Conditions: Neurogenic Orthostatic Hypotension Multiple System Atrophy (MSA) With Orthostatic Hypotension Pure Autonomic Failure Parkinson Disease Hypotension, Orthostatic Orthostatic Hypotension Pure Autonomic Failure With Orthostatic Hypotension Parkinson Disease With Orthostatic Hypotension
Keywords: Neurogenic Orthostatic Hypotension (nOH) Multiple System Atrophy (MSA) Pure Autonomic Failure Parkinson Disease(PD) nOH MSA PD PAF Orthostatic Hypotension ampreloxetine TD-9855
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
This multiple-center, 3-part, single-blind dose escalation (Part A), randomized, double-blind (Part B), and open-label multiple dose extension (Part C) study will be conducted in male and female subjects with neurogenic orthostatic hypotension to evaluate the effect of TD-9855 in improving symptoms of orthostatic intolerance.

Detailed description:
Part A followed a daily, single-escalating-dose design, starting with placebo on Day 1, followed by a dose of 2.5 mg TD-9855 on Day 2, and proceeding to higher daily doses of TD-9855 up to a maximum dose of 20 mg based on safety, tolerability, and determination of a pressor effect.

The starting dose in Part A was initially set to 1 mg (Day 2), escalating to a maximum dose of 10 mg (Day 5), but this was revised to start at 2.5 mg (Day 2) and escalate to 20 mg (Day 5) in protocol amendment 2 (Section 9.8.1).

Part B followed a randomized, placebo-controlled, parallel design, evaluating an acute dose of TD-9855 that was determined to have a pressor effect and to be generally well tolerated for a given subject from Part A.

Subjects who completed Part A, demonstrated a pressor effect in Part A, and remained otherwise eligible, had the option to receive open-label TD-9855 by tablet daily for up to 5 months (20 weeks) during Part C.

Arms:
arm 1: Subjects will receive placebo and escalating single doses of TD-9855 arm 2: Subjects will receive a single dose of TD-9855 or placebo. arm 3: Subjects will receive once daily doses of TD-9855 for up to 5 months as part of an optional outpatient open-label extension arm.

Interventions: intervention 1: TD-9855 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2 Study to Assess the Effect and Safety of TD-9855 in 
Subjects with Neurogenic Orthostatic Hypotension 
Study Short Title: 
TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH) 
Sponsor Study No.: 
0145 
Date: 
08 November 2017,
 
 
Test Product: 
TD-9855 
Sponsor: 
Theravance Biopharma R&D, Inc. 
c/o Theravance Biopharma US, Inc. 
901 Gateway Boulevard 
South San Francisco, CA  94080 
 
Clinical Study Director: 
 
 Clinical Development 
Theravance Biopharma US, Inc. 
 
 
Telephone: 
 
 
Email: 
 
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 0145: A Phase 2 Study to Assess the Effect and Safety of 
TD-9855 in Subjects with Neurogenic Orthostatic Hypotension 
Study Short Title:  TD-9855 Phase 2 in Neurogenic Orthostatic Hypotension (nOH) 
Estimated Number of Study Centers and Countries or Regions:  Approximately 
 
study centers in the United States. 
Background and Rationale:  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 


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Objectives:  The primary objective of the study is as follows: 
• To determine if TD-9855 has an acute (Parts A and B) and sustained (Part C) pressor 
response and improves symptoms of orthostatic intolerance in subjects with nOH due to 
MSA, PAF, or Parkinson’s disease. 
The secondary objective(s) of the study is as follows: 
• To evaluate the safety and tolerability of TD-9855 in subjects with nOH. 
• To evaluate the PK and PD (NE and DHPG) of TD-9855 after single and multiple doses 
in subjects with nOH. 
Study Design: 
This is a multicenter, randomized, 3 part, single-blind (Part A), double-blind (Part B), and 
open-label multiple dose extension (Part C) study of TD-9855 versus placebo in subjects 
with nOH.  However, beginning with Amendment 2 of this protocol, Part B of the study has 
been discontinued.  Therefore, any new subjects enrolled after Amendment 2 will not be 
enrolled in Part B.  Details regarding Part B are still included in this document but where 
appropriate the reader is referred to prior version of this protocol for more specific 
information related to Part B. 
This study now consists of 2 Parts, A and C.  Part A follows a daily, single, escalating dose 
design starting with placebo on Day 1, followed by a dose of 
 TD-9855 on Day 2, and 
proceeding to escalating higher doses of TD-9855 on a daily basis up to a maximum dose of 
 based on safety, tolerability, and determination of a pressor effect.  In Part C, 
subjects who demonstrate a pressor effect in Part A, who complete Part A, and remain 
otherwise eligible will have the option to receive open-label TD-9855 by tablet daily for up to 
  
Study Procedures: 
Part A – Dose Escalation 
On Day -2 of Part A, eligible subjects will be admitted to the clinical research center (CRC), 
where they will remain during the entire dose escalation period.  On Day 1, subjects will 
receive a single dose of placebo in a single-blind manner (ie, subject remains blinded).  This 
will be followed by daily single-blind dose escalations, beginning with 
of TD-9855 on 
Day 2.  On each subsequent day, subjects will receive a single escalating dose of TD-9855 


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 [Day 3], 
 [Day 4], 
 [Day 5]) until Day 5 or until reaching the preset 
stopping criteria described below, whichever occurs first.  The stopping criteria are: 
• A determination from the Investigator (in collaboration with the Sponsor) that 
administration of the subsequent dose may pose a safety concern 
• SBP ≥ 180 mm or DBP ≥ 110 mm in the sitting position replicated 2 more times over 
an hour 
• Intolerable side effects as determined by the Investigator 
• Received maximum dose of study medication specified by the protocol 
Once the subject meets any of the above criteria, no further dose escalation will be 
performed.  However, based on the daily evaluation of tolerability, the Investigator 
(in collaboration with the Sponsor), may decide to not escalate the dose, but rather 
re-administer the previous dose from the prior day.  Once the decision has been made to 
not escalate the dose, the subject may remain at the current dose through Day 5 of dosing. 
Following a post dosing observation day in the clinic, the subject will have discharge 
procedures completed and will be released from the CRC.   
Subjects who do not demonstrate a clinically meaningful pressor effect based on 
Investigator determination (in collaboration with the Sponsor), or who discontinue study drug 
prior to reaching the stopping criteria, should have discharge procedures completed, but will 
not continue to study Part C. 
Washout Period 
Following the completion of Part A, eligible subjects will be discharged from the CRC and 
undergo a washout period (
  On a daily basis during the first 72 hours from 
discharge, and then weekly for the first 4 weeks after discharge from Part A during the 
washout period, the Investigator or designee will contact the subject by telephone to review 
the subject’s health status.  Any adverse events reported by phone will be recorded and 
followed as medically appropriate determined by the Investigator. Under the direction of the 
Investigator, subjects will manage their nOH symptoms using fludrocortisone as prescribed.  
Part B – Randomized, Double-blind, Parallel Design 
Beginning with Amendment 2 of this protocol, Part B of the study has been discontinued.  
Refer to prior versions of this protocol for specific details regarding Part B. 
Part C – Open Label Extension 
In Part C, subjects who demonstrate a pressor effect in Part A, who complete Part A and 
remain otherwise eligible will have the option to participate in Part C and receive open-label 
TD-9855 by tablet once daily for up to 
   
The dose level administered on Day 1 in Part C will be equal to
 of the highest tolerated 
dose level (rounded-up to the nearest 1 mg) administered during Part A for that subject (or a 
lower dose at the discretion of the principal investigator to manage individual subject safety). 
Subjects will be discharged from the research clinic on Day 2, and continue at the same 
dose level as Day 1 of Part C.  At the subsequent scheduled visits until Day 29, the 
Investigator has the option to double the subject’s dose level at their discretion, if in their 
opinion the subject will benefit from, and can tolerate, a higher dose level. After Day 29, 
dose increases will need to be discussed with the Sponsor.  It is recommended that the 
subject receives at least 7 daily doses of TD-9855 at any single dose level before escalation 
to a higher dose to allow TD-9855 exposure to reach steady state at the lower dose.  
 


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 The schedule for potential dose increases is 
shown in the table below. 
Part A 
Maximum 
Dose 
Part C Day 1 
dose 
Part C Day 8 
dose 
Part C Day 
15 dose 
Part C Day 
22 dose 
Part C Day 
29 dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the case where a subject develops the presence or worsening of supine hypertension 
(as determined by the Investigator with agreement from the Sponsor) or other adverse 
events suggesting intolerability, the dose can be withheld for 3 days and resumed at a dose 
level 50% (rounded up to the nearest 1 mg) of the prior dose level.  If supine hypertension 
or other adverse events persist after the dose has been reduced, dosing in that subject 
should be discontinued and appropriate alternative therapy and care provided to the subject 
as determined by the principal investigator. 
In Part C, subjects will enter the research center on Day -2 and remain resident in the 
research facility to undergo safety, PD, PK and diseases assessments through the morning 
of Day 2 of Part C, after which they will be discharged home.  Subjects will return on an 
outpatient basis and undergo safety, PK/PD and disease assessments as described in the 
schedule of assessments. In addition, telephone assessments for safety and disease 
assessment will be performed on a weekly (during Month 1) and monthly basis (Months 
2 through 5) where no clinic visit is scheduled.  In such a case that the dose is reduced, the 
subject should be scheduled for a clinic visit to occur within approximately 2 weeks of the 
dose reduction. Following completion of the 
 dosing period, or in the case of early 
discontinuation from the study, subjects will return 2 and 4 weeks after the final dose for 
follow-up visits to undergo safety, PK/PD and diseases assessments and end of study 
procedures. In cases where the subject is unable to return to the clinic due to significant 
physical or geographic limitations, or at the Investigator’s discretion, a nurse may be sent to 
the subject’s home and the study visit procedures performed in the subject’s home, except 
for the day 29 visit which must be done within the research center. 
Adverse events will be assessed throughout the study duration in each Part and will be 
recorded in the case report form when reported. 
Study procedures are further described in Table 1 for Part A and Table 2 for Part C and in 
Section 6. 
Duration of Study Participation:   
The duration of study involvement for each subject will be up to approximately 36 days for 
Part A (including up to 30 days for screening), and 169 days for Part C.   


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Number of Subjects per Group:   
Up to 
 will be enrolled.  Subjects who demonstrate a pressor effect in Part A, 
who complete Part A, and who remain otherwise eligible are eligible to participate in Part C.  
 
Study Population: 
This study will enroll adult subjects with confirmed nOH due to MSA, PAF, or Parkinson’s 
disease and who meet other inclusion and exclusion criteria defined below.   
Inclusion Criteria: 
1. Male or female at least 40 years of age. 
2. Subject is able to communicate well with the Investigator and understands the 
expectations of the study. 
3. Subject is willing and able to comply with the study procedures, requirements and 
restrictions, and to understand and signed the informed consent form. 
4. Subject has been diagnosed with symptomatic orthostatic hypotension due to 
Parkinson's disease, multiple system atrophy, or pure autonomic failure, (ie, neurogenic 
orthostatic hypotension). 
5. Subjects must meet the diagnostic criteria of neurogenic orthostatic hypotension, as 
demonstrated by a ≥30 mm Hg drop in SBP within 5 minutes of standing. If additional 
Autonomic Function Testing is required to confirm the diagnosis of autonomic 
dysfunction, sinus arrhythmia and Valsalva maneuver may be conducted, as 
appropriate. 
6. Impaired autonomic reflexes, as determined by absence of BP overshoot during phase 
IV of the Valsalva maneuver, in subjects where Valsalva is performed, as appropriate. 
7. Experiencing dizziness, light-headedness, or fainting when standing. 
8. Absence of other identifiable causes of autonomic neuropathy. 
9. Female subjects must be non-pregnant and non-lactating. If a female subject is of 
childbearing potential, must have a documented negative pregnancy test at screening. 
 
NOTE: All females are considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile 
(bilateral tubal ligation or total hysterectomy). A subject may be admitted to the study on 
the basis of a negative urine pregnancy test (local lab), pending the result of the serum 
pregnancy test. 
10. If sexually active, must agree to use a highly effective method of birth control with 
partners of childbearing potential during the study and for 1 month after study drug 
dosing. 
NOTE: A highly effective method of birth control is defined as one that results in a low 
failure rate (ie, < 1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intra-uterine devices (IUDs), sexual 
abstinence, or a vasectomized partner. Male subjects must agree to use medically 


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acceptable birth control for at least 1 month following last dose of study medication. 
A vasectomy or a condom used with a spermicide is a medically acceptable birth control 
method for males. 
Additional criteria for subjects participating in Part C only: 
11. Demonstrated a pressor effect in Part A and completed dosing in Part A. 
12. Willing to sign an IRB-approved informed consent form for Part C. 
13. Able to comply with the visit requirements for Part C. 
Exclusion Criteria: 
1. Systemic illnesses known to produce autonomic neuropathy, including but not limited to 
diabetes mellitus, amyloidosis, and autoimmune neuropathies. 
2. Known intolerance to other NRIs or SNRIs. 
3. Pre-existing sustained hypertension (BP ≥ 150/100 mm Hg in the sitting position 
determined from three independent assessments), and not explained by the use of 
pressor agents. 
4. Concomitant use of vasoconstricting agents for the purpose of increasing BP such as 
ephedrine, dihydroergotamine, or midodrine must be stopped at least 2 days or five 
half-lives (whichever is longer) prior to dosing on Day 1 of Part A and C, and throughout 
the duration of Part C. Subjects previously enrolled in Part A under previous versions of 
the protocol will continue taking fludrocortisone during the washout period and in Part C 
at the dose and regimen used in Part A.  For new subjects enrolling in Part A under 
Amendment 3, fludrocortisone use in both Parts of the study and during the washout 
period will be limited to 0.1 mg QD.  
5. Concomitant use of anti-hypertensive medication for the treatment of essential 
hypertension unrelated to autonomic dysfunction. 
6. Have changed dose, frequency or type of prescribed medication, within two weeks of 
dosing on Day 1 with the following exceptions: 
• Vasoconstricting agents such as ephedrine, dihydroergotamine, midodrine, or 
fludrocortisone  
• Short courses (less than 2 weeks) of medications or treatments that do not interfere 
with, or exacerbate the subject’s condition under study (eg, antibiotics) 
7. Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV 
definition of alcohol or substance abuse). 
8. Clinically unstable coronary artery disease, or major cardiovascular or neurological event 
in the past 6 months. 
9. Use of any monoamine oxidase inhibitor (MAO-I) within 14 days of dosing on Day 1. 
10. History of untreated closed angle glaucoma, or treated closed angle glaucoma that, in 
the opinion of an ophthalmologist, might result in an increased risk to the subject. 
11. Any significant uncontrolled cardiac arrhythmia. 
12. Myocardial infarction in the past 6 months, or current unstable angina. 


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13. Congestive heart failure (NYHA Class 3 or 4). 
14. Diabetes insipidus, insulin-dependent diabetes mellitus, or diabetic neuropathy. 
15. History of cancer within the past 2 years other than a successfully treated, 
non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in 
situ. 
16. Gastrointestinal condition, which in the Investigator’s judgment, may affect the 
absorption of study drug (eg, ulcerative colitis, gastric bypass). 
17. Any major surgical procedure within 30 days of dosing on Day 1. 
18. Any other significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurologic, 
psychiatric, immunologic, hematologic, gastrointestinal, or metabolic disease not 
currently controlled with medical treatment (eg, a stable medication dosing regimen). 
19. Currently receiving any investigational drug or have received an investigational drug 
within 30 days of dosing on Day 1.  An investigational drug is defined as non-FDA 
approved drug. 
20. Allergic to or unable to drink apple juice (Part A only). 
21. Any condition or laboratory test result which, in the Investigator's judgment, might result 
in an increased risk to the subject, or would affect their participation in the study. 
22. Additionally, the Investigator has the ability to exclude a subject if for any reason they 
feel the subject is not a good candidate for the study or will not be able to follow study 
procedures. 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment: 
Detailed storage and preparation instructions for test product will be provided in a separate 
pharmacy manual. 
 
 
 
 
 
  
 
 
 
  
 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:   
In Parts A (and previously in Part B which was discontinued), placebo solution for individual 
subject administration will be prepared to match TD-9855 doses but will not contain 
TD-9855. Details regarding placebo preparation will be provided in a separate pharmacy 


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manual. Part C is open-label and all eligible subjects will receive active TD-9855. 
Study Evaluations 
Safety Assessments: 
• Adverse events (AE) [including serious adverse events (SAE)], clinical laboratory tests 
(including hematology, serum chemistry, and urinalysis), vital signs (including supine 
blood pressure), 12-lead ECGs, use of concomitant medications, and physical 
examination will be used to assess safety. 
Efficacy Assessments: 
• Efficacy assessments include measurement of seated and standing systolic blood 
pressure and completion of Orthostatic Hypotension Symptom Assessment (OHSA) 
questionnaire. 
Pharmacokinetic Assessments: 
• In Part A, blood samples for assessment of TD-9855 plasma concentration will be taken 
before dosing (within 30 minutes before the dose) and again between 6 and 9 hours post 
dose on dosing Days 3 (5 mg) and 5 (20 mg) as appropriate. One additional PK sample 
will be taken at 24 hours post dose following the last administered dose after the subject 
has reached the stopping criteria or at the end of the dose escalation sequence. 
• In Part B, refer to prior versions of this Protocol for specific information related to Part B 
which was discontinued in Amendment 2. 
• In Part C, PK samples are collected at selected visits as indicated in the schedule of 
assessments Table 2. 
Pharmacodynamic Assessments: 
• In Part A, blood samples for analysis of NE and dihydroxyphenylglycol (DHPG) will be 
collected on dosing Days 1 (placebo), 3 (5 mg) and 5 (20 mg), as appropriate, at the 
time points including once before dosing (after sitting for 10 minutes) and once again 
between 6 and 9 hours post dose (after sitting for 10 minutes). One additional PD 
sample will be taken at 24 hours post dose following the last administered dose after the 
subject has reached the stopping criteria or at the end of the dose escalation sequence  
• In Part B, refer to prior versions of this Protocol for specific information related to Part B 
which was discontinued since Amendment 2. 
• In Part C, PD samples are collected at selected visits as indicated in the schedule of 
assessments.  
Details related to PK and PD sample collection, handling, storage and shipping will be 
provided in a separate manual. 
Statistical Methods 
Sample Size: 
 
 


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Study Endpoints: 
For Part A, the primary study endpoint is the change from time-matched placebo in seated 
systolic blood pressure at 6 to 8 hours after drug administration.  For Part C, the primary 
endpoint is the improvement from baseline in the Likert scale “dizziness, lightheadedness, 
feeling faint, or feeling like you might black out” (OHSA, question 1) at week 4. 
The secondary endpoints for Part A include: 
• Improvement in the Likert scale for “dizziness, lightheadedness, feeling faint, or feeling 
like you might black out” (OHSA, question 1). 
• The composite OHSA score.  
• Change from time-matched placebo in standing SBP  
• Change from time-matched placebo in seated SBP (area under the curve for 0-12 hours 
following drug administration). 
• Duration of standing during the orthostatic standing test 
The secondary endpoints for Part C include: 
• The composite OHSA and OHDAS score.  
• Change from time-matched placebo in standing SBP  
• Change from time-matched placebo in seated SBP (area under the curve for 0-12 hours 
following drug administration). 
• Duration of standing during the orthostatic standing test 
 


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For all Parts of the study, safety and tolerability assessments will include adverse events, 
laboratory abnormalities, ECGs, and vital sign measurements including supine blood 
pressure. Exploratory PK and PD analysis will also be performed for all parts of the study. 
Analysis: 
All analyses will be presented separately by part. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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SCHEDULE OF STUDY ASSESSMENTS 
 
Table 1: 
Schedule of Study Procedures/Assessments – Part A 
Procedure 
Screening 
(Day -30 
to -1) 
Admission 
(Day -2) 
Admission 
(Day -1) 
(Day 1a) 
Dose 
Escalation 
 (Day 2 - 5) 
Discharge 
(Day 3, 4, 5, 
or 6)b 
Washout 
Min (8 
days) 
Overnight residency and Standardized Meal 
 
X 
X 
X 
X 
 
 
Informed Consent (may be signed up to 30 days 
prior to screening) 
X 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
Medication and Medical History 
X 
 Xc 
 Xc 
 
 
 
 
Height/Weight/BMId 
X 
 
 Xd 
 Xd 
 Xd 
 Xd 
 
Temperature and respiratory rate 
 Xq 
 
Xq 
 Xq 
 Xq 
 Xq 
 
Autonomic Function Testinge 
 Xe 
 
 
 
 
 
 
Orthostatic Standing Testf 
 Xf 
 
Xf 
 Xf 
 Xf 
 Xf 
 
Supine Blood Pressure (after supine for 10 mins)g 
 
 
 
 Xg 
 Xg 
 
 
ECG (12-lead)h 
 Xh 
 
Xh 
 Xh 
 Xh 
 Xh 
 
Physical Examinationi 
 Xg 
 
Xi 
 Xi 
 Xi 
 Xi 
 
Pregnancy Test (females only)j 
Xj 
 
 
 
 
 
 
Hematology, Serum Chemistry, and Urinalysis 
X 
 
X 
 
 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
Urine Collection and Volume Measurement 
 
 
 Xk 
 Xk 
 Xk 
 Xk 
 
PK Samplingl 
 
 
 
 
 Xl 
Xl 
 
PD Sampling: NE and DHPGm 
 
 
 
 Xm 
 Xm 
 Xm 
 
OH Questionnaire (OHSA)n 
 Xn 
 
 Xn 
 Xn 
 Xn 
 Xn 
 
Clinician’s/Subject’s Global Impressionp 
 
 
 Xp 
 Xp 
 Xp 
 Xp 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
Adverse Eventso 
X 
X 
X 
X 
X 
X 
Xo 
Study Drug Administration (placebo/TD-9855) 
 
 
 
X 
X 
 
 
a. 
Study Day 1 is defined as the day of first study dosing (placebo).  The preceding day is Study Day -1.  Note that there is no Study Day 0. 
b. 
Actual day of discharge will be on day following preset stopping criteria. 
c. 
History update, if any changes since the Screening Visit, will be obtained. 


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d. 
Body weight will be measured daily during Days -1 through 5 in the AM (predose) and PM (approximately 12 hours post dose), and the AM of Day 6 (or on 
discharge).  The Day -1 “postdose” weight assessment should be prospectively calculated, based on the target Day 1 dosing time. Measurements will occur at 
approximately the same time each day (± 15 minutes) using the same scale and without clothing (or where necessary with the same light clothing). 
e. 
Where appropriate, autonomic function testing will be conducted to confirm the diagnosis of autonomic dysfunction.   
f. 
During Day -1 through Day 6, the orthostatic standing test will be performed in the morning at approximately the same time of day for each test, under fasting 
conditions after midnight to avoid the confounding effect of post-prandial hypotension. Additionally, during Days 1 through 5, the standing test will be repeated 
at 4, 7, 9 and 12 hours after dosing. At each time point, BP and HR measurements will be recorded with automated (or manual) sphygmomanometer while 
supine at 5 and 10 min (with the torso and head elevated 30 degrees from horizontal), after seated at 5 and 10 min and after 1, 3, 5, and 10 min while 
standing. The standing time will be measured with a chronometer and the duration of standing will be recorded. Additionally at each time point, the standing 
time will be measured with a chronometer and the duration of standing will be recorded.   
g. 
Additional supine (30 degree head up) blood pressure readings will be measured at 14, 16, 18, and 20 hours after dosing each day in Part A for safety 
assessment.  All times have a window of ± 15 minutes. 
h. 
Electrocardiogram (12-lead) will be collected at Screening, on Day -1, predose and between 6 and 8 hours post dose on Days 1 through 5, and on Discharge. 
i. 
Physical examinations after the Screening Visit may be abbreviated, focusing on abnormalities identified on the Screening examination and as related to 
adverse events. 
j. 
For women of child bearing potential a serum pregnancy test will be performed at screening. 
k. 
Where feasible, beginning with the morning void on Day -1, all urine will be collected and the volume measured and recorded at each void or as a total daily 
volume through discharge.  
l. 
Blood samples for assessment of TD 9855 plasma concentration will be taken before dosing (within 30 minutes before the dose) and again between 6 and 
9 hours post dose on dosing Days 3 and 5 as appropriate. One additional PK sample will be taken at 24 hours post dose following the last administered dose 
after the subject has reached the stopping criteria or at the end of the dose escalation sequence.   
m. Blood samples for analysis of PD (NE and DHPG) will be collected once before dosing (after sitting for 10 minutes) and once again between 6 and 9 hours 
post dose (after sitting for 10 minutes) on dosing Days 1 (placebo), 3 and 5 (20 mg) as appropriate. One additional PD sample will be taken at 24 hours post 
dose (after sitting for 10 minutes) following the last administered dose after the subject has reached the stopping criteria or at the end of the dose escalation 
sequence. Please refer to the PK manual for more specific information related to sample handling, labeling, storage and shipping. 
n. 
OHSA to be administered at screening, on Day -1, daily on Day 1 through Day 5 both predose and between 6 and 8 hours following dosing, and on the day of 
discharge (approximately 24 hours after the last dose). Assessments should be performed by a trained clinician or qualified designee and recorded on a 
standardized paper form. 
o. 
On a daily basis during the first 72 hours from discharge, and then weekly during the first 4 weeks after discharge in Part A, the Investigator or designee will 
contact the subject by telephone to review the subject’s health status.  Any adverse events reported by phone will be recorded and followed as medically 
appropriate determined by the Investigator. Under the direction of the Investigator, subjects will manage their nOH symptoms using fludrocortisone as 
prescribed. 
p. 
The Clinician’s/Subject’s Global Impression scale are to be administered on Day -1, daily on Day 1 through Day 5 both predose and between 6 and 8 hours 
following dosing, and on the day of discharge.  The Clinician’s Global Impression scale must be administered by a trained clinician.  The subject will complete 
the Subject’s Global Impression scale under supervision of the Investigator or qualified designee.  
q. 
On dosing days (Days 1 through 5), temperature and respiratory rate will be measured twice – predose and then again between 6-8 hours postdose.   
 


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Table 2: 
Schedule of Study Procedures/Assessments – Part C 
 
Admit 
Treatment period 
Follow-up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
EOS 
Study week (beginning of week except Day 140) 
1 
2 
3 
4 
5 
9 
13 
17 
20 
23 
25 
Procedure (Study Day) 
Admit 
Day -2 
Day 
-1b 
Day 
1b 
Day 
2b  
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
57 
Day 
85 
Day 
113 
Day  
140m 
Day 
155 
Day  
169 
Overnight Residency 
 Xa 
 Xa 
 Xa 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication and Medical History 
 Xc 
 
 
 
 
  
 
 
 
 
 
 
 
 
Weight/BMI & Temperature 
X 
X 
 X 
X 
 
 X 
 
X 
 
X 
  
X 
X  
X 
Orthostatic Standing Test including supine blood 
pressured 
 
 Xd 
  Xd 
 Xd 
 
 Xd 
 
 Xd 
 
 Xd 
 
 Xd 
 Xd 
 Xd 
Supine blood pressuree 
 Xe 
 
 
 
 Xe 
 
 Xe 
 
Xe 
 
Xe 
 
 
 
24 hour blood pressure monitoringf 
 
 Xf 
 
 
 
 Xf 
 
 Xf 
 
 Xf 
 
 
 
 Xf 
ECG (12-lead) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical Examinationg 
 
 Xg 
 Xg 
 Xg 
 
 Xg 
 
 Xg 
 
 Xg 
 
 Xg 
 Xg 
 Xg 
Urine Pregnancy Testh 
 Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety labs: Hematology, Chemistry, and UA 
Xo 
 
 
 
 
 
 
 
 
 
 
 
X 
PK Samplingi 
 
 
 Xi 
 Xi 
 
  Xi 
 
 Xi 
 
 Xi 
 
 
 Xi 
 
DHPG Samplingj 
 
 
 Xj 
 Xj 
 
 
 
 Xj 
 
 
 
 
 
 
NE Samplingk 
 
 
 Xk 
 
 
 
 
 Xk 
 
 
 
 
 
 
OHQ (OHSA and OHDAS)l 
 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
Xl 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
Clinician’s/Subject’s Global Impressionl 
 
 Xl 
Xl 
 Xl 
Xl 
 Xl 
Xl 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
 Xl 
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 
Study Drug Administrationm 
 
 
 Xm 
 Xm 
 Xm 
 Xm 
 Xm 
 Xm 
Xm  Xm 
 Xm 
 Xm 
 
 
Subject Satisfaction Surveyn 
 
 Xn 
 
 
 
Xn 
 
 Xn 
 
 
 
 Xn 
 
 
Telephone Assessments (highlighted in gray) 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 


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a. 
Subjects will admit to the research unit on Day -2 and remain resident through the completion of study procedures on the morning of Day 2. 
b. 
The timing of Day -1 “postdose” assessments should be prospectively calculated, based on the target Day 1 dosing time (eg, orthostatic standing test and 
Clinical Impression and OHQ assessments). Study Day 1 is defined as the day of first study dosing with TD-9855 in Part C.  On Day 2 subjects are 
discharged from the research facility after all study procedures are completed the morning of Day 2. 
c. 
History update, if any changes since participation in Part A (and B if appropriate) of the study. 
d. 
The orthostatic standing test will be performed in the morning before eating breakfast at approximately the same time of day each visit under fasting 
conditions after midnight to avoid the confounding effect of post-prandial hypotension.  In addition, at least 4 hours after dosing (but no more than 7 hours) 
and before lunch, the standing test will be repeated.  At each time point, BP and HR measurements will be recorded with automated (or manual) 
sphygmomanometer while supine at 5 and 10 min (with the torso and head elevated 30 degrees from horizontal), after seated at 5 and 10 min and after 1, 
3, 5, and 10 min while standing. The standing time will be measured with a chronometer and the duration of standing will be recorded.  More details related 
to the sequence of dosing and orthostatic assessments are described below.  For the Day 155 and 169 assessments, the timing of the “postdose” 
orthostatic test should be calculated based on the Day 1 dosing time. 
e. 
On Days 8, 22, 57 and 113, supine blood pressures will be collected twice in the morning before eating (after 5 and 10 minutes resting at 30° elevation), 
and twice again at least 4 hours after dosing (but no more than 7 hours and before lunch) after 5 and 10 minutes resting at 30° elevation.  On Day -2, 
supine blood pressures should be measured (after 5 and 10 minutes resting at 30° elevation).  
f. 
In Part C, at sites where ambulatory blood pressure monitoring equipment is available, on Day -1, beginning approximately 24 hours before dosing on 
Day 1, ambulatory blood pressure monitoring equipment will be attached to the subject and blood pressure monitored during the 24 hour period before 
dosing.  In addition, approximately 72 to 48 hours before a subject returns to the clinic for the Day 15, Day 29, Day 85 and Day 169 visits, subjects will put 
on the 24 hour blood pressure monitoring equipment and initiate the recording.  Once the 24 hour session is complete subjects will remove and return the 
equipment to the research center during the next visit.  During each 24 hour session, the blood pressure monitoring device will be programmed to 
automatically measure blood pressure every 2 hours beginning at the top of the hour.  In addition, subjects should be instructed to manually initiate 2 
recordings to occur approximately 30 and 20 minutes before eating each morning after sitting supine (30 degree elevation) for at least 10 minutes.  During 
each 24-hour session subjects should also maintain a log of their posture at the time of each blood pressure measurement.  For sites where ambulatory 
equipment are not available, desk top blood pressure devices may be used and provided to the subject for home use.  Subjects will be instructed to 
measure and record blood pressure on the days and time points described above and in Table 2.  More details regarding the ambulatory monitoring will be 
provided in a separate manual. 
g. 
Physical examinations after the Day -1 visit may be abbreviated, focusing on abnormalities identified on the Day -1 examination and as related to adverse 
events. 
h. 
For women of child bearing potential a urine pregnancy test will be performed at screening.  If urine pregnancy test is positive, confirm with serum 
pregnancy test. 
i. 
Blood collection for PK analysis will be collected on Day 1 (within 30 minutes before dosing and again between 6 and 9 hours post dose), predose Day 2, 
and upon return to the clinic on Days 29, 85, and 155. Please refer to the central laboratory manual for more specific information related to sample 
handling, labeling, storage and shipping. 
j. 
Blood collection for DHPG analysis will be collected on Day 1 (within 30 minutes before dosing and again between 6 and 9 hours post dose), predose on 
Day 2, and upon return to the clinic on Day 29. Please refer to the central laboratory manual. 
k. 
Blood collection for NE analysis will be collected on Day 1 (within 30 minutes before dosing) and upon return to the clinic on Day 29. Please refer to the 
central laboratory manual.  


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l. 
Clinician’s/Subject’s Global Impression and OHQ (OHSA and OHDAS components) to be administered during clinic visits by a trained clinician and 
recorded on standardized paper forms (See Appendix 4). In addition while at home, the Clinician’s/Subject’s Global Impression and OHQ will be completed 
by telephone with the study coordinator.  On all visit days the OHQ and Global Impression assessments should be completed at least 4 hours after dosing 
(but no more than 7 hours) and before lunch.  For the Day 155 and 169 assessments, the timing of the “postdose” questionnaires should be calculated 
based on the Day 1 dosing time. 
m. On the study visit days marked above, subjects will receive a dose of study medication in the morning after supine blood pressures and the orthostatic 
standing test has been completed.  On non-study visit days the subjects should take their dose of study medication in the morning at approximately the 
same time of day.  On study days where the subject is traveling to the clinic, the subject should take their dose of study medication at home before 
traveling to the clinic.  Subjects will return to the clinic on the day of their final dose.  Day 140 is the day of the last dose received at the end of 5 months 
(20 weeks). 
n. 
Subjects will complete the Subject Satisfaction Survey on Days -1, 15, 29 and 140 (or at the time of early discontinuation) using the appropriate 
questionnaire listed in Appendix 5. 
o. 
 Safety labs should be collected Day -2 or on Day -1. 
 
 
Sequence of study procedures during study visits (with hypothetical times for illustration): 
 
• 
7:00 am -Wake up 
• 
7:30 am - supine blood pressure after 5 and 10 minutes resting at 30 degrees elevation and orthostatic standing test 
(where applicable) 
• 
8:00 am - Dose with TD-9855 and eat breakfast 
After a minimum of 4 hours but no more than 7 hours after dosing and before lunch: 
 
• 
12:00 pm - supine blood pressure after 5 and 10 minutes resting at 30 degrees elevation and orthostatic standing test 
(where applicable) 
• 
12:30 pm - Clinician/subject impression and OH Questionnaires (OHDAS and OHSA)  
• 
12:45 pm - lunch 


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TABLE OF CONTENTS 
 
PAGE 
 
PROTOCOL SYNOPSIS ....................................................................................................... 2 
SCHEDULE OF STUDY ASSESSMENTS .......................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 20 
1 
INTRODUCTION ..................................................................................................... 22 
1.1 
Background and Rationale ........................................................................... 22 
1.2 
Nonclinical Profile ......................................................................................... 23 
1.3 
Clinical Experience ....................................................................................... 24 
1.4 
Risks and Benefits ....................................................................................... 25 
2 
OBJECTIVES .......................................................................................................... 27 
3 
STUDY DESIGN ...................................................................................................... 27 
3.1 
Overview ...................................................................................................... 27 
3.2 
Rationale for Study Design ........................................................................... 29 
3.3 
Selection of Doses and Regimen ................................................................. 29 
3.4 
Study Endpoints ........................................................................................... 29 
3.4.1 
Primary and Secondary Endpoints .................................................... 29 
3.4.2 
Safety Endpoints .............................................................................. 30 
3.5 
Minimization of Bias ..................................................................................... 30 
3.5.1 
Blinding............................................................................................. 30 
3.5.2 
Treatment Assignment ...................................................................... 30 
4 
STUDY POPULATION ............................................................................................ 32 
4.1 
Inclusion Criteria .......................................................................................... 32 
4.2 
Exclusion Criteria ......................................................................................... 33 
5 
STUDY DRUGS ...................................................................................................... 35 
5.1 
Description of Study Drugs ........................................................................... 35 
5.2 
Dosage and Administration .......................................................................... 35 
5.3 
Drug Accountability and Reconciliation ........................................................ 38 
6 
STUDY PROCEDURES .......................................................................................... 39 
6.1 
Schedule of Study Procedures ..................................................................... 39 
6.2 
Total Blood Volume ...................................................................................... 40 
6.3 
Description of Study Procedures / Assessments .......................................... 40 
6.3.1 
Informed consent .............................................................................. 40 
6.3.2 
Overnight Residency, Standardized Meals, and Restrictions ............ 40 
6.3.3 
Inclusion and Exclusion Criteria ........................................................ 40 
6.3.4 
Medication and Medical History ........................................................ 41 
6.3.5 
Body Height, Weight and BMI ........................................................... 41 
6.3.6 
Temperature and Respiratory Rate ................................................... 41 
6.3.7 
Orthostatic Standing Test ................................................................. 41 
6.3.8 
Supine Blood Pressure ..................................................................... 42 
6.3.9 
Autonomic Function Testing ............................................................. 42 
6.3.10 24-Hour Blood Pressure Monitoring .................................................. 43 
6.3.11 Electrocardiogram ............................................................................ 43 
6.3.12 Physical Examination ........................................................................ 43 
6.3.13 Pregnancy Test ................................................................................ 44 


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6.3.14 Laboratory Tests ............................................................................... 44 
6.3.14.1 
Hematology ..................................................................... 44 
6.3.14.2 
Serum Chemistry............................................................. 44 
6.3.14.3 
Urinalysis ........................................................................ 44 
6.3.14.4 
Urine Drug Screen ........................................................... 45 
6.3.15 Urine Collection and Volume Measurement ...................................... 45 
6.3.16 Pharmacokinetic Assessments ......................................................... 45 
6.3.17 Norepinephrine and Dihydroxyphenylglycol Assessments ................ 45 
6.3.18 Orthostatic Hypotension Questionnaire ............................................ 45 
6.3.19 Clinician’s / Subject’s Global Impression ........................................... 46 
6.3.20 Concomitant Medications ................................................................. 46 
6.3.21 Adverse Events ................................................................................ 46 
6.3.22 Subject Satisfaction Survey .............................................................. 47 
6.3.23 Telephone Assessments .................................................................. 47 
6.4 
Discontinuation ............................................................................................ 47 
6.4.1 
Subject Discontinuation .................................................................... 47 
6.4.2 
Subject Replacement ........................................................................ 48 
6.4.3 
Study Discontinuation ....................................................................... 48 
6.5 
Pregnancy .................................................................................................... 49 
7 
ADVERSE EVENTS ................................................................................................ 49 
7.1 
Regulatory Definition of an Adverse Event ................................................... 49 
7.2 
Adverse Event Definition for the Purposes of This Study .............................. 49 
7.3 
Assessment of Adverse Events .................................................................... 50 
7.4 
Serious Adverse Events ............................................................................... 51 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ............................................ 52 
7.6 
Serious Adverse Event Reporting ................................................................ 52 
7.7 
Adverse Event Follow-up ............................................................................. 53 
8 
STATISTICAL CONSIDERATIONS ......................................................................... 53 
8.1 
Sample Size and Power ............................................................................... 53 
8.2 
Analysis Populations .................................................................................... 54 
8.3 
Analyses ...................................................................................................... 54 
8.3.1 
Demographics and Other Baseline Characteristics ........................... 55 
8.3.2 
Analysis of Efficacy ........................................................................... 55 
8.3.2.1 
Primary Endpoint ............................................................. 55 
8.3.2.2 
Secondary Endpoints ...................................................... 55 
8.3.3 
Analysis of Pharmacokinetics ........................................................... 56 
8.3.4 
Analysis of Pharmacodynamics ........................................................ 56 
8.3.5 
Analysis of Safety ............................................................................. 56 
8.3.6 
Extent of Exposure ........................................................................... 56 
8.3.7 
Adverse Event Data .......................................................................... 57 
8.3.8 
Concomitant Medications ................................................................. 57 
8.3.9 
Laboratory Data ................................................................................ 57 
8.3.10 Vital Signs Data ................................................................................ 58 
8.3.11 ECG Data ......................................................................................... 58 
8.3.12 Other Analyses ................................................................................. 59 


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8.4 
Handling of Missing Data ............................................................................. 59 
8.5 
Data Monitoring Committees ........................................................................ 59 
9 
STUDY ADMINISTRATION ..................................................................................... 59 
9.1 
Principal Investigator Responsibilities .......................................................... 59 
9.2 
Institutional Review Board/Independent Ethics Committee ........................... 60 
9.3 
Informed Consent ......................................................................................... 61 
9.4 
Data Recording and Quality Assurance ........................................................ 61 
9.5 
Document Retention .................................................................................... 62 
9.6 
Confidentiality .............................................................................................. 63 
9.7 
Access to Data and Documents ................................................................... 63 
9.8 
Quality Control: Study Monitoring and Auditing ............................................ 64 
9.9 
Publication ................................................................................................... 65 
10 
REFERENCES ........................................................................................................ 66 
11 
APPENDICES ......................................................................................................... 67 
 
LIST OF TABLES 
 
Table 1: 
Schedule of Study Procedures/Assessments – Part A .............................. 12 
Table 2: 
Schedule of Study Procedures/Assessments – Part C .............................. 14 
Table 3: 
Weekly Dose Escalation Plan for Subject in Part C ................................... 31 
Table 4: 
ECG Test Outlier Thresholds .................................................................... 58 
 
LIST OF APPENDICES 
 
Appendix 1: 
Orthostatic Hypotension Questionnaire OHQ for Part A Only .................... 67 
Appendix 2: 
Orthostatic Hypotension Questionnaire (OHQ) for Part C Only ................. 68 
Appendix 3: 
Physician/Subject Global Impression for Part A Only ................................ 70 
Appendix 4: 
Physician/Subject Global Impression for Part C Only ................................ 72 
Appendix 5: 
Subject Satisfaction Survey ....................................................................... 74 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
5-HT 
serotonin 
ITT 
Intent-To-Treat population 
ADHD 
attention-deficit/hyperactivity disorder 
AE 
adverse event 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CA 
Cochran-Armitage linear trend test 
CI 
confidence interval 
CFR 
(United States) Code of Federal Regulations 
CNS 
central nervous system 
CRC 
clinical research center 
CRF 
case report form 
CTSA 
Clinical and Translational Science Award Center 
DHPG 
dihydroxyphenylglycol 
DPB 
diastolic blood pressure 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FM 
fibromyalgia 
GCP 
Good Clinical Practice 
HR 
heart rate 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
intra-uterine device 
LDH 
lactose dehydrogenase 
LS 
least square 
MAO-I 
monoamine oxidase inhibitor 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MSA 
multiple system atrophy 
NE 
norepinehprine 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
NET 
norepinephrine transporter 
nOH 
neurogenic orthostatic hypotension 
NRI 
norepinephrine Reuptake Inhibitor 
NYHA 
New York Heart Association 
OH 
Orthostatic Hypotension 
OHDAS 
Orthostatic Hypotension Daily Activity Scale 
OHQ 
Orthostatic Hypotension Questionnaire 
OHSA 
Orthostatic Hypotension Symptom Assessment 
PAF 
pure autonomic failure 
PD 
Parkinson’s disease 
PD 
pharmacodynamic(s) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QTcF 
corrected QT interval 
REB 
Research Ethics Board 
SA 
sinus arrhythmia 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SERT 
serotonin transporter 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TOEPH 
heterogeneous banded Toeplitz structure 
WBC 
white blood cell count 
 


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1 
INTRODUCTION 
1.1 
Background and Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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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).  


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1.3 
Clinical Experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4 
Risks and Benefits 
 
 
 suggesting that TD-9855 has the potential to provide a novel treatment option for 
nOH. 
While it is not known whether TD-9855 will provide clinical efficacy, this study will provide a 
number of beneficial services to subjects. These include autonomic evaluations, 
neurohumoral evaluation and information on new research developments in the field.  
Subjects will have access to routine autonomic follow up that may improve orthostatic 
symptoms. They will have symptom rating testing performed that may assist in educational 
planning. 
During the conduct of the TD-9855 clinical development program, the following have been 
recognized as important potential risks, with none characterized as identified risks 
associated with the administration of TD 9855: 
• 
Increase in heart rate 
• 
Increase in BP 
• 
Syncope 
 


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Possible risks to subjects participating in this study include adverse events associated with 
other SNRIs, such as nausea, dry mouth, headache, dizziness, somnolence, fatigue, 
diarrhea, insomnia, vomiting, syncope, seizures, constipation, hyponatremia, hyperhidrosis, 
urinary retention, and decrease appetite. 
Furthermore, subjects may experience adverse effects as a result of study procedures, such 
as repeated blood sampling and associated procedures. 
To help ensure subject safety, subjects will be closely monitored during this study.  The 
study will be conducted in the Clinical and Translational Science Awards Centers (CTSAs) 
of the respective participating institutions comprising the Autonomic Disorders Consortium 
whenever possible. When a CTSA is not available, study visits will be conducted in the 
Investigator’s autonomic disorders clinic or appropriately qualified research facility.  The 
schedule of procedures conducted during the open-label out-patient extension requires 
subjects to return to the clinic on a regular basis during the dosing and follow up periods and 
participate in telephone based evaluations on a weekly basis.  If subjects are unable to 
return to the clinic as indicated by the schedule of procedures, home visits will be conducted 
by protocol-trained nurses.  If any participant should incur any unexpected and untoward 
event during the testing procedure, the emergency caregivers (cardiologists, 
anesthesiologists, social workers, and psychologists) would become available on an 
immediate basis to provide necessary emergent management. 
A summary of known and potential risks to human subjects is provided in the IB in the 
Summary of Data and Guidance for the Investigator. 


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2 
OBJECTIVES 
The primary objective of the study is as follows: 
• 
To determine if TD-9855 has an acute (Parts A and B) and sustained (Part C) 
pressor response and improves symptoms of orthostatic intolerance in subjects with 
nOH due to MSA, PAF, or Parkinson’s disease.  
The secondary objective(s) of the study is as follows: 
• 
To evaluate the safety and tolerability of TD-9855 in subjects with nOH. 
• 
To evaluate the PK and PD (NE and DHPG) of TD-9855 after single and multiple 
doses in subjects with nOH. 
3 
STUDY DESIGN 
3.1 
Overview 
This is a multicenter, randomized, 3 part, single-blind (Part A), double-blind (Part B), and 
open-label multiple dose extension (Part C) study of TD 9855 versus placebo in subjects 
with nOH.  However, beginning with Amendment 2 of this protocol, Part B of the study has 
been discontinued.  Therefore, any new subjects enrolled after Amendment 2 will not be 
enrolled in Part B.  Details regarding Part B are still included in this document but where 
appropriate the reader is referred to the prior version of this protocol for more specific 
information related to Part B. 
This study now consists of 2 Parts, A and C.  Part A follows a daily, single, escalating dose 
design starting with placebo on Day 1, followed by a dose of 
 TD-9855 on Day 2, and 
proceeding to escalating higher doses of TD-9855 on a daily basis up to a maximum dose of 
 based on safety, tolerability, and determination of a pressor effect.  In Part C, 
subjects who demonstrate a pressor effect in Part A, who complete Part A, and remain 
otherwise eligible will have the option to receive open-label TD-9855 by tablet daily for up to 
   


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3.2 
Rationale for Study Design 
This study is designed to evaluate the acute (Part A and B) and sustained (Part C) efficacy 
and safety of TD-9855 in improving BP and reducing orthostatic symptoms in subjects with 
nOH.  The study should provide important information between BP, orthostatic symptom 
relief and the potential correlation with changes in NE and dihydroxyphenylglycol (DHPG) 
release. The information to be learned could be useful in optimizing diagnosis and clinical 
management.  Safety and tolerability will be assessed throughout the study treatment period 
via laboratory measurements (eg, hematology, chemistry, and urinalysis) and monitoring 
of AEs. 
3.3 
Selection of Doses and Regimen 
This study aims to evaluate the effects of single and multiple doses of TD-9855 on systolic 
blood pressure, symptoms associated with nOH, safety, and tolerability.  The current doses 
of TD 9855 for this trial were chosen using pharmacokinetic (PK) and pharmacodynamic 
(PD) modeling to achieve a range of NET inhibition and to determine a minimum dose 
required to yield an increase in sitting systolic blood pressure.  An ascending dose design 
was chosen in Part A to allow the subjects to start at a low dose because of the intrinsic 
hyper adrenergic responsiveness in these patients. The maximum dose levels (
 single 
dose or 
 multiple doses QD) were selected to provide maximal steady state NET 
inhibition in all subjects despite inter-individual PK variability. A single dose of 
 and 
multiple doses QD of 
 are below or equal to doses examined and tolerated in single 
and multiple dose studies in healthy volunteers respectively. The maximum dose in Part C 
 QD) is equal to the well-tolerated
 dose that was studied in two Phase 2 trials 
in patients with ADHD and FM where 
 was administered over 6 to 8 weeks. 
3.4 
Study Endpoints 
3.4.1 Primary and Secondary Endpoints 
For Part A, the primary study endpoint is the change from time-matched placebo in seated 
systolic blood pressure at 6 to 8 hours after drug administration. For Part C, the primary 
endpoint is the improvement from baseline in the Likert scale “dizziness, lightheadedness, 
feeling faint, or feeling like you might black out” (OHSA, question 1) at week 4. 
 


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The secondary endpoints for Part A include: 
• 
Improvement in the Likert scale for “dizziness, lightheadedness, feeling faint, or 
feeling like you might black out” (OHSA, question 1). 
• 
The composite OHSA score.  
• 
Change from time-matched placebo in standing SBP  
• 
Change from time-matched placebo in seated SBP (area under the curve for 
0-12 hours following drug administration). 
• 
Duration of standing during the orthostatic standing test 
The secondary endpoints for Part C include: 
• 
The composite OHSA and OHDAS score.  
• 
Change from time-matched placebo in standing SBP  
• 
Change from time-matched placebo in seated SBP (area under the curve for 
0-12 hours following drug administration). 
• 
Duration of standing during the orthostatic standing test 
3.4.2 Safety Endpoints 
For all Parts of the study, safety and tolerability assessments will include adverse events, 
laboratory abnormalities, ECGs, and vital sign measurements including supine blood 
pressure. Exploratory PK and PD assessments will also be made in all parts of the study as 
indicated in the schedule of assessments. 
3.5 
Minimization of Bias 
Bias will be minimized through the use of randomization and blinding. 
3.5.1 Blinding 
In Part A, study subjects will be blinded to dose levels and escalation. Pre-defined stopping 
rules will be used to guide procedures.  For Part B, which has been discontinued, refer to 
previous versions of this protocol. Part C will be an open-label extension study and therefore 
blinding considerations are not applicable. 
3.5.2 Treatment Assignment 
Subjects in Part A will begin by receiving placebo in a single-blind manner (ie, subject 
remains blinded). This will be followed by daily dose escalations, beginning with 
 of 
TD-9855 on Day 2. On each subsequent day, subjects will receive a single escalating dose 
of TD-9855 
 until Day 5 or until reaching the preset stopping criteria 


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(Section 5.2). However, based on the daily evaluation of tolerability, the Investigator 
(in collaboration with the Sponsor), may decide to not escalate the dose, but rather 
re-administer the previous dose from the prior day.  Once the decision has been made to 
not escalate the dose, the subject should remain at the current dose through Day 5 of 
dosing. 
The dose level administered on Day 1 in Part C will be equal to 50% of the highest tolerated 
dose level (rounded up to the nearest 1 mg) administered during Part A for that subject (or a 
lower dose at the discretion of the principal investigator to manage individual subject safety). 
Subjects will be discharged from the research clinic on Day 2 and continue at the same 
dose level as Day 1 of Part C.  At the subsequent scheduled visits until Day 29, the 
Investigator has the option to double the subject’s dose level at their discretion, if in their 
opinion the subject will benefit from, and can tolerate, a higher dose level.  After Day 29, 
dose increases will need to be discussed with the Sponsor.  It is recommended that the 
subject receives at least 7 daily doses of TD-9855 at any single dose level before escalation 
to a higher dose to allow TD-9855 exposure to reach steady state at the lower dose. Due to 
the half-life of TD-9855 multiple dose increases within a 7 day period might lead to greater 
than 2-fold increase in TD-9855 exposure and are not recommended.  The maximum dose 
administered to any subject is 
 The schedule for dose increases is shown in 
Table 3. 
Table 3: 
Weekly Dose Escalation Plan for Subject in Part C  
Part A 
Maximum 
Dose 
Part C Day 1 
dose 
Part C Day 8 
dose 
Part C Day 
15 dose 
Part C Day 
22 dose 
Part C Day 
29 dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the case where a subject develops the presence or worsening of supine hypertension 
(as determined by the Investigator with agreement from the Sponsor) or other adverse 
events suggesting intolerability, the dose can be withheld for 3 days and resumed at a dose 
level 50% (rounded up to the nearest 1 mg) of the prior dose level.  If supine hypertension or 
other adverse events persists after the dose has been reduced, dosing in that subject 
should be discontinued and appropriate alternative therapy and care provided to the subject 
as determined by the principal investigator. 


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4 
STUDY POPULATION 
Subjects who meet all of the inclusion and none of the exclusion criteria will be eligible for 
enrollment into this study. 
4.1 
Inclusion Criteria 
1. Male or female at least 40 years of age. 
2. Subject is able to communicate well with the Investigator and understands the 
expectations of the study. 
3. Subject is willing and able to comply with the study procedures, requirements and 
restrictions, and to understand and signed the informed consent form. 
4. Subject has been diagnosed with symptomatic orthostatic hypotension due to 
Parkinson's disease, multiple system atrophy, or pure autonomic failure (ie, neurogenic 
orthostatic hypotension). 
5. Subjects must meet the diagnostic criteria of neurogenic orthostatic hypotension, as 
demonstrated by a ≥30 mm Hg drop in SBP within 5 minutes of standing. If additional 
Autonomic Function Testing is required to confirm the diagnosis of autonomic 
dysfunction, sinus arrhythmia and Valsalva maneuver may be conducted, as 
appropriate.  
6. Impaired autonomic reflexes, as determined by absence of BP overshoot during phase 
IV of the Valsalva maneuver, in subjects where Valsalva is performed, as appropriate. 
7. Experiencing dizziness, light-headedness, or fainting when standing. 
8. Absence of other identifiable causes of autonomic neuropathy. 
9. Female subjects must be non-pregnant and non-lactating. If a female subject is of 
childbearing potential, must have a documented negative pregnancy test at screening. 
NOTE: All females are considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile 
(bilateral tubal ligation or total hysterectomy). A subject may be admitted to the study on 
the basis of a negative urine pregnancy test (local lab), pending the result of the serum 
pregnancy test. 
10. If sexually active, must agree to use a highly effective method of birth control with 
partners of childbearing potential during the study and for 1 month after study drug 


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dosing. 
NOTE: A highly effective method of birth control is defined as one that results in a low 
failure rate (ie, < 1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intra-uterine devices (IUDs), sexual 
abstinence, or a vasectomized partner. Male subjects must agree to use medically 
acceptable birth control for at least 1 month following last dose of study medication. 
A vasectomy or a condom used with a spermicide is a medically acceptable birth control 
method for males. 
Additional criteria for subjects participating in Part C only: 
11. Demonstrated a pressor effect in Part A and completed dosing in Part A.  
12. Willing to sign an IRB-approved informed consent form for Part C. 
13. Able to comply with the visit requirements for Part C. 
4.2 
Exclusion Criteria 
1. Systemic illnesses known to produce autonomic neuropathy, including but not limited to 
diabetes mellitus, amyloidosis, and autoimmune neuropathies. 
2. Known intolerance to other NRIs or SNRIs. 
3. Pre-existing sustained hypertension (BP ≥ 150/100 mm Hg in the sitting position 
determined from three independent assessments, and not explained by the use of 
pressor agents). 
4. Concomitant use of vasoconstricting agents for the purpose of increasing BP such as 
ephedrine, dihydroergotamine, or midodrine must stop taking these drugs at least 2 days 
or five half-lives (whichever is longer) prior to dosing on Day 1 of Part A and C, and 
throughout the duration of Part C. Subjects previously enrolled in Part A under previous 
versions of the protocol will continue taking fludrocortisone during the washout period 
and in Part C at the dose and regimen used in Part A.  For new subjects enrolling in Part 
A under Amendment 3, fludrocortisone use in both Parts of the study and during the 
washout period will be limited to 0.1 mg QD. 
5. Concomitant use of anti-hypertensive medication for the treatment of essential 
hypertension unrelated to autonomic dysfunction. 
6. Have changed dose, frequency or type of prescribed medication, within two weeks of 
dosing on Day 1 with the following exceptions: 


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• 
Vasoconstricting agents such as ephedrine, dihydroergotamine, midodrine, or 
fludrocortisone  
• 
Short courses (less than 2 weeks) of medications or treatments that do not interfere 
with, or exacerbate the subject’s condition under study (eg, antibiotics) 
7. Known or suspected alcohol or substance abuse within the past 12 months 
(DSM-IV definition of alcohol or substance abuse). 
8. Clinically unstable coronary artery disease, or major cardiovascular or neurological event 
in the past 6 months. 
9. Use of any monoamine oxidase inhibitor (MAO-I) within 14 days of dosing on Day 1. 
10. History of untreated closed angle glaucoma, or treated closed angle glaucoma that, in 
the opinion of an ophthalmologist, might result in an increased risk to the subject. 
11. Any significant uncontrolled cardiac arrhythmia. 
12. Myocardial infarction in the past 6 months, or current unstable angina. 
13. Congestive heart failure (NYHA Class 3 or 4). 
14. Diabetes insipidus, insulin-dependent diabetes mellitus, or diabetic neuropathy. 
15. History of cancer within the past 2 years other than a successfully treated, 
non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in 
situ. 
16. Gastrointestinal condition, which in the Investigator’s judgment may affect the absorption 
of study drug (eg, ulcerative colitis, gastric bypass). 
17. Any major surgical procedure within 30 days of dosing on Day 1. 
18. Any other significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurologic, 
psychiatric, immunologic, hematologic, gastrointestinal, or metabolic disease not 
currently controlled with medical treatment (eg, a stable medication dosing regimen). 
19. Currently receiving any investigational drug or have received an investigational drug 
within 30 days of dosing on Day 1.  An investigational drug is defined as a non-FDA 
approved drug. 
20. Allergic to or unable to drink apple juice (Part A only). 


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21. Any condition or laboratory test result which, in the Investigator's judgment, might result 
in an increased risk to the subject, or would affect their participation in the study. 
22. Additionally, the Investigator has the ability to exclude a subject if for any reason they 
feel the subject is not a good candidate for the study or will not be able to follow study 
procedures. 
5 
STUDY DRUGS 
All study drug supplied by the Sponsor must be stored in a secure location accessible only 
to designated study personnel. 
5.1 
Description of Study Drugs 
In Part A (and previously in Part B of the study which was discontinued), TD-9855 will be 
provided by the Sponsor as a bulk active pharmaceutical ingredient (API), appearing as a 
white powder. Doses for individual subject administration will be prepared as a solution in 
filtered apple juice by the designated unblinded pharmacist at the CRC. In Part C, TD-9855 
will be provided as a 
packaged in open-labeled 40-count high density 
polyethylene bottles. Detailed storage and preparation instructions will be provided in a 
separate pharmacy manual. 
5.2 
Dosage and Administration 
Part A Dose Escalation 
On Day -2 of Part A, eligible subjects will be admitted to the CRC, where they will remain 
during the entire dose escalation period.  On Day 1, subjects will receive a single dose of 
placebo in a single-blind manner (ie, subject remains blinded).  This will be followed by daily 
dose escalations, beginning with 
 TD-9855 on Day 2.  On each subsequent day, 
subjects will receive a single escalating dose of TD-9855 
 [Day 3], 
[Day 4], and 
[Day 5]) until Day 5 or until reaching the preset stopping criteria described below, 
whichever occurs first.   
The stopping criteria are: 
• 
A determination from the Investigator (in collaboration with the Sponsor) that 
administration of the subsequent dose may pose a safety concern 
• 
SBP ≥ 180 mm or DBP ≥ 110 mm in the sitting position replicated 2 more times 
over an hour 
• 
Intolerable side effects as determined by the Investigator 


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• 
Received maximum dose of study medication specified by the protocol 
Once the subject meets any of the above criteria, no further dose escalation will be 
performed. However, based on the daily evaluation of tolerability, the Investigator 
(in collaboration with the Sponsor), may decide to not escalate the dose, but rather 
re-administer the previous dose from the prior day.  Once the decision has been made to 
not escalate the dose, the subject should remain at the current dose through Day 5 of 
dosing. Following a post dosing observation day in the clinic, the subject will have discharge 
procedures completed and will be released from the CRC.  
Subjects who do not demonstrate a clinically meaningful pressor effect based on 
Investigator determination (in collaboration with the Sponsor), or who discontinue study drug 
prior to reaching the stopping criteria, should have discharge procedures completed, but will 
not continue to Part C of the study. 
Washout Period 
Following the completion of Part A, subjects will be discharged from the CRC and undergo a 
washout period (minimum 8 days).  On a daily basis following the first 72 hours from 
discharge, and then at least weekly during the first 4 weeks after discharge, the Investigator 
or designee will contact the subject by telephone to review the subject’s health status.  Any 
adverse events reported by phone will be recorded and followed as medically appropriate 
determined by the Investigator. Under the direction of the Investigator, subjects will manage 
their nOH symptoms using fludrocortisone as prescribed.  
Part B – Randomized Parallel Design 
In Part B, refer to prior versions of this Protocol for specific information related to Part B 
which was discontinued in Amendment 2. 
Part C – Outpatient Extension 
The dose level administered on Day 1 in Part C will be equal to 50% of the highest tolerated 
dose level (rounded-up to the nearest 1 mg) administered during Part A for that subject (or a 
lower dose at the discretion of the principal investigator to manage individual subject safety). 
Subjects will be discharged from the research clinic on Day 2, and continue at the same 
dose level as Day 1 of Part-C.  At the subsequent scheduled visits until Day 29, the 
Investigator has the option to double the subject’s dose level at their discretion, if in their 
opinion the subject will benefit from, and can tolerate, a higher dose level.  After Day 29, 


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dose increases will need to be discussed with the Sponsor.  It is recommended that the 
subject receives at least 7 daily doses of TD-9855 at any single dose level before escalation 
to a higher dose to allow TD-9855 exposure to reach steady state at the lower dose. 
 
 
  The maximum dose 
administered to any subject is 
  The schedule for potential dose increases is 
shown below in Table 3. 
Table 3: 
Weekly Dose Escalation Plan for Subject in Part C 
Part A 
Maximum 
Dose 
Part C Day 1 
dose 
Part C Day 8 
dose 
Part C Day 
15 dose 
Part C Day 
22 dose 
Part C Day 
29 dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the case where a subject develops the presence or worsening of supine hypertension 
(as determined by the Investigator with agreement from the Sponsor) or other adverse 
events suggesting intolerability, the dose can be withheld for 3 days and resumed at a dose 
level 50% (rounded up to the nearest 1 mg) of the prior dose level.  If supine hypertension or 
other adverse events persist after the dose has been reduced, dosing in that subject should 
be discontinued and appropriate alternative therapy and care provided to the subject as 
determined by the principal investigator. 
In Part A, subjects will be administered study drug by qualified study personnel under the 
supervision of the Investigator. Study personnel will observe and record date and time of 
dosing and in the event any deviations or incomplete administrations will be noted in the 
source records. 
In Part C, subjects will be administered study drug by qualified study personnel under the 
supervision of the Investigator on Day 1 and Day 2.  On all other dosing days, subjects will 
record the date and time of their daily dose in a dosing diary. Any dose increases, missed 
doses, or issues with dosing should be noted in the dosing diary. Site staff will also record 
any dose increase in the subject’s source documents.  Subjects are expected to bring the 


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dosing diary and any empty and/or partially used bottles of study drug to the clinic on their 
return visits. 
5.3 
Drug Accountability and Reconciliation 
The unblinded pharmacist 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 records for study medication 
(TD-9855) will be maintained in a secure location, accessible only to authorized staff 
members. The accountability record will include entries for receipt, distribution or dispensing, 
and destruction of the material(s). 
The pharmacist must retain all unused, and expired product until the site monitor has 
confirmed accountability data. No study drug (used, partially used, and unused bottles) may 
be destroyed without prior approval from the Sponsor. Compliance with the dosing regimen 
will also be assessed by reconciliation of used and unused study drug. 
Unused and expired study drugs will be disposed of in accordance with written instructions 
from the Sponsor. Copies of the study medication accountability records will be provided to 
the Sponsor at completion of the study and will be made available for review by the site 
monitor during the course of the study. 


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6 
STUDY PROCEDURES 
6.1 
Schedule of Study Procedures 
The schedule of study procedures/assessments are summarized in Table 1 for Part A and 
Table 2 for Part C of the study.  Study procedures listed in each row of the table should be 
performed at the visits designated in each column where an “X” is marked, and as indicted 
in the footnote, where applicable.  Further information related to each study procedure type 
are described in Section 6.3.3.  
The calendar day of the first study drug administration is designated as Day 1; subsequent 
calendar days are Days 2, 3, etc.  Note that each parts of the study (Parts A and C) has 
their own unique numbering of calendar days. 
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. 
Part C, which is an optional long-term extension study will require subjects to sign a 
separate informed consent form from that in Part A.  
The site should make every effort to perform procedures at the scheduled times, and the 
actual time should be recorded in the source documents and on the case report forms.  
Acceptable deviations from the timing of assessments are as follows: 
• 
Day 8 through Day 29: ± 3 days 
• 
Day 57 through Day 169: ± 7 days 
Additional safety tests, such as vital signs (BP, heart rate, respiratory rate, and body 
temperature), physical exams, ECGs, and laboratory safety tests, may be obtained during 
the course of the study on the basis of newly available data to ensure appropriate safety 
monitoring.  
In Part C, in cases where the subject is unable to return to the clinic for a clinic visit for 
reasons due to significant physical or geographic limitations, or at the Investigator’s 
discretion, a protocol-trained nurse may be sent to the subject’s home and the study visit 
procedures performed in the subject’s home.  The only exception to this is for the day 29 
visit of Part C which must be done at the research center. 


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6.2 
Total Blood Volume 
The total volume of blood to be drawn from each subject for safety, PK, and PD laboratory 
assessments is approximately 
  
Additional safety laboratory tests may be drawn as needed to manage any emergent health 
needs as directed by the Investigator.  
6.3 
Description of Study Procedures / Assessments 
6.3.1 Informed consent 
Written informed consent using an IRB-approved informed consent form must be obtained 
prior to performing any protocol specific procedures. Within 30 days 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. Part C, which is an optional 
long-term extension study will require subjects to sign a separate informed consent form 
from that in Part A. 
6.3.2 Overnight Residency, Standardized Meals, and Restrictions 
Subjects will be admitted and remain resident in the clinical research center (CRC) 
beginning Day -2 through the morning of Day 6 in Part A, and Day -2 through the morning of 
Day 2 for Part C. 
 
 
   
 
 
Should there be a clinically significant change between Screening and Day 1 of either Part A 
or Part C such that subjects no longer meet the eligibility criteria, they will no longer be 
eligible for the study and should be listed as a screen failure.  
6.3.3 Inclusion and Exclusion Criteria 
Section 4 provides a listing of inclusion criteria which subjects must meet to be eligible.  Any 
subjects meeting exclusion criteria should not be enrolled in the study.  


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6.3.4 Medication and Medical History 
Complete medication record and medical history at the pretreatment screening evaluation 
will include evaluation and therapies for past and present cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, hematologic, 
immunologic, dermatologic, psychiatric, genitourinary, substance abuse, surgical history, or 
any other diseases or disorders. If any worsening in severity or frequency occurs for an 
existing condition or a new event occurs after signing of the informed consent, this must be 
recorded as an AE. Prior to initiating Part C, the medication and medical history should be 
reevaluated and updated accordingly.  Any events occurring < 30 days since the last dose of 
study drug in part A (or Part B) should be recorded as an AE.  Any event that occurs 
≥ 30 days since the last dose of study drug in Part A (or Part B) but prior to Part C should be 
recorded as medical history (unless the Investigator deems the event related to prior study 
drug use). 
6.3.5 Body Height, Weight and BMI 
Body height and weight will be measured at the time points described in Table 1 for Part A 
and Table 2 for Part C. Care will be taken to ensure the measurements for weight occur at 
approximately the same time each day (± 15 minutes) using the same scale and without 
clothing (or where necessary with the same light clothing).  BMI will be automatically 
calculated in the EDC system once weight and height are entered. 
6.3.6 Temperature and Respiratory Rate 
Temperature and respiratory rate are to be measured at the time points described in Table 1 
for Part A. 
Temperature is to be measured at time points described in Table 2 for Part C. 
6.3.7 Orthostatic Standing Test   
The orthostatic standing test (including supine blood pressures) will be performed at the 
time points listed in Table 1 for Part A and Table 2 for Part C and according to the details 
provided in the footnotes of each table. 
At each time point, BP and HR measurements will be recorded with automated (or manual) 
sphygmomanometer while supine at 5 and 10 min (with the torso and head elevated 
30 degrees from horizontal), after seated at 5 and 10 min and after 1, 3, 5, and 10 min while 


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standing. The standing time will be measured with a chronometer and the duration of 
standing will be recorded.  The total duration of standing may occur in between the 
timepoints (ie, 1, 3, 5, and 10 minutes) for the standing test, or the subject may be able to 
stand for longer than the 10-minute standing test.  In either case, the total duration should 
be recorded.  More details related to the sequence of dosing and orthostatic assessments 
are described in Table 1 for Part A and Table 2 for Part C.  
Blood pressure and HR collected after 10 minutes supine and seated from the orthostatic 
standing test will be used for safety vital sign assessment. 
6.3.8 Supine Blood Pressure 
Supine blood pressure will be measured at specified time points in the Schedule of 
Procedures / Assessments Table 1 for Part A and Table 2 for Part C. 
In Part C, on Days 8, 22, 57 and 113, supine blood pressures will be collected twice in the 
morning before eating (after 5 and 10 minutes resting at 30° elevation), and twice again at 
least 4 hours after dosing (but no more than 7 hours and before lunch) after 5 and 
10 minutes resting at 30° head and torso elevation (Table 2). On Day -2, supine blood 
pressures should be measured after 5 and 10 minutes resting at 30° head and torso 
elevation. 
6.3.9 Autonomic Function Testing 
Where appropriate, autonomic function testing will be conducted to confirm the diagnosis of 
autonomic dysfunction and will include the following assessments. Note that the results of 
this testing will be recorded in the subject source notes but will not be collected in the case 
report form.   
• 
HR will be monitored by ECG and BP continuously with tonometry or finger 
plethysmography and intermittently with an oscillometric device. These tests include 
sinus arrhythmia and Valsalva maneuver.  
• 
Deep breathing-vagally-mediated sinus arrhythmia (SA) is assessed during controlled 
breathing (pattern of 5 seconds inhalation and 5 seconds exhalation repeated over 
90 seconds).  


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• 
Valsalva maneuver. The subject will exhale against a 40 mm Hg pressure. Changes in 
intrathoracic pressure produce autonomically modulated transient changes in HR and 
BP. 
6.3.10 24-Hour Blood Pressure Monitoring 
In Part C, at sites where ambulatory blood pressure monitoring equipment is available, on 
Day -1, beginning approximately 24 hours before dosing on Day 1, ambulatory blood 
pressure monitoring equipment will be attached to the subject and blood pressure monitored 
during the 24 hour period before dosing.  In addition, approximately 72 to 48 hours before 
the subject returns to the clinic for the Day 15, Day 29, Day 85 and Day 169 visits, subjects 
will put on the 24 hour blood pressure monitoring equipment and initiate the recording.  
Once the 24 hour session is complete subjects will remove and return the equipment to the 
research center during the next visit.  During each 24 hour session, the blood pressure 
monitoring device will be programmed to automatically measure blood pressure every 
2 hours beginning after the monitoring device is powered on.  In addition, subjects should be 
instructed to manually initiate 2 recordings to occur approximately 30 and 20 minutes before 
eating each morning after sitting supine (30 degree elevation) for at least 10 minutes.  
During each 24-hour session subjects should also maintain a log of their posture at the time 
of each blood pressure measurement.  For sites where ambulatory equipment are not 
available, desk top blood pressure devices may be used and provided to the subject for 
home use.  Subjects will be instructed to measure and record blood pressure on the days 
and time points described above and in Table 2.  More details regarding the ambulatory 
monitoring will be provided in a separate manual. 
6.3.11 Electrocardiogram 
At time points specified in the Schedule of Study Procedures / Assessments (Table 1 for 
Part A and Table 2 for Part C) subject will have a 12-lead ECG following a 10 minute rest 
period. QTc corrections will be made using the Fredericia correction formula. 
6.3.12 Physical Examination 
The physical examinations at the pretreatment screening visit for Part A and the Day -1 visit 
for Part C will be performed by an appropriately qualified individual (eg, physician, nurse 
practitioner, physician’s assistant or equivalent under the supervision of a physician), and 
will include examination of the following:  general appearance; head, ears, eyes, nose, and 


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throat; neck, skin; cardiovascular system; respiratory system; abdominal system; lymphatic 
system, dermatologic system, musculoskeletal system, and nervous system. Subsequent 
physical examinations after the screening visit for Part A and the Day -1 visit for Part C can 
be abbreviated and symptomatic, largely focused on evaluation of AEs, if any, and any 
abnormalities identified on the screening (Part A)/Day -1 (Part C) examination. 
6.3.13 Pregnancy Test 
For female subjects of child bearing potential, serum beta–human chorionic gonadotropin 
pregnancy tests will be conducted at the screening visit in Part A. 
For Part C, a urine pregnancy test will be conducted at the Day -2 visit.  If the urine 
pregnancy test is positive, a serum pregnancy test will be done to confirm the result.   
Pregnancy tests must be negative for a subject to participate in the study. 
6.3.14 Laboratory Tests 
Blood (for hematology and serum chemistry) and urine (for urinalysis) should be sent to the 
local or central laboratory according to the schedule of procedures/assessments in Table 1 
for Part A and Table 2 for Part C. 
6.3.14.1 Hematology 
Hematology analytes to be tested include the following:  hematocrit; hemoglobin; white 
blood cell count (WBC), including differential count by microscopy with percentage of 
immature neutrophils (bands), mature neutrophils, and eosinophils; and platelet count. 
6.3.14.2 Serum Chemistry 
Serum chemistry analytes to be tested include the following:  potassium, magnesium, blood 
urea nitrogen (BUN), creatinine, C-reactive protein, creatine kinase, albumin, total bilirubin, 
alkaline phosphatase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and 
aspartate aminotransferase (AST). 
6.3.14.3 Urinalysis 
Urinalysis analytes to be tested include the following: presence of blood, bilirubin, 
urobilinogen, nitrite, leukocytes, and (if dipstick positive) microscopic examination of 
sediment (sediment results will not be collected in the case report form). 


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6.3.14.4 Urine Drug Screen 
At screening a urine drug screen for drugs of abuse will be performed. 
6.3.15 Urine Collection and Volume Measurement 
In Part A, at clinical sites where feasible, beginning with the morning void on Day -1 through 
discharge, all urine will be collected and the volume measured and recorded at each void or 
as a total volume for each day (eg, 7 am to 7 am).  Urine will not be measured in Part C. 
6.3.16 Pharmacokinetic Assessments 
At the time points described in Table 1 for Part A and Table 2 for Part C blood samples for 
PK assay of TD-9855 will be collected, centrifuged, and split into aliquots.  Collection and 
handling instruction will be provided in a separate manual. 
6.3.17 Norepinephrine and Dihydroxyphenylglycol Assessments 
At the time points described in Table 1 for Part A and Table 2 for Part C, blood samples for 
NE and the metabolite DHPG may be measured using high-performance liquid 
chromatography with electrochemical detection.  Collection and handling instructions will be 
provided in a separate manual. 
6.3.18 Orthostatic Hypotension Questionnaire 
The Orthostatic Hypotension Questionnaire (OHQ) is a 2 components scale made up of a 
6-item symptoms assessment scale referred to as Orthostatic Hypotension Symptom 
Assessment Questionnaire (OHSA) and a 4-item daily activity scale referred to as the 
Orthostatic Hypotension Daily Activity Scale (OHDAS) {6}.  The items are scored on an 
11-point scale from 0 to 10, with 0 indicating no symptoms/no interference and 10 indicating 
the worst possible symptoms/complete interference, and the option of selecting “cannot be 
done for other reasons.”  Activities that are marked as zero or ‘cannot be done for other 
reasons’ at baseline are not included in the scoring.  Samples of the questionnaire for Part A 
are provided in Appendix 1 and for Part C in Appendix 2. 
In Part A, only the OHSA will be used and will be assessed at the time points described in 
Table 1.  In Part C both the OHSA and OHDAS will be used and will be assessed at the time 
points listed in Table 2 and as described in the table footnotes. 


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6.3.19 Clinician’s / Subject’s Global Impression 
A Clinician’s / Subject’s Global Impression assessment (Appendix 3) for Part A and 
Appendix 4 for Part C will be completed at the time points described in the Schedule of 
Assessments / Procedures (Table 1 for Part A and Table 2 for Part C). 
6.3.20 Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.21 Adverse Events 
Adverse events will be reviewed and recorded from signing of the informed consent through 
the end of follow up or after 30 days following the final dose of TD-9855, whichever is 


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longer, in each part of the study.  Adverse events may be observed by the site study 
personnel or spontaneously reported by the subject. 
All adverse events must be recorded in the subject’s case report form and, if applicable, 
reported as described in Section 7. 
The Investigator must take all therapeutic measures necessary for resolution of adverse 
events.  Any medications necessary for the treatment of an adverse event must be recorded 
in the subjects CRF.  Refer to Section 7. 
Except where described above, the Investigator may prescribe medications to provide 
adequate supportive care. However, the Investigator should use judgment to avoid 
medications that may confound the interpretation of this study.  
6.3.22 Subject Satisfaction Survey 
Subjects will complete the Subject Satisfaction Survey (Appendix 5) on Day -1, Day 15, 
Day 29 and at the time of end of study therapy (either Day 140 or at the time of early 
discontinue, as appropriate).   
6.3.23 Telephone Assessments 
On a daily basis during the first 72 hours from discharge in Part A, and then weekly for the 
first 4 weeks after discharge from Part A during the washout period, the Investigator or 
designee will contact the subject by telephone to review the subject’s health status.  Any 
adverse events reported by phone will be recorded and followed as medically appropriate 
determined by the Investigator. 
Additionally, in Part C, telephone visit assessments will occur at the designated visits and 
will include the procedures listed in Table 2.   
6.4 
Discontinuation 
6.4.1 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 


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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: 
• 
Adverse event 
• 
Subject choice 
• 
Major violation of the protocol 
• 
Termination of the study by the Sponsor 
• 
Other 
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. 
6.4.2 Subject Replacement 
 
6.4.3 Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 


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6.5 
Pregnancy 
If a female subject becomes pregnant during the study, the Sponsor clinical study director 
(or designee) must be notified immediately. Follow-up information regarding the outcome of 
the pregnancy and any postnatal sequelae in the infant will be required. 
7 
ADVERSE EVENTS 
7.1 
Regulatory Definition of an Adverse Event 
In the International Council for Harmonization (ICH) E6 Guideline for Good Clinical Practice, 
Section 7.2 defines an AE as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
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 (investigational) product, whether or not considered 
related to the medicinal (investigational) product. 
7.2 
Adverse Event Definition for the Purposes of This Study 
For the purposes of this clinical study, AEs will be defined as follows:  
An AE is any untoward medical occurrence in a subject who has signed an informed 
consent form and is participating in a clinical investigation. An AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease, 
whether or not considered related to the study drug (investigational product). 
Pre-existing events that increase in frequency or severity or change in nature during or as a 
consequence of participation in clinical studies will also be considered as adverse events. 
An AE may also include pre- or post-treatment complications that occur as a result of a 
protocol-mandated procedure (such as a biopsy). 
Any medical condition or clinically significant laboratory abnormality with an onset date prior 
to the time the subject signed the informed consent form is considered to be preexisting and 
should be documented in the medical history CRF, if applicable for the study. 
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) 
should be recorded as the AE term. 


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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 
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 medication. 
Clinical severity should be recorded and graded using mild, moderate or severe as 
described below. 
Mild 
= Awareness of signs or symptoms, but easily tolerated 
Moderate 
= Discomfort sufficient to cause interference with usual activities 
Severe 
= Incapacitation with inability to work or perform usual activities 
The relationship to study drug therapy should be assessed using the following definitions: 
• 
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). 
• 
Possibly/Probably 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 
rechallenge. It should be emphasized that ineffective treatment should not be considered 
as causally related in the context of adverse event reporting. 
These criteria in addition to good clinical judgment should be used as a guide for 
determining the causal assessment. If it is felt that the event is not related to study drug 
therapy, then an alternative explanation should be provided. 


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7.4 
Serious Adverse Events 
A SAE is defined as any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
• 
Death 
• 
Life-threatening situation (subject is at immediate risk of death) 
• 
Inpatient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other 
serious events) 
• 
Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• 
Other: 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 
Additional Considerations for Serious Adverse Events 
• 
Death is an outcome of an adverse event and not an adverse event in itself. In reports of 
death due to disease progression, where no other information is provided, the death will 
be assumed to have resulted from progression of the disease being treated with the 
study drug(s). 
• 
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. 
• 
“Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death, if it had 
occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is an SAE. 
• 
“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. 
• 
The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 


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7.5 
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 7.2 and 7.4, 
respectively. 
If there are any AE questions, the Investigator is encouraged to contact the Sponsor to 
discuss. 
7.6 
Serious Adverse Event Reporting 
Any SAE that occurs after a subject signs an informed consent form through the follow-up 
visit (or at the time a subject is determined to be ineligible for the study or who does not 
enroll in the study), regardless of causal relationship, must be reported to the Sponsor within 
24 hours of the Investigator’s knowledge of the event. To report an SAE, complete and fax 
the Serious Adverse Event Report Form to the following: 
Theravance Biopharma Clinical Drug Safety 
Fax: 
(
 
For medical questions regarding an SAE, contact the Sponsor medical monitor by telephone 
as follows: 
Sponsor Medical Monitor Contact Information: 
 
Telephone: (
 
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 Investigator’s Brochure. 
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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7.7 
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. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size and Power 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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8.2 
Analysis Populations 
 
 
 
 
 
 
 
  
 
 
 
 
  
8.3 
Analyses 
 
 
 
 
 
 
 
 


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8.3.1 Demographics and Other Baseline Characteristics 
 
 
 
 
 
 
  
8.3.2 Analysis of Efficacy 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 


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8.3.7 Adverse Event Data 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will be presented by system organ class (SOC), preferred 
term (PT) and severity, and the frequency and percentage of subjects reporting each 
observed event. 
A 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 washout or follow-up 
period.  AEs observed during the period from obtaining informed consent to the start of 
administration of study drug will be regarded separately from TEAEs. 
 
 
 
 
Data listings will be provided for all subjects who experience an SAE.  Data listings will also 
be provided for subjects who discontinued the study due to any AE or SAE.  
8.3.8 Concomitant Medications 
Medications will be summarized both prior and during the treatment period.  
8.3.9 Laboratory Data 
Laboratory data will be summarized in terms of observed values, changes from baseline, 
values relative to normal ranges, and changes from baseline relative to normal ranges. 
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.   
Cumulative urine volume over the 24-hour period for each dosing day will be summarized by 
Study Day and dose. 


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8.3.10 Vital Signs Data 
Vital signs data, including body weight, will be summarized in terms of observed values 
(by time point), changes from baseline (by time point).  
When multiple values exist for the same nominal time point (eg, duplicate reading), the 
average of the readings taken for vital signs will be used in the data analysis. All recorded 
values for vital signs data will be presented in a by-subject listing. 
8.3.11 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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When multiple values exist for the same nominal time point (eg, triplicate reading), the 
average of the readings taken for ECG parameters will be used in the data analysis, 
including the outlier analysis stated below. 
All recorded values for the ECG parameters will be presented in a by-subject listing.  
A listing of subjects with outliers will also be provided. 
8.3.12 Other Analyses 
 
 
   
8.4 
Handling of Missing Data 
 
 
 
 
 
8.5 
Data Monitoring Committees 
There will be no data monitoring committee. 
9 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1 
Principal Investigator Responsibilities 
Before beginning the study, the Principal Investigator (PI) at each site must provide to the 
Sponsor or its designee a fully executed and signed Form FDA 1572 and, if applicable, a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all subinvestigators who will be directly involved in the treatment or evaluation 
of research subjects in this study. (A subinvestigator 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 [eg, associates, residents, research fellows].) 


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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. 
• 
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 
requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional 
review board (IRB) review and approval in 21 CFR Part 56 are met.  
• 
He or she will report to the Sponsor adverse experiences that occur in the course of the 
investigation in accordance with 21 CFR 312.64. 
• 
He or she has read and understands the information in the TD-9855 Investigator’s 
Brochure, 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 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• 
He or she will ensure that the IRB, Independent Ethics Committee (IEC), or Research 
Ethics Board (REB) complies with the requirements of 21 CFR Part 56, and other 
applicable regulations, and conducts initial and ongoing reviews and approvals of the 
study. He or she will also ensure that any change in research activity and all problems 
involving risks to human subjects or others are reported to the IRB/IEC. Additionally, he 
or she will not make any changes in the research without IRB/IEC approval, except 
where necessary to eliminate apparent immediate hazards to human subjects. 
• 
He or she agrees to comply with all other requirements regarding the obligations of 
clinical Investigators and all other pertinent requirements in 21 CFR Part 312. 
9.2 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the Investigator will obtain written confirmation 
that the IRB, IEC, or 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 


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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 case report form (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. 
Electronic data capture (EDC) technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the electronic case report forms approved by 
the Sponsor, or via other data collection methods, eg, electronic laboratory data transfer. 
Study site personnel will enter (in English) study data into the CRFs for each randomized 
subject. Training on the EDC application will be completed and documented before access 
to the EDC system is given. 


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In the event of a CRF data change (eg, 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 will be sent to the site for retention with other 
study documents after full completion of the study, ie, after database lock. 
The Investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The Investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, 
computer discs, tapes, and worksheets). In most cases the source is the subject’s medical 
record. Data collected on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a 
document should be available at the Investigator’s site and clearly identify those data that 
will be recorded in the CRF and for which the CRF will stand as the source document. 
9.5 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled 
manner all study documents required by the Sponsor and by the applicable regulations. The 
investigative site must take measures to prevent accidental or premature destruction of 
essential documents, that is, documents that individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, including paper copies of 
study records (eg, subject charts) and any original source documents that are electronic, as 
required by applicable regulations. 
The Investigator must consult the Sponsor representative before disposal of any study 
records and must notify the Sponsor of any change in the location or disposition of the study 
files. If an Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study documents, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian and must approve this transfer of responsibility. 


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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, 
ie, 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 
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regulatory authorities, and they may be used for submission to regulatory authorities. In 
addition, all source data should be attributable (signed and dated), consistent with local 
medical practice. The Investigator must therefore agree to allow direct access to all source 
data. Subjects (or their legally authorized representatives) must also allow access to their 
medical records, and subjects will be informed of this and will confirm their agreement when 
giving informed consent. 
9.8 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the study 
according to GCP and 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. 


Protocol 0145, 
 
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TD-9855 
Page 65 
 
Confidential – Property of Theravance Biopharma, Inc. 
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. 


Protocol 0145, 
 
Version 1.0, 08NOV2017 
TD-9855 
Page 66 
 
Confidential – Property of Theravance Biopharma, Inc. 
10 
REFERENCES 
1. Consensus statement on the definition of orthostatic hypotension, pure autonomic 
failure, and multiple system atrophy. The Consensus Committee of the American 
Autonomic Society and the American Academy of Neurology. Neurology. 1996 
May;46(5):1470.  
2. Goldstein DS, Polinsky RJ, Garty M, Robertson D, Brown RT, Biaggioni I, et al. Patterns 
of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol. 1989 
Oct;26(4):558–63.  
3. Goldstein DS, Holmes C, Cannon RO, Eisenhofer G, Kopin IJ. Sympathetic 
cardioneuropathy in dysautonomias. N Engl J Med. 1997 Mar 6;336(10):696–702.  
4. Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, et al. Norepinephrine 
transporter blockade with atomoxetine induces hypertension in patients with impaired 
autonomic function. Hypertension. 2007;50(1):47–53.  
5. Ramirez CE, Okamoto LE, Arnold AC, Gamboa A, Diedrich A, Choi L, et al. Efficacy of 
atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic 
failure. Hypertension. 2014;64(6):1235–40.  
6. Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic 
Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale. 
Clin Auton Res. 2012 Apr;22(2):79–90.  
 


Protocol 0145, 
 
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TD-9855 
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11 
APPENDICES 
Appendix 1: 
Orthostatic Hypotension Questionnaire OHQ for Part A Only 
AUTONOMIC DYSFUNCTION SCORES 
ORTHOSTATIC HYPOTENSION QUESTIONNAIRE (OHQ) 
Patient Instructions: 
 
We are interested in measuring the symptoms that occur because of your problem with low blood 
pressure (orthostatic hypotension) and the degree that those symptoms may interfere with your daily 
activity.  It is important that we measure the symptoms that are due ONLY to your low blood pressure, 
and not something else (like diabetes or Parkinson’s disease). Many people know which of their 
symptoms are due to low blood pressure.  Some people who have recently developed problems with 
low blood pressure may not easily distinguish symptoms of low blood pressure from symptoms 
caused by other conditions.  In general, symptoms of your low blood pressure problem will appear 
either upon standing or after you have been standing for some time, and will usually improve if you sit 
down or lie down.  Some patients even have symptoms when they are sitting which might improve 
after laying down. Some people have symptoms that improve only after sitting or lying down for quite 
some time. 
 
Please answer the questions on the following pages keeping in mind that we want to know only about 
those symptoms that are from your problem with low blood pressure. 
 
OH SYMPTOM ASSESSMENT (OHSA) 
 
Please tick the number on the scale that best rates how severe your symptoms are from low blood 
pressure at this moment (right now).   
 
1. Dizziness, lightheadedness, feeling faint, or feeling like you might black out 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
2. Problems with vision (blurring, seeing spots, tunnel vision, etc.) 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
3. Weakness 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
4. Fatigue 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
5. Trouble concentrating 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
6. Head/neck discomfort 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
Date completed: ____________ time: __________  Initials: ____________ 


Protocol 0145, 
 
Version 1.0, 08NOV2017 
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Confidential – Property of Theravance Biopharma, Inc. 
Appendix 2: 
Orthostatic Hypotension Questionnaire (OHQ) for Part C Only 
AUTONOMIC DYSFUNCTION SCORES 
ORTHOSTATIC HYPOTENSION QUESTIONNAIRE (OHQ) 
Patient Instructions: 
 
We are interested in measuring the symptoms that occur because of your problem with low blood 
pressure (orthostatic hypotension) and the degree that those symptoms may interfere with your 
daily activity.  It is important that we measure the symptoms that are due ONLY to your low blood 
pressure, and not something else (like diabetes or Parkinson’s disease). Many people know which 
of their symptoms are due to low blood pressure.  Some people who have recently developed 
problems with low blood pressure may not easily distinguish symptoms of low blood pressure from 
symptoms caused by other conditions.  In general, symptoms of your low blood pressure problem 
will appear either upon standing or after you have been standing for some time, and will usually 
improve if you sit down or lie down.  Some patients even have symptoms when they are sitting 
which might improve after laying down. Some people have symptoms that improve only after sitting 
or lying down for quite some time. 
 
Please answer the questions on the following pages keeping in mind that we want to know only 
about those symptoms that are from your problem with low blood pressure. 
 
OH SYMPTOM ASSESSMENT (OHSA) 
 
Please tick the box on the scale that best rates how severe your symptoms from low blood 
pressure have been on the average over the past week.  Please respond to every symptom.  If you 
do not experience the symptom, tick zero (O).  PLEASE RATE THE SYMPTOMS THAT ARE DUE 
ONLY TO YOUR LOW BLOOD PRESSURE PROBLEM.  
 
1. Dizziness, lightheadedness, feeling faint, or feeling like you might black out 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
2. Problems with vision (blurring, seeing spots, tunnel vision, etc.) 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
3. Weakness 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
4. Fatigue 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
5. Trouble concentrating 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
 
6. Head/neck discomfort 
None   0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
   Worst possible 
Date completed: ____________ time: __________  Initials: ____________ 
 


Protocol 0145, 
 
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Confidential – Property of Theravance Biopharma, Inc. 
OH Daily Activity Scale  (OHDAS) 
We are interested in how the low blood pressure symptoms you experience affect your daily life.  
Please rate each item by ticking the number that best represents how much on the activity has been 
interfered with on the average over the past week by the low blood pressure symptoms you 
experienced. 
If you cannot do the activity for reasons other than low blood pressure, please tick the box at the right. 
1. Activities that require standing for a short time 
Cannot 
do for 
other 
reasons 
No 
interference 
0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
 
Complete 
Interference 
 
2. Activities that require standing for a long time 
 
No 
interference 
0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
 
Complete 
Interference 
 
3. Activities that require walking for a short time 
 
No 
interference 
0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
 
Complete 
Interference 
 
4. Activities that require walking for a long time 
 
No 
interference 
0
   1
   2
   3
   4
   5
   6
   7
   8
   9
   10
 
Complete 
Interference 
 
Date completed: ____________ time: __________  Initials: ____________ 
 


Protocol 0145, 
 
Version 1.0, 08NOV2017 
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Confidential – Property of Theravance Biopharma, Inc. 
Appendix 3: 
Physician/Subject Global Impression for Part A Only 
CLINICAL GLOBAL IMPRESSIONS – CLINICIAN (Part A only) 
Clinical Global Impressions – Clinician 
Questions to be answered at Day -1 (Admission), each Day of Dosing (Days 1 to 5 predose 
and at 6 to 8 hours post dose), and Day of Discharge (Final Evaluations). 
1) Severity of Illness 
Considering your total clinical experience with the particular population, how severe is the 
patient’s orthostatic hypotension (OH) at this time? 
 
0 – Not assessed 
1 – Normal, no OH 
2 – Borderline OH 
3 – Mild OH 
4 – Moderate OH 
5 – Marked OH 
6 – Severe OH 
7 – Among those patients most extremely ill with OH 
2) Global Improvement – Rate total improvement regardless as to whether or not you 
believe it is due entirely to drug treatment. 
Compared to the patient’s condition at Day -1 (Admission), how much has his/her orthostatic 
hypotension changed? 
0 – Not assessed 
1 – Very much improved 
2 – Much improved 
3 – Slightly improved 
4 – No change 
5 – Slightly worse 
6 – Much worse 
7 – Very much worse 
 
 
Date completed: ____________ time: __________  Initials: ____________ 
 
 


Protocol 0145, 
 
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CLINICAL GLOBAL IMPRESSIONS – PATIENT (Part A only) 
Clinical Global Impressions – Patient 
Questions to be answered at Day -1 (Admission), each Day of Dosing (Days 1 to 5 predose 
and 6 to 8 hours post dose), and Day of Discharge (Final Evaluations). 
1) Severity of Illness 
How severe is your orthostatic hypotension (OH) at this time? 
0 – Not assessed 
1 – Normal, no OH 
2 – Borderline OH 
3 – Mild OH 
4 – Moderate OH 
5 – Marked OH 
6 – Severe OH 
7 – Most extremely ill with OH 
 
2) Global Improvement – Rate total improvement regardless as to whether or not you 
believe it is due entirely to drug treatment. 
Compared to your condition at your Day -1 (Admission) visit when you rated the severty of 
your orthostatic hypotension after being off medication, how much has your condition 
changed? 
0 – Not assessed 
1 – Very much improved 
2 – Much improved 
3 – Slightly improved 
4 – No change 
5 – Slightly worse 
6 – Much worse 
7 – Very much worse 
 
 
Date completed: ____________ time: __________  Initials: ____________ 
 


Protocol 0145, 
 
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Appendix 4: 
Physician/Subject Global Impression for Part C Only 
CLINICAL GLOBAL IMPRESSIONS – CLINICIAN (Part C only) 
Clinical Global Impressions – Clinician 
1) Severity of Illness 
Considering your total clinical experience with the particular population, how severe is the 
patient’s orthostatic hypotension (OH) at this time? 
 
0 – Not assessed 
1 – Normal, no OH 
2 – Borderline OH 
3 – Mild OH 
4 – Moderate OH 
5 – Marked OH 
6 – Severe OH 
7 – Among those patients most extremely ill with OH 
2) Global Improvement – Rate total improvement regardless as to whether or not you 
believe it is due entirely to drug treatment. 
Compared to the patient’s condition at Day -1 (Admission) for Part C, how much has his/her 
orthostatic hypotension changed? 
0 – Not assessed 
1 – Very much improved 
2 – Much improved 
3 – Slightly improved 
4 – No change 
5 – Slightly worse 
6 – Much worse 
7 – Very much worse 
 
 
 
Date completed: ____________ time: __________  Initials: ____________ 
 
 


Protocol 0145, 
 
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Confidential – Property of Theravance Biopharma, Inc. 
CLINICAL GLOBAL IMPRESSIONS – PATIENT (Part C only) 
Clinical Global Impressions – Patient 
1) Severity of Illness 
How severe is your orthostatic hypotension (OH) at this time? 
0 – Not assessed 
1 – Normal, no OH 
2 – Borderline OH 
3 – Mild OH 
4 – Moderate OH 
5 – Marked OH 
6 – Severe OH 
7 – Most extremely ill with OH 
 
2) Global Improvement – Rate total improvement regardless as to whether or not you 
believe it is due entirely to drug treatment. 
Compared to your condition at your Day -1 (Admission) visit when you rated the severty of 
your orthostatic hypotension after being off medication, how much has your condition 
changed? 
0 – Not assessed 
1 – Very much improved 
2 – Much improved 
3 – Slightly improved 
4 – No change 
5 – Slightly worse 
6 – Much worse 
7 – Very much worse 
 
 
 
Date completed: ____________ time: __________  Initials: ____________ 
 
 


Protocol 0145, 
 
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Appendix 5: 
Subject Satisfaction Survey 
Patient Satisfaction Questionnaire – Day -1 Questions 
To be completed by the subject on Study Day -1  
 
1.  Please circle the number below that represents how satisfied you are currently with your 
ability to manage your orthostatic hypotension (OH) symptoms.  Consider both how 
effectively you can manage your symptoms and any side effects resulting from the 
products you currently use. 
 
Very 
Very 
Dissatisfied w/ Current  
Satisfied w/ Current 
OH Symptoms Management 
OH Symptoms Management 
 
                                         1          2           3            4           5          6    
 
 
Subject initials: _______________ 
 
Date Completed: ______________ 
 
 
 
 


Protocol 0145, 
 
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Patient Satisfaction Questionnaire – Day 15 and Day 29 Questions 
 
To be completed by the subject on Study Day 15 and Study Day 29 
 
1.  Thinking over the past week, please circle the number below that best indicates how 
satisfied you have been with the ability of the medication you are taking in this clinical trial 
to manage your orthostatic hypotension (OH) symptoms:  
 
Very 
Very 
Dissatisfied with 
Satisfied with 
Trial Medication 
Trial Medication 
 
                                            1           2           3            4           5           6         
 
2.  Thinking over the past week, which statement best describes your impression of how well 
the study medication worked? (check one)  
 
The study medication didn’t seem to work for me at all. 
 
The study medication provided some relief of my orthostatic hypotension 
(OH), but not as much as I would like. 
 
The study medication worked very well. 
3.  Thinking over the past week, which statement best describes your impression of the side 
effects that you experienced from the study medication?  (check one)  
 
I experienced no/minimal side effects. 
 
I experienced some side effects, but they were acceptable given the efficacy 
of the study medication. 
 
I experienced significant side effects. 
 
4. Thinking about your responses to questions 2 and 3 above; please circle the number that 
represents how likely would you be to continue taking this medication if you were not 
currently enrolled in a clinical trial? 
 
Very 
Very 
Likely to Discontinue 
Likely to Continue  
 
                                         1         2           3            4           5          6         
 
Subject initials: _______________ 
Date Completed: ______________ 


Protocol 0145, 
 
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Patient Satisfaction Questionnaire – End of Therapy Visit Questions 
To be completed by the subject at the end of study therapy (Study Day 140 or at the time of 
early discontinue, as applicable)  
 
 
1. Based on your overall experience thus far in this clinical trial, how likely do you think you 
would be to use the medication if it were offered to you by a physician after it is approved 
by the FDA? (check one) 
 
 
Extremely likely  
 
Somewhat likely  
 
Somewhat unlikely (answer Question 2) 
 
Extremely unlikely (answer Question 2) 
2.  Answer only if you responded “Somewhat unlikely” or “Extremely unlikely” to Question 1, 
otherwise leave this question blank.  
 
We’d like to understand, based on your overall experience thus far in this clinical study, 
why you would be unlikely to use the medication.  Listed below are three reasons why 
you might choose not to use the medication.  For each reason, please circle the number 
below that reflects the importance of each reason in explaining why you are unlikely to 
use the medication. 
 
 
Not at all 
important 
in deciding 
not to use 
 
Very 
important 
in deciding 
not to use 
Not effective enough 
1 
2 
3 
4 
5 
6 
Side effects too 
bothersome 
1 
2 
3 
4 
5 
6 
Assume that it would 
be too expensive 
1 
2 
3 
4 
5 
6 
 
 
Subject initials: _______________ 
 
Date Completed: ______________ 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Study 0145 
Version 1.2, 22JUN2018 
TD-9855 
Page 1 
STATISTICAL ANALYSIS PLAN 
Compound: 
TD-9855 
Study Number: 
Study 0145 
Study Title: 
A Phase 2 Study to Assess the Effect and Safety of TD-9855 
in Subjects with Neurogenic Orthostatic Hypotension 
Protocol Version: 
 
 
 
 08 Nov 2017 
Sponsor: 
Theravance Biopharma, Inc. 
c/o Theravance Biopharma US, Inc. 
901 Gateway Boulevard 
South San Francisco, CA 94080 
Plan Version: 
Version 1.2, 22JUN 2018 
Plan History: 
No prior versions 
Plan Prepared by: 
 
Director, Biometrics 
 
 
 
 
 
 
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. 
2015 Theravance Biopharma US, Inc. 




 
 
 
 
 
Statistical Analysis Plan 
Study 0145 
 
Version 1.1, 22JUN2018 
TD-9855 
 
Page 3 of 42 
 
Confidential – Property of Theravance Biopharma, Inc. 
TABLE OF CONTENTS 
 
PAGE 
 
TABLE OF CONTENTS ........................................................................................................ 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................. 5 
1 
INTRODUCTION ....................................................................................................... 6 
2 
STUDY OBJECTIVES ............................................................................................... 6 
2.1 
Primary Objective ........................................................................................... 6 
2.2 
Secondary Objectives .................................................................................... 6 
3 
OVERVIEW OF STUDY DESIGN .............................................................................. 6 
4 
SAMPLE SIZE AND POWER .................................................................................... 9 
5 
STUDY ENDPOINTS ............................................................................................... 10 
5.1 
Efficacy Endpoints ........................................................................................ 10 
5.2 
Safety Endpoints .......................................................................................... 11 
6 
GENERAL ANALYSIS CONSIDERATIONS ............................................................ 11 
6.1 
Global Definitions and Conventions.............................................................. 11 
6.2 
Baseline Definition ....................................................................................... 11 
6.3 
Analysis Windows ........................................................................................ 11 
6.4 
Missing Data ................................................................................................ 12 
6.5 
AEs .............................................................................................................. 14 
6.6 
Medications .................................................................................................. 14 
6.7 
Medical History ............................................................................................ 14 
6.8 
General Considerations for Summaries ........................................................ 14 
7 
ANALYSIS SETS ..................................................................................................... 16 
7.1 
Intent-to-Treat .............................................................................................. 16 
7.2 
Safety ........................................................................................................... 16 
7.3 
Examination of Subgroups ........................................................................... 16 
7.4 
Inclusion and Exclusion Deviations .............................................................. 17 
7.5 
Major Analysis Protocol Deviations .............................................................. 17 
8 
DEFINITION OF ANALYSIS VARIABLES ............................................................... 17 
8.1 
Demographic and Baseline Characteristics .................................................. 17 
8.2 
Efficacy Variables ......................................................................................... 18 
8.3 
Safety Variables ........................................................................................... 19 
9 
ANALYSES.............................................................................................................. 19 
9.1 
General Analyses ......................................................................................... 19 
9.1.1 
Subject Disposition ........................................................................... 20 
9.1.2 
Demographics and Baseline Characteristics ..................................... 20 
9.2 
Efficacy Analyses ......................................................................................... 21 
9.2.1 
Primary Efficacy Evaluation .............................................................. 21 
9.2.2 
Secondary Efficacy Evaluation ......................................................... 22 


 
 
 
 
 
Statistical Analysis Plan 
Study 0145 
 
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TD-9855 
 
Page 4 of 42 
 
TABLE OF CONTENTS (CONTINUED) 
 
PAGE 
 
Confidential – Property of Theravance Biopharma, Inc. 
9.2.3 
Other Efficacy Evaluation ................................................................. 22 
9.2.4 
Multiplicity Adjustment ...................................................................... 23 
9.3 
Safety Analyses ........................................................................................... 24 
9.3.1 
Exposure .......................................................................................... 24 
9.3.2 
Adverse Events ................................................................................ 24 
9.3.3 
Prior and Concomitant Medications .................................................. 25 
9.3.4 
Vital Signs ........................................................................................ 25 
9.3.5 
ECG ................................................................................................. 27 
9.3.6 
Clinical Laboratory Results ............................................................... 28 
9.4 
Interim Analyses........................................................................................... 29 
 
 
LIST OF APPENDICES 
 
Appendix 1: 
Reporting Structures for Data Summary ........................................... 30 
Appendix 2: 
 
List of TFLs………………………………………………………………..33 
 
 


 
 
 
 
 
Statistical Analysis Plan 
Study 0145 
 
Version 1.2, 22JUN2018 
TD-9855 
 
Page 5 of 42 
 
Confidential – Property of Theravance Biopharma, Inc. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
ADAM 
Analysis data model 
AE 
adverse event 
BLQ 
Below level of quantification 
BMI 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
CFB 
Change from baseline 
CRO 
contract research organization 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
HR  
heart rate 
LOD 
Limit of detection 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
non-calculable 
NQ 
non-quantifiable 
PK 
pharmacokinetic 
PP 
Per-protocol 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WHODD 
World Health Organization Drug dictionary 
 
 
 
 
 


 
 
 
 
 
Statistical Analysis Plan 
Study 0145 
 
Version 1.2, 22JUN2018 
TD-9855 
 
Page 6 of 42 
 
Confidential – Property of Theravance Biopharma, Inc. 
1 
INTRODUCTION 
This document outlines the initial plan for the summarization and analysis of clinical data 
collected in STUDY 0145 for TD-9855, Part C only. 
This is the proof of concept study to determine if the norepinephrine reuptake inhibitor TD-
9855 produces an acute pressor effect in patients with primary forms of autonomic failure, 
and if this is associated with a reduction in symptoms of orthostatic intolerance. Results of 
this study will guide decisions about the further development. 
 
 
This document describes the a priori plan for analysis. Once the analysis is in progress, it 
may become apparent from the data that the planned analysis should be modified. Any 
substantive modification to the original analysis plan will be identified in the clinical study 
report (CSR). 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to determine if TD-9855 has sustained pressor 
response and improves symptoms of orthostatic intolerance in subjects with nOH due to 
MSA, PAF, or Parkinson’s disease. 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
 
to evaluate the safety and tolerability of TD-9855 in the control of nOH. and 
 
to evaluate the PK and PD (NE and DHPG) of TD-9855 after single and multiple 
doses in subjects with nOH.  
3 
OVERVIEW OF STUDY DESIGN 
This is a multicenter, randomized, 3 part, single-blind (Part A), double-blind (Part B), and 
open-label multiple dose extension (Part C) study of TD-9855 versus placebo in subjects 


 
 
 
 
 
Statistical Analysis Plan 
Study 0145 
 
Version 1.2, 22JUN2018 
TD-9855 
 
Page 7 of 42 
 
Confidential – Property of Theravance Biopharma, Inc. 
with nOH. However, beginning with Amendment 2 of this protocol, Part B of the study has 
been discontinued.  
This study consists of three Parts, A, B and C. Part A follows a daily, single, escalating dose 
design starting with placebo on Day 1, followed by a dose of 
 TD-9855 on Day 2, and 
proceeding to escalating higher doses of TD-9855 on a daily basis up to a max dose of 
 
 based on safety, tolerability, and determination of a pressor effect. Starting from protocol 
Amendment 2, TD-9855 escalation doses changed to
 from Day 2 to 
Day 5. 
 
 
 
Part B follows a randomized, placebo–controlled, parallel design evaluating a dose that was 
determined to be generally well tolerated and to have a pressor effect for a given subject 
from Part A.  
 


 
 
 
 
 
Statistical Analysis Plan 
Study 0145 
 
Version 1.2, 22JUN2018 
TD-9855 
 
Page 8 of 42 
 
Confidential – Property of Theravance Biopharma, Inc. 
In Part C, subjects who demonstrate a pressor effect in Part A, who complete Part A and 
remain otherwise eligible will have the option to participate in Part C and receive open-label 
TD-9855 by tablet once daily for up to
  
 
 
 
  
For subjects enrolled under Amendment 2, the dose administered on Day 2 of Part C will be 
reduced to a dose level equal to
 of the dose level administered on Day 1 of Part C 
(rounded up to the nearest 1 mg).  Subjects will continue receiving the dose level from Day 
2 of Part C for the remainder of the study.  However in the case where a subject develops 
the presence or worsening of previously described supine hypertension or other adverse 
events suggesting intolerability, 
 
l. 
Under Amendment 3, subjects will be discharged from the research clinic on Day 2, and 
continue at the same dose level as Day 1 of Part C. At the subsequent scheduled visits until 
Day 29, the Investigator has the option to double the subject’s dose level at their discretion, 
if in their opinion the subject will benefit from, and can tolerate, a higher dose level. After 
Day 29, dose increases will need to be discussed with the Sponsor. It is recommended that 
the subject receives at least 7 daily doses of TD-9855 at any single dose level before 
escalation to a higher dose to allow TD-9855 exposure to reach steady state at the lower 
dose. 
 
 
. The schedule for potential dose 
increases is shown in the table below. 
 
Part A 
Maximum 
Dose 
Part C Day 1 
dose 
Part C Day 8 
dose 
Part C Day 
15 dose 
Part C Day 
22 dose 
Part C Day 
29 dose 
 
 
 
 
 
 


 
 
 
 
 
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Part A 
Maximum 
Dose 
Part C Day 1 
dose 
Part C Day 8 
dose 
Part C Day 
15 dose 
Part C Day 
22 dose 
Part C Day 
29 dose 
 
 
 
 
 
 
 
 
 
 
 
 
In the case where a subject develops the presence or worsening of supine hypertension (as 
determined by the Investigator with agreement from the Sponsor) or other adverse events 
suggesting intolerability, 
 
  
Regardless of the protocol amendment, if supine hypertension or other adverse events 
persist after the dose has been reduced, dosing in that subject should be discontinued and 
appropriate alternative therapy and care provided to the subject as determined by the 
principal investigator. 
 
 
 
4 
SAMPLE SIZE AND POWER 
 
 


 
 
 
 
 
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Table 1. Sample size for Part C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
STUDY ENDPOINTS 
5.1 
Efficacy Endpoints 
For Part C, the primary endpoint is the improvement from baseline in the Likert scale 
“dizziness, lightheadedness, feeling faint, or feeling like you might black out” (OHSA, 
question 1) at week 4.  
The secondary endpoints for Part C include:  
 
Change from baseline in the composite OHSA, OHDAS, and OHQ score   
 
Change from baseline in standing SBP  
 
Change from baseline in seated SBP   
 
Duration of standing during the orthostatic standing test 
 
Change from Supine SBP to Seated SBP  


 
 
 
 
 
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5.2 
Safety Endpoints 
For all Parts of the study, safety and tolerability assessments will include adverse events, 
laboratory abnormalities, ECGs, and vital sign measurements including supine blood 
pressure. 
. 
6 
GENERAL ANALYSIS CONSIDERATIONS 
6.1 
Global Definitions and Conventions 
All data from scheduled and unscheduled visits will be presented in the subject listings; 
however, unless noted otherwise, only data from scheduled visits will be included in the 
summaries, statistical analysis, and calculation of derived parameters. 
6.2 
Baseline Definition 
 
For the OHQ (OHSA and OHDAS) scores and Clinician’s/Subject’s Global Impression, 
baseline is defined as the pre-lunch measurement on Day -1. For the blood pressure, heart 
rate, and duration of standing, baseline is defined as the pre-breakfast measurement on Day 
1.  For laboratory abnormalities and ECGs, baseline is defined as the measurement on Day 
-1. 
6.3 
Analysis Windows 
All assessments will be summarized using analysis windows. The terminology of 
unscheduled will be applied to assessments that are outside an analysis window regardless, 
of the nominal label associated with the assessments in the EDC system. 
All data (scheduled and unscheduled visits) will be presented in the subject listings; 
however, unless noted otherwise, only data from assessments within analysis windows will 
be included in the summaries, statistical analysis, and calculation of derived parameters. 
In part C, the analysis window will be +/-3 days for the scheduled visits from Day 8 through 
Day 29, ±7 days for scheduled visits between Day 57 through Day 169 as defined below. 
  
Nominal Day 
Start (days) 
Stop (days) 
8 
5 
11 
15 
12 
18 


 
 
 
 
 
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Nominal Day 
Start (days) 
Stop (days) 
22 
19 
25 
29 
26 
32 
57 
50 
64 
85 
78 
92 
113 
106 
120 
140 
133 
147 
155 
148 
162 
169 
163 
175 
 
If the scheduled visit is outside of the analysis window, data will not be counted in the 
summary tables. In each part, the summary tables by the scheduled visit will only use data 
recorded for the scheduled visit. Data collected at the unscheduled visit will not be counted 
in the summary table, however will be included in the subject listings. 
General Selection Process for Multiple Records in an Analysis Window 
In general, if multiple, valid, non-missing observations exist at a visit or collection time point 
then records will be chosen based on the following: 
 
The record closest to the nominal time point in question, or, 
 
The later record if the two visits are equidistant from the time point, or, 
 
The average (arithmetic mean) if there is more than one record at the time point 
(generally applies to assessments done in triplicate). 
6.4 
Missing Data 
In general, missing data will not be imputed. 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.  
 Missing data for the following specific endpoints will be handled as follows: 
Primary Efficacy Endpoint 
Missing data in the analysis of the primary endpoint is assumed as missing at random 
(MAR) and will not be imputed in the primary analysis. 


 
 
 
 
 
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Adverse Events (AE) 
For graded AE summaries, subjects with an AE and no grade on the CRF will be graded as 
severe.  AEs without assigned relationship to study drug will be counted as AEs related to 
study drug in the AE summaries. 
Missing dates/time for AEs and Concomitant Medications  
Missing dates will be handled as follows: 
 
Complete missing start date will be imputed as the same as first dose date;  
 
Partial missing start date imputation: 
o Missing start day with same month as first dose: maximum day (1, first dose day); 
o Missing start day with different month as first dose: 1 
o Missing start month with same year as first dose: maximum (January, first dose 
month); 
o  Missing start month with different year as first dose: January 
 
Complete missing stop date will be considered as ongoing and not imputed;  
 
Partial missing stop date imputation: 
o Missing stop day: last day of month; 
o Missing stop month with same year as last dose: minimum (December, last dose 
month); 
o Missing stop month with different year as last dose: December 
Missing times will be handled as follows: 
 
If a start or stop time is missing, the start time is imputed as 1 minute after a.m. 
midnight (12:01) and stop time is imputed to be 1 min before p.m. midnight (23:59).  
Laboratory Data 
For non-efficacy laboratory data, a missing baseline value will be replaced with the last 
available assessment before the first dose, generally the screening assessment. A retest 
value will be used if the first test is invalidated, e.g., specimen hemolyzed.  


 
 
 
 
 
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Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be, in general, 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 of “< x”; and x.e where e = d−1, will be used for analysis if the data are reported 
in the form of “< x.d”; 
 
The LOD will be used for calculation of descriptive statistics if the data is reported in 
the form of “≤x” or “≥x. 
6.5 
AEs 
Recorded AEs will be mapped according to the MedDRA thesaurus by the data 
management CRO for this study, with Theravance Biopharma review and approval of the 
mappings. 
 will use 
 
6.6 
Medications 
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) by the data management CRO for this study 
with Theravance Biopharma review and approval of the mappings. The CRO will use the 
. 
6.7 
Medical History 
Medical history will be mapped according to 
 and will be provided in 
listings.  
6.8 
General Considerations for Summaries 
Analyses and tabulations will generally be prepared using SAS, version 9.3 or later. 
Ordering of Treatment Headers in Summary Tables 
For the efficacy endpoints, including OHSA question 1, composite OHSA, OHDAS, and 
OHQ score, duration of standing, and SBP, treatment headers will be presented as subject’s 
dose receive on the day of visit in the following order: 


 
 
 
 
 
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 
TD-9855 
 / TD-9855 
 / TD-9855 
 / TD-9855 
 / TD-9855 Total 
For all other endpoints and general analysis, only TD-9855 on the header of the treatment 
group. 
Rounding 
In general, the convention for rounding percentages is as follows: 
 
Values greater than or equal to x.x5 are rounded up, 
 
Values between 0 and less than x.x5 are rounded down, 
 
Values between –x.x5 and 0 are rounded up, 
 
Values less than or equal to x.x5 are rounded down. 
Significant Digits 
Raw measurements will be reported the same as the data captured electronically or on the 
CRFs. Exceptions will be made for values reported with greater than 4 significant digits 
(round to 4 significant digits using a similar criterion as for percentages with the 5 in the last 
digit)). 
 
Raw measurements, Minimum, and Maximum will be reported to the same precision as 
the raw data captured. 
 
Mean, Median, Q1, Q3, 95% CI will be reported to the same number of decimal places 
+1 as the raw data captured. 
 
Standard deviation and standard error will be reported to the same number of decimal 
places +2 as the raw data captured. 
 
The number of decimal places in reporting p-value should be as follows. If more 
precision for the p-value is desired, it should be specified in the study TFL mock shell 
document. 
 Value is less than 0.001                         ->           <0.001 
 Value 0.001 to less than 0.10               ->           round to 3 decimal places 
 Value 0.10 and greater                          ->           round to 2 decimal places 


 
 
 
 
 
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7 
ANALYSIS SETS 
7.1 
Intent-to-Treat 
For Part C, the ITT analysis set will include all subjects who have enrolled for Part C and 
received at least one dose of study drug (TD-9855).  
The ITT analysis set is the primary analysis set for general and efficacy analyses in each 
part of the study. 
7.2 
Safety 
The Safety analysis set is the same as the ITT analysis set. 
7.3 
Examination of Subgroups 
The following tables will be summarized by the following pre-defined subgroups in Part C: 
1. MSA vs. Non-MSA   
2. Symptomatic vs. Non-Symptomatic: Symptomatic and Non- Symptomatic are defined 
as subject with baseline (pre-lunch measurement on Day -1) OHSA question #1 
scale of > 4 and ≤ 4, respectively.   
3. Orthostatic hypotension vs. Non-orthostatic hypotension at baseline (pre-breakfast 
measurement on Day 1): Orthostatic hypotension subjects are those whose ‘Change 
from Supine SBP to Seated SBP’ ≤ - 20 mm Hg or ‘Change from Supine DBP to 
Seated DBP’ ≤ - 10 mm Hg at baseline. 
4. Average daily dose of ≤ 5 mg vs. > 5 mg up to Day 29  
5. Duration of Standing at Baseline - ≤ 1 min vs. > 1 min 
Combination of these subgroups may also be explored, such as MSA, Symptomatic, and 
Average daily dose ≤ 
 vs. MSA, Symptomatic, and Average daily dose > 
.  
Analysis by other subgroups may be performed if adequate number of subjects (at least 5) 
are enrolled in the categories. 


 
 
 
 
 
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7.4 
Inclusion and Exclusion Deviations 
Deviations to inclusion and exclusion criteria will be identified prior to database lock and will 
be summarized in a listing with the deviation and the protocol version associated with the 
deviation. 
7.5 
Major Analysis Protocol Deviations 
Major analysis protocol deviations that could potentially affect the conclusions of the study 
will be identified prior to database lock. Major analysis protocol deviations may include, but 
are not limited to: 
 
Subjects who received an excluded concomitant treatment or medication, 
 
Subjects who are less than 80% compliant with study medication, 
 
Subjects who are out of window for the primary efficacy assessment. 
Subjects with major analysis protocol deviations will be identified before the database lock 
and provided in a listing. 
In addition, a listing of all major deviations will be provided whether they impact analysis. 
8 
DEFINITION OF ANALYSIS VARIABLES 
8.1 
Demographic and Baseline Characteristics 
Age 
Age will be calculated as of the date of informed consent form (ICF) and truncated to its 
integer value. The following formula is used: 
 
𝑎𝑔𝑒= 𝑓𝑙𝑜𝑜𝑟(
𝐼𝐶𝐹 𝑆𝑖𝑔𝑛𝑖𝑛𝑔−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐵𝑖𝑟𝑡ℎ
365.25
)  
BMI 
BMI will be calculated and converted to metric units by the following: 
 





2
2
/
.
weight kg
BMI kg m
height m

 


 
 
 
 
 
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8.2 
Efficacy Variables 
Primary Efficacy Endpoint 
For Part C, the primary endpoint is the improvement from baseline in the Likert scale 
“dizziness, lightheadedness, feeling faint, or feeling like you might black out” (OHSA, 
question 1) at week 4. A responder in Part C is defined as a subject who demonstrates at 
least a 2 unit decrease (improvement) from baseline in the OHSA question 1 at week 4. The 
raw data is in ordinal scale and will be treated as continuous variable to get the descriptive 
statistics.  
Secondary Efficacy Endpoint 
  
The secondary endpoints for Part C include:  
 
Change from baseline in the composite OHSA, OHDAS, and OHQ score 
 
Change from baseline in standing SBP  
 
Change from baseline in seated SBP   
 
Duration of standing during the orthostatic standing test  
 
Change from Supine SBP to Seated SBP 
For the Supine and Seated blood pressure, the summary table will be based on the average 
value of the 5 minutes and 10 minutes measurements. The composite OHSA score is 
calculated by the non-missing average score of the 6 OHSA items. Similarly for the 
composite OHDAS score is the non-missing average of the 4 items. The composite OHQ 
score is the average of the OHSA and OHDAS composite scores. 
 
For Change from time-matched placebo in seated SBP, calculate the area under the effect 
curve from 0 to 12 hours (AUC0_12) using the following trapezoidal rule. Calculation of 
AUC0_12 will use observed data points (actual time). If there is missing data for seated 
SBP, AUC will not be calculated. Here is the formula for AUC: 
 
 
where 


 
 
 
 
 
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yi = the value of the parameter at the i-th time point, 
ti = the i-th time point, and 
I = the number of time points used in the AUC calculation. 
A hypothetical example is given below to illustrate the calculation. 
  
  
  
AUC Calculation 
  
Nominal 
Time 
Point 
(H) 
Actual 
Time 
Point 
(H) 
Parameter 
Value 
(Y_i) 
T_diff= 
T_(i+1) 
 T_i 
Y_sum= 
Y_(i+1) 
+ Y_i 
T_diff x 
Y_sum 
AUC0_12 
0 
0 
1.5 
 
 
 
 
4 
2.01 
2.2 
2.01 
3.7 
7.437 
 
7 
3.91 
3.4 
1.9 
5.6 
10.64 
 
9 
8.05 
2.8 
4.14 
6.2 
25.668 
 
12 
23.95 
2.1 
11.87 
4.8 
56.976 
50.361 
 
 
8.3 
Safety Variables 
For all Parts of the study, safety and tolerability assessments will include adverse events, 
laboratory abnormalities, ECGs, and vital sign measurements. 
9 
ANALYSES 
Table, figures and listing titles are denoted in underlined text. 
9.1 
General Analyses 
Generally, summary statistics including N, mean, median, standard deviation, Q1, Q3, Min, 
and max will be generated for continuous variables. For the ordinal data such as OHSA 
scales, it will be treated as continuous variable for summary statistics. For categorical 
variables, count and % will be summarized.  
Figures including serial plot, box plot, bar chart, and heatmap will be employed to depict the 
data. For the longitudinal data, such as vital signs, blood pressures in seated, supine, and 
standing positions, OHSA scales, lab data, etc., serial pot or box plot will be generated to 
describe the changes. Bar chart will be used to depict the changes in scales of categorical 
data, e.g. OHSA scales. Heatmap will be used to depict the changes in blood pressure by 


 
 
 
 
 
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individual patient, with x-dimension as visit (study days), y-dimension as time points, and the 
colored heatmap to represent the categories of changes from baseline.  
9.1.1 Subject Disposition 
Subject disposition information will be summarized for all subjects by study Part (A and C) 
and by dose. Summaries will include:  
 
Number of subjects enrolled in Part A  
 
Number of subjects enrolled in Part C 
 
Number and percentage of subjects treated with study drug (Part C)   
 
Number and percentage of subjects completing the study (Part C) 
 
Number and percentage of subjects by reason discontinuing the study drug (Part C) 
 
Number and percentage of subjects by reason discontinuing the study (Part C) 
For Part C, the subject disposition table will include the number (%) of subjects who were 
rolled over from Part A into the open-label extension study. 
A listing of subject disposition will include the ITT analysis set status, the date of informed 
consent signed, the date of first dose and last dose of study drug, primary reason for subject 
discontinuation of study medication, the date of last visit, study completion status, and 
primary reason for study termination. 
9.1.2 Demographics and Baseline Characteristics 
Demographics including age, sex, race, ethnicity, height, weight, and BMI will be 
summarized for the ITT analysis set.  
The following baseline characteristics data will be summarized descriptively:  
 
Underlying diagnosis of nOH (MSA, PAF, Parkinson’s disease) 
 
Symptomatic (yes or no) 
 
OHSA question 1 at baseline 
In addition, the following baseline characteristics will also be summarized descriptively for 
Part C: 


 
 
 
 
 
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 
OHSA composite score at baseline 
 
OHDAS composite score at baseline 
 
OHQ composite score at baseline 
 
Orthostatic hypotension (yes or no) at baseline 
 
Duration of Standing at baseline 
 
SBP (Seated, Supine, Standing) at baseline  
A listing will be provided. 
9.2 
Efficacy Analyses 
For all efficacy data analyses, the ITT group will be used unless otherwise specified.  
9.2.1 Primary Efficacy Evaluation 
For Part C, the primary endpoint is the improvement from baseline in the Likert scale 
“dizziness, lightheadedness, feeling faint, or feeling like you might black out” (OHSA, 
question 1) at week 4. The scales will be treated as continuous variable, and a summary 
table including descriptive statistics will be generated. A responder in Part C is defined as a 
subject who demonstrates at least a 2 unit decrease (improvement) from baseline in the 
OHSA question 1 at week 4. The proportion of subject who demonstrate ≥ 1 unit, ≥ 2 units, ≥ 
3 units, ≥ 4 units improvement, no change, and worsen (by 1 and >1 unit) at each visit will 
be calculated with exact 90% confidence intervals and summarized by visit and dose level 
per each visit. In addition, OHSA question 1 improvement will be summarized by baseline 
value categories (baseline OHSA #1 ≥ 2). 
The example SAS code for summary of proportion of responders is following:  
proc freq data = xxx; 
        by timepoint cat; 
        tables yes_no / binomial(exact) alpha=.1 cl; 
        ods output BinomialCLs = result_1; 
run; 


 
 
 
 
 
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Where ‘timepoint’ is the time points for the measurements, ‘cat’ is the category of 
improvement (or no change, worsen) by number of unit, and ‘yes_no’ is the indicator for 
subjects in each category. 
9.2.2 Secondary Efficacy Evaluation 
  
For Part C, actual score and its change from baseline in composite OHSA, OHDAS, and 
OHQ will be generated descriptively by study visit. For Standing and Seated SBP, as well as 
duration of standing, the actual value (in minutes) and its change from baseline will also be 
summarized descriptively by time point (pre-breakfast, pre-lunch) and study visit. In addition, 
categorical shift (categories from 0 to 10 by 1 minute, and ≥ 10 minutes) of change from 
baseline for standing duration will also be summarized. For Standing SBP, number and 
percent of subjects with SBP > 80 mmHg by time point will also be analyzed.  
For primary and secondary endpoints, graphic display of the data will be generated. Mean+/-
SD line plot and boxplot will be used to depict the change over time point for vital signs and 
scores in OHSA, OHDAS and composite OHQ. Heatmap will be used to plot the individual 
change over time points on the data for vital signs (Seated, Standing, and Supine SBP and 
DBP). Bar chart will be used to depict the changes in scales of categorical data, e.g. OHSA 
scales, and in change subgroup for Seated SBP and Duration of Standing. 
9.2.3 Other Efficacy Evaluation 
The following efficacy endpoints will also be explored: 
 
Physician Global Assessment - descriptive summary on actual score and change 
from baseline over time, and number (%) of subjects by level of score and study visit  
 
Subject Global Assessment - descriptive summary on actual score and change from 
baseline over time, and number (%) of subjects by level of score and study visit 
 
Subject Satisfaction Survey - number (%) of subjects by level of score and study visit 
 
Supine SBP - descriptive summary on actual value and change from baseline by 
study visit 


 
 
 
 
 
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 
Change from Seated SBP to Standing SBP, Change from Supine SBP to Standing 
SBP, Change from Supine to Seated SBP - descriptive summary on actual value and 
change from baseline by time point and visit 
 
24 Hour Blood Pressure monitoring – including number (%) of subjects with outliers 
in 24 Hours SBP, subject listing of 24 Hour BP monitoring 
Additional graphic display of the following efficacy endpoints will be generated:  
 
Individual plots in subject’s actual scales over time in OHSA question 1, composite 
scores in OHSA, OHDAS, and OHQ. Plots for both all subjects enrolled in Part C and 
only the Part C completers will be generated.   
 
Individual plots in subject’s actual values by time point and visit in Seated SBP, 
Supine SBP, Standing SBP, Change from Seated SBP to Standing SBP, Change 
from Supine SBP to Standing SBP, Change from Supine to Seated SBP, and 
Duration of Standing. For Change from Seated SBP to Standing SBP and Duration 
of Standing, plots for both all subjects enrolled in Part C and only the Part C 
completers will be generated.   
 
Mean+/-SD (from descriptive summary) line plot and boxplot for actual values over 
time in Seated SBP, Supine SBP, and Standing SBP.   
 
Mean+/-SD (from descriptive summary) line plot and boxplot for change from 
baseline over time in Change from Supine SBP to Seated SBP.   
 
Mean+/-SD (from descriptive summary) line plot for the percent change from 
baseline over time - Duration of Standing.  
 
Bar chart for the percent change from baseline in Duration of Standing. 
 
Individual plots in 24 Hours Vital Signs Monitor in SBP, DBP, HR, and Mean Arterial 
Pressure 
9.2.4 Multiplicity Adjustment 
Multiplicity adjustment is not applicable since only descriptive summaries are provided. 


 
 
 
 
 
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9.3 
Safety Analyses 
For all safety analyses, the safety analysis population will be used. 
Safety variables to be summarized include vital signs, adverse events, clinical laboratory 
results (hematology, chemistry, and urinalysis), and quantitative parameters from 12-lead 
ECGs. Vital signs will be summarized in terms of observed values and changes from 
baseline. 
9.3.1   Exposure 
A subject’s data for the extent of exposure to study drug will be generated from the study 
drug administration page of the CRF. Dosing information for individual subjects will be listed. 
Extent of exposure will be summarized by number of days on TD-9855 and cumulative 
doses of TD-9855 in Part C.   
In Part C, the following will be summarized as an analysis of exposure:  
 
Number and percent of subjects with at least one dose of TD-9855 by dose level (  
) (overall and by visits)  
 
Individual subject’s change of dose level over time (graph) 
 
Descriptive summary of dose by visits  
 
Study drug compliance using the categories (100%; 95%; 90%; 80%; < 80%)   
Study drug compliance (as percentage) can be derived as (Number of doses taken / Total 
expected dose) x 100, where, 
 
Number of doses taken = total number of doses released (number of pills x dose 
level) - total number of doses returned (number of pills x dose level)  
 
Total expected dose = dose level x number of days 
Study drug administration (date/time and study day) will be provided in a data listing.  
9.3.2 Adverse Events 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will be presented by system organ class (SOC), 


 
 
 
 
 
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preferred term (PT) and severity, and the frequency and percentage of subjects reporting 
each observed event.  
A 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 30 days. AEs observed during the period from 
obtaining informed consent to the start of administration of study drug will be regarded 
separately from TEAEs. 
All AEs and all TEAEs will be listed by subject. AEs will also be summarized by relationship 
to treatment (study drug) and severity.  
Data listings will be provided for all subjects who experience an SAE. Data listings will also 
be provided for subjects who discontinued the study due to any AE, as well as for a SAE. 
9.3.3 Prior and Concomitant Medications 
Medications will be summarized both prior and during the treatment period. Listing will be 
provided for prior and concomitant medications overall.  
9.3.4 Vital Signs 
Vital signs will be summarized in terms of observed values (by time point), changes from 
baseline (by time point). When multiple values exist for the same nominal time point (e.g., 
duplicate reading), the average of the readings taken for vital signs will be used in the data 
analysis. All recorded values for vital signs data will be presented in a by-subject listing.  
Vital signs outliers will be flagged in the listing (Table 2). 
Table 2. Vital Signs Outlier Thresholds  
Heart Rate 
(bpm) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
<40 
>110 
<85 
>160 
<45 
>100 
A sustained elevation in supine vital signs (the mean value of BP or HR) is defined as the 
elevation above a given threshold at three or more consecutive on-treatment 
measurements.   For example, elevation at pre-breakfast, pre-lunch measurement on one 
visit as well as pre-breakfast measurement at the subsequent visit will be considered as 


 
 
 
 
 
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sustained elevation; on the other hand, elevation at pre-breakfast but not at pre-lunch for 3 
consecutive visits will not constitute as “sustained” elevation. 
Categorical elevated vital signs are defined in Table 3 and Table 4. Number of subjects with 
elevated vital signs will be summarized by visits in Part C. 
Table 3. Threshold for Elevated Supine Vital Sign  
Measurements 
Threshold 
Increase from Baseline in SBP 
(mmHg) 
≥ 20 
≥ 30 
Increase from Baseline in DBP 
(mmHg) 
≥ 10 
≥ 20 
Increase from Baseline in HR 
(bpm) 
≥ 10 
≥ 20 
Post-baseline value SBP (mmHg) 
≥ 140  
≥ 160 
Post-baseline value DBP (mmHg) 
≥ 90  
≥ 100 
Post-baseline value HR (bpm) 
≥ 100  
≥ 120 
 
 
 


 
 
 
 
 
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Table 4.  Combined Criteria for Elevated Supine Vital Sign 
Combined Criteria 
SBP ≥ 140 and Increase from Baseline ≥ 20 
DBP ≥ 90 and Increase from Baseline ≥ 10 
HR ≥ 100 and Increase from Baseline ≥ 20 
SBP ≥ 160 and Increase from Baseline ≥ 20 
DBP ≥ 100 and Increase from Baseline ≥ 10 
HR ≥ 120 and Increase from Baseline ≥ 20 
 
In addition, the following will also be summarized. 
 
a decrease in systolic blood pressure (a mean value of SBP) from supine to standing 
of ≥ 20 ( and 30) mmHg and/or  
 
a decrease in diastolic blood pressure (a mean value of DBP) from supine to standing 
of ≥ 10 mmHg  
 
an increase in heart rate (a mean value of HR) from supine to standing of ≥ 30 bpm 
and/or  
 
an observed HR ≥ 120 bpm upon standing 
 
9.3.5 ECG 
The QTcF, PR interval, QT interval, QRS duration, and HR from standard digital ECGs will 
be summarized by study visit in terms of observed values, changes from baseline, and 
counts and percentages within appropriately defined categories Table 5.  
 
 


 
 
 
 
 
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Table 5. 
Vital Sign and ECG Outlier Thresholds 
 
Heart 
Rate 
(bpm) 
Heart Rate 
Change from 
Baseline 
(bpm) 
PR 
Interval 
(msec) 
PR Percentage 
Change From 
Baseline (%) 
QRS 
 Interval 
(msec) 
QTcF 
(msec) 
QTcF 
change from 
Baseline 
(msec) 
>120 
≥20 
 200 
≥ 15 
 120 
Males: 
 
>130 
≥30 
 220 
≥ 25 
 
 
>30, ≤ 60 
 
 
Optional: 
 
 
≥ 430 
> 60 
 
 
≥ 240 
 
 
≥ 450 
 
 
 
≥ 260 
 
 
≥ 470 
 
 
 
≥ 280 
 
 
≥ 480 
 
 
 
≥ 300 
 
 
≥ 500 
 
 
 
 
 
 
Females: 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥ 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. 
When multiple values exist for the same nominal time point (eg, triplicate reading), the 
average of the readings taken for ECG parameters will be used in the data analysis, 
including the outlier analysis stated above in table 4.  
All recorded values for the ECG parameters will be presented in a by-subject listing. A listing 
of subjects with outliers will also be provided. 
9.3.6 Clinical Laboratory Results 
The study used a mixture of local and central labs, lab units, normal ranges will be 
converted using the Standard International lab unit if possible. Lab data will be counted as 
Low, Normal, and High for each visit by applying the local lab normal ranges. Lab shift 
tables from baseline to discharge/follow-up will be summarized.  


 
 
 
 
 
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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.  
Cumulative urine volume over the 24-hour period for each dosing day will be summarized by 
Study Day and dose. 
9.4 
Interim Analyses 
This interim analysis will be performed after all enrolled subjects have completed 4 weeks of 
study in Part C. The interim will include the analyses for primary, secondary, additional 
efficacy endpoints, and safety endpoints. The final analysis (includes all visits) will be 
performed after all subjects have completed Part C.  
 
 
 


 
 
 
 
 
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Appendix 1: 
Reporting Structures for Data Summary 
Reporting Structures  
C: Continuous endpoints will be presented with an 8-point summary using the following 
reporting structure, unless otherwise noted, 
N 
x 
Mean (SD) 
x.xx (x.xx) 
Median 
x 
Q1, Q3 
xx.x, xx.x 
Minimum, Maximum 
xx.x, xx.x 
F: Frequency endpoints will be presented by a 3-point summary using the following 
reporting structure, unless otherwise noted, 
n 
X 
Count (%) 
x (xx.x) 
MF Categorical variables (multiple frequency) will be presented by a 3-point summary using 
the following reporting structure, unless otherwise noted, where the sum of the category n’s 
is the total n 
n 
X 
Category 1 count (%) x (x.x) 
Category 2 count (%) x (x.x) 
NLSM: Normal distribution (continuous) endpoint least-square mean (LS mean) summaries 
will be presented using the following structure, unless otherwise noted: 
Evaluable n 
xx 
LS Mean (SE) 
xxx.x (xx.xx) 
LS Mean Difference (SE) 
xxx.x (xx.xx) 
95% CI for LS Mean Difference 
(xxx.x, xxx.x) 
 
 
P-value vs. {Placebo} 
0.xxx 
BLSM: Binomial distribution (binary/proportion) endpoint generalized least-square mean 
(LS mean) summaries will be presented using the following structure, unless otherwise 
noted: 
Count / Evaluable n 
xx / xx 
LS Proportion (SE) 
0.xx (xx.x) 
Odds Ratio (TD-XXXX / {Placebo} xx.x 
95% CI for Odds Ratio 
(xx.x, xx.x) 
 
 
P-value vs. {Placebo} 
0.xxx 
PLSM: Poisson distribution (count) endpoint generalized least-square mean (LS mean) 
summaries will be presented using the following structure, unless otherwise noted: 
Evaluable n 
xx 
LS Mean Count (SE) 
xxx.x (xx.xx) 


 
 
 
 
 
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LS Mean Difference (SE) 
xxx.x (xx.xx) 
95% CI for LS Mean Difference 
(xxx.x, xxx.x) 
 
 
P-value vs. {Placebo} 
0.xxx 
NBLSM: Negative binomial distribution (rate/ratio) endpoint generalized least-square mean 
(LS mean) summaries will be presented using the following structure, unless otherwise 
noted: 
Evaluable n 
xx 
LS Mean Annual Rate 
x.xx 
Ratio (TD-XXXX / {placebo}) 
x.xx 
95% CI for Ratio 
(x.xx, x.xx) 
 
 
Percent Reduction vs. {Placebo} 
0.xx 
95% CI for Percent Reduction 
(0.xx, 0.xx) 
 
 
P-value vs. {Placebo} 
0.xxx 
KM: Time to event summaries will be summarized with the following reporting structure: 
Time to First Event 
Median (95% CI) 
xx.x (xx.x, xx.x) 
Q1, Q3 
xx.x, xx.x 
Minimum, Maximum 
xx.x, xx.x 
Total Number Censored 
x 
P-Value vs. Placebo 
0.xxxx 
For the primary endpoint and secondary endpoints under multiplicity control, an additional 
p-value line will be included in the reporting summary: 
Adjusted P-value vs. Placebo 
0.xxx 
 
 


 
 
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Appendix 2: 
List of TFLs (Part C only) 
Table Number 
Table Name 
14.1 
Subject Disposition, Demographic and Baseline Characteristics 
14.1.1 
Subject disposition 
14.1.2 
Demographics and Baseline Characteristics 
14.1.2.2 
Baseline Characteristics (additional) 
14.1.3 
Medical History 
14.1.4 
Summary of Exposure 
14.1.4.1 
Prior medications by ATC class and preferred term 
14.1.4.2 
Concomitant medications by ATC class and preferred term 
  
 
14.2 
Efficacy   
14.2.1 
Summary of Change in the Likert Scale Post Study Drug Administration by Visit   
14.2.1.1 
Summary of Change in the Likert Scale Post Study Drug Administration by Visit and 
Dose 
14.2.1.2 
Summary of Change in the Likert Scale Post Study Drug Administration by Subgroups 
(over time and at Day 29 only)   
14.2.2 
Summary of Change in Composite OHSA Score Post Study Drug Administration by 
Visit  
14.2.2.1 
Summary of Change in Composite OHSA Score Post Study Drug Administration by 
Visit and Dose 
14.2.2.2 
Summary of Change in Composite OHSA Score Post Study Drug Administration by 
Subgroups 
14.2.3.1 
Summary of Change in Physician Global Assessment Post Study Drug Administration  
14.2.3.2 
Summary of Change in Subject Global Assessment Post Study Drug Administration  


 
 
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14.2.3.3  
Summary of Physician Global Assessment Post Study Drug Administration  
14.2.3.4 
Summary of Subject Global Assessment Post Study Drug Administration  
14.2.4 
Summary of Change in OH Daily Activity Scale Post Study Drug Administration 
14.2.5 
Summary of Change in Composite OHDAS Score Post Study Drug Administration by 
Visit  
14.2.5.1 
Summary of Change in Composite OHDAS Score Post Study Drug Administration by 
Visit and Dose 
14.2.5.2 
Summary of Change in Composite OHDAS Score Post Study Drug Administration by 
Subgroups 
14.2.14 
Summary of Change in Composite OHQ Score Post Study Drug Administration by Visit  
14.2.14.1 
Summary of Change in Composite OHQ Score Post Study Drug Administration by Visit 
and Dose 
14.2.14.2 
Summary of Change in Composite OHQ Score Post Study Drug Administration by 
Subgroups 
14.2.6 
Summary of Subject Satisfaction Survey Post Study Drug Administration 
14.2.13 
Summary of proportion of responders on OHSA #1 by Visit  
14.2.13.1 
Summary of proportion of responders on OHSA #1 by Visit and Dose  
14.2.13.2 
Summary of proportion of responders on OHSA #1 by Visit (and at Day 29) and Dose 
and Subgroups 
 
 
14.2.7 
Summary of Change in Standing Duration Post Study Drug Administration by Visit  
14.2.7.1 
Summary of Change in Standing Duration Post Study Drug Administration by Visit and 
Dose 
14.2.7.2 
Summary of Change in Standing Duration Post Study Drug Administration by 
Subgroups 


 
 
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14.2.7.3 
Summary of Actual Value in Standing Duration Post Study Drug Administration 
14.2.7.4 
Shift from Baseline to Day 29 on Actual Value - Standing Duration 
14.2.8.1 
Summary of Change in Seated SBP Post Study Drug Administration by Visit 
14.2.8.1.1 
Summary of Change in Seated SBP Post Study Drug Administration by Visit and Dose 
14.2.8.1.2 
Summary of Change in Seated SBP Post Study Drug Administration by Subgroups 
14.2.8.2 
Summary of Change in Seated DBP Post Study Drug Administration  
14.2.9.1 
Summary of Change in Supine SBP Post Study Drug Administration by Visit 
14.2.9.1.1 
Summary of Change in Supine SBP Post Study Drug Administration by Visit and Dose 
14.2.9.1.2 
Summary of Change in Supine SBP Post Study Drug Administration by Subgroups 
14.2.9.2 
Summary of Change in Supine DBP Post Study Drug Administration  
14.2.10.1 – 14.2.10.4 Summary of Change in 1 min Standing SBP Post Study Drug Administration (and 3 
min, 5 min, 10 min) by Visit 
14.2.10.1.1 – 
14.2.10.4.1 
Summary of Change in 1 min Standing SBP Post Study Drug Administration (and 3 
min, 5 min, 10 min) by Visit and Dose 
14.2.10.1.2 – 
14.2.10.4.2 
Summary of Change in 1 min Standing SBP Post Study Drug Administration by 
Subgroups (and 3 min, 5 min, 10 min) 
14.2.11.1 – 14.2.11.4 Summary of Change from Seated SBP to 1 min Standing SBP Post Study Drug 
Administration (and 3 min, 5 min, 10 min) 
14.2.12.1 – 14.2.12.4 Summary of Change from Supine SBP to 1 min Standing SBP Post Study Drug 
Administration (and 3 min, 5 min, 10 min) 
14.2.15.1   
Summary of Change from Supine SBP to Seated SBP Post Study Drug Administration 
by Visit 
14.2.15.1.1   
Summary of Change from Supine SBP to Seated SBP Post Study Drug Administration 
by Visit and Dose 


 
 
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Figure 15.2.1.1  
Individual Change from Baseline in Vital Signs - Seated SBP over Time  
Figure 15.2.1.2  
Mean+/-SD Change from Baseline in Vital Signs - Seated SBP over Time  
Figure 15.2.1.2.1  
Mean+/-SD Change from Baseline in Vital Signs - Seated SBP over Time by 
Subgroups  
Figure 15.2.1.3 
Individual Actual Value in Vital Signs - Seated SBP over Time  
Figure 15.2.1.4 
Mean +/ SD Actual Value in Vital Signs - Seated SBP over Time  
Figure 15.2.2.1  
Individual Change from Baseline in Vital Signs - Seated DBP over Time  
Figure 15.2.2.2  
Mean+/-SD Change from Baseline in Vital Signs - Seated DBP over Time  
Figure 15.2.3.1.1  
Individual Change from Baseline in Vital Signs - 1 min Standing SBP over Time  
Figure 15.2.3.1.2  
Mean+/-SD Change from Baseline in Vital Signs - 1 min Standing SBP over Time  
Figure 15.2.3.1.2.1 
Mean+/-SD Change from Baseline in Vital Signs - 1 min Standing SBP over Time by 
Subgroups  
Figure 15.2.3.1.3 
Individual Actual Value in Vital Signs - 1 min Standing SBP over Time   
Figure 15.2.3.1.4 
Mean +/ SD Actual Value in Vital Signs - 1 min Standing SBP over Time   
Figure 15.2.3.2.1  
Individual Change from Baseline in Vital Signs - 3 min Standing SBP over Time  
Figure 15.2.3.2.2  
Mean+/-SD Change from Baseline in Vital Signs - 3 min Standing SBP over Time  


 
 
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Figure 15.2.3.2.2.1  
Mean+/-SD Change from Baseline in Vital Signs - 3 min Standing SBP over Time by 
Subgroups 
Figure 15.2.3.2.3 
Individual Actual Value in Vital Signs - 3 min Standing SBP over Time   
Figure 15.2.3.2.4 
Mean +/ SD  Actual Value in Vital Signs – 3 min Standing SBP over Time   
Figure 15.2.3.3.1  
Individual Change from Baseline in Vital Signs - 5 min Standing SBP over Time  
Figure 15.2.3.3.2  
Mean+/-SD Change from Baseline in Vital Signs - 5 min Standing SBP over Time  
Figure 15.2.3.3.2.1  
Mean+/-SD Change from Baseline in Vital Signs - 5 min Standing SBP over Time by 
Subgroups 
Figure 15.2.3.3.3 
Individual Actual Value in Vital Signs - 5 min Standing SBP over Time   
Figure 15.2.3.3.4 
Mean +/ SD Actual Value in Vital Signs – 5 min Standing SBP over Time   
Figure 15.2.3.4.1  
Individual Change from Baseline in Vital Signs - 10 min Standing SBP over Time  
Figure 15.2.3.4.2  
Mean+/-SD Change from Baseline in Vital Signs - 10 min Standing SBP over Time  
Figure 15.2.3.4.2.1  
Mean+/-SD Change from Baseline in Vital Signs - 10 min Standing SBP over Time by 
Subgroups 
Figure 15.2.3.4.3 
Individual Actual Value in Vital Signs - 10 min Standing SBP over Time   
Figure 15.2.3.4.4 
Mean +/ SD Actual Value in Vital Signs – 10 min Standing SBP over Time   
Figure 15.2.4.1.1  
Individual Change from Baseline in Vital Signs - Change from Seated SBP to 1 min 
Standing SBP over Time  
Figure 15.2.4.1.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Seated SBP to 1 min 
Standing SBP over Time  


 
 
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Figure 15.2.4.2.1  
Individual Change from Baseline in Vital Signs - Change from Seated SBP to 3 min 
Standing SBP over Time  
Figure 15.2.4.2.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Seated SBP to 3 min 
Standing SBP over Time  
Figure 15.2.4.3.1  
Individual Change from Baseline in Vital Signs - Change from Seated SBP to 5 min 
Standing SBP over Time  
Figure 15.2.4.3.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Seated SBP to 5 min 
Standing SBP over Time  
Figure 15.2.4.4.1  
Individual Change from Baseline in Vital Signs - Change from Seated SBP to 10 min 
Standing SBP over Time  
Figure 15.2.4.4.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Seated SBP to 10 min 
Standing SBP over Time  
Figure 15.2.5.1.1  
Individual Change from Baseline in Vital Signs - Change from Supine SBP to 1 min 
Standing SBP over Time  
Figure 15.2.5.1.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Supine SBP to 1 min 
Standing SBP over Time  
Figure 15.2.5.2.1  
Individual Change from Baseline in Vital Signs - Change from Supine SBP to 3 min 
Standing SBP over Time  
Figure 15.2.5.2.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Supine SBP to 3 min 
Standing SBP over Time  
Figure 15.2.5.3.1  
Individual Change from Baseline in Vital Signs - Change from Supine SBP to 5 min 
Standing SBP over Time  
Figure 15.2.5.3.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Supine SBP to 5 min 
Standing SBP over Time  
Figure 15.2.5.4.1  
Individual Change from Baseline in Vital Signs - Change from Supine SBP to 10 min 
Standing SBP over Time  
Figure 15.2.5.4.2  
Mean+/-SD Change from Baseline in Vital Signs - Change from Supine SBP to 10 min 
Standing SBP over Time  
Figure 15.2.6.1  
Individual Change from Baseline in Vital Signs - Supine SBP over Time  
Figure 15.2.6.2  
Mean+/-SD Change from Baseline in Vital Signs - Supine SBP over Time  


 
 
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Figure 15.2.6.2.1  
Mean+/-SD Change from Baseline in Vital Signs - Supine SBP over Time by 
Subgroups 
Figure 15.2.6.3 
Individual Actual Value in Vital Signs - Supine SBP over Time   
Figure 15.2.6.4 
Actual Value in Vital Signs - Supine SBP over Time   
Figure 15.2.7.1  
Individual Change from Baseline in Vital Signs - Supine DBP over Time  
Figure 15.2.7.2  
Mean+/-SD Change from Baseline in Vital Signs - Supine DBP over Time  
Figure 15.2.8.1  
Individual Change from Baseline in Vital Signs - Standing Duration over Time  
Figure 15.2.8.2  
Mean+/-SD Change from Baseline in Vital Signs - Standing Duration over Time  
Figure 15.2.8.2.1  
Mean+/-SD Change from Baseline in Vital Signs - Standing Duration over Time by 
Subgroups 
Figure 15.2.8.3 
Individual Percent Change from Baseline in Vital Signs - Standing Duration over Time  
Figure 15.2.8.4 
Individual Percent Change from Baseline in Vital Signs - Standing Duration over Time – 
All Subjects 
Figure 15.2.8.5 
Mean+/-SD Percent Change from Baseline in Vital Signs - Standing Duration over Time 
Figure 15.2.8.6 
Individual Actual Value in Vital Signs - Standing Duration over Time  
Figure 15.2.8.7 
Individual Actual Value in Vital Signs - Standing Duration over Time – All Subjects and 
Part C Completers 
Figure 15.2.8.8 
Mean+/-SD Actual Value in Vital Signs - Standing Duration over Time 
Figure 15.2.9.1  
Individual Vital Signs - Seated and Standing SBP Heatmap  
Figure 15.2.10.1  
Individual Vital Signs - Seated and Standing DBP Heatmap  


 
 
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Figure 15.2.11.1  
Individual Vital Signs - Supine SBP Heatmap  
Figure 15.2.12.1  
Individual Vital Signs - Supine DBP Heatmap  
Figure 15.2.13.1  
Bar Plot of Change from Baseline in Vital Signs - Seated SBP by Dose and Change 
Subgroup  
Figure 15.2.14.1  
Bar Plot of Change from Baseline in Vital Signs - Standing Duration by Dose and 
Change Subgroup  
Figure 15.2.14.2 
Bar Plot of Percent Change from Baseline in Vital Signs - Standing Duration by Dose 
and Percent Change Subgroup 
Figure 15.2.15.1  
Bar Plot of OHSA Question 1 Change from Baseline Pre-Lunch  
Figure 15.2.15.2  
Bar Plot of OHSA Question 1 Change from Baseline Pre-Lunch for Baseline Value > 2  
Figure 15.2.15.3 
OHSA Question 1 - Actual Value for Individual Subject over Time   
Figure 15.2.15.4 
OHSA Question 1 - Actual Value for Individual Subject over Time - All Subjects and 
Part C Completers  
Figure 15.2.15.5 
Mean +/ SD Change from Baseline in OHSA Question 1 over Time   
Figure 15.2.15.6 
OHSA Composite Score - Actual Value for Individual Subject over Time   
Figure 15.2.15.7 
OHSA Composite Score - Actual Value for Individual Subject over Time - All Subjects 
and Part C Completers   
Figure 15.2.15.8 
Mean +/ SD Change from Baseline in OHSA Composite Score over Time   
Figure 15.2.15.9 
OHDAS Composite Score - Actual Value for Individual Subject over Time   
Figure 15.2.15.10 
OHDAS Composite Score - Actual Value for Individual Subject over Time - All Subjects 
an Part C Completers  
Figure 15.2.15.11 
Mean +/ SD Change from Baseline in OHDAS Composite Score over Time   


 
 
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Figure 15.2.15.12 
OHQ Composite Score - Actual Value for Individual Subject over Time   
Figure 15.2.15.13 
OHQ Composite Score - Actual Value for Individual Subject over Time - All Subjects 
and Part C Completers  
Figure 15.2.15.14 
Mean +/ SD Change from Baseline in OHQ Composite Score over Time   
Figure 15.2.16.1  
Individual Plots in 24 Hours Vital Signs Monitor - Systolic Blood Pressure over Time 
Figure 15.2.16.2  
Individual Plots in 24 Hours Vital Signs Monitor - Diastolic Blood Pressure over Time 
Figure 15.2.16.3  
Individual Plots in 24 Hours Vital Signs Monitor - Heart Rate over Time 
Figure 15.2.16.4  
Individual Plots in 24 Hours Vital Signs Monitor - Mean Arterial Pressure over Time 
Figure 15.2.17.1 
Individual Change from Baseline in Vital Signs - Change from Supine SBP to Seated 
SBP over Time   
Figure 15.2.17.2 
Mean +/ SD Change from Baseline in Vital Signs - Change from Supine SBP to Seated 
SBP over Time   
Figure 15.2.17.3 
Mean +/ SD Change from Baseline in Vital Signs - Change from Supine SBP to Seated 
SBP over Time by Subgroups   
Figure 15.2.17.4 
Individual Actual Value in Vital Signs - Change from Supine SBP to Seated SBP over 
Time for All Subjects and Part C Completers   
Figure 15.2.17.5 
Mean +/ SD Actual Value in Vital Signs - Change from Supine SBP to Seated SBP over 
Time   
 
 
14.3 
Safety 
14.3.1 
Extent of Exposure 
14.3.1.1 
Study Drug compliance 
14.3.1.2 
Summary of Exposure by Visit  
14.3.1.3 
Number (%) of Subjects with Exposure by Visit 
13.3.2 
Overview of adverse events 
14.3.3.1 
Treatment-emergent adverse events by system organ class and preferred term 


 
 
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14.3.3.2 
Treatment-emergent adverse events by preferred term 
14.3.4 
Treatment-emergent adverse events occurring in >2% subjects by preferred term and 
sorted by decreasing frequency 
14.3.5 
Treatment-emergent adverse events by system organ Class, preferred term, and 
maximum severity 
14.3.6 
Treatment-emergent adverse events by system organ Class, preferred term, and 
Treatment Relationship 
14.3.7 
Study drug related treatment emergent adverse events by system organ 
class and preferred term 
14.3.8.1 
Serious adverse events by preferred term 
14.3.8.2 
Serious adverse events by system organ class and preferred term 
14.3.10.1 
Shift Table of Laboratory values from baseline to Worst Increase 
by laboratory test group, lab parameters 
14.3.10.2 
Shift Table of Laboratory values from baseline to Worst Decrease 
by laboratory test group, lab parameters 
14.3.11.1 
Summary of vital signs and Change from baseline by parameter and visit 
14.3.11.2 
Number (%) of patients with potentially clinically significant Changes in vital signs by 
visit 
14.3.12.1 
Summary of ECG and Change from Baseline by parameters and visit 
14.3.12.2 
Number (%) of patients with abnormal ECG and Changes by categories by parameters 
and visit 
 
 
Figure 14.3.1 
Individual Change of Exposure over Time - All Subjects  
 
 
 
 


 
 
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Listings 
 
Number 
Title 
16.2.1 
Subject disposition 
16.2.2 
Demographic and baseline characteristics 
16.2.4 
Prior and concomitant medications 
16.2.5 
OHSA score 
16.2.6 
OHDAS score 
16.2.7 
Clinical global impression (Global Assessment Score from Physician and Subject) 
16.2.8 
Extent of exposure   (including duration between Part A and Part C) 
16.2.9.1 
Adverse events 
16.2.9.2 
Serious adverse events 
14.2.9.3 
Adverse events leading to drug discontinuation  
14.2.9.4 
Treatment Emergent Adverse Events with Concomitant Medications 
16.2.10 
Vital signs (Seated BP, Standing BP, Supine BP, Standing Duration) 
16.2.10.2 
24 Hours Vital Signs Monitor 
16.2.11 
ECGs 
16.2.12 
Clinical laboratory results (hematology, chemistry, urinalysis) 
16.2.13 
Study Drug Accountability 
16.2.14 
Major Protocol Deviation