Clinical trial NCT04150341
Conditions: Asthma
Keywords: TD-8236 Asthma Proof of concept
Sponsor: Theravance Biopharma
Start date: 2019-11-06; Completion date: 2020-09-03
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This will be a randomized, double-blind, placebo-controlled study. The study will use a three-period, six-sequence, complete-block, cross-over study design to characterize two doses of inhaled TD-8236 compared to placebo in subjects with mild asthma and a known response to an allergen. Each of the three periods will be 14 days, followed by a washout period before the next period.

Detailed description:

Arms: arm 1: TD-8236 Dose A (QD x 14 days) arm 2: TD-8236 Dose B (QD x 14 days) arm 3: Placebo (QD x 14 days)
Interventions: intervention 1: TD-8236 intervention 2: Placebo
Intervention descriptions: intervention 1: The study drug will be administered by inhalation in the morning for 14 days during each period. A washout period of at least 21 days will exist between subsequent periods. intervention 2: The placebo will be administered by inhalation in the morning for 14 days during each period. A washout period of at least 21 days will exist between subsequent periods.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, 3-period 
Crossover Study to Evaluate the Effects of Repeated Doses of 
Inhaled TD-8236 and Impact on Airway Responses Following 
Allergen Challenge in Patients with Asthma 
Study Short Title: 
Effect of inhaled TD-8236 on allergen-induced asthmatic 
response 
Sponsor Study No.: 
0178 
Date: 
05 November 2019,
  
 
 
Test Product: 
TD-8236 
EudraCT No.: 
2019-002915-24 
Sponsor: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
Clinical Study Director: 
 
 
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© Theravance Biopharma (Unpublished Work).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 0178: A Randomized, Double-blind, Placebo-controlled, 
3-period Crossover Study to Evaluate the Effects of Repeated Doses of Inhaled TD-8236 and 
Impact on Airway Responses Following Allergen Challenge in Patients with Asthma 
Study Short Title: Effect of inhaled TD-8236 on allergen-induced asthmatic response 
Estimated Number of Study Centers and Countries or Regions:  Up to 
 in the 
United Kingdom 
Background and Rationale:   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
   
Objectives:   
The primary objective of the study is as follows: 
• Characterize the late asthmatic response (LAR) in terms of area under the FEV1 
curve after inhaled allergen challenge in mild asthmatic subjects receiving 14 days 
of TD-8236 or placebo 
 


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The secondary objectives of the study are as follows: 
• Characterize the late asthmatic response (LAR) in terms of maximum decline in 
FEV1 and area under the percent change FEV1 curve after inhaled allergen 
challenge in mild asthmatic subjects receiving 14 days of TD-8236 or placebo 
• Assess the plasma pharmacokinetics (PK) of TD-8236 in subjects with mild asthma 
• Evaluate the safety and tolerability of inhaled TD-8236 administered for 14 days in 
subjects with mild asthma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design:  This will be a randomized, double-blind, placebo-controlled, three-period, 
six-sequence, complete-block, cross-over study to characterize two doses of inhaled TD-8236 
compared to placebo in subjects with mild asthma and a known response to an allergen 
challenge.  
Subjects will undergo an allergen challenge test at Screening as described by 
 
.  Briefly, the challenge at Screening will consist of i
 
 
 
 
 
 At the investigator’s discretion, a subject may be required to stay resident in the 
research unit the evening following the Screening allergen challenge assessment.  
Once a subject meets inclusion and exclusion criteria and following a Screening period of up 
to 35 days, the subject will be randomized to one of six treatment sequences.  Within each 
treatment sequence, subjects will receive each of three treatments in one of three treatment 


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periods separated by a washout of at least 21 days between the last dose of the previous period 
and first dose of the next period. 
Each treatment period will consist of 14 days of treatment with one dose level of TD-8236 or 
placebo. Subjects will return to the clinic on Day 7 (±1 day) of each period for safety 
assessments, trough PK and PD sampling, as well as reconciliation and dispensing of study 
drug.  Subjects will be in-residence at the clinic for Day 14 of each period, including an 
overnight stay to allow for serial PK sampling through 24 hours after the last dose.  At the 
investigator’s discretion, subjects may be discharged the evening of Day 14 and return to the 
clinic the morning of Day 15. 
  
Subjects will undergo an allergen challenge test 1 hour after the last dose (Day 14) in each 
period.  The cumulative dose of allergen required to achieve a successful response at 
Screening will be administered as a bolus during the Treatment Periods. This bolus dose may 
be modified by the investigator for reasons of subject safety.  The modified bolus dose should 
thereafter remain consistent throughout the Treatment Periods. 
Duration of Study Participation:   
Individual subject participation will require approximately 20 weeks, as follows:  
• 
up to 35 days for Screening,  
• 
14 days of treatment in Period 1,  
• 
at least 21 days Washout from Period 1,  
• 
14 days in Period 2,  
• 
at least 21 days Washout from Period 2,  
• 
14 days in Period 3,  
• 
and 14 days of Follow-up.   
This will include 3 occasions of a one-night- residency in the clinic occurring during screening 
and on Day 14 of each study period following the allergen challenge procedures. The decision 
whether a subject remains resident in the clinic on these occasions will be at the discretion of 
the investigator on a case by case basis. The subjects will be discharged following the 
Screening allergen challenge and will return the following day for Screening Visit 3 
procedures (or if necessary, at investigator discretion, the subject may stay overnight at the 
research center and the subject will be discharged after Visit 3 procedures are completed). The 
actual length of individual subject participation will be determined by the length of the 
Screening and washout periods. 
Number of Subjects per Group: Approximately 21 subjects will be enrolled, targeting at 
least 18 subjects to complete the study, consisting of a crossover design with 3 periods 
containing 2 active doses of TD-8236 and a matching placebo.   


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Study Population: 
Men and women ages 18 to 65 inclusive who have stable, mild asthma and are a responder to 
dual inhaled bronchial allergen challenge and who meet other eligibility criteria as described 
below.  
Inclusion Criteria: 
1. Male or female, 18 to 65 years of age, inclusive, at Screening. 
2. BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening and weighs ≥ 50 kg at Screening. 
3. Documented physician-diagnosed asthma for ≥ 4 months prior to Screening. 
4. Pre-bronchodilator FEV1 ≥ 70% predicted at Screening and prior to Day 1 dosing in 
Treatment Period 1. 
5. Documented allergy to at least one common allergen as confirmed by the skin prick 
test, with wheal diameter ≥3mm greater than the negative control.  Historical data up to 
one year prior to screening, can be used. 
6. Subject should be a dual responder to inhaled bronchial allergen challenges as 
manifested by positive allergen-induced early (EAR) and late airway 
bronchoconstriction (LAR) at screening, defined as follows: 
 
 
  
 
 
 
7. Able to correctly use the Dry Powder Inhaler (DPI) and to generate sufficient peak 
inspiratory flow rate (PIFR) (at least 40 L/min) using the 
 device at 
Screening and prior to dosing on Day 1 of Treatment Period 1.   
8. Subject has no clinically significant abnormalities as determined by the PI in the 
results of laboratory evaluations at Screening, including: 
• Liver function tests (i.e., ALT, AST, ALP, GGT, and bilirubin) ≤ upper limit of 
normal or deemed medically acceptable at the discretion of the PI and Sponsor’s 
Medical Monitor 
• Absolute lymphocyte counts within normal range or should be deemed medically 
acceptable at the discretion of the PI and Sponsor’s Medical Monitor 
9. Subject must have a negative
 
 result at Screening. 
10. Pregnancy concerns: 
• Female subjects must be either of non-childbearing potential or if of childbearing 
potential use a highly effective birth control method (Section 6.3.10) during the 
study and through 30 days after the last dose of TD-8236. 


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• Male subjects (with partners of child-bearing potential) must use acceptable 
contraception (Section 6.3.10) during the study and through 30 days after the last 
dose of study medication  
• Male subjects must agree not to donate semen during the study and for 30 days 
after the last dose of study medication 
11. Understands the study procedures in the ICF and is willing and able to comply with the 
protocol-defined study procedures and expectations. 
Exclusion Criteria: 
1. Is mentally or legally incapacitated at the time of the Screening visit, prior to dosing on 
Day 1 of Treatment Period 1, or expected during the conduct of the study that in the 
opinion of the PI or designee indicates the subjects is inappropriate for the study. 
2. Have abnormal ECG measurements at Screening (any of the three individual ECG 
measurements) or prior to dosing on Day 1 of Treatment Period 1 indicating: 
• Second or third-degree AV block  
• QRS >120 msec 
• QTcF >450 msec (male) or >460 msec (female) 
• PR interval >220 msec 
3. Subject has a known personal or family history of congenital long QT syndrome or 
known family history of sudden death. 
4. Subject has a supine resting bradycardia (pulse <40 bpm) or a supine resting 
tachycardia (pulse >100 bpm) at Screening or prior to dosing on Day 1 of Treatment 
Period 1.  
5. Lung disease other than stable, mild asthma; worsening of asthma that requires a 
change in asthma therapy or is deemed clinically significant by the PI or Sponsor 
Medical Monitor. 
6. History of clinically significant hypotensive episodes or symptoms of fainting, 
dizziness, or light-headedness. 
7. History of lymphoma, leukemia, or other types of malignancy (except for completely 
resected squamous or basal cell cancer. 
8. Any signs of respiratory tract infection within 6 weeks of screening or prior to dosing 
on Day 1 of Treatment Period 1 that are deemed clinically significant by the PI or 
Sponsor Medical Monitor. 
9. Subject who has a current bacterial, parasitic, fungal, or viral infection; any infection 
requiring hospitalization or intravenous antibiotics within 6 months prior to Screening; 
any infection requiring oral or topical antimicrobial treatment within 2 weeks prior to 
Screening or prior to dosing on Day 1 of Treatment Period 1; a history of more than 
one episode of herpes zoster infection. 


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10. Any evidence of current or previous clinically significant disease (with the exception 
of stable, mild asthma): e.g., uncontrolled hyperthyroidism, uncontrolled diabetes 
mellitus or other endocrine disease; clinically relevant hepatic impairment; clinically 
relevant renal impairment; cardiovascular disease (e.g., uncontrolled coronary artery 
disease, uncontrolled hypertension, uncontrolled hypercholesterolemia); uncontrolled 
gastrointestinal disease (e.g., active peptic ulcer); neurological disease (including 
transient ischemic attack (TIA), stroke, seizure disorder, or behavioral disturbances); 
uncontrolled hematological disease; uncontrolled autoimmune disorders, or other 
which may impact the feasibility of the results of the study according to the judgment 
of the PI or Sponsor Medical Monitor. 
11. History of life-threatening asthma, defined as an asthma episode that required 
intubation and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic 
seizures or hospitalization (including emergency room visits) for the treatment of 
asthma within 3 months of Screening, or have been hospitalized or have attended 
emergency room visits for asthma more than twice in last 12 months.  
12. Subject has any condition of the oro-laryngeal or respiratory tract (including, but not 
limited to, prior surgery) that could possibly affect drug administration, deposition, or 
absorption, or ability to perform lung function measurements (spirometry), inhaled 
allergen challenge, or sputum induction, as determined by the PI or Sponsor Medical 
Monitor. 
13. Positive urine or breath alcohol results at Screening or Day 1 of Treatment Period 1, or 
history or presence of alcoholism within the past 2 years prior to dosing on Day 1 of 
Treatment Period 1. 
14. Alcohol consumption of >21 units per week for males or >14 units per week for 
females, with one unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of 
wine depending on type. 
15. Positive urine drugs of abuse test result (unless in the opinion of the investigator this 
can be explained by the patient’s current medications) at Screening or prior to dosing 
on Day 1 of Treatment Period 1. 
16. Positive urine cotinine test result at Screening or prior to dosing on Day 1 in Treatment 
Period 1.  
17. Uses or has used tobacco or nicotine-containing products (e.g., cigarettes, cigars, 
vaping devices, chewing tobacco, snuff, patches etc.) within 6 months prior to 
Screening, or has history of >5 pack-years. 
18. History of hypersensitivity to drugs, latex allergy, band aids, adhesive dressing, or 
medical tape, with a clinically significant reaction as determined by the PI or designee.  
19. History of serious adverse reaction, severe hypersensitivity or allergy to any drug or in 
any other circumstance (e.g., anaphylaxis). 
20. Female subjects with a positive pregnancy test at Screening or prior to dosing on Day 1 
of Treatment Period 1, or who are breastfeeding or lactating. 


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21. Subjects who have had a live viral vaccine (e.g., MMR, varicella zoster, herpes zoster, 
oral polio virus, FluMist, attenuated typhoid fever vaccine, or attenuated rotavirus 
vaccine) within 8 weeks prior to Screening and/or are unwilling to avoid live viral 
vaccines for until at-least 8 weeks following completion of the final study visit. 
22. Positive results at screening for HIV, HAV antibodies (anti-HAV: both IgG and IgM 
positive, IgG positive in the absence of IgM positive is acceptable), HBsAg, or HCV. 
23. Subject who has a history of latent or active tuberculosis. 
24. Unable to refrain from or anticipates the use of any drug including prescription and 
non-prescription medications, herbal remedies, or vitamin supplements beginning 
14 days prior to Screening and throughout the study.  
• Paracetamol (up to 1 g per 24 hours) will be allowed from Screening and 
throughout the study.  
• Hormone replacement therapy will be allowed.  
• Medication listed as part of acceptable birth control methods will be allowed 
(Section 6.4).  
• Oral and inhaled corticosteroids (ICS) (or ICS/long acting beta agonist) are 
prohibited for 6 weeks prior to Screening and throughout the study.  
• A short-acting inhaled beta agonist may be used as required, with the exception of 
8 hours before lung function assessments.  
• Stable treatment (same medication and dose) of medications for at least 3 months 
prior to dosing on Day 1 of Treatment Period 1 (other than prohibited medications 
that the PI and Sponsor consider to neither compromise subject safety or not to 
affect study data) may be permitted on a case-by-case basis. 
25. Subject has dietary restrictions incompatible with the diet that can be provided by the 
study site, in the opinion of the PI or designee. 
26. Donation of blood (≥400 mL) or plasma, or significant blood loss within 56 days prior 
to dosing on Day 1 of Treatment Period 1. 
27. Donation of bone marrow within the last 6 months prior to dosing on Day 1 of 
Treatment Period 1. 
28. Subject has previously received TD-8236. 
29. Participation in another clinical study (including medical device study) within 60 days, 
or < 5.5 half-lives of the last administration of an investigational drug, whichever is 
longer. The 60-day / 5.5 half-lives window will be derived from the date of the last 
dosing in the previous study to Day 1 of the current study. 
30. Exposure to biologic therapies (approved or experimental, e.g., monoclonal antibodies, 
allergen immune therapy) within the last 6 months prior to dosing on Day 1 of 
Treatment Period 1. 


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Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:   
TD-8236 
  administered by 
inhalation in the morning daily for 14 days 
TD-8236
  administered by inhalation in the morning daily 
for 14 days. 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:   
Placebo 
 administered by inhalation in the morning daily for 
14 days.  
Study Evaluations: 
Safety Assessments 
Subject safety will be assessed throughout the study using standard measures, including vital 
signs, 12-lead ECGs, blood and urine safety laboratory tests, physical examinations, 
concomitant medication usage, and adverse event (AE) monitoring. 
Pharmacokinetic Assessments 
• Day 14 blood samples for assessment of TD-8236 plasma concentrations will be 
collected pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose 
• Only pre-dose blood samples will be collected on Day 1 and Day 7 for assessment 
of TD-8236 plasma concentrations 
• 
 
Pharmacodynamic Assessments 
• Inhaled allergen challenge 
 
 
 
 
 
 
 
 
 
 
Statistical Methods: 
Sample Size 
 


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Study Endpoints 
The primary endpoint(s) of this study are: 
• Area under the curve (AUC) of change from baseline FEV1 from 3 to 8 hours after 
inhaled allergen challenge at Day 14 
The key secondary endpoint(s) are: 
• AUC of percentage change from baseline in FEV1 from 3 to 8 hours after inhaled 
allergen challenge at Day 14 
• Maximum decline in FEV1 from 3 to 8 hours after inhaled allergen challenge at 
Day 14 
• Maximum percentage decline in FEV1 from 3 to 8 hours after inhaled allergen 
challenge at Day 14 
• Day 14 plasma PK parameters of TD-8236 in subjects with mild asthma 
• Safety and tolerability of TD-8236 over 14 days of dosing, including frequency and 
severity of adverse events, vital signs, clinical laboratory evaluations, and 12-lead 
ECG changes from baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Analysis 
All safety data will be presented in listings. Descriptive summary tables will be provided for 
treatment-emergent adverse events, clinical laboratory evaluations, vital signs, 12-lead ECG 
parameters, and concomitant medications.  
 
 
 
 
 
 
 
 
 
 
 


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SCHEDULE OF STUDY PROCEDURES 
Table 1:  
Schedule of Study Procedures—Daily Assessments Screening through End of Study 
Study Procedures a  
Days → 
Screening 
Treatment Phase  
(for each Treatment Period [TP]) 
FU/ ET  
S1 
(-35 to -8)b 
S2 
(-35 to -8)b 
S3 
(S2+1)  
1  
7  
(±1) 
14  
15   
+14 
(±2)c  
General Procedures 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
X d  
 
 
 
 
Demographics and Medical history 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
X e 
 
 
 
X 
Inhaler training and PIF testing with In-check f 
X 
 
 
X e 
X e 
X e 
 
 
Study drug reconciliation 
 
 
 
 
X 
X 
 
 
Study drug dispensing 
 
 
 
X 
X 
 
 
 
TD-8236 administrationg 
 
 
 
X 
X 
X 
 
 
Subject Dosing Diary h 
 
 
 
X 
X 
X 
 
 
Safety Evaluations  
 
 
 
 
 
 
 
 
Physical examination i 
X 
 
 
 
 
 
 
 
Symptom-driven physical examination j 
 
X 
X 
X 
X 
X 
X 
X 
12-Lead safety ECG k 
X 
 
 
X e 
X e 
X e 
 
X 
Vital Signs (pulse, BP, temp, RR) 
X 
 
 
X e 
X e 
X e 
 
X 
Hematology, serum chemistry, and urinalysis l 
X 
 
 
X e 
X e 
X e 
X 
X 
Immunophenotyping (NK, T, and B cell counts) 
 
 
 
X e 
 
X e 
 
X 
Coagulation  
X 
 
 
X 
 
X 
 
X 


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Table 1:  
Schedule of Study Procedures—Daily Assessments Screening through End of Study 
Study Procedures a  
Days → 
Screening 
Treatment Phase  
(for each Treatment Period [TP]) 
FU/ ET  
S1 
(-35 to -8)b 
S2 
(-35 to -8)b 
S3 
(S2+1)  
1  
7  
(±1) 
14  
15   
+14 
(±2)c  
Serum FSH (postmenopausal females only) m 
X 
 
 
 
 
 
 
 
Urine or serum pregnancy test (WOCBP only) n 
X 
X 
 
X 
 
X 
 
X 
Urine drug test 
X 
 
 
X 
 
 
 
 
Urine cotinine test 
X 
 
 
X 
 
 
 
 
Breath or urine alcohol screen 
X 
 
 
X 
 
 
 
 
HIV/Hepatitis test 
X 
 
 
 
 
 
 
 
Tuberculosis (Quantiferon) test 
X 
 
 
 
 
 
 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
Salbutamol dispensing o 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics / Pharmacodynamics 
 
 
 
 
 
 
 
 
Allergen skin test 
X 
 
 
 
 
 
 
 
Inhaled allergen challenge 
 
X 
 
 
 
X p 
 
 
Spirometry q 
X 
 
 
X 
X 
X 
 
X 
  
 
  
  
  
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
  
 
 
 
 
 
  
  
  
 
 


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Table 1:  
Schedule of Study Procedures—Daily Assessments Screening through End of Study 
Study Procedures a  
Days → 
Screening 
Treatment Phase  
(for each Treatment Period [TP]) 
FU/ ET  
S1 
(-35 to -8)b 
S2 
(-35 to -8)b 
S3 
(S2+1)  
1  
7  
(±1) 
14  
15   
+14 
(±2)c  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Other Procedures 
 
 
 
 
 
 
 
 
Study visits 
X 
X v 
X v 
X 
X 
 
 
X 
Residence in the CRU 
 
 
 
 
 
X w 
X w 
 
a 
For details on Procedures, refer to Section 6. 
b 
Screening procedures (including informed consent) may be performed over more than 1 day. Repeats of study procedures are permitted on the day and/or on 
another day during screening or treatment period (as appropriate) at the discretion of the PI(s).  Additionally screening visits S1 and S2 may be combined 
into 1 visit day and in such a case procedures scheduled for both visits are only needed to be performed once (e.g., FeNO, pregnancy test). 
c 
The followup visit is performed 14 days +/- 2 days following the last dose of study medication in Treatment Period 3 only 
d 
Inclusion & exclusion criteria for initial study entry are evaluated only in Treatment Period 1; for subsequent periods assessment for study continuation 
should be evaluated as described in Section 6.6. 
e 
To be perform prior to dosing 
f 
At Screening and pre-dose on Day 1, Day 7 (+ 1 day) and Day 14 of each Treatment Period, the correct use of the inhaler will be explained to the subject and 
each subject will train with an empty capsule, and PIF will be measured using an 
. Generation of sufficient PIF at all sessions will be 
considered a requirement for participation/continuation in the study (Section 4.1, item 7).  
g 
Study drug will be administered at the CRU by study staff following any pre-dose procedures associated with the Study Visit. 
h 
Subject will be provided a daily dosing diary on Day 1 and will be reviewed by study staff and reissued to the subject on Day 7 and reviewed again and 
collected by study staff on Day 14 of each period.   Any deviations or missed doses will be noted in the source documents.  
i 
Full PE is required at the Screening Visit. A symptom-driven PE will be conducted at other scheduled time points as described below. 
j 
Symptom-driven physical examinations will be performed at the PI’s or designee’s discretion, as needed, and at other times to focus on evaluation of AEs 
throughout the study, if any, including any emergence of symptoms or worsening of any abnormalities identified, but found by the PI to be non-clinically 
significant, on the screening or check-in examination(s) since the last study day or physical exam. Symptom-driven examinations should be performed for 
any AE or existing AE that increases in severity or frequency. Refer to Section 7 of the protocol for more information. 
k 
At screening, triplicate 12-lead ECG will be conducted. At all other scheduled time points, safety 12-lead ECGs will be conducted as a single 12-lead ECG. 
l 
Samples for serum chemistry will be obtained following a fast of at least 9 hours (water permitted), however, in case of dropouts or rechecks, subjects are 
not required to have fasted for 9 hours ahead of the serum chemistry sample draw. 


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m To be conducted for postmenopausal women who did not undergo any sterilization procedures as detailed in Section 6.3.10 and where postmenopausal state 
is in question. 
n 
Serum pregnancy test will be conducted at Screening and at the follow-up visit. Urine pregnancy test will be conducted prior to each allergen challenge, and 
predose on Days 1 and 14 of each Treatment Period. 
o 
Salbutamol will be dispensed at screening and can be dispensed at other times during the study as required. 
p 
The inhaled allergen challenge will be performed 1-hour post-dose on Day 14. 
q 
Spirometry testing will be performed prior to the dose, as applicable.  Spirometry that is conducted as part of other study procedures, e.g., bronchial 
challenges and sputum induction, will be covered in a separate Allergen Challenge Study manual. 
r 
 
 
 
  
 
 
 
 
. 
u 
Blood for PK assessments will be collected predose and 0.5, 1, 2, 4, 6, 8, and 24 hours following the dose on Day 14 in each Treatment Period. Note Day 14 
Post dose PK samples are to be taken on the timepoint with the exception that if a post-allergen FEV1 coincides with a PK collection (e.g., 1 hr sample) the 
FEV1 measurement will be prioritized; blood sample collection for PK analysis will be performed at the earliest convenience either before or after the FEV1 
(within allowed permitted windows). 
v 
Subjects will be discharged home after the screening allergen challenge and will return the following day for S3 procedures. Subjects may be required to stay 
overnight on S2 visit if required to do so for reasons of safety at the discretion of the investigator. 
w Subjects will be resident overnight on Day 14 and will be discharged on Day 15.  Subjects may be allowed to be discharged on the evening of Day 14 and 
return to the clinic on the morning of Day 15 at the discretion of the investigator. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................21 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Background and Rationale ..........................................................................................24 
1.2. 
Nonclinical Profile ......................................................................................................24 
1.2.1. 
Pharmacology .............................................................................................................24 
1.2.2. 
Toxicology ..................................................................................................................25 
1.2.3. 
Pharmacokinetics ........................................................................................................27 
1.3. 
Clinical Experience .....................................................................................................28 
1.4. 
Risks and Benefits ......................................................................................................29 
1.4.1.1. 
Risks of Allergen Challenge .......................................................................................30 
1.4.1.2. 
Risks of Lung Function Tests Including Sputum Induction .......................................31 
1.4.1.3. 
Risks of Skin Prick Testing ........................................................................................31 
2. 
OBJECTIVES .............................................................................................................32 
3. 
STUDY DESIGN .......................................................................................................33 
3.1. 
Overview .....................................................................................................................33 
3.2. 
Rationale for Study Design .........................................................................................34 
3.3. 
Selection of Doses and Duration of Treatment ...........................................................35 
3.4. 
Study Endpoints ..........................................................................................................35 
3.5. 
Minimization of Bias ..................................................................................................37 
3.5.1. 
Blinding ......................................................................................................................37 
3.5.2. 
Procedures for Breaking the Blind Prior to Study Completion ..................................37 
3.5.3. 
Revealing of Randomization ......................................................................................38 
3.5.4. 
Treatment Assignment ................................................................................................38 
4. 
STUDY POPULATION .............................................................................................39 
4.1. 
Inclusion Criteria ........................................................................................................39 
4.2. 
Exclusion Criteria .......................................................................................................40 
5. 
STUDY DRUGS ........................................................................................................44 
5.1. 
Description of Study Drugs ........................................................................................44 
5.1.1. 
TD-8236 ......................................................................................................................44 
5.1.2. 
Placebo ........................................................................................................................44 


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5.2. 
Dosage and Administration ........................................................................................44 
5.2.1. 
Training with In-Check DIAL Device ........................................................................44 
5.2.2. 
Training with Empty Capsules ...................................................................................45 
5.3. 
Treatment Compliance ................................................................................................45 
5.4. 
Drug Accountability and Reconciliation ....................................................................45 
6. 
STUDY PROCEDURES ............................................................................................46 
6.1. 
Schedule of Study Procedures ....................................................................................46 
6.2. 
Total Blood Volume ...................................................................................................46 
6.3. 
Description of Study Assessments ..............................................................................47 
6.3.1. 
Informed Consent .......................................................................................................47 
6.3.2. 
Allergen Challenge .....................................................................................................47 
6.3.3. 
Spirometry ..................................................................................................................47 
6.3.4. 
Skin Prick Test ............................................................................................................48 
6.3.7. 
Safety Assessments .....................................................................................................48 
6.3.7.1. 
Physical Examination .................................................................................................48 
6.3.7.2. 
Vital Signs ..................................................................................................................48 
6.3.7.3. 
12-Lead ECGs ............................................................................................................49 
6.3.7.4. 
Body Weight ...............................................................................................................49 
6.3.7.5. 
Clinical Laboratory Tests ...........................................................................................49 
6.3.8. 
Meals ...........................................................................................................................51 
6.3.9. 
Activity .......................................................................................................................51 
6.3.10. 
Contraception ..............................................................................................................51 
6.3.11. 
Pharmacokinetic Assessments ....................................................................................52 
6.3.12. 
Blood Pharmacodynamic Assessments ......................................................................52 
6.4. 
Concomitant Medications ...........................................................................................52 
6.5. 
Restrictions .................................................................................................................53 
6.6. 
Continuation and Discontinuation ..............................................................................55 
6.6.1. 
Subject Discontinuation ..............................................................................................55 
6.6.2. 
Subject Replacement ..................................................................................................55 
6.6.3. 
Study Discontinuation ................................................................................................56 


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6.6.4. 
End of Trial .................................................................................................................56 
6.7. 
Pregnancy ...................................................................................................................56 
7. 
ADVERSE EVENTS ..................................................................................................57 
7.1. 
Definitions ..................................................................................................................57 
7.1.1. 
Adverse Events (AE) ..................................................................................................57 
7.1.2. 
Serious Adverse Event (SAE) ....................................................................................58 
7.1.3. 
Additional Considerations for Serious Adverse Events .............................................58 
7.2. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ................................................................59 
7.3. 
Assessment of Adverse Events ...................................................................................59 
7.3.1. 
Severity .......................................................................................................................59 
7.3.2. 
Causal Relationship to Study Medication ...................................................................59 
7.4. 
AE Reporting and Recording ......................................................................................60 
7.4.1. 
AE Reporting ..............................................................................................................60 
7.4.2. 
AE and SAE Recording ..............................................................................................60 
7.4.3. 
SAE Reporting Timeline ............................................................................................61 
7.5. 
Adverse Event Follow-up ...........................................................................................62 
8. 
STATISTICAL CONSIDERATIONS .......................................................................63 
8.1. 
General Considerations ...............................................................................................63 
8.2. 
Sample Size and Power ..............................................................................................63 
8.3. 
Analysis Sets ...............................................................................................................63 
8.3.1. 
Examination of Subgroups .........................................................................................63 
8.3.2. 
Major Protocol Analysis Deviations ...........................................................................64 
8.4. 
General Analyses ........................................................................................................64 
8.4.1. 
Demographics Characteristics ....................................................................................64 
8.4.2. 
Analysis of Pharmacodynamics/Efficacy ...................................................................64 
8.4.2.1. 
Pharmacodynamics/Efficacy endpoints ......................................................................64 
8.4.2.2. 
Primary Pharmacodynamics/Efficacy Evaluation ......................................................65 
8.4.3. 
Secondary and Exploratory Pharmacodynamics/Efficacy Evaluations ......................66 
8.4.4. 
Multiplicity Adjustment ..............................................................................................66 
8.4.5. 
Analysis of Pharmacokinetics .....................................................................................66 
8.5. 
Safety Analyses ..........................................................................................................66 


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8.5.1. 
Extent of Exposure .....................................................................................................66 
8.5.2. 
Adverse Event Data ....................................................................................................66 
8.5.3. 
Concomitant Medications ...........................................................................................67 
8.5.4. 
Laboratory Data ..........................................................................................................67 
8.5.5. 
Vital Signs Data ..........................................................................................................67 
8.5.6. 
ECG Data ....................................................................................................................68 
8.6. 
Missing Data Handling ...............................................................................................69 
8.7. 
Interim Analysis ..........................................................................................................69 
8.8. 
Data Monitoring Committee .......................................................................................69 
9. 
STUDY ADMINISTRATION ...................................................................................70 
9.1. 
Principal Investigator Responsibilities .......................................................................70 
9.2. 
Institutional Review Board/Independent Ethics Committee ......................................71 
9.3. 
Informed Consent .......................................................................................................71 
9.4. 
Data Recording and Quality Assurance ......................................................................71 
9.5. 
Document Retention ...................................................................................................72 
9.6. 
Confidentiality ............................................................................................................72 
9.7. 
Access to Data and Documents ..................................................................................73 
9.8. 
Quality Control: Study Monitoring and Auditing ......................................................73 
9.9. 
Publication ..................................................................................................................74 
10. 
REFERENCES ...........................................................................................................75 
APPENDIX 2. PROTOCOL SIGNATURE FORM ...................................................................78 
 


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LIST OF TABLES 
Table 1:  
Schedule of Study Procedures—Daily Assessments Screening through End 
of Study .......................................................................................................................12 
Table 2: 
Summary of NOAELs from Nonclinical Inhalation Repeat-Dose Studies and 
Corresponding Pulmonary Deposited Dose Multiples Compared to a Clinical 
Dose of 4000 µg TD-8236 ..........................................................................................26 
Table 3: 
Plasma Exposure Multiples at the NOAELs of Repeat-Dose, Embryo­Fetal 
Development, and Safety Pharmacology Studies Compared to Human 
Exposures at a Clinical Dose of 4000 µg TD-8236 ....................................................27 
Table 4: 
Outlier Threshold for Vital Signs ...............................................................................67 
Table 5: 
ECG Test Outlier Thresholds .....................................................................................68 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................34 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
AE 
adverse event 
ACQ-5 
Asthma control questionnaire – 5 question version 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the curve 
BMI 
body mass index 
BP 
blood pressure 
CFR 
(United States) Code of Federal Regulations 
CS 
clinically significant 
CRF 
case report form 
CRU 
clinical research unit 
DPI 
dry powder inhaler 
EAR 
early asthmatic response 
ECG 
electrocardiogram 
ECP 
eosinophilic cationic protein 
EDC 
electronic data capture 
ERS 
European Respiratory Society 
FEV1 
forced expiratory volume in 1 minute 
FeNO 
fractional exhaled nitric oxide 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HED 
human equivalent dose 


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Abbreviation 
Description 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator's Brochure 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
ICF 
informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
ICS 
inhaled corticosteriod 
IEC 
Independent Ethics Committee 
IH 
inhalation 
INR 
international normalization ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
intravenous 
JAK 
Janus kinase 
JAK/STAT 
Janus kinase and signal transducers and activators of transcription 
pathway 
LAR 
late asthmatic response 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
MMR 
measles, mumps and rubella 
NCS 
not clinically significant 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect-level 
NSAIDS 
non-steroidal anti-inflammatory drugs 
OA 
oral aspiration 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PI 
principal investigator 


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Abbreviation 
Description 
PIFR 
peak inspiratory flow rate 
PIF 
peak inspiratory flow 
PK 
pharmacokinetic(s) 
PO 
orally 
PRO 
patient reported outcome 
QD 
once a day, daily 
QTc 
corrected QT interval 
REC 
Research Ethics Committee 
SAD 
single ascending dose 
SAE 
serious adverse event 
SC 
subcutaneous 
SOP 
standard operating procedure 
STAT 
signal transducers and activators of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
TYK2 
tyrosine kinase 2  
WOCBP 
woman of child-bearing potential 
 


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1. 
INTRODUCTION 
1.1. 
Background and Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2. 
Nonclinical Profile 
A review of the nonclinical profile of TD-8236 can be found in the current version of the 
TD-8236 Investigator’s Brochure (IB).6  The following is a brief summary of the pertinent 
findings. 
1.2.1. 
Pharmacology 
 
 
 
 
 
 


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1.2.2. 
Toxicology 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 


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1.3. 
Clinical Experience 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.4. 
Risks and Benefits 
TD-8236 is potentially effective for the treatment of asthma. However, since this study will be 
evaluating multiple doses of limited duration in subjects with well-controlled, mild asthma, no 
health benefits are anticipated. An indirect health benefit to the subjects enrolled in this study is 
the free medical tests received at screening and during the study. 
Preliminary results from the completed portions of the ongoing Phase 1 study with TD-8236 in 
healthy subjects and subjects with mild asthma have demonstrated TD-8236 to be generally well 
tolerated without clinically significant effects on laboratory parameters or adverse event 
incidence 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
Pregnancy prevention procedures and avoidance of semen donation for 30 days after the last 
dose of TD-8236 should be followed by all male subjects, based on the same rationale and 
conservative timeframe required for females prior to obtaining human PK data. 
Subjects receiving repeated oral doses of other compounds in this pharmacological class 
(e.g., tofacitinib, a systemically available JAK inhibitor) on a longer term basis have exhibited 
alterations in cholesterol, liver function tests, decreased red blood cell and white blood cell 
subset (neutrophils and lymphocytes) counts, and risk of infection, cancer, intestinal perforation, 
headache, diarrhea, rhinorrhea, nasopharyngitis, and sore throat.10  Given the low systemic 


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exposures of TD-8236 measured in the Phase 1 study relative to the systemic exposure of 
tofacitinib published in the literature, these risks are anticipated to be minimal with TD-8236.  
In clinical studies to date, no sign of systemic immunosuppression or adverse effect on lipid 
parameters has been observed in laboratory evaluation or in adverse events reported in healthy 
subjects receiving single doses up to 4500 µg or mild asthmatic subjects dosed up to 4000 µg per 
day for 7 days. 
The potential for findings in human subjects will be carefully assessed in this study with an 
anticipated treatment duration of three periods of 14 days each. Assessments include scheduled 
and symptom-driven physical exam (including temperature measurements), spirometry testing, 
and monitoring of complete blood cell counts with differential (including Natural Killer [NK] 
cells as a marker for systemic immunosuppression). The safety monitoring practices employed 
by this protocol (i.e., 12-lead ECG, vital signs, spirometry, clinical laboratory tests, AE 
questioning, and physical examinations) are adequate to protect the subjects’ safety and should 
detect all expected treatment-emergent AEs. 
The approximate volume of blood planned for collection from each subject over the course of the 
study (Section 6.2), presents no undue risk to the subjects nor does the possibility of collection of 
additional blood in the event an indwelling cannula (for wasting to ensure clean sample) is 
utilized and the possibility of additional blood for recheck of safety labs if deemed necessary by 
the PI. 
Subjects must consent to four inhaled allergen challenge and eight induced sputum procedures.   
1.4.1.1. 
Risks of Allergen Challenge  
When conducted by experienced investigators in the appropriate setting, bronchial allergen 
challenge is safe and well-tolerated in the patient population proposed for this study. However, 
because there is a risk of inducing severe, acute bronchoconstriction or anaphylaxis,11 bronchial 
allergen challenge will not be performed on subjects with severe or unstable asthma. The 
procedures produce a reaction that might be similar to a mild asthma attack such as cough, chest 
tightness and/or wheezing. Many subjects do not have any symptoms at all (typically 70 to 80%). 
Symptoms (if they occur) are mild, last only a few minutes, and disappear following the 
inhalation of a bronchodilator medication (e.g., salbutamol), which will be administered to the 
subject. The test is carried out in such a way that the danger of a severe asthmatic reaction is 
minimized. However, there is still a rare possibility (less than 1 in 1000) of severe narrowing of 
the subject’s airways. The subject will be carefully monitored and if this occurs, the subject will 
be immediately treated. The cumulative dose of allergen required to achieve a successful 
response at Screening will be administered as a bolus during the treatment periods. This bolus 
dose may be modified by the PI for reasons of subject safety.  The “new” bolus dose should 
thereafter remain consistent throughout the Treatment Periods. 


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1.4.1.2. 
Risks of Lung Function Tests Including 
  
 
 
 
 
 
1.4.1.3. 
Risks of Skin Prick Testing 
The skin prick test is performed at screening. The test is used to confirm the subject’ sensitivity 
to allergen used in the bronchial challenges. The subject may experience discomfort from the 
skin testing procedures. The discomfort may result from being pricked with a needle and/or from 
the itching or swelling that may occur at the site of the skin test. This usually goes away within 
30 to 60 minutes after the skin test, although it sometimes lasts 24 to 48 hours. Hives (itchy rash) 
and wheezing may occur in rare cases. Symptoms such as itching all over the body, sneezing, 
and eyelid swelling occur in 1 per 10,000 people. Any such reaction will be treated if necessary. 
 


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2. 
OBJECTIVES 
The primary objective of the study is as follows: 
• Characterize the late asthmatic response (LAR) in terms of area under the FEV1 curve 
after inhaled allergen challenge in mild asthmatic subjects receiving 14 days of 
TD-8236 or placebo 
The secondary objectives of the study are as follows: 
• Characterize the late asthmatic response (LAR) in terms of maximum decline in FEV1 
and area under the percent change FEV1 curve after inhaled allergen challenge in 
mild asthmatic subjects receiving 14 days of TD-8236 or placebo 
• Assess the pharmacokinetics (PK) of TD-8236 in subjects with asthma 
• Evaluate the safety and tolerability of inhaled TD-8236 administered for 14 days in 
subjects with mild asthma 
The exploratory objectives of the study are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overview 
This will be a randomized, double-blind, placebo-controlled, three-period, six-sequence, 
complete-block, cross-over study to characterize two doses of inhaled TD-8236 compared to 
placebo in subjects with mild asthma and a known response to an allergen challenge.  
Subjects will undergo an allergen challenge test at Screening as described by 
 
  Briefly, the challenge at Screening will consist of
 
 
administered as a bolus for subsequent challenges during the treatment periods. At the 
investigator’s discretion a subject may be required to stay resident in the research unit the 
evening following the screening allergen challenge assessment.  
Once a subject meets inclusion and exclusion criteria, and following a Screening period of up to 
35 days, the subject will be randomized to one of six treatment sequences.  Within each 
treatment sequence, subjects will receive each of three treatments in one of three treatment 
periods separated by a washout of at least 21 days between the last dose of the previous period 
and first dose of the next period. 
Each treatment period will consist of 14 days of treatment with one dose level of TD-8236 or 
placebo. Subjects will return to the clinic on Day 7 (±1 day) of each period for safety 
assessments, trough PK and PD sampling, as well as reconciliation and dispensing of study drug.  
Subjects will be in-residence at the clinic for Day 14 of each period, including an overnight stay 
to allow for serial PK sampling through 24 hours after the last dose.  At the investigator’s 
discretion subjects may be discharged the evening of Day 14 and return to the clinic the morning 
of Day 15. 
 
  
Subjects will undergo an allergen challenge test 1 hour after the last dose (Day 14) in each 
period.  The cumulative dose of allergen required to achieve a successful response at Screening 
will be administered as a bolus during the Treatment Periods. This bolus dose may be modified 
by the investigator for reasons of subject safety.  The modified bolus dose should thereafter 
remain consistent throughout the Treatment Periods. 


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Figure 1: 
Study Design Schematic 
 
3.2. 
Rationale for Study Design 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 


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expected to provide important guidance toward the next stage of 
TD-8236 development. 
3.3. 
Selection of Doses and Duration of Treatment 
 
  
 
 
 
 
 
 
 
 
3.4. 
Study Endpoints 
The primary endpoint(s) of this study are: 
• Area under the curve (AUC) of change from baseline FEV1 from 3 to 8 hours after 
inhaled allergen challenge at Day 14 


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The secondary endpoint(s) are: 
• AUC of percentage change from baseline in FEV1 from 3 to 8 hours after inhaled 
allergen challenge at Day 14 
• Maximum decline in FEV1 from 3 to 8 hours after inhaled allergen challenge at Day 
14 
• Maximum percentage decline in FEV1 from 3 to 8 hours after inhaled allergen 
challenge at Day 14 
• Day 14 plasma PK parameters of TD-8236 in subjects with mild asthma 
• Safety and tolerability of TD-8236 over 14 days of dosing, including frequency and 
severity of adverse events, vital signs, clinical laboratory evaluations, and 12-lead 
ECG changes from baseline 
The exploratory endpoint(s) are: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5. 
Minimization of Bias 
This study is a randomized, double-blind, placebo-controlled, three-period, six-sequence, 
complete-block, cross-over study. The study subjects, site investigators, and site study staff will 
be blinded throughout the duration of the study (except for the unblinded site pharmacist and/or 
designee[s] and Sponsor’s drug supply representative, unblinded pharmacy monitor and PK 
bioanalyst).  
A computerized randomization scheme will be created and shall be considered blinded (as per 
the following). The randomization is available only to the clinical research unit (CRU) pharmacy 
staff that is preparing the drug who will not be involved in any other aspect of the study 
including administration of the drug. It will not be made available to the subjects, site(s) PI(s), or 
members of the staff responsible for the monitoring and evaluation of safety assessments, except 
as described in Section 3.5.1. 
3.5.1. 
Blinding 
TD-8236 and placebo capsules will be of the same shape, size, and color to ensure that the blind 
is maintained. Also, subjects who are randomized to receive placebo will receive the equivalent 
number of capsules as those randomized to receive TD-8236. A subject’s treatment assignment 
will only be unblinded when knowledge of the treatment is essential for the further clinical 
management of the subject on this study or may potentially impact the safety of subjects 
currently enrolled or subjects in subsequent enrollment.  Unblinding at the study site for any 
other reason will be considered a protocol deviation. In case of an emergency, the investigator 
has the sole responsibility for determining if unblinding of a participant’s treatment assignment 
is warranted. Participant safety must always be the first consideration in making such a 
determination.  
Sponsor Drug Safety personnel may independently unblind cases for expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs). With these exceptions, Sponsor 
personnel involved in the conduct of the study, data cleaning, or data analysis will remain 
blinded to study treatment assignments until the database has been locked for final analysis. To 
facilitate PK analysis, the analyst at the PK bioanalytical lab may be unblinded however any PK 
data provided to the sponsor for analysis will be provided in a blinded fashion (i.e., PK data 
cannot be linked to an individual subject).  
3.5.2. 
Procedures for Breaking the Blind Prior to Study Completion  
One set of sealed envelopes containing the randomization code will be supplied to the PI or 
designee at each study site at the start of the study. 
If breaking the blind is required because of a medical emergency, the treatment identity would be 
revealed by the PI or designee for that subject only. In the event that the emergency is one in 
which it appears that the other subjects may be at imminent risk, the blind may be broken for all 
subjects dosed at that dose level. The unblinding will be properly documented in the study file. 
The responsibility to break the blind resides solely with the PI (or designee), however, it is 
requested that the PI or designee will make every effort to contact the Medical Monitor or 
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practicable, granting that these efforts should not stall or delay the unblinding of trial subject 
treatment in emergency situations. 
In all cases where the code is broken, the PI or designee should record the date and reason for 
code breaking. 
At the end of the study, envelopes will be retained according to site procedures. 
3.5.3. 
Revealing of Randomization  
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed to any blinded person, as defined in Section 3.5.1, until all data are entered in the 
database, edits checks are performed, queries closed, eCRFs signed by the PI(s), and the database 
is officially locked.  
3.5.4. 
Treatment Assignment 
Each subject will be assigned a unique subject identification number upon consent. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique randomization number prior to the first dose, different from the screening number, and 
will receive the corresponding product according to a randomization scheme. 
 


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4. 
STUDY POPULATION 
Subjects who do not qualify based on a reversible condition or mild concurrent illness may be re-
screened after the condition is resolved. Screening procedures may be performed over more than 
1 day. Repeats of study procedures are permitted on the day and/or on another day during 
screening or treatment period (as appropriate) at the discretion of the PI(s).  
 
Re-screening will be allowed for a subject who could not be dosed within the permitted 
screening window for any reason, or as a pre-treatment failure (i.e., subject has not been treated); 
the reason for failure must be temporary and expected to resolve. If re-screened, the subject must 
be re-consented. 
4.1. 
Inclusion Criteria 
Subjects who meet the following criteria will be eligible for study enrollment: 
Inclusion Criteria: 
1. Male or female, 18 to 65 years of age, inclusive, at Screening. 
2. Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening and weighs ≥ 50 kg at 
Screening. 
3. Documented physician-diagnosed asthma for ≥ 4 months prior to Screening. 
4. Pre-bronchodilator FEV1 ≥ 70% predicted at Screening and prior to Day 1 dosing in 
Treatment Period 1. 
5. Documented allergy to at least one common allergen as confirmed by the skin prick test, 
with wheal diameter ≥3mm greater than the negative control.  Historical data up to one 
year can be used. 
6. Subject should be a dual responder to inhaled bronchial allergen challenges as manifested 
by positive allergen-induced early (EAR) and late airway bronchoconstriction (LAR) at 
screening, defined as follows: 
• 
 
  
 
 
 
 
7. Able to correctly use the dry powder inhaler (DPI) and to generate sufficient peak 
inspiratory flow rate (PIFR) (at least 40 L/min) using the 
 at 
Screening and prior to dosing on Day 1 of Treatment Period 1. 
8. Subject has no clinically significant abnormalities as determined by the PI in the results 
of laboratory evaluations at Screening, including: 
• Liver function tests (i.e., ALT, AST, ALP, GGT, and bilirubin) ≤ upper limit of 
normal or deemed medically acceptable at the discretion of the PI and Sponsor’s 
Medical Monitor 


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•
Absolute lymphocyte counts within normal range or should be deemed medically
acceptable at the discretion of the PI and Sponsor’s Medical Monitor
9. Subject must have a negative 
 Test result at Screening.
10. Pregnancy concerns:
•
Female subjects must be either of non-childbearing potential or if of childbearing
potential use a highly effective birth control method (Section 6.3.10) during the study
and through 30 days after the last dose of TD-8236.
•
Male subjects (with partners of childbearing potential) must use acceptable 
contraception (Section 6.3.10) during the study and through 30 days after the last 
dose of study medication
•
Male subjects must agree not to donate semen during the study and for 30 days after
the last dose of study medication
11. Understands the study procedures in the ICF and is willing and able to comply with the
protocol-defined study procedures and expectations.
4.2. 
Exclusion Criteria 
Subjects who satisfy any of the following criteria are not eligible for study enrollment: 
Exclusion Criteria: 
1. Is mentally or legally incapacitated at the time of the Screening visit, prior to dosing on
Day 1 of Treatment Period 1, or expected during the conduct of the study that in the
opinion of the PI or designee indicates the subjects is inappropriate for the study.
2. Have abnormal ECG measurements at Screening (any of the three individual ECG
measurements) or prior to dosing on Day 1 of Treatment Period 1 indicating:
•
Second or third-degree AV block
•
QRS >120 msec
•
QTcF >450 msec (male) or >460 msec (female)
•
PR interval >220 msec
3. Subject has a known personal or family history of congenital long QT syndrome or
known family history of sudden death.
4. Subject has a supine resting bradycardia (pulse <40 bpm) or a supine resting tachycardia
(pulse >100 bpm) at Screening or prior to dosing on Day 1 of Treatment Period 1.
5. Lung disease other than stable, mild asthma; worsening of asthma that requires a change
in asthma therapy or is deemed clinically significant by the PI or Sponsor Medical
Monitor.
6. History of clinically significant hypotensive episodes or symptoms of fainting, dizziness,
or light-headedness.


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7. History of lymphoma, leukemia, or other types of malignancy (except for completely 
resected squamous or basal cell cancer). 
8. Any signs of respiratory tract infection within 6 weeks of screening or prior to dosing on 
Day 1 of Treatment Period 1 that are deemed clinically significant by the PI or Sponsor 
Medical Monitor. 
9. Subject who has a current bacterial, parasitic, fungal, or viral infection; any infection 
requiring hospitalization or intravenous antibiotics within 6 months prior to Screening; 
any infection requiring oral or topical antimicrobial treatment within 2 weeks prior to 
Screening or prior to dosing on Day 1 of Treatment Period 1; a history of more than one 
episode of herpes zoster infection. 
10. Any evidence of current or previous clinically significant disease (with the exception of 
stable, mild asthma): e.g., uncontrolled hyperthyroidism, uncontrolled diabetes mellitus 
or other endocrine disease; clinically relevant hepatic impairment; clinically relevant 
renal impairment; cardiovascular disease (e.g., uncontrolled coronary artery disease, 
uncontrolled hypertension, uncontrolled hypercholesterolemia); uncontrolled 
gastrointestinal disease (e.g., active peptic ulcer); neurological disease (including 
transient ischemic attack (TIA), stroke, seizure disorder, or behavioral disturbances); 
uncontrolled hematological disease; uncontrolled autoimmune disorders, or other which 
may impact the feasibility of the results of the study according to the judgment of the PI 
or Sponsor Medical Monitor. 
11. History of life-threatening asthma, defined as an asthma episode that required intubation 
and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic seizures or 
hospitalization (including emergency room visits) for the treatment of asthma within 
3 months of Screening, or have been hospitalized or have attended emergency room visits 
for asthma more than twice in last 12 months.  
12. Subject has any condition of the oro-laryngeal or respiratory tract (including, but not 
limited to, prior surgery) that could possibly affect drug administration, deposition, or 
absorption, or ability to perform lung function measurements (spirometry), inhaled 
allergen challenge, or sputum induction, as determined by the PI or Sponsor Medical 
Monitor. 
13. Positive urine or breath alcohol results at Screening or Day 1 of Treatment Period 1, or 
history or presence of alcoholism within the past 2 years prior to dosing on Day 1 of 
Treatment Period 1. 
14. Alcohol consumption of >21 units per week for males or >14 units per week for females, 
with one unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine 
depending on type. 
15. Positive urine drugs of abuse test result (unless in the opinion of the investigator this can 
be explained by the patient’s current medications) at Screening or prior to dosing on 
Day 1 of Treatment Period 1. 
16. Positive urine cotinine test result at Screening or prior to dosing on Day 1 in Treatment 
Period 1.  


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17. Uses or has used tobacco or nicotine-containing products (e.g., cigarettes, cigars, vaping 
devices, chewing tobacco, snuff, patches etc.) within 6 months prior to Screening, or has 
history of >5 pack-years. 
18. History of hypersensitivity to drugs, latex allergy, band aids, adhesive dressing, or 
medical tape, with a clinically significant reaction as determined by the PI or designee.  
19. History of serious adverse reaction, severe hypersensitivity or allergy to any drug or in 
any other circumstance (e.g., anaphylaxis). 
20. Female subjects with a positive pregnancy test at Screening or prior to dosing on Day 1 
of Treatment Period 1, or who are breastfeeding or lactating. 
21. Subjects who have had a live viral vaccine (e.g., MMR, varicella zoster, herpes zoster, 
oral polio virus, FluMist, attenuated typhoid fever vaccine, or attenuated rotavirus 
vaccine) within 8 weeks prior to Screening and/or are unwilling to avoid live viral 
vaccines for until at-least 8 weeks following completion of the final study visit. 
22. Positive results at screening for HIV, HAV antibodies (anti-HAV: both IgG and IgM 
positive, IgG positive in the absence of IgM positive is acceptable), HBsAg, or HCV. 
23. Subject who has a history of latent or active tuberculosis. 
24. Unable to refrain from or anticipates the use of any drug including prescription and 
non-prescription medications, herbal remedies, or vitamin supplements beginning 
14 days prior to Screening and throughout the study.  
• Paracetamol (up to 1 g per 24 hours) will be allowed from Screening and throughout 
the study.  
• Hormone replacement therapy will be allowed.  
• Medication listed as part of acceptable birth control methods will be allowed 
(Section 6.4).  
• Oral and inhaled corticosteroids (ICS) (or ICS/long acting beta agonist) are prohibited 
for 6 weeks prior to Screening and throughout the study.  
• A short-acting inhaled beta agonist may be used as required, with the exception of 
8 hours before lung function assessments.  
• Stable treatment (same medication and dose) of medications for at least 3 months 
prior to randomization (other than prohibited medications that the PI and Sponsor 
consider to neither compromise subject safety or not to affect study data) may be 
permitted on a case-by-case basis. 
25. Subject has dietary restrictions incompatible with the diet that can be provided by the 
study site, in the opinion of the PI or designee. 
26. Donation of blood (≥400 mL) or plasma, or significant blood loss within 56 days prior to 
dosing on Day 1 of Treatment Period 1. 
27. Donation of bone marrow within the last 6 months prior to dosing on Day 1 of Treatment 
Period 1. 


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28. Subject has previously received TD-8236. 
29. Participation in another clinical study (including medical device study) within 60 days, or 
< 5.5 half-lives of the last administration of an investigational drug, whichever is longer. 
The 60-day / 5.5 half-lives window will be derived from the date of the last dosing in the 
previous study to Day 1 of the current study. 
30. Exposure to biologic therapies (approved or experimental, e.g., monoclonal antibodies, 
allergen immune therapy) within the last 6 months prior to dosing on Day 1 of Treatment 
Period 1. 
 
 


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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 
Investigational materials will be provided by the Sponsor as describe below.  In addition, 
 dry powder inhaler (DPI) devices will be provided by the Sponsor.  Further 
details are provided in a separate pharmacy manual. 
5.1.1. 
TD-8236 
TD-8236 capsules are prepared 
 
 
 
. 
Doses of TD-8236 to be evaluated include 
 
TD-8236 capsules will be packaged in individual-capsule blister packs and prepared as a 7-day, 
multi-fold blister card with labeling that is blinded to treatment identity. 
5.1.2. 
Placebo 
Placebo capsules will match the TD-8236 capsules in size, color and shape, and will contain the 
same 
.    
Placebo treatment will be administered as 
 
Placebo capsules will be packaged in identical packaging as the TD-8236 active drug product. 
5.2. 
Dosage and Administration 
Subjects will receive daily inhaled doses beginning Day 1 at Hour 0 through Day 14 in each 
period. Following the first dose, subsequent doses will be administered within ± 3 hour of the 
scheduled dosing time(s).  Hour 0 will be defined as the beginning of first capsule inhalation in 
each dose administration.  
The exact clock time for all doses administered in the CRU (i.e., Days 1, 7 and 14) will be 
recorded. 
Additional information regarding study drug dispensing, administration, handling and storage 
will be provided in a separate pharmacy manual. 
Doses may be administered without regard to timing relative to meals. 
5.2.1. 
Training with 
 
 
 
  


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5.2.2. 
Training with Empty Capsules 
Training will be conducted prior to dosing: at Screening, pre-dose on Day 1, Day 7 (+1 day), and 
Day 14 (in each period). The correct use of the inhaler will be explained to the subjects and 
training will be performed using empty capsules identical to the ones used for the study drug 
administration. 
The training kits will be kept at the site by the PI and will not be dispensed to the subjects. 
Subject will not be enrolled if the training is not completed with success. Training evidence will 
be recorded in the eCRF. 
5.3. 
Treatment Compliance 
At each return visit to the clinical site, staff will review the returned study medication and will 
record the number of capsules used and unused in the subject’s source records, including 
checking for any unexpected, unpierced capsules.  Any missed doses will be discussed with the 
subject to understand the reasons for the missed doses and subject retraining will be performed 
as needed.  Missed doses will be recorded in the eCRF. 
Subjects will be required to complete a daily dosing diary recording dosing each day.  
5.4. 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all study 
drug(s) received from the Sponsor, in accordance with applicable government regulations and 
study procedures. The accountability record will include entries for receipt, distribution or 
dispensing, and destruction of the material(s). Unused and expired study drugs will be disposed 
of in accordance with written instructions from the Sponsor. 
Subjects will be instructed to return all used and unused study drug containers at each visit. 
Compliance with the dosing regimen will be assessed by reconciliation of used and unused study 
drug. 
Refer to the separate pharmacy manual for more information. 


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6. 
STUDY PROCEDURES 
6.1. 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1. 
6.2. 
Total Blood Volume 
The total volume of blood to be drawn from each subject for 
 
  
Additional PK and/or PD samples may be added (Sections 6.3.11 and 6.3.12). Additional safety 
laboratory tests may be drawn, as required for safety assessments. 
Sample type 
Number of 
Time 
Points 
Approximate 
Volume per Time 
Point * (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology, and 
coagulation), FSH (for 
postmenopausal female subjects only, 
if postmenopausal status is in 
question) and serum pregnancy (for 
WOCBP only) as applicable. 
1 
 
 
Tuberculosis Test (
 
1 
 
 
On-study hematology and serum 
chemistry 
12 
 
 
On-study coagulation 
6 
 
 
 
 
 
 
 
 
 
 
 
Blood for TD-8236 PK 
30 
 
 
Follow-up laboratory safety tests 
(including hematology, serum 
chemistry, and coagulation) and 
serum pregnancy (for WOCBP only) 
as applicable. 
1 
 
 
Total Blood Volume (mL)→ 
 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** If additional PK analysis is necessary or if larger collection tubes are required to obtain sufficient plasma/serum for analysis, 
additional blood may be obtained (up to a maximum of 50 mL).  
 


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6.3. 
Description of Study Assessments 
The Schedule of Study Procedures (Table 1) summarizes the clinical procedures to be performed 
at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI or designee and/or the Sponsor for 
reasons related to subject safety. 
Safety will be determined by evaluating physical examinations, vital signs, safety 12-lead ECGs 
monitoring, clinical laboratory tests, and AEs as outlined in Table 1.  
During the study, every effort should be made to perform study procedures as listed in the Study 
Schedule of Procedures (Table 1).  For procedures scheduled to be performed at common times, 
collection of TD-8236 PK samples should be collected as close as possible to the designated time 
unless otherwise noted.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
6.3.1. 
Informed Consent 
Before any study specific procedures or study requirements are conducted on or expected of a 
subject, the subject must review and sign an IEC/IRB/REC-approved informed consent form. 
6.3.2. 
Allergen Challenge 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
6.3.3. 
Spirometry 
Spirometry (FEV1 and FVC) will be assessed as outlined in the Study Schedule of Procedures 
(Table 1) and measured using a spirometer that meets the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) recommendations. Spirometry will be performed in 
accordance with 
 
 


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6.3.4. 
Skin Prick Test 
A skin prick test will be performed at screening according to the Schedule of Study Procedures 
(Table 1), unless historical data is available within one year of screening.  Further information 
regarding the skin prick test and the allergen tests to be used will be covered in a separate study 
reference manual. 
6.3.5. 
 
 
6.3.6. 
 
 
 
  
6.3.7. 
Safety Assessments 
6.3.7.1. 
Physical Examination 
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Table 1).  
Symptom-driven physical examinations will be performed at the PI’s or designee’s discretion, as 
needed, and at other times to focus on evaluation of AEs throughout the study, if any, including 
any emergence of symptoms or worsening of any abnormalities identified, but found by the PI to 
be non-clinically significant, on the screening or check-in examination(s) since the last study day 
or physical exam. Symptom-driven examinations should be performed for any AE or existing AE 
that increases in severity or frequency. Symptom-driven examinations may include the 
assessment of the following body systems: general appearance; head, ears, eyes, nose, and throat; 
neck; skin/dermatologic system; cardiovascular system; respiratory system; 
abdomen/gastrointestinal system; lymphatic system; musculoskeletal system; and nervous 
system. 
6.3.7.2. 
Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure (BP), and pulse, will 
be measured as outlined in the Schedule of Study Procedures (Table 1). Additional vital signs 
may be taken at any other times, if deemed necessary. 
Blood pressure and pulse measurements will be performed after subjects have been resting for at 
least 5 minutes in the supine position. Where possible, subject position, measurement device, and 
arm (left versus right) should be kept consistent throughout the study, except when subjects are 
placed in a supine or semi-reclined position because of AEs (e.g., nausea, dizziness) or if deemed 
necessary by the PI or designee. 
Any vital may be repeated at the discretion of the PI or designee. Collection of additional vital 
sign measurements for routine safety monitoring at additional time points or study days may be 
performed at the discretion of the PI or designee, or upon request by the Sponsor. 


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6.3.7.3. 
12-Lead ECGs  
Electrocardiograms (ECG) will be performed as outlined in the Study Schedule of Procedures 
(Table 1).  
A subject will be withdrawn from the study by the Investigator or his/her designee if, in their 
medical judgment, safety 12-lead ECG findings are present which make continued study 
participation not in the subject’s best interest. 
At the Screening visit, triplicate 12-lead ECG will be performed. Triplicate 12-lead ECG 
recordings will be taken within a 5-minute time window. Single 12-lead ECGs will be performed 
at all other times. 
ECGs will be taken following resting for at least 10 minutes in the supine position in a quiet 
environment. Single 12-lead ECGs may be taken at any other times, if deemed necessary.  
ECGs will be interpreted and signed and dated by the Investigator or his/her designee. The ECGs 
will be classified as normal, having a non-clinically significant abnormality (NCS), or having a 
clinically significant abnormality (CS). In addition, ECG parameters of ventricular heart rate 
(HR), PQ interval, PR interval, QRS duration, and QT interval (corrected and uncorrected) will 
be noted on the eCRF. All CS findings will be recorded as AEs. 
6.3.7.4. 
Body Weight 
Body weight (kg) will be reported as outlined in the Study Schedule of Procedures (Table 1).  
6.3.7.5. 
Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Table 1). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the PI or designee. 


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Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or AEs 
during the study (including after follow up visit) may be performed at the discretion of the PI or 
upon request of the Sponsor. 


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6.3.8. 
Meals 
Food and water will be restricted for 1 hour prior to each 
 At all other times, 
water will be allowed ad libitum.  
When subjects are confined (Day 14 in each period), meals and snacks will be provided at 
appropriate times, except when subjects are required to fast. When confined in the CRU, subjects 
will be required to fast from all food and drink except water between meals and snacks. 
6.3.9. 
Activity 
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports from 48 hour prior to and during all visits and 
throughout each treatment period (i.e., 48 hrs prior to Day 1 until discharged on Day 15). 
6.3.10. 
Contraception 
Female subjects of childbearing potential must use one of the following highly effective 
contraceptive measures during the study and for at least 30 days after the last dose of study drug: 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal occlusion 
• vasectomised partner * 
• sexual abstinence ** 
* Vasectomised partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the woman of childbearing potential (WOCBP) trial participant and that 
the vasectomised partner has documented medical assessment of the surgical success. 
** True abstinence is defined as refraining from heterosexual intercourse in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of 
exposure to study drug, and withdrawal are not acceptable methods of contraception. 


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To be considered a female of non-childbearing potential, the subject must have undergone one of 
the following sterilization procedures at least 6 months prior to dosing: 
• bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy. 
or be postmenopausal with amenorrhea for at least 2 years prior to dosing without an alternative 
medical cause. FSH levels will be measured only in cases when postmenopausal status is in 
question. 
All male subjects (with partners of child-bearing potential) must agree to use a condom with 
spermicide and also one of the following contraception methods during the study until 30 days 
after the last dose of study drug: 
• vasectomized male subjects with documented medical assessment of the surgical 
success 
• Non-vasectomized male subjects must confirm female partner of childbearing 
potential is using a highly effective method of contraception as defined above 
• be sexually abstinent* 
* True abstinence is defined as refraining from heterosexual intercourse in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of 
exposure to study drug, and withdrawal are not acceptable methods of contraception. 
6.3.11. 
Pharmacokinetic Assessments 
Instruction for TD-8236 PK blood sampling, collection, processing, and sample shipment will be 
provided in a separate PK Laboratory Manual. 
6.3.12. 
 
 
6.4. 
Concomitant Medications 
 
 
 
 
  
 
  


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6.5. 
Restrictions 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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6.6. 
Continuation and Discontinuation 
Upon return for initiation of subsequent periods of the study (i.e., Periods 2 and 3), the 
appropriateness for a subject to continue in the study will be decided by the investigator, in 
consultation with the sponsor medical monitor, where appropriate.   
Subjects are free to withdraw from the study at any time for any reason.  
Subjects will be withdrawn from the study if they exhibit an SAE and/or any AEs that in the 
opinion of the PI may jeopardise their safety (Section 7). 
In addition, subjects may be withdrawn from the study by the PI or designee for difficulties in 
blood collection. 
A subject may be withdrawn by the PI (or designee) or the Sponsor if enrollment into the study is 
inappropriate, the study plan is violated, or for administrative and/or other safety reasons. 
6.6.1. 
Subject Discontinuation 
Any subject (or his or her legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The investigator must withdraw from the 
study any subject who requests to be withdrawn. A subject’s participation in the study may be 
discontinued at any time at the discretion of the investigator and in accordance with his or her 
clinical judgment. When possible, the tests and evaluations listed for the termination visit should 
be carried out. If a subject withdraws before completing the study, the reason for withdrawal is to 
be documented on the CRF. 
The Sponsor will be notified of all subject withdrawals. 
Reasons for which the investigator or the Sponsor may withdraw a subject from the study or a 
subject may choose to terminate participation before completion of the study include, but are not 
limited to, the following: 
• 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. 
6.6.2. 
Subject Replacement 
 
 
 


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6.6.3. 
Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
6.6.4. 
End of Trial 
The end of this trial is defined as the date that the last protocol defined study visit occurs for the 
last subject enrolled in the study.   
6.7. 
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.  Instructions related to 
contraception are described in Section 6.3.10. 


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


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


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


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• Whether the AE resolved or improved with decreasing the dose or stopping the study 
medication (“dechallenge”) or recurred or worsened upon re-exposure to the study 
medication (“rechallenge”).  
The causal relationship between the study medication and the AE will be described using one of 
the following categories: 
• Not Related:  Evidence exists that the adverse event has an etiology other than the 
study drug (such as a preexisting condition, underlying disease, intercurrent illness, or 
concomitant medication). 
• Related: A temporal relationship exists between the event onset and administration 
of the study drug. It cannot be readily explained by the subject’s clinical state or 
concomitant therapies and appears with some degree of certainty to be related based 
on the known therapeutic and pharmacologic actions of the drug. In case of cessation 
or reduction of the dose, the event abates or resolves and reappears upon rechallenge. 
It should be emphasized that ineffective treatment should not be considered as 
causally related in the context of adverse event reporting. 
7.4. 
AE Reporting and Recording 
7.4.1. 
AE Reporting 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials is 
crucial for the protection of patients and is mandated by regulatory agencies.  Sponsor has 
established standard operating procedures in compliance with regulatory requirements 
worldwide to ensure appropriate reporting of safety information.  All clinical trials sponsored by 
TBPH will be conducted in accordance with these procedures.  
7.4.2. 
AE and SAE Recording 
All AEs, regardless of seriousness, severity, or causal relationship to study medication, will be 
recorded from signing informed consent through the last study visit (or last subject contact in the 
case of a follow-up telephone call).  AEs will be recorded on the AE page of the CRF.  SAEs, 
regardless of relationship to study medication will be recorded from signing informed consent 
through the last study visit (or last subject contact in the case of a follow-up telephone call).  
Additionally, investigators may report SAEs assessed as related to study medication through 
30 days following the last study visit (or last subject contact in the case of a follow-up telephone 
call). All SAEs will be recorded on both the SAE Report Form and the AE page of the CRF and 
should include the following:   
Description of event:   
• Signs and symptoms due to a common etiology should be reported as a single 
diagnosis; for example, cough, runny nose, sneezing, sore throat, and head congestion 
would be reported as “upper respiratory infection”.   
• A diagnosis or description must be as specific and as complete as possible 
(e.g., “lower extremity edema” instead of “edema”).  


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• Hospitalization or surgical procedures should not be used as adverse event terms 
(e.g., if a subject was hospitalized for cholecystectomy due to cholecystitis, the 
adverse event term should be recorded as cholecystitis, and not as the procedure, 
cholecystectomy).   
• “Death” should not be used as an adverse event term unless the cause of death is 
unknown.  For events with a fatal outcome, the cause of death should be the adverse 
event term (e.g., if a subject died of an acute myocardial infarction, the adverse event 
term should be recorded as “Myocardial Infarction” and the event outcome as fatal).     
Relationship to study medication: The Investigator will make an assessment of the causal 
relationship of the study medication to the AE using the guidelines in Section 7.3.2.  
Severity: The severity of the AE will be assessed using the guidelines in Section 7.3.1. 
Outcome:  The outcome of AEs will be recorded.   
Therapeutic measures:  Measures taken for the treatment or management of the AEs will be 
recorded. 
7.4.3. 
SAE Reporting Timeline 
SAEs will be reported to Clinical Safety and Pharmacovigilance within 24 hours of the time the 
Investigator or his/her designee becomes aware that an SAE has occurred, whether or not the 
event is considered to be related to study medication.  If the initial SAE is reported by telephone, 
a written report signed by the Investigator must be submitted within 24 hours.   
The SAE Report Form must be completed in accordance with the SAE Report Form Completion 
Guidelines.  If all information on the SAE Report Form is not available at the time of the initial 
report, follow-up SAE reports will be completed and submitted.   
To report an SAE, complete and fax the Serious Adverse Event Report Form to the following: 
Theravance Biopharma Clinical Safety and Pharmacovigilance 
 
 
 
For medical questions regarding an SAE, contact the Sponsor medical monitor by telephone as 
follows: 
Sponsor Medical Monitor Contact Information: 
 
 
Clinical Development 
Theravance Biopharma US, Inc. 
 
 


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For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, and 
other documents when requested. Additional information may be requested from the investigator 
to ensure the timely completion of accurate safety reports. 
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable to 
the study drug and is unexpected/unlisted based on the current TD-8236 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. 
7.5. 
Adverse Event Follow-up 
A subject experiencing an AE or SAE will be followed by the investigator or his/her trained 
delegate(s) through the follow-up visit or until the investigator and/or the Sponsor has 
determined that the AE or SAE has resolved or a stable clinical endpoint is reached, whichever is 
longer. The Sponsor may request follow-up of certain adverse events until resolution and 
documentation of assessments made during this period. 
The investigator must take all therapeutic measures necessary for resolution of an SAE. Any 
medications necessary for treatment of the SAE must be recorded in the concomitant medication 
section of the case report form. 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
General Considerations 
 
   
 
 
 
   
 
 
 
 
8.2. 
Sample Size and Power 
 
 
 
 
 
 
 
 
8.3. 
Analysis Sets 
The Intent-to-Treat (ITT) analysis set will include all randomized subjects who received at least 
one dose of study drug. The ITT analysis set will be the primary analysis set for the 
summarization of efficacy analyses. 
The Per-protocol (PP) analysis set will include all subjects in the ITT analysis set who completed 
the study and had no major protocol deviations. 
The Safety (Safety) analysis set will include all subjects receiving at least one dose of study drug 
summarized by actual drug received. The Safety analysis set will be the primary analysis for 
General and Safety analyses. 
The Pharmacokinetic (PK) analysis set will include all randomized subject who received at least 
one dose of active TD-8236 study drug and have at least one evaluable PK profile. 
8.3.1. 
Examination of Subgroups 
Analysis of subgroups will be outlined in the statistical analysis pan (SAP). 


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8.3.2. 
Major Protocol Analysis Deviations 
The following protocol deviations are defined as major and would be considered to have an 
impact on the analysis of efficacy data 
 
 
 
 
 
 
 
 
Additional criteria may be specified in the SAP. 
8.4. 
General Analyses 
8.4.1. 
Demographics Characteristics 
Demographics and baseline characteristics including age, sex, race, ethnicity, height, weight, 
BMI, disease characteristics, previous and current asthma medications, and other medical history 
will be summarized. 
8.4.2. 
Analysis of Pharmacodynamics/Efficacy 
8.4.2.1. 
Pharmacodynamics/Efficacy endpoints 
The primary endpoint(s) of this study are: 
• Area under the curve (AUC) of change from baseline FEV1 from 3 to 8 hours after 
inhaled allergen challenge at Day 14 
The key secondary endpoint(s) are: 
• AUC of percentage change from baseline in FEV1 from 3 to 8 hours after inhaled 
allergen challenge at Day 14 
• Maximum decline in FEV1 from 3 to 8 hours after inhaled allergen challenge at Day 
14 
• Maximum percentage decline in FEV1 from 3 to 8 hours after inhaled allergen 
challenge at Day 14 
• Day 14 plasma PK parameters of TD-8236 in subjects with mild asthma 
• Safety and tolerability off TD-8236 over 14-days of dosing, including frequency and 
severity of adverse events, vital signs, clinical laboratory evaluations, and 12-lead 
ECG changes from baseline 
 
 


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The exploratory endpoint(s) are: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.2.2. 
Primary Pharmacodynamics/Efficacy Evaluation 
 
 
 
  
 
 
 
 
 
  


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8.4.3. 
Secondary and Exploratory Pharmacodynamics/Efficacy Evaluations 
 
 
 
 
 
 
 
8.4.4. 
Multiplicity Adjustment 
  
 
8.4.5. 
Analysis of Pharmacokinetics 
 
 
 
 
8.5. 
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 corrected QT interval (QTcF) from standard safety 
digital ECGs. Vital signs will be summarized in terms of observed values and changes from 
baseline. 
8.5.1. 
Extent of 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.  Using 
drug administration data, compliance for each subject by period will be summarized.  Dose 
discontinuations and reasons for study drug discontinuation will be listed and summarized. 
8.5.2. 
Adverse Event Data 
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will presented by system organ class (SOC), preferred term 
(PT) and severity, the frequency and percentage of subjects reporting each observed event. 
Adverse events observed during the period from obtaining informed consent to the start of 
administration of study drug will be regarded separately from adverse events observed after 
study drug administration (i.e., treatment-emergent adverse events [TEAEs]). 


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A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after 
the subjects first dose in their first treatment period and up to the date of last dose in their final 
treatment period plus the number of days in the 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. 
 
 
All AEs and all TEAEs will be listed by subject.  The frequency of subjects who experience 
TEAEs will be summarized overall and by treatment group.  AEs will also be summarized by 
relationship to treatment (study drug) and severity. 
A listing 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. 
8.5.3. 
Concomitant Medications 
Medications will be summarized both prior and during each the treatment period separately.  
8.5.4. 
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.   
8.5.5. 
Vital Signs Data 
Vital Signs data will be summarized in terms of observed values (by time point), changes from 
baseline (by time point), and counts and percentages within appropriately defined categories 
(Table 4). 
Table 4: 
Outlier Threshold for Vital Signs 
 
 
 
 
 
 
 
 
 
 


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8.5.6. 
ECG Data 
The QTcF, PR interval, QT interval, QRS duration, and HR from standard digital ECGs will be 
summarized in terms of observed values, changes from baseline, and counts and percentages 
within appropriately defined categories 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
When multiple values exist for the same nominal time point (e.g., triplicate reading), the average 
of the readings taken for ECG parameters will be used in the data analysis, including the outlier 
analysis stated below. 
There will be no imputation of missing data. Subjects without post-baseline measurement for a 
given treatment period will be excluded from the summary statistic (e.g., denominator of the 
summary statistic) for that time point.   
All recorded values for the ECG parameters will be presented in a by-subject listing. A separate 
listing of subjects with values of QTcF > 500 msec or an increase > 60 msec will be provided, as 
necessary. 
Cumulative distribution plots will be provided for maximum change in QTcF by day. 


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8.6. 
Missing Data Handling 
  
  
8.7. 
Interim Analysis 
 
 
 
8.8. 
Data Monitoring Committee 
No data monitoring committee is planned for this study. 
 


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9. 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1. 
Principal Investigator Responsibilities 
Before beginning the study, the 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 [e.g., 
associates, residents, research fellows].) 
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-8236 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/IEC 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. 


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9.2. 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the investigator will obtain written confirmation that 
the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant with ICH 
and GCP requirements, applicable laws, and local regulations. A copy of the confirmation from 
the IRB/IEC/REB will be provided to the Sponsor or its designee. The protocol, informed 
consent form (ICF), IB, and any other appropriate written information provided to the subjects 
that the IRB/IEC/REB may require to fulfill its responsibilities will be submitted to the 
IRB/IEC/REB in advance of the study. The Sponsor or its designee must approve the ICF and all 
subject recruitment materials before they are submitted to the IRB/IEC/REB. The study will not 
proceed until appropriate documents from the IRB/IEC/REB confirming unconditional approval 
of the protocol and the ICF are obtained by the investigator and copies are received by the 
Sponsor or its designee. If possible, the approval document should refer to the study by study 
protocol title and the Sponsor study number, identify the documents reviewed, and include the 
date of the review and approval. The written approval of the IRB/IEC/REB will be retained as 
part of the study file. The study may proceed before approval of consent forms and other study 
documents translated to a language other than the native language of the clinical site, provided 
that written IRB/IEC/REB approval of the translated documents is obtained before they are used. 
Any amendments to the protocol should be reviewed promptly. 
The investigator must provide the appropriate periodic reports on the progress of the study to the 
IRB/IEC/REB and the Sponsor in accordance with local IRB/IEC/REB requirements and 
applicable governmental regulations, whichever is strictest. 
9.3. 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (GCP Guideline, Section 4.8), 
21 CFR §50, and other applicable local regulations, will be obtained for each subject before 
enrollment of the subject into the study. The investigator will prepare the ICF or revise the 
template ICF and provide the documents to the Sponsor (or designee) for approval before 
submission to the IRB/IEC/REB. The Sponsor and the IRB/IEC/REB must approve the 
documents before they are implemented. 
The investigator will provide copies of the signed ICF to each subject 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, e.g., 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 (e.g., correction of an error or addition of new information), 
corrections will be made to the CRF. Corrections to the CRFs, including the reason for change, 
will be automatically documented through the EDC system’s audit trail. 
The investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The investigator is designated as the signatory 
coordinating investigator. 
An electronic copy of the CRF casebooks will be sent to the site for retention with other study 
documents after full completion of the study, i.e., after database lock. 
The investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The investigator is also responsible for ensuring the availability of any 
original source documentation related to the study (including any films, tracings, computer discs, 
tapes, and worksheets). In most cases the source is the subject’s medical record. Data collected 
on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the investigator’s site and clearly identify those data that will be recorded 
in the CRF and for which the CRF will stand as the source document. 
9.5. 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled manner 
all study documents required by the Sponsor and by the applicable regulations. The investigative 
site must take measures to prevent accidental or premature destruction of essential documents, 
that is, documents that individually and collectively permit evaluation of the conduct of a study 
and the quality of the data produced, including paper copies of study records (e.g., subject charts) 
and any original source documents that are electronic, as required by applicable regulations. 
The investigator must consult the Sponsor representative before disposal of any study records 
and must notify the Sponsor of any change in the location or disposition of the study files. If an 
investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping 
the study documents, custody must be transferred to a person who will accept the responsibility. 
The Sponsor must be notified in writing of the name and address of the new custodian and must 
approve this transfer of responsibility. 
9.6. 
Confidentiality 
The investigator or designee must explain to each subject, before enrollment into the study, that, 
for evaluation of study results, the subject’s confidential medical information obtained during the 
study may be shared with the study sponsor, the study sponsor’s affiliated companies, the study 
sponsor’s designated service providers, regulatory agencies, and the 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 


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investigator is responsible for documenting that no further data from the subject will be 
collected. 
Subject medical information obtained during this study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by the 
subject identification number, subject initials, date of birth, and study number, and not by the 
subject’s full name, except the subject consent form, which is archived at the study center only. 
The subject’s name will not be used in any public report of the study. 
During the course of the study, a confidential subject identification list will be maintained by the 
investigator and archived at the investigative site. 
Before and during the conduct of the study, no study-related details may be disclosed, i.e., placed 
on the internet, published, or otherwise publicized, or provided to a third party without prior 
written permission from the Sponsor. The policy for publication of data after completion of the 
study is described in Section 9.9 (Publication). 
9.7. 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original recordings, 
laboratory reports, and subject records generated by this study must be available to the Sponsor, 
representatives of the Sponsor, the IRB/IEC/REB, and applicable regulatory authorities, and they 
may be used for submission to regulatory authorities. In addition, all source data should be 
attributable (signed and dated), consistent with local medical practice. The investigator must 
therefore agree to allow direct access to all source data. Subjects (or their legally authorized 
representatives) must also allow access to their medical records, and subjects will be informed of 
this and will confirm their agreement when giving informed consent. 
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. 
 
 


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Representatives of the FDA or other Regulatory Agencies, including IRB/IEC representatives 
may also conduct an audit of the study. If informed of such an inspection, the investigator should 
notify the Sponsor immediately. The investigator will ensure that the auditors have access to the 
clinical supplies, study site facilities, laboratory and all data (including original source 
documentation) and all study files are available, if requested. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
investigator, institution, institution staff, or representatives of the Sponsor will lead to prompt 
action by the Sponsor to secure compliance. Continued noncompliance may result in termination 
of the investigator’s involvement in the study. The IRB/IEC/REB and relevant regulatory 
authority will be informed. 
9.9. 
Publication 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and presentation at seminars or 
conferences. The Sponsor will retain the ownership of the data collected in this study. The 
investigator will provide any proposed manuscript or abstract to the Sponsor before submission 
for publication or presentation of any results or data obtained in this study. 
Additional details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Study 
Agreement between the Sponsor and the investigator. 


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10. 
REFERENCES 
1. Pernis AB and Rothman PB, JAK-STAT signaling in asthma. J Clin Invest, 2002. 109: 
1279 1283. 
2. Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet 2015; 
386: 1086 96. 
3. Barnes PJ, New anti-inflammatory targets for chronic obstructive pulmonary disease. 
Nature Rev Drug Disc, 2013. 12: 543-559. 
4. Southworth T, Plumb J, Gupta V, Pearson J, Ramis I, Lehner MD, Miralpeix M and 
Singh D, Anti-inflammatory potential of PI3K and JAK inhibitors in asthma patients. 
Respiratory Research, 2016. 17: 124. 
5. Clark JD, Flanagan ME, and Telliez JB, Discovery and development of Janus kinase 
(JAK) inhibitors for inflammatory diseases. J Med Chem, 2014. 57(12): 5023-38. 
6. Theravance Biopharma R&D, Inc., TD-8236, Investigator’s Brochure, Edition 2.0, 
July 2019. 
7. Nikula KJ, McCartney JE, McGovern T, Miller GK, Odin M, Pino MV, Reed MD. STP 
position paper: Interpreting the significance of increased alveolar macrophages in rodents 
following inhalation of pharmaceutical materials. Toxicol Pathol. 2014;42(3):472-86. 
8. Jones RM, Neef N, Interpretation and prediction of inhaled drug particle accumulation in 
the lung and its associated toxicity. Xenobiotica. 2012;42(1):86-93. 
9. Tepper JS, Kuehl PJ, Cracknell S, Nikula KH, Pei L, and Blanchard JD. Symposium 
Summary: Breathe In, Breathe Out, Its Easy: What You Need to Know About 
Developing Inhaled Drugs. Int J Toxicol. 2016;35(4):376-92. 
10. Xeljanz® oral tablets, Pfizer Laboratories, full prescribing information (electronic 
monograph; document revised: 8/2017). Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203214s014s016,208246s00
1s002lbl.pdf 
11. Diamant, Z, Gauvreau GM, Cockcroft DW, Boulet LP, Sterk PJ, de Jongh FH, Dahlen B, 
and O'Byrne PM. Inhaled allergen bronchoprovocation tests. J Allergy Clin Immunol. 
2013.132:1045-1055 e1046. 
 
 
 
 
14. Boulet LP, Gauvreau G, Boulay ME, O'Byrne P, Cockcroft DW. Clinical Investigative 
Collaboration, Canadian Network of Centers of Excellence AllerGen. The allergen 
bronchoprovocation model: an important tool for the investigation of new asthma 
anti-inflammatory therapies. Allergy. 2007 Oct;62(10):1101-10. 


Protocol 0178, 
 
Version 1.0, 05NOV2019 
TD-8236 
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15. O'Byrne PM. Allergen-induced airway inflammation and its therapeutic intervention. 
Allergy Asthma Immunol Res. 2009 Oct;1(1):3-9. doi: 10.4168/aair.2009.1.1.3. Epub 
2009 Sep 25. 
16. Oliver A. Modulation of allergen-induced bronchoconstriction by ﬂuticasone furoate and 
vilanterol alone or in combination. Allergy 2013; 68: 1136–1142. 
17. Singh D, Leaker B, Boyce M, et al. A novel inhaled phosphodiesterase 4 inhibitor 
(CHF6001) reduces the allergen challenge response in asthmatic patients. Pulm 
Pharmacol Ther. 2016 Oct;40:1-6. doi: 10.1016/j.pupt.2016.06.011. Epub 2016 Jun 29. 
18. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson 
JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative, Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations, Eur Respir J. 2012. 40(6):1324-1343. 
.


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Protocol 0178, 
 
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APPENDIX 2. PROTOCOL SIGNATURE FORM 
 
Protocol Signature Form 
 
Protocol #:  
TD-8236 Study 0178 
Protocol Title:   
A Randomized, Double-blind, Placebo-controlled, 3-period Crossover 
Study to Evaluate the Safety of Repeated Doses of Inhaled TD-8236 and 
Impact on Airway Responses Following Allergen Challenge in Patients 
with Asthma 
Version: 
 
Version Date: 
05 November 2019 
 
 
I have read the protocol described above and agree to conduct this study in accordance with 
procedures described therein.  I also agree to conduct the study in compliance with all 
applicable regulations. 
 
 
 
Investigator’s Name (print) 
 
 
 
Investigator’s Signature 
 
Date 
 
 

SAP_001.pdf: 
Statistical Analysis Plan – Protocol 0178 
 
21SEP2020 
TD-8236 
 
Page 1 of 45 
 
. 
STATISTICAL ANALYSIS PLAN 
Clinical Study Report 
Protocol Title:  
A Randomized, Double-blind, Placebo-controlled, 3-period 
Crossover Study to Evaluate the Effects of Repeated Doses of 
Inhaled TD-8236 and Impact on Airway Responses 
Following Allergen Challenge in Patients with Asthma 
Protocol Number:   
0178 
Compound Number: 
TD-8236 
Short Title: 
Effect of inhaled TD-8236 on allergen-induced asthmatic 
response 
Sponsor Name:  
Theravance Biopharma Ireland Limited 
Legal Registered Address: 
Connaught House 
1 Burlington Road 
Dublin 4 
D04 C5Y6 
Ireland 
 
Regulatory Agency Identifier Number(s) 
 
EuDraCT No.  
2019-002915-24 
 
 
 
 
 
 
 
 
This study will be conducted in compliance with 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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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................7 
SAP VERSION HISTORY .............................................................................................................8 
1. 
INTRODUCTION ........................................................................................................9 
1.1. 
Objectives and Endpoints .............................................................................................9 
1.1.1. 
Primary Objective(s) and Endpoint(s) ..........................................................................9 
1.1.2. 
Secondary Objective(s) and Endpoint(s) ......................................................................9 
1.1.3. 
Exploratory Objective(s) and Endpoint(s) ..................................................................10 
1.2. 
Study Design ...............................................................................................................11 
1.3. 
Treatment Assignment ................................................................................................12 
1.4. 
Schedule of Assessments ............................................................................................13 
1.5. 
Sample Size Determination ........................................................................................17 
2. 
ANALYSIS SETS ......................................................................................................18 
3. 
STATISTICAL ANALYSES .....................................................................................19 
3.1. 
General Considerations ...............................................................................................19 
3.1.1. 
Visit Windows ............................................................................................................20 
3.2. 
Study Subjects ............................................................................................................21 
3.2.1. 
Enrollment ..................................................................................................................21 
3.2.2. 
Subject Disposition and Completion Status ...............................................................21 
3.2.3. 
Demographic and Baseline Characteristics ................................................................21 
3.2.4. 
Protocol Deviations ....................................................................................................21 
3.2.5. 
Medical History ..........................................................................................................22 
3.2.6. 
Prior/Concomitant Medications ..................................................................................23 
3.2.7. 
Allergen Skin Test ......................................................................................................23 
3.3. 
Primary Endpoint(s) Analysis .....................................................................................23 
3.3.1. 
Definition of Primary Endpoint ..................................................................................23 
3.3.2. 
Statistical Hypotheses .................................................................................................23 
3.3.3. 
Main Analysis Methods ..............................................................................................24 
3.3.3.1. 
Missing Data Handling ...............................................................................................24 
3.3.4. 
Sensitivity Analyses ....................................................................................................24 
3.3.5. 
Supplementary Analyses ............................................................................................24 


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3.3.5.1. 
Carryover Effect .........................................................................................................25 
3.4. 
Secondary Endpoint(s) Analyses ................................................................................26 
3.4.1. 
Definition of Secondary Endpoint(s) ..........................................................................26 
3.4.2. 
Statistical Hypotheses .................................................................................................26 
3.4.3. 
Main Analysis Methods ..............................................................................................26 
3.4.3.1. 
Missing Data Handling ...............................................................................................27 
3.4.4. 
Sensitivity Analyses ....................................................................................................27 
3.4.5. 
Supplementary Analyses ............................................................................................27 
3.5. 
Exploratory Endpoint(s) Analyses ..............................................................................27 
3.5.1. 
Definition of Exploratory Endpoints ..........................................................................27 
3.5.2. 
Main Analytical Approach .........................................................................................29 
3.5.2.1. 
FEV1 Endpoints: .........................................................................................................29 
3.5.2.4. 
Missing Data Handling ...............................................................................................29 
3.5.3. 
Other Analyses ............................................................................................................30 
3.6. 
Safety Analyses ..........................................................................................................30 
3.6.1. 
Extent of Exposure .....................................................................................................30 
3.6.2. 
Treatment Compliance ................................................................................................30 
3.6.3. 
Adverse Events ...........................................................................................................30 
3.6.3.1. 
Adverse Events of Special Interest .............................................................................31 
3.6.4. 
Additional Safety Assessments ...................................................................................31 
3.6.4.1. 
Clinical Laboratory Parameters ..................................................................................31 
3.6.4.2. 
Vital Signs ..................................................................................................................31 
3.6.4.3. 
Electrocardiogram .......................................................................................................32 
3.7. 
Other Analyses ............................................................................................................34 
3.7.1. 
FEV1 at Screening .......................................................................................................34 
3.7.2. 
Subgroup Analyses .....................................................................................................35 
3.7.3. 
COVID-19 Data ..........................................................................................................35 
3.7.4. 
Screening Laboratory Data .........................................................................................35 
3.7.5. 
Pregnancy Test Results ...............................................................................................35 
3.8. 
Interim Analyses .........................................................................................................36 


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3.8.1. 
Data Monitoring Committee .......................................................................................36 
4. 
REFERENCES ...........................................................................................................36 
5. 
SUPPORTING DOCUMENTATION........................................................................37 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses .................................................37 
5.2. 
Appendix 2: Data Conventions and Transformations ................................................37 
5.2.1. 
Derived and Transformed Data ..................................................................................37 
5.2.2. 
Missing Date Imputation ............................................................................................39 
5.2.2.1. 
Missing/Incomplete AE/Start Date .............................................................................39 
5.2.2.2. 
Missing/Incomplete AE End Date/Time ....................................................................39 
5.2.2.3. 
Missing/Incomplete Start for Medication ...................................................................39 
5.2.2.4. 
Missing/Incomplete End Date/Time for Medication ..................................................41 
5.2.2.5. 
Laboratory Data ..........................................................................................................41 
5.2.2.6. 
AE Severity .................................................................................................................41 
5.3. 
Appendix 3: Sample SAS Code ..................................................................................41 
5.3.1. 
Pre- vs Post Allergen Challenge on FEV1 Endpoints .................................................41 
5.3.2. 
Pre- vs Post Allergen Challenge in Serial FEV1 by Timepoints on Day 14 ...............41 
5.3.3. 
Change from Day 1 Predose in FEV1 on Day 7 or Day 14 Pre-dose .........................42 
5.3.4. 
Pre- vs Post Allergen Challenge on FeNO on Day 14 post 8 and 24 hours ...............42 
5.3.5. 
Change from Pre-Dose Day 1 in FeNO on Day 7 and Day 14 Pre-dose ....................42 
5.3.6. 
Change from Baseline in ACQ-5 Total Score ............................................................42 
5.3.7. 
Carryover Effect .........................................................................................................43 
5.4. 
Appendix 4: AUC Calculation Using Trapezoidal Rule ............................................43 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
SAP Version History Summary ....................................................................................8 
Table 3: 
Dosing Regimens ........................................................................................................13 
Table 4: 
Schedule of Study Procedures ....................................................................................14 
Table 5:  
Analysis Sets ...............................................................................................................18 
Table 6: 
Safety Analysis Windows ...........................................................................................20 
Table 7: 
Definition of Secondary Endpoints ............................................................................26 
Table 8: 
Definition of Exploratory Endpoints ..........................................................................27 
Table 9: 
Outlier Threshold in Vital Signs .................................................................................32 
Table 10: ECG Interval Categories .............................................................................................32 
Table 11: Definition of FEV1 Endpoints at Screening ................................................................34 
Table 12: Endpoints for Subgroup Analyses ..............................................................................35 
Table 13: Calculation of Change from Pre Allergen AUC(0-8)H in FEV1 ................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................12 


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LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AUC 
area under curve  
AUC(3-))H 
AUC 3 to 8 Hours  
AUC(0-2)H 
AUC 0 to 2 Hours  
AU(0-8)H 
AUC 0 to 8 hours  
ACQ 
Asthma Control Questionnaire  
BMI 
body mass index 
CSR 
clinical study report 
EAR 
Early asthmatic response  
ECG 
electrocardiogram 
FEV 
Forced expiratory volume 
ITT 
intent-to-treat 
HR 
heart rate 
LAR 
Late asthmatic response   
LOD 
Limit of detection 
LS 
Least Squares 
LSM 
Least Squares Mean 
MedDRA 
Medical Dictionary For Regulatory Activities Terminology 
NA  
Not Applicable  
PP 
Per Protocol Population 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 


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SAP VERSION HISTORY 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides comprehensive and detailed descriptions of the 
statistical analyses of the efficacy and safety data as outlined and specified in the final protocol 
of study 0178 for TD-8236. 
This study is a randomized, double-blind, placebo-controlled, three-period, six-sequence, 
complete-block, crossover study to characterize two doses of inhaled TD-8236 compared to 
placebo in subjects with mild asthma and a known response to an allergen challenge. 
The SAPs for 
 
 will be prepared separately. 
Specifications of tables, figures, and data listings are contained in a separate document.  
1.1. 
Objectives and Endpoints 
1.1.1. 
Primary Objective(s) and Endpoint(s) 
As stated in the protocol, the primary objective of the study is as follows: 
• Characterize the late asthmatic response (LAR) in terms of area under the Forced 
Expiratory Volume (FEV1) curve after inhaled allergen challenge in mild asthmatic 
subjects receiving 14 days of TD-8236 or placebo 
The primary endpoint is: 
• Area under the curve (AUC) of change from baseline FEV1 from 3 to 8 hours after 
inhaled allergen challenge (FEV1 AUC Change (3-8)H) at Day 14 
1.1.2. 
Secondary Objective(s) and Endpoint(s) 
The secondary objectives of the study are as follows: 
• Characterize the late asthmatic response (LAR) in terms of maximum decline in FEV1 
and area under the percent change FEV1 curve after inhaled allergen challenge in 
mild asthmatic subjects receiving 14 days of TD-8236 or placebo 
• Assess the pharmacokinetics (PK) of TD-8236 in subjects with asthma 
• Evaluate the safety and tolerability of inhaled TD-8236 administered for 14 days in 
subjects with mild asthma 
The secondary endpoint(s) are: 
• AUC of percent change from baseline in FEV1 from 3 to 8 hours after inhaled 
allergen challenge (FEV1 AUC % Change (3-8)H) at Day 14 
• Maximum (Max) decline in FEV1 from 3 to 8 hours after inhaled allergen challenge 
(FEV1 Max Decline(3-8)H) at Day 14 
• Max percent decline in FEV1 from 3 to 8 hours after inhaled allergen challenge at 
(FEV1 Max % Decline(3-8)H) at Day 14 


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• Safety and tolerability of TD-8236 over 14 days of dosing, including frequency and 
severity of adverse events (AEs) vital signs, clinical laboratory evaluations, and 
12-lead electrocardiogram (ECG) changes from baseline 
1.1.3. 
Exploratory Objective(s) and Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 


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Confidential – Property of Theravance Biopharma, Inc. 
 
 
  
 
  
 
1.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, three-period, six-sequence, 
complete-block, crossover study to characterize two doses of inhaled TD-8236 compared to 
placebo in subjects with mild asthma and a known response to an allergen challenge. 
Subjects will undergo an allergen challenge test at Screening as described by 
 
Following a Screening period of up to 35 days, subjects who meet inclusion and 
exclusion criteria will be randomized to receive each of three treatments (TD-8236 
 
TD-8236 
 or placebo) in one of the three treatment periods separated by a washout 
 
 between the last dose of the previous period and first dose of the next period. 
Each treatment period will consist of 14 days of treatment with one dose level of TD-8236 or 
placebo (Figure 1). Subjects will return to the clinic on Day 7 (±1 day) of each period for safety 
and pharmacodynamic (PD) assessments as well as reconciliation and dispensing of study drug. 
Subjects will be in-residence at the clinic for Day 14 of each period. At the investigator’s 
discretion subjects may be discharged the evening of Day 14 and return to the clinic the morning 
of Day 15. 
 
 
Subjects will undergo an allergen challenge test 1 hour after the last dose (Day 14) in each 
period.  
 
 
 and LAR will be assessed between 3 and 
8 hours after allergen challenge.  


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Table 3: 
Dosing Regimens 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
1.4. 
Schedule of Assessments 
The schedule of assessments is presented in Table 4.  


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Table 4: 
Schedule of Study Procedures 
Study Procedures a 
Days →  
Screening  
Treatment Phase 
(for each Treatment Period (TP))  
FU/ ET   
S1 
(-35 to -8)b  
S2 
(-35 to -8)b  
S3 
(S2+1)   
1   
7 
(±1)  
14   
15    
+14 
(±2)c   
General Procedures  
  
  
  
  
  
  
  
  
Informed consent  
X  
  
  
  
  
  
  
  
Inclusion/exclusion criteria  
X  
X  
  
X d   
  
  
  
  
Demographics and Medical history  
X  
  
  
  
  
  
  
  
Height  
X  
  
  
  
  
  
  
  
Weight  
X  
  
  
X e  
  
  
  
X  
Inhaler training and PIF testing with In-check f  
X  
  
  
X e  
X e  
X e  
  
  
Study drug reconciliation  
  
  
  
  
X  
X  
  
  
Study drug dispensing  
  
  
  
X  
X  
  
  
  
TD-8236 administrationg  
  
  
  
X  
X  
X  
  
  
Subject Dosing Diary h  
  
  
  
X  
X  
X  
  
  
Safety Evaluations   
  
  
  
  
  
  
  
  
Physical examination i  
X  
  
  
  
  
  
  
X  
Symptom-driven physical examination j  
  
X  
X  
X  
X  
X  
X  
  
12Lead safety ECG k  
X  
  
  
X e  
X e  
X e  
  
X  
Vital Signs (pulse, BP, temp, RR)  
X  
  
  
X e  
X e  
X e  
  
X  
Hematology, serum chemistry, and urinalysis l  
X  
  
  
X e  
X e  
X e  
X  
X  
Immunophenotyping (NK, T, and B cell counts)  
  
  
  
X e  
  
X e  
  
X  
Coagulation   
X  
  
  
X  
  
X  
  
X  
Serum FSH (postmenopausal females only) m  
X  
  
  
  
  
  
  
  
Urine or serum pregnancy test (WOCBP only) n  
X  
X  
  
X  
  
X  
  
X  
Urine drug test  
X  
  
  
X  
  
  
  
  
Urine cotinine test  
X  
  
  
X  
  
  
  
  
Breath or urine alcohol screen  
X  
  
  
X  
  
  
  
  
HIV/Hepatitis test  
X  
  
  
  
  
  
  
  
Tuberculosis (Quantiferon) test  
X  
  
  
  
  
  
  
  
AE monitoring  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant medication monitoring  
X  
X  
X  
X  
X  
X  
X  
X  


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Study Procedures a 
Days →  
Screening  
Treatment Phase 
(for each Treatment Period (TP))  
FU/ ET   
S1 
(-35 to -8)b  
S2 
(-35 to -8)b  
S3 
(S2+1)   
1   
7 
(±1)  
14   
15    
+14 
(±2)c   
Salbutamol dispensing o  
X  
X  
X  
X  
X  
X  
X  
  
Pharmacokinetics / Pharmacodynamics  
  
  
  
  
  
  
  
  
Allergen skin test  
X  
  
  
  
  
  
  
  
Inhaled allergen challenge  
  
X  
  
  
  
X p  
  
  
Spirometry q  
X  
  
  
X  
X  
X  
  
X  
   
  
   
   
   
   
   
   
  
   
  
  
  
  
  
  
  
  
  
  
   
   
   
  
   
   
  
  
  
  
  
   
   
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
  
Other Procedures  
  
  
  
  
  
  
  
  
Study visits  
X  
X v  
X v  
X  
X  
  
  
X  
Residence in the CRU  
  
  
  
  
  
X w  
X w  
  
S = Screening.  
a. For details on Procedures, refer to Section 6 of protocol. 
b. Screening procedures (including informed consent) may be performed over more than 1 day. Repeats of study procedures are permitted on the day and/or on another day 
during screening or treatment period (as appropriate) at the discretion of the PI(s). Additionally. screening visits S1 and S2 may be combined into 1 visit day and in such case 
procedures scheduled for both visits are only needed to be performed once (e.g., FeNO, pregnancy test). 
c. The followup visit is performed 14 days + following the last dose of study medication in Treatment Period 3 only 
d. Inclusion & exclusion criteria for initial study entry are evaluated only in Treatment Period 1; for subsequent periods assessment for study continuation should be evaluated as 
described in Section 6.6 of protocol. 
e. To be perform prior to dosing 
f. At Screening and pre-dose on Day 1 of each Treatment Period, the correct use of the inhaler will be explained to the subject and each subject will train with an empty capsule, 
and PIF will be measured using an 
 Generation of sufficient PIF at all sessions will be considered a requirement for participation/continuation in the 
study (Section 4, item 7 of protocol). 
g. Study drug will be administered at the CRU by study staff following any pre-dose procedures associated with the Study Visit. 
h. Subject will be provided a daily dosing diary on Day 1 and will be reviewed by study staff and reissued to the subject on Day 7 and reviewed again and collected by study staff 
on Day 14 of each period. Any deviations or missed doses will be noted in the source documents. 
i. Full PE is required at the Screening Visit. A symptom-driven PE will be conducted at other scheduled time points as described below. 


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j. Symptom-driven physical examinations will be performed at the PI’s or designee’s discretion, as needed, and at other times to focus on evaluation of AEs throughout the study, 
if any, including any emergence of symptoms or worsening of any abnormalities identified, but found by the PI to be non-clinically significant, on the screening or check-in 
examination(s) since the last study day or physical exam. Symptom-driven examinations should be performed for any AE or existing AE that increases in severity or frequency. 
Refer to Section 7 of the protocol for more information. 
k. At screening, triplicate 12-lead ECG will be conducted. At all other scheduled time points, safety 12-lead ECGs will be conducted as a single 12-lead ECG. 
l. Samples for serum chemistry (screening and Day 1 of each period only) will be obtained following a fast of at least 9 hours (water permitted), however, in case of dropouts or 
rechecks, subjects are not required to have fasted for 9 hours ahead of the serum chemistry sample draw. 
m. To be conducted for postmenopausal women who did not undergo any sterilization procedures as detailed in Section 6.3.10 of protocol and where postmenopausal state is in 
question. 
n. Serum pregnancy test will be conducted at Screening and at the follow-up visit. Urine pregnancy test will be conducted prior to each allergen challenge, and predose on Days 1 
and 14 of each Treatment Period. 
o. Salbutamol will be dispensed at screening and can be dispensed at other times during the study as required. 
p. The inhaled allergen challenge will be performed 1-hour post-dose on Day 14. 
q. Spirometry testing will be performed prior to the dose, as applicable. Spirometry that is conducted as part of other study procedures, e.g., bronchial challenges and sputum 
induction, will be covered in a separate Allergen Challenge Study manual. 
 
 
 
 
 
 
u. Blood for PK assessments will be collected predose and 0.5, 1, 2, 4, 6, 8, and 24 hours following the dose on Day 14 in each Treatment Period. Note Day 14 Post dose PK 
samples are to be taken on the timepoint with the exception that if a post-allergen FEV1 coincides with a PK collection (e.g., 1 hr sample) the FEV1 measurement will be 
prioritized; blood sample collection for PK analysis will be performed at the earliest convenience either before or after the FEV1 (within allowed permitted windows). 
v. Subjects will be discharged home after the screening allergen challenge and will return the following day for S3 procedures. Subjects may be required to stay overnight on 
S2 visit if required to do so for reasons of safety at the discretion of the investigator. 
w. Subjects will be resident overnight on Day 14 and will be discharged on Day 15. Subjects may be allowed to be discharged on the evening of Day 14 and return to the clinic on 
the morning of Day 15 at the discretion of the investigator. 
 


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1.5. 
Sample Size Determination 
 
 
 
 
 
 
 
 
 
 


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2. 
ANALYSIS SETS 
The analysis sets and the treatment assignments that will be used for each type of analysis are 
shown in Table 5. 
Table 5:  
Analysis Sets 
Analysis Set 
Definition 
Treatment 
Assignment 
Randomized 
Subjects who are randomized to study treatments  Randomized 
treatment  
Intent-to-Treat 
(ITT) 
Subjects who are randomized to study treatments 
and who received at least one dose of study drug.  
Randomized 
treatment 
Safety 
All treated subjects 
Treatment 
received 
Pharmacodynamic 
(PD) 
Subjects who are randomized to study treatment, 
who received at least one dose of study drug, and 
who have at least one baseline and postbaseline 
PD measurement (e.g.,
,  
Treatment 
received  
Per-Protocol (PP; 
membership to be 
determined before 
unblinding) 
Intent-to-Treat subjects with no protocol 
deviations during the study that would affect the 
primary efficacy analyses.  
Treatment 
received 
 


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3. 
STATISTICAL ANALYSES 
3.1. 
General Considerations 
• The primary analysis will be performed after the database is locked and the 
randomization schedule is released. 
• All efficacy analyses will be performed using the ITT analysis set. Safety analyses 
will be performed using the Safety analysis set. Analysis for 
 
   
• Primary and secondary efficacy analyses will also be performed using the PP analysis 
set.  
• Change from baseline will be computed as the postbaseline value minus the baseline 
value, unless otherwise indicated. 
• 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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3.1.1. 
Visit Windows 
No visit window will be used in summaries of efficacy points.  The analyses will be based on the 
nominal CRF visits.  
Safety events (AEs, Concomitant Medications) occurring in washout periods are assigned to the 
previous treatment period as follows: 
Table 6: 
Safety Analysis Windows 
Actual 
Period 
Nominal Period 
Start Date/Time 
Stop Date/time 
 
Screening  
Informed consent  
Period 1 first dose/time 
1 
Treatment 1 
Period 1 first dose date/time 
Period 2 first dose 
date/time  
2 
Washout 1 
Included with Period 1 
3 
Treatment 2 
Period 2 first dose date/time 
Period 3 first dose 
date/time  
4 
Washout 2 
Included with Period 2 
5 
Treatment 3 
Period 3 first dose date/time 
Last Follow-up 
6 
Follow-Up 
Included with Period 3 
 


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3.2. 
Study Subjects 
3.2.1. 
Enrollment 
Number and percentage of subjects enrolled in the study will be summarized by treatment group 
and total for each investigator by frequency distributions, sorted by highest enroller first. The 
randomized analysis set is used for this summary. 
3.2.2. 
Subject Disposition and Completion Status 
For subject study status, number and percentage of subjects in each of the following categories 
will be presented by treatment group and total. 
• Randomized subjects 
• Randomized and treated 
• Completed the study 
• Discontinued from the study 
• Reasons discontinued from the study 
For all categories, the percentages will be calculated using the number of randomized patients as 
the denominator. 
Reasons for not completing the study will be presented based on eCRF categories, including 
AEs, lost to follow-up, physician decision, pregnancy, protocol violation, study termination by 
sponsor, withdrawal by subject, other. 
A listing of subject disposition will include analysis set flags (ITT, Safety (Yes/No)), date the 
informed consent form was signed, dates of first and last dose of study drug, primary reason for 
discontinuation of study treatment, study completion status, and date of last contact. 
A listing of subject eligibility (inclusion or exclusion criteria exceptions) will be provided. 
3.2.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics including age, sex, race, ethnicity, height, weight and 
body mass index (BMI) will be summarized in total and by treatment group. Age will be 
analyzed with descriptive statistics. Sex, race and ethnicity will be analyzed with frequency 
distribution. The analyses will be based on ITT and Safety populations, separately. 
Subject listings for demographic and baseline characteristics will be provided.   
3.2.4. 
Protocol Deviations 
Unique subjects reporting major protocol deviations that have significant impact on primary 
efficacy analyses (major analysis protocol deviations) will be summarized overall and by 
treatment group for the ITT analysis set. 
 
 


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Major analysis protocol deviations that will exclude subjects from the PP analysis set include: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
    
 
 
 
 
 
A summary of protocol deviations by site and treatment group based on randomized analysis set 
will be provided. 
A subject listing with all protocol deviations identified prior to database lock will be provided. In 
addition, a subject listing with newly identified nonmajor protocol deviations identified during 
site closeout visits following database lock will be provided as applicable. Moreover, a listing of 
all major analysis protocol deviations will be provided. All subject listings will be based on the 
randomized analysis set. 
Subjects with major analysis protocol deviations will be identified before unblinding. 
3.2.5. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 23 or newer. 
The number and percentage of subjects with medical history in each system organ class and 
preferred term will be summarized by treatment group using the Safety analysis set. 
 
 


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3.2.6. 
Prior/Concomitant Medications 
Prior medications include all medications taken prior to the first dose of study drug in treatment 
period 1, regardless of medication end date. Concomitant medications, prescribed and 
over-the-counter, encompass all nonstudy medicinal products that the subject was taking prior to 
the Day 1 visit of each respective treatment period that are ongoing at the visit, in addition to all 
medications that have a start date on or after the first dose of study drug of each respective 
treatment period. 
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) for this study with Theravance review and 
approval of the mappings. The 1Q2020 C3 or later version of the WHODD will be used. 
Prior and concomitant medication will be tabulated by major drug class, minor drug class, and 
generic name for treatment group and for all safety subjects, separately. The frequency (number 
and percentages) of subjects who have taken each medication will be tabulated for each 
treatment regimen.  
3.2.7. 
Allergen Skin Test  
A subject listing displaying the allergen solution received (
 
and test results (i.e., positive, negative, Not Applicable (NA)) will be provided.   
3.3. 
Primary Endpoint(s) Analysis 
3.3.1. 
Definition of Primary Endpoint 
 
 
 
 
 
   
 
      
3.3.2. 
Statistical Hypotheses 
 
  
 
 
 


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3.3.3. 
Main Analysis Methods 
 
 
 
 
   
   
 
   
3.3.3.1. 
Missing Data Handling 
3.3.3.1.1. AUC and Weighted Mean Spirometry Endpoints  
 
 
  
 
 
 
 
 
 
 
3.3.4. 
Sensitivity Analyses 
  
 
 
3.3.5. 
Supplementary Analyses 
 
 


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Line Graphs 
 
 
 
   
 
  
 
 
  
 
  
 
  
3.3.5.1. 
Carryover Effect  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4. 
Secondary Endpoint(s) Analyses 
3.4.1. 
Definition of Secondary Endpoint(s) 
Table 7: 
Definition of Secondary Endpoints 
Secondary Endpoints  
Definition  
AUC of percent change from baseline in FEV1 
from 3 to 8 hours after inhaled allergen challenge 
at Day 14  
 
 
 
 
 
Max decline in FEV1 from 3 to 8 hours after 
inhaled allergen challenge at Day 14  
  
 
 
 
 
 
Max percent decline in FEV1 from 3 to 8 hours 
after inhaled allergen challenge at Day 14 
 
 
 
Note: AUC: Area under curve, WM: Weighted Mean, Max: Maximum.  
 
3.4.2. 
Statistical Hypotheses 
 
  
 
 
 
3.4.3. 
Main Analysis Methods 
 
  


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3.4.3.1. 
Missing Data Handling 
   
3.4.4. 
Sensitivity Analyses 
3.4.5. 
Supplementary Analyses 
 
  
 
 
 
 
 
3.5. 
Exploratory Endpoint(s) Analyses 
3.5.1. 
Definition of Exploratory Endpoints 
Table 8: 
Definition of Exploratory Endpoints 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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Table 8: 
Definition of Exploratory Endpoints (Continued) 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
        
 
 
 
 
        
 
     
 
 
 
        
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 


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3.5.2. 
Main Analytical Approach 
3.5.2.1. 
 
 
   
 
 
   
 
  
 
 
 
 
3.5.2.2. 
  
  
 
 
 
 
 
 
  
 
 
     
3.5.2.3. 
 
 
 
 
 
3.5.2.4. 
Missing Data Handling  
 
 
 


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3.5.3. 
Other Analyses 
 
  
 
  
 
  
3.6. 
Safety Analyses 
For all safety analyses, the safety analysis population will be used. Safety variables to be 
summarized include vital signs, AEs, clinical laboratory results (hematology, chemistry, and 
urinalysis), and Fridericia’s-corrected QT interval (QTcF) from standard safety digital ECGs. 
Vital signs will be summarized in terms of observed values and changes from baseline. 
Safety events (labs and AEs) occurring in washout periods are assigned to the previous treatment 
periods. 
3.6.1. 
Extent of Exposure 
A subject’s data for the extent of exposure (i.e., duration of study medication within each period) 
to study drug will be summarized by treatment using the 8-point descriptive summary. 
Dosing information for individual subjects will be listed. 
3.6.2. 
Treatment Compliance 
The rate of study drug compliance within each period is calculated as 0[((total number of 
capsules dispense within each period – total number of capsules returned within each 
period)/(Days of exposure in each period x 3)]x 100.   
The rate of study drug compliance will be summarized with descriptive statistics as well as the 
categories of ≥ 120%, 100% to < 120%, ≥ 90% to < 100%, ≥ 80% to <90% and < 80%, and will 
be presented by treatment groups for the Safety Set using frequency distributions. 
3.6.3. 
Adverse Events 
Recorded adverse events will be mapped according to the MedDRA thesaurus with Theravance 
review and approval of the mappings. MedDRA version 23.0 or later will be used. 
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date (and time, if known) of 
the first dose of study drug in each period. 
•
Adverse events with a start date/time after the follow-up period are nontreatment-
emergent.
•
If more than one AE with the same preferred term is reported before the first dose of
investigational product, the AE with the greatest severity will be used as the


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benchmark for comparison with the AEs occurring during the study coded to that 
preferred term. 
An AE will be considered a treatment-emergent serious AE (TESAE) if it is a TEAE that 
additionally meets any SAE criteria. 
The following TEAE summaries will be generated: 
•
Overall Summary of Adverse Events
− The overall summary of adverse events will include the following summary lines:
(any AE, any AE related to Study Drug, Moderate or severe AEs, Moderate or 
severe AEs related to Study Drug, Serious AEs, Serious AEs related to Study 
Drug, AEs leading to discontinuation, Deaths during Study). 
•
TEAEs by primary System Organ Class (SOC) and Preferred Term (PT)
•
Drug-Related TEAEs by SOC and PT
•
TEAEs by SOC, PT and Severity
•
Drug-related TEAEs by SOC, PT and Severity
•
Moderate or Severe TEAEs by SOC and PT
•
Moderate or Severe Drug-Related TEAEs by SOC and PT
•
Serious TEAEs by SOC and PT
•
Drug-related Serious TEAEs by SOC and PT
•
Adverse events leading to premature study drug discontinuation
•
TEAEs by PT with Overall Frequency ≥ 10% of overall population
3.6.3.1. 
Adverse Events of Special Interest 
Not applicable. 
3.6.4. 
Additional Safety Assessments 
3.6.4.1. 
Clinical Laboratory Parameters 
Laboratory data (hematology, serum chemistry, immunophenotyping and coagulation) will be 
summarized in terms of observed values, changes from baseline for each period, and changes 
from baseline for each period relative to normal ranges (e.g., shifts from normal to abnormal 
high/low). Listings will flag laboratory values that are outside of normal range. 
3.6.4.2. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, heart rate, respiratory 
rate, temperature and weight) and changes from baseline values (predose of each period) at each 
visit by treatment group. 
Vital signs data will be summarized in terms of counts and percentages within appropriately 
defined categories (Table 9). For each nominal time point, vital signs will be summarized in 


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terms of observed values and changes from baseline (predose) for each period.  Marked 
abnormalities as defined in Table 9 will be flagged in the listing. 
Table 9: 
Outlier Threshold in Vital Signs 
Heart Rate (bpm) 
Systolic Blood Pressure 
(mm Hg) 
Diastolic Blood Pressure 
(mm Hg) 
< 40 
< 85 
< 45 
> 110 
> 160 
> 100 
3.6.4.3. 
Electrocardiogram 
Descriptive statistics for ECG parameters (heart rate, PR interval, QRS interval, QT interval, and 
QTcF) and changes from baseline values at each assessment time point to the end of study will 
be presented by treatment group. 
Subjects without a postbaseline measurement for a given treatment period will be excluded from 
the summary statistics (i.e., denominator of the summary statistic) for that time point. 
All recorded values by central reader at ECG core lab for the standard 12-lead ECG parameters 
will be presented in a by-subject listing. 
Categorical Analyses 
The number (percentage) of subjects with ECG values in the ranges shown in Table 10 will be 
presented in a by-visit categorical summary.  
Table 10: 
ECG Interval Categories 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 10: 
ECG Interval Categories (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.7. 
Other Analyses 
3.7.1. 
 FEV1 at Screening 
Subject listings displaying FEV1 endpoints at Screening will be provided as described in 
Table 11.  
In addition, the time course of FEV1 change from prechallenge baseline during the 8-hour serial 
measurements postchallenge will be presented using line graphs. LS mean with 95% confidence 
intervals (CIs) will be shown on the y-axis and scheduled time points following allergen 
inhalation (in hours) will be shown on the x-axis.    
Table 11: 
Definition of FEV1 Endpoints at Screening  
Endpoints at Screening  
Definition  
AUC of change from baseline FEV1 3 to 8 hours 
after inhaled allergen challenge at Screening   
 
 
   
AUC of percent change from baseline in FEV1 3 
to 8 hours after inhaled allergen challenge at 
Screening 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.7.2. 
Subgroup Analyses 
The following efficacy endpoints will be analyzed by study site and type of allergen used
 
 using descriptive statistics.   
Table 12: 
Endpoints for Subgroup Analyses  
Endpoints  
WM AUC of change from baseline FEV1 3 to 8 hours after inhaled allergen challenge at Day 14  
WM AUC of percent change from baseline in FEV1 3 to 8 hours after inhaled allergen challenge at 
Day 14 
Maximum decline from baseline in FEV1 3 to 8 hours after inhaled allergen challenge at Day 14 
Maximum percent decline from baseline in FEV1 3 to 8 hours after inhaled allergen challenge at 
Day 14  
  
 
 
 
 
 
 
Note: AUC: Area under curve, WM: Weighted Mean, Max: Maximum. 
 
3.7.3. 
COVID-19 Data  
A subject listing with results of COVID-19 testing will be provided.  
3.7.4. 
Screening Laboratory Data  
Subject listings for screening laboratory data related to eligibility (i.e., urine drug test, breath or 
urine alcohol screen, HIV/Hepatitis test, Tuberculosis Test) will be provided. 
3.7.5. 
Pregnancy Test Results  
The screening laboratory data related to eligibility (i.e., serum follicle-stimulating hormone (for 
postmenopausal female subjects only, if postmenopausal status is in question)), urine or serum 
pregnancy (for Women of childbearing potential only) will be provided.  


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3.8. 
Interim Analyses 
 
 
 
 
3.8.1. 
Data Monitoring Committee 
Not applicable.  
4. 
REFERENCES 
1. Taylor DA, Harris JG, O’Connor BJ. Comparison of incremental and bolus dose inhaled 
allergen challenge in asthmatic patients. Clin Exp Allergy. 2000 Jan; 30(1):56-63. 
 


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5. 
SUPPORTING DOCUMENTATION 
5.1. 
Appendix 1: Changes to Protocol-Planned Analyses 
• 
 
 
  
 
 
 
  
 
 
 
  
 
5.2. 
Appendix 2: Data Conventions and Transformations 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


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 𝑡𝑡
 
 
 
 


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