments done in triplicate) 


 
 
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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. 
7.2. 
Subject Disposition and Completion Status 
The subject disposition summary will include the counts and percentages of subjects who: 
• Completed study treatment 
• Discontinued study treatment early, overall and by reason for not completing study 
treatment 
• Completed the study 
• Discontinued from the study early, overall and by reason for not completing the study 
The subject disposition listing will include the date the informed consent form was signed, dates 
of first dose and last dose of study drug, primary reason for discontinuation of study treatment, 
and primary reason for study discontinuation. (If the treatment and study discontinuation reasons 
are the same for all subjects, as expected, a single column with the heading “Primary Reason for 
Discontinuation” may be shown.) A listing of premature discontinuation for reasons other than 
termination of the study by the sponsor will also be provided. 
7.3. 
Protocol Deviations 
A subject listing of all protocol deviations identified prior to database lock will be provided. 
7.4. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized by system organ class and preferred term. 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: age (years), 
age category (< 65 years, ≥ 65 years), sex, race, ethnicity, weight (kg), height (cm), 
BMI (kg/m2), and diagnosis of primary autonomic failure (Multiple System Atrophy, 
Parkinson’s Disease, Pure Autonomic Failure). In addition, a summary of previous treatment 
during the Study 0170 randomized withdrawal period and a listing of previous treatment during 
the Study 0170 randomized withdrawal period and (if applicable) previous treatment during 
Study 0169 will be provided. 


 
 
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8. 
SAFETY AND TOLERABILITY 
Safety and tolerability summaries include an overall summary of adverse events and summaries 
of drug exposure (duration of treatment), dosing information/compliance, concomitant 
medications, clinical laboratory results, vital signs, ECGs, incidence of falls/near-falls, C-SSRS 
responses, and 
 
8.1. 
Adverse Events 
Adverse events are collected from signing of the informed consent form through the end of the 
study. Adverse events will be coded to the preferred terms of the Medical Dictionary for 
Regulatory Activities (MedDRA®, version 24.1). 
A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after 
the date of first dose of Study 0171 study drug up through 14 days after the date of last dose of 
study drug. AEs that begin more than 14 days after the date of last dose of study drug and AEs 
that begin during the period from obtaining informed consent to the start of administration of 
study drug will not be considered treatment-emergent and will be listed only. 
The following AE summaries will be provided: 
• TEAE overall summary 
• TEAEs by preferred term 
• TEAEs by system organ class and preferred term 
• Moderate or severe TEAEs by system organ class and preferred term 
• TEAEs by preferred term with frequency > 3% of safety analysis set subjects 
• TEAEs by system organ class, preferred term, and severity 
• Drug-related TEAEs by system organ class and preferred term 
• Drug-related TEAEs by system organ class, preferred term, and severity 
• Drug-related moderate or severe TEAEs by system organ class and preferred term 
• Serious TEAEs by system organ class and preferred term 
• Drug-related serious TEAEs by system organ class and preferred term 
• TEAEs resulting in on-study deaths 
• TEAEs leading to premature study drug discontinuation 
• TEAEs leading to temporary interruption of study drug 
• TEAEs of special interest by system organ class and preferred term (Section 8.1.1) 
If no adverse events meeting a specific table definition were reported, the body of the table will 
contain only a statement that no events met the table definition. 


 
 
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The following AE listings will be provided: 
• TEAEs 
• AEs leading to premature study drug discontinuation 
• AEs resulting in temporary interruption of study drug 
• Serious adverse events 
• Deaths 
• Non-treatment-emergent adverse events 
8.1.1. 
Adverse Events of Special Interest 
An AE of special interest (AESI) is one of scientific and medical interest specific to 
understanding the investigational product and may require close monitoring and rapid 
communication by the investigator to the sponsor. The following are the AESIs defined for the 
study: 
• Supine Hypertension 
• Myocardial Infarction 
• Cerebrovascular Accident 
• Cardiac Arrhythmia 
• Congestive Heart Failure 
• Convulsion 
The incidence of treatment-emergent AESIs will be summarized, overall (any AESI) and by 
system organ class and preferred term. A listing of AESIs will be provided. 
8.2. 
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 take their assigned study medication 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 returned)/(date of last dose – date of first dose + 1) 


 
 
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Treatment compliance as a percentage of expected total dose over the interval from first to last 
dose will be summarized 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. 
8.3. 
Concomitant and Other Medications 
Medications will be coded using the World Health Organization Drug Dictionary (WHODD, 
version 1Q 2021 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 taken before the first dose of study drug. Concomitant 
medications are medications taken after the first dose up through 14 days after the last dose, and 
include ongoing prior medications. 
The number and percentage of subjects receiving prior medications, the number and percentage 
receiving concomitant medications, and the number and percentage receiving prohibited 
concomitant medications will be summarized by medication class and standardized medication 
name (preferred name). If available, ATC level 4 will be used to determine the medication class. 
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. 
All medications will be listed. 
On-treatment midodrine usage will be summarized by providing a categorical summary of 
number of uses and descriptive summaries (n, mean, SD, etc.) of usage rate (uses/month), 


 
 
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calculated as (number of uses)/(treatment period duration in days, divided by 28) and total dose 
(mg). For number of uses, counts and percentages will be provided for the following categories: 
• 0 
• 1 
• 2 
• 3 
• 4 
• 5 
• 6 – 10 
• 11 – 20 
• > 20 
A use is defined as taking 1 or more 2.5-mg midodrine tablets on a single occasion, e.g., 2 tablets 
taken at 0900 and 2 tablets taken at 1200 would be counted as 2 uses, for a total daily dose of 
10 mg. 
8.4. 
Laboratory Data 
Laboratory data hematology and serum chemistry summaries will include summary statistics for 
observed values and for changes from baseline at each postdose 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 test results. (Urinalysis 
data will be listed only.) 
Listings will flag laboratory values that are outside the normal range. 
8.5. 
Vital Signs 
Vital sign (HR, systolic and diastolic BP, respiratory rate, and body temperature) values and their 
changes from baseline at each visit will be summarized. If baseline BP and HR were collected as 
a part of the orthostatic standing test at Visit 9 (Day 155) in Study 0170, the seated values will be 
used to calculate the change from baseline. The counts and percentages of subjects with vital 
signs in the following categories will be presented in a vital signs extreme values summary. 
Extreme values will be flagged in the listing. 
Table 5: 
Vital Signs Thresholds 
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
< 40 
> 110 
< 85 
> 160 
< 45 
> 100 


 
 
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8.6. 
12-Lead Safety ECGs 
ECG summaries will include summary statistics for observed values and changes from baseline. 
Heart rate and the following intervals will be included: PR, QRS, QT, and QTcF. A listing of 
12-lead safety ECG data collected will be provided. A separate listing of data for subjects with 
postbaseline values of QTcF ≥ 500 msec or a QTcF increase from baseline > 60 msec will also 
be provided. 
In addition, QTcF (msec) will be summarized by the following categories: Normal (males < 430, 
females < 450), Borderline (males [≥ 430, < 450], females [≥ 450, < 470]), and Prolonged 
(males ≥ 450, females ≥ 470). 
Investigator Assessment of ECGs 
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. 
Categorical ECG Summary 
The number of subjects with absolute ECG values and changes from baseline in the ranges 
shown in Table 6 will be presented by visit. 
Table 6: 
ECG Thresholds and Ranges 
Heart Rate 
(bpm) 
Heart Rate 
Change 
from 
Baseline 
(bpm) 
PR 
 Interval 
(msec) 
PR Percent 
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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8.7. 
Incidence of Falls 
The numbers and percentages of subjects with at least one fall during the interval beginning on 
Study Day 1 and ending on Day 189 (the end of the Week 26 analysis window) will be provided, 
together with the corresponding numbers and percentages of subjects with at least one fall or 
near-fall. 
In addition, the following categorical summaries with counts and percentages will be provided 
for falls and falls + near-falls: 
• None 
• 1 
• 2 
• 3 or more 
8.8. 
Columbia-Suicide Severity Rating Scale (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 Since Last Visit Version will be used in this study. 
The following 11 C-SSRS categories include 5 subtypes of suicidal ideation (1–5), 5 subtypes of 
suicidal behavior (6–10), and self-injurious behavior without suicidal intent. They all have binary 
responses (yes/no). 
1. Wish to be Dead 
2. Non-specific Active Suicidal Thoughts 
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 visit at which the items were collected. 


 
 
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9. 
REFERENCES 
 
 
 
 
 
 
 


 
 
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10. 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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10.2. 
Handling of Missing Data 
10.2.1. 
Adverse Events Severity and Relationship to Study Drug 
AEs with severity not reported will be counted as severe, and AEs with relationship to study 
drug not reported will be counted as related. 
10.2.2. 
Missing Start and Stop Dates for Adverse Events 
Missing start date and times will be handled as follows: 
• AE onset date completely missing: 
− If AE is not ongoing and AE onset date missing and AE end date missing, then 
impute AE onset as date/time of first dose. 
− Else if AE is not ongoing and AE onset date missing and AE end date not missing 
and date/time of first dose <= AE end date, then impute AE onset as date/time of 
first dose of study drug. 
− Else if AE is not ongoing and AE onset date missing and AE end date not missing 
and AE end date is BEFORE first dose of study drug, then impute AE onset as 
AE end date YEAR and MONTH with 01 as the day and 00:00 as time. 
− Else if AE IS ongoing and AE onset date missing, then impute AE onset as 
date/time of first study drug dose. 
• AE onset date has year and month only: 
− If AE onset date has year and month only and they are the year and month of first 
dose of study drug, then impute AE onset as date/time of first dose: 
− Else if AE onset date has year and month only and date/time of first dose is not 
missing, then impute AE onset as AE onset year and month with 01 as the date 
and 00:00 as the time. 
• AE onset date has year only: 
− If AE onset date has year only and it is year of first dose of study drug, then 
impute AE onset as date/time of first dose of study drug. 
− Else if AE onset date has year only and date of first study drug dose is not missing 
and year of AE onset is NOT the year of first dose of study drug, then impute AE 
onset as Jan. 1 of the AE onset year and 00:00 as the time. 
• AE onset missing (where it was not handled by the above cases): 


 
 
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− If AE onset date is missing, then impute AE onset as date/time of first study drug 
dose. 
• AE onset has complete date but missing time: 
− If AE onset date is a date only and is same as date of first study drug dose, then 
impute AE onset as date/time of first study drug dose. 
− Else if AE onset date is a date only and is NOT = date of first study drug dose, 
then impute AE onset as AE onset date with 00:00 as the time. 
Missing end date and times will be handled as follows: 
• AE end date - completely missing: 
− If AE is not ongoing and both AE onset and AE end dates are missing, then 
impute AE end date as date/time of last study drug dose. 
− Else if AE is not ongoing and AE onset date not missing and AE end date missing 
AND AE onset date <= date/time of last dose, then impute AE end date as 
date/time of last study drug dose. 
− Else if AE is not ongoing and AE onset date is not missing and AE end date is 
missing and date of last dose is not missing and AE onset is AFTER date of last 
dose, then impute AE end date as the last day of the month of AE onset date, with 
23:59 as time. 
• AE end date = year and month only: 
− If AE is NOT ongoing and AE end date consists of year and month only, then 
impute AE end date as the last day of the month of AE end date month and year, 
with 23:59 as time. 
• AE end date = year only: 
− If AE is NOT ongoing and AE end date consists of a year only, and year = year of 
AE onset and AE onset date <= date of last study drug dose, then impute AE end 
date as the date of last study drug dose. 
− Else if AE is NOT ongoing and AE end date consists of a year only, and year = 
year of AE onset and AE onset date > date of last study drug dose, then impute 
AE end date as the year and month of AE onset, with the last day of the month as 
the day, and 23:59 as the time. 
• AE end date = complete date but no time: 
− If AE is NOT ongoing and AE end date consists of a complete date but no time, 
then impute AE end date = trim (AE end date) || "T23:59". 


 
 
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10.2.3. 
Missing Start and Stop Dates for Medications 
To determine whether medications were used before dosing started and whether they were used 
after dosing started, missing or partial dates for medications will be imputed according to the 
following rule: 
Missing medication start date/time: 
• If only have a YEAR, impute as Jan. 1, at one minute after midnight. 
• Else if only have YEAR and MONTH, impute as Day 1 of month, at one minute after 
midnight. 
• Else if have a complete date, impute TIME as one minute after midnight. 
• Else if completely missing, and ((end date is present and >= date of first dose) or (end 
date is missing and is marked as “ONGOING”)), impute as date and time of first 
dose. If missing and end date/time is present and prior to date of first dose, then leave 
as missing. 
Missing medication end date/time: 
• If only have a YEAR and it is same as year of study completion, impute as date of 
study completion with time of 23:59. 
• Else if only have a YEAR, impute as December 31 with time of 23:59. 
• Else if only have YEAR and MONTH, then impute to last day of the month, with 
time of 23:59. 
• Else if have a complete date but no time, impute time of 23:59. 
• Else if end date/time completely missing and not flagged as Ongoing, impute as date 
of study completion with time of 23:59. 
Otherwise missing, no imputation. 
10.2.4. 
Laboratory Data 
For laboratory data, a missing baseline value will be replaced with the last available assessment. 
A retest value will be used if the first test result is invalid, e.g., specimen hemolyzed. 
Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be imputed as follows: 
• A value that is 1 unit less than the LOD will be used for calculation of descriptive 
statistics if the data are reported in the form of “< x” (x is considered as the LOD). 
More specifically, x−1 is used for data summarization if the data are reported in the 
form “< x”; and x.e where e = d−1 will be used for analysis if the data are reported in 
the form “< x.d”. 
• The LOD will be used for calculation of descriptive statistics if the data are reported 
in the form “≤ x” or “≥ x.”