Clinical trial NCT03473236
Conditions: Safety Issues
Sponsor: GB002, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.
Start date: 2017-09-06; Completion date: 2018-12-03
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a phase 1A randomized double blind placebo controlled single ascending dose and multiple ascending dose trial of inhaled PK10571 (GB002) in healthy adult subjects.

Detailed description:
This is a first-in-human, single-center, randomized, double-blind, placebo-controlled, two-part study in healthy adult males and females of non-childbearing potential. "Double-Blind" means neither the study subject nor the investigator knows if PK10571 or placebo is being given. "Placebo" means a capsule filled with a powder that does not contain the active drug, PK10571. Because the safety profile of PK10571 in humans is unknown and this is the first clinical study to assess PK10571 in humans, a single-ascending dose design will be used in Part A of the study going from a low dose to higher doses based on safety. Part B will be a multiple-ascending dose design to be run only after review of safety and measurement of drug levels in the blood from Part A.

In the single ascending dose study (Part A) up to five doses may be given to different groups of study subjects based on safety and measurement of drug levels in the blood. Subjects will be randomized into one dose cohort to receive either PK10571 or placebo. Within each cohort, 6 subjects will receive active drug and 2 subjects will receive placebo.

In the multiple ascending dose study (Part B), up to three doses of PK10571 will be tested. The daily dose will be administered daily for 7 days with close clinical monitoring. The dose for the first cohort of Part B will be determined by review of the safety and drug levels from Part A by the Safety Review Committee. The dose interval for the first cohort of Part B (i.e., once daily, twice daily, or up to three times daily) will be determined by review of the safety and drug levels in the blood from Part A by the Safety Review committee. Subsequent doses and dosing intervals will be determined by review of the safety and drug levels from the prior cohort.

Arms: arm 1: Dose 1 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 2: Dose 2 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 3: Dose 3 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 4: Dose 4 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 5: Dose 5 Single Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 6: Dose 1 Multiple Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 7: Dose 2 Multiple Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo. arm 8: Dose 3 Multiple Ascending Dose Protocol: within the cohort, 6 participants receive active drug (GB002) and 2 participants receive placebo.
Interventions: intervention 1: GB002 intervention 2: Generic Dry Powder Inhaler intervention 3: Placebo
Intervention descriptions: intervention 1: Inhaled GB002 intervention 2: dry powder inhaler used for inhalation of active drug or placebo intervention 3: Inhaled placebo

Protocol documents:
Prot_000.pdf: 
Cover Page 
 
GB002, Inc. 
Gossamer Bio, Inc. 
CONFIDENTIAL 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 1A Single Ascending Dose and Multiple Ascending Dose 
Double-Blind, Placebo-Controlled, Randomized Trial of Oral Inhalation 
PK10571 in Healthy Adult Subjects 
Protocol Number: 4004002 
 
VERSION 5.3  
DATE: 31 Jul 2018 
 
 
 
NCT NUMBER:  NCT03473236 
 


Protocol 4004002 V.5.3 Final 
 
CLINICAL STUDY PROTOCOL 
A Phase 1A Single Ascending Dose and Multiple Ascending Dose 
Double-Blind, Placebo-Controlled, Randomized Trial of Oral Inhalation 
PK10571 in Healthy Adult Subjects 
PROTOCOL NUMBER 
4004002 
FINAL VERSION 5.3 DATE 
31 Jul 2018 
 
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information herein to others without written 
authorization from Worldwide Clinical Trials Early Phase Services, LLC, except to the 
extent necessary to obtain informed consent from persons who participate as subjects in 
this study. 
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Table of Contents 
1 
INTRODUCTION .............................................................................................................................................. 5 
1.1 
Background ............................................................................................................................... 5 
1.2 
Dose Selection Rationale ........................................................................................................... 8 
1.3 
Study Rationale ....................................................................................................................... 11 
2 
OBJECTIVES ................................................................................................................................................... 12 
3 
STUDY DESIGN SUMMARY ........................................................................................................................ 12 
3.1 
Part A ...................................................... ................................................................................ 13 
3.2 
Part B ...................................................... ................................................................................ 14 
3.3 
Safety Review Team ............................................................................................................... 16 
3.4 
Dose Escalation ....................................................................................................................... 17 
3.5 
Stopping Rules for Dose Escalation ........................................................................................ 17 
3.6 
Stopping Rules for Study Discontinuation .............................................................................. 18 
4 
SUBJECT SELECTION ................................................................................................................................... 18 
4.1 
Inclusion Criteria ..................................................................................................................... 18 
4.2 
Exclusion Criteria .................................................................................................................... 19 
4.3 
Restrictions .............................................................................................................................. 22 
4.4 
Screening ................................................................................................................................. 23 
4.5 
Laboratory Tests ...................................................................................................................... 24 
5 
STUDY PROCEDURES .................................................................................................................................. 25 
5.1 
Subject Assignment ................................................................................................................. 25 
5.2 
Blinding ................................................................................................................................... 26 
5.3 
Check-In Procedures ............................................................................................................... 27 
5.4 
Confinement ............................................................................................................................ 28 
5.5 
Fasting/Meals/Beverages ......................................................................................................... 28 
5.6 
Drug Administration ................................................................................................................ 29 
5.7 
Blood Sampling, Processing and Shipment ............................................................................. 29 
5.8 
Urine Sampling, Processing and Shipment ............................................................................. 31 
5.9 
End-of-Study/Early Termination Procedures .......................................................................... 31 
5.10 
Safety Monitoring and Procedures .......................................................................................... 32 
6 
ADVERSE EVENTS ........................................................................................................................................ 35 
6.1 
Definitions ............................................................................................................................... 35 
6.2 
Serious Adverse Event Reporting ........................................................................................... 36 
6.3 
Relationship to Study Treatment ............................................................................................. 37 
6.4 
Pregnancies .............................................................................................................................. 38 
7 
GENERAL CONSIDERATIONS .................................................................................................................... 38 
7.1 
Basic Principles ....................................................................................................................... 38 
7.2 
Institutional Review Board ...................................................................................................... 38 
7.3 
Informed Consent .................................................................................................................... 38 
7.4 
Indications for Subject Withdrawal ......................................................................................... 38 
7.5 
Termination of the Study ......................................................................................................... 39 
7.6 
Documentation ........................................................................................................................ 39 
7.7 
Trial Monitoring ...................................................................................................................... 39 
7.8 
Reimbursement, Indemnity, and Insurance ............................................................................. 39 
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8 
PHARMACOKINETIC ANALYSIS ............................................................................................................... 40 
8.1 
Analytical Methodology .......................................................................................................... 40 
8.2 
Pharmacokinetic Analysis ....................................................................................................... 40 
8.3 
Statistical Analysis .................................................................................................................. 40 
9 
FACILITIES ..................................................................................................................................................... 41 
10 
DRUG SUPPLIES ............................................................................................................................................ 41 
11 
ADMINISTRATIVE ISSUES .......................................................................................................................... 42 
12 
EVENTS SCHEDULES ................................................................................................................................... 43 
13 
REFERENCES ................................................................................................................................................. 51 
APPENDIX 1  PHARMACOKINETIC BLOOD SAMPLE COLLECTION, PROCESSING, AND SHIPMENT 
INSTRUCTIONS ........................................................................................................................................................ 52 
APPENDIX 2  PHARMACOKINETIC URINE SAMPLE COLLECTION, PROCESSING, AND SHIPMENT 
INSTRUCTIONS ........................................................................................................................................................ 55 
APPENDIX 3  BUFFY COAT SAMPLE COLLECTION, PROCESSING, AND SHIPMENT INSTRUCTIONS .. 57 
APPENDIX 4  PART B: MAD TWICE DAILY (BID) DOSING .............................................................................. 59 
APPENDIX 5  PART B: MAD THREE TIMES DAILY (TID) DOSING ................................................................. 65 
APPENDIX 6  SUMMARY OF CHANGES .............................................................................................................. 72 
 
 
 
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1 
INTRODUCTION 
Unless noted otherwise, the information provided in Section 1 was excerpted from the 
Investigational Brochure for PK10571.1  
1.1 
Background 
Gossamer Bio, Inc. plans to develop PK10571 for the treatment of pulmonary arterial 
hypertension (PAH), an orphan disease associated with high morbidity and mortality. 
Despite recent advances in vasodilator therapy for PAH, more effective treatments are 
needed.  
PK10571 has not been previously studied in humans. 
1.1.1 
Pharmacology 
PK10571 is a potent and selective tyrosine kinase inhibitor which has shown efficacy in 
animal models of PAH.   
The following studies of PK10571 have been performed:  
• In vitro kinase assays 
• In-cell Westerns to measure inhibition of platelet-derived growth factor 
BB (PDGFBB) stimulated AKT (also known as protein kinase B) phosphorylation 
• Enzyme-linked immunosorbent assays (ELISA) to estimate IC50 for inhibition of 
phosphorylation of PDGF receptors in human lung fibroblasts 
• Endothelial cell permeability assays 
• Human ether-à-go-go-related gene (hERG) channel activity assay 
• Metabolism study in human hepatocytes 
• Biliary excretion study 
• Metabolism in lung microsomes 
• Preclinical efficacy study in the rat monocrotaline plus pneumonectomy model 
• Preclinical efficacy study in the rat Sugen 5416 (SU5416) hypoxia model 
• Platelet aggregation studies 
PK10571is well absorbed from the lung 
 
 in both rats and dogs and accumulation did not 
appear to be an issue in either species. 
 
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1.2 
Dose Selection Rationale 
The first in human exposure of PK10571 will be a single dose ranging study followed 
by multiple dose (7 day) administration in healthy volunteers. The results from the 
preclinical program were used to select the starting dose for this phase IA clinical trial.  
The starting dose is based on the Food and Drug Administration (FDA) Guidance for 
Industry “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers” dated July 2005.
 
 
 
 
 
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 Escalation will be carried 
out with careful clinical monitoring and in accordance with dose escalation and halting 
rules described in the protocol. It should be noted that if a higher maximum dose of 
 is warranted in the clinical trial, the nonclinical data would also support 
this dose with an animal:human dose multiple of 15.  
1.3 
Study Rationale 
Because PAH represents a serious orphan medical condition with a critical need for 
better therapies, Gossamer Bio, Inc. plans to work closely with the Food and Drug 
Administration (FDA) in order to ensure an efficient development program. 
Gossamer Bio, Inc. will evaluate PK10571 in an initial Phase 1A single-dose/multiple-
dose study in normal, healthy volunteers,
 
.  
Part A of the phase 1A study is a single ascending dose (SAD) double-blind, placebo-
controlled randomized trial of inhaled dry powder PK10571 in healthy human 
volunteers for determination of safety. Part A will consist of at least 4 cohorts and up to 
5 cohorts. Within each cohort, subjects will be randomly assigned to receive either 
active drug or placebo. The initial dose will be determined based on the results of 
animal toxicology studies.  
After completion and review of the SAD trial (Part A), the multiple ascending dose 
(MAD) clinical trial (Part B) will be performed. The MAD clinical trial is a double-
blind, placebo-controlled randomized repeat dose trial of inhaled dry powder PK10571 
in healthy human volunteers. There will be up to 3 dose cohorts, and within each cohort 
subjects will be randomly assigned to receive either active drug or placebo. Study 
subjects will be administered active drug or placebo once daily for 7 days. 
 
 
 
 
 
 
 
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2 
OBJECTIVES 
The objectives of this study are: 
• To determine the safety and tolerability of single ascending inhalation doses of 
PK10571 formulated as a dry powder with excipient L-leucine in healthy adult 
subjects (Part A) 
• To determine the safety and tolerability of multiple ascending inhalation doses of 
PK10571 formulated as a dry powder with excipient L-leucine in healthy adult 
subjects (Part B) 
• To evaluate the bioavailability of PK10571 following single- and multiple-dose 
regimens 
• 
 
3 
STUDY DESIGN SUMMARY 
This is a first-in-human, single-center, randomized, double-blind, placebo-controlled, 
two-part study in healthy adult males and females of non-childbearing potential. 
Because the safety profile of PK10571 in humans is unknown and this is the first 
clinical study to assess PK10571 in humans, a single-ascending dose escalation design 
will be used in Part A of the study. Part B will be a multiple-ascending dose escalation 
design, to be run only after review of safety and pharmacokinetic data from Part A. 
In the single ascending dose study (Part A) at least 4 dose levels of PK10571 will be 
tested: 
 
 An optional fifth dose level of up to 
 may be added, based on safety 
and pharmacokinetic data from the first 4 cohorts. Subjects will be randomized into one 
dose cohort and receive either PK10571 or placebo. Within each cohort, 6 subjects will 
receive active drug and 2 subjects will receive placebo.  
In the multiple ascending dose study (Part B), up to three dose levels of PK10571 will 
be tested. The daily dose will be administered daily for 7 days with close clinical 
monitoring. The dose for the first cohort of Part B will be determined by review of the 
safety and pharmacokinetic data from Part A by the Safety Review Committee. The 
dose interval for the first cohort of Part B (i.e., once daily, twice daily, or up to three 
times daily) will be determined by review of the safety and pharmacokinetic data from 
Part A by the Safety Review committee. Subsequent doses and dosing intervals will be 
determined by review of the safety and pharmacokinetic data from the prior cohort. 
 
 
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For both Part A and Part B, for each cohort, randomization will occur in 2 blocks as 
follows: In the first block, 2 subjects (sentinel subjects) will be randomized 1:1 to 
receive PK10571 or placebo; in the second block, 6 subjects will be randomized 5 
PK10571: 1 placebo. If PK10571 is well-tolerated in the sentinel subjects, the 
remainder of the cohort (n = 6) will be randomized. There will be a minimum of 48 
hours between dosing of the 2 sentinel subjects and the remainder of the cohort. 
The safety, tolerability, and pharmacokinetics of PK10571 will be evaluated in each 
sequential cohort prior to each dose cohort escalation, assessing the totality of all the 
safety data prior to initiating the next cohort. 
 
Gender distribution will be based on sequential screening of volunteers who meet entry 
criteria, with a minimum of 4 females per cohort, in order to ensure 2 females per 
active dose group. Subjects will be assigned numbers in an ascending order, based on 
successful completion of the screening process. Each subject will participate in only 
one cohort. 
Subjects who withdraw from the study may be replaced at the discretion of the 
Principal Investigator and Sponsor. Replacement subjects will be given a new 
randomization number in the 9000 series and assigned to the same treatment as the 
subject they replace.  
Safety assessments will include adverse events; vital signs; oxygen saturation; physical 
examination; 12-lead electrocardiogram (ECG); clinical laboratory examinations; and 
pulmonary function tests (spirometry).  
Blood and urine will be collected for pharmacokinetic analysis.  
Blood will be collected for buffy coat analysis. 
3.1 
Part A 
Part A of the study is a single ascending dose study design. Up to 5 dose levels will be 
studied. Subjects will receive either PK10571 
 
 or 
placebo. Part A will enroll up to 40 subjects; 8 subjects per cohort. The data from each 
cohort will be analyzed before deciding whether to proceed with the next cohort. 
Each cohort will include a sentinel group of 2 subjects (1 active and 1 placebo) who 
will be dosed at least 48 hours before the remaining subjects (5 active and 1 placebo). 
Dosing of the remaining subjects will occur following a safety evaluation of the 
sentinel group. 
 
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Subjects will receive one of the treatments listed in Table 1. Within each cohort, 
subjects will be assigned to either active treatment or placebo in randomized fashion. 
Table 2 
Part A: Planned Doses for Cohorts 1, 2, and 3 
Cohort 
Test Formulation Dose 
Placebo 
1 - starting dose 
PK10571 
 (n= 6)* 
Placebo (n=2) 
2 - second dose 
PK10571 
 (n=6)* 
Placebo (n=2) 
3 - third dose 
PK10571 
 (n=6)* 
Placebo (n=2) 
4 – fourth dose 
PK10571 up to 
 (n=6)¶  
Placebo (n=2) 
5 – fifth dose 
PK10571 up to 
 (n=6)ρ 
Placebo (n=2) 
FPD = fine particle dose; n = number of subjects 
* 
Capsules with a nominal fill weight of 
 will be administered sequentially to achieve the 
target FPD for Doses 1-3. 
¶ 
Capsules with a nominal fill weight of 
 will be administered to achieve the dose for 
cohort 4 (nominal 18 mg FPD (5 capsules) 
Ρ 
The capsule fill weight, FPD, and number of capsules to be administered will be determined to achieve the 
target dose for cohort 5, if the Safety Review Committee decides to proceed with this dose. 
Each dose will be administered using an oral inhalation device following a 10-hour 
overnight fast. After dosing, no food will be allowed until 4 hours postdose. Meals will 
be standard and scheduled at approximately the same times relative to dose for each 
cohort. 
No water may be consumed for 1 hour prior through 1 hour after dose, except for 
60 mL of room temperature water which will be given to subjects to rinse their mouths 
after dosing. Subjects will swish the 60 mL of water in their mouths then spit it out.  
Blood samples for pharmacokinetic evaluation will be obtained prior to dose 
administration and following dose administration at selected times through 48 hours 
postdose. A total of 14 pharmacokinetic blood samples will be collected from each 
subject. Plasma pharmacokinetic samples will be analyzed for PK10571 using a 
validated analytical method. Appropriate pharmacokinetic parameters will be calculated 
for each formulation using non-compartmental methods.  
Subjects will be housed at the clinical research site for observation for 3 days and then 
followed up by phone daily for the next 7 days. Subjects will return to the clinical 
research site for a safety evaluation on Day 11. 
3.2 
Part B 
Part B is a multiple ascending dose study design. Subjects will receive either PK10571 
or placebo. Approximately 24 subjects will be enrolled in Part B. Subjects will be 
enrolled in 3 cohorts of 8 subjects each.  
 
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The initial dose for Part B will be determined after review of the safety and 
pharmacokinetic data from Part A by the Safety Review Committee. 
Data from the lower dose cohort will be analyzed before deciding whether to proceed 
with the higher dose cohort. Alternatively, a lower dose may be administered, 
depending upon review of previous cohort’s safety and pharmacokinetic data.  
Subjects will receive one of the treatments listed in Table 3. The assigned treatment 
will be given either as a single daily dose (QD), or divided into two daily doses (BID), 
or divided into three daily doses (TID; each dose to be separated by 6 hours on a given 
day).  
Subjects will be assigned to either active treatment or placebo in randomized fashion.  
Table 3 
Part B: Planned Doses for Cohorts 1–3 
Cohort 
Test Formulation (n = 6) 
Placebo (n = 2) 
1 
PK10571 initial dose 
Placebo 
2 
PK10571 mid dose* 
Placebo 
3 
PK10571 high dose* 
Placebo 
n = number of subjects 
Note: The dosing regimen will be either once daily (QD), twice daily (BID), or three times daily (TID) for 7 
consecutive days. For TID dosing, each daily administration will be separated by 6 hours. 
* Alternately, Cohort 2 or 3 will receive a lower dose, depending upon safety and pharmacokinetic data from Cohort 
1 or 2, respectively. 
 
Each dose will be administered using an oral inhalation device. Meals will be the same 
and scheduled at approximately the same times relative to dose for each cohort, if 
possible. Refer to Section 5.5.1 for details regarding timing of meals for each proposed 
dosing regimen (QD, BID, and TID). 
No water may be consumed for 1 hour prior through 1 hour after each dose, except for 
60 mL of room temperature water which will be given to subjects to rinse their mouths 
after dosing. Subjects will swish the 60 mL of water in their mouths then spit it out.  
Blood samples for pharmacokinetic evaluation will be obtained before the first dose of 
the day on Day 1 and Day 7 and at selected times through 36 hours after the first dose 
on Day 1, before the first dose on Days 3-6, through 36 hours after the first dose on 
Day 7, and on Day 9, Day 10, Day 14, and Day 35. 
For QD dosing, a total of 34 pharmacokinetic blood samples will be collected from 
each subject in Part B. 
For BID dosing, a total of 30 pharmacokinetic blood samples will be collected from 
each subject in Part B. 
 
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For TID dosing, a total of 30 pharmacokinetic blood samples will be collected from 
each subject in Part B. Plasma pharmacokinetic samples will be analyzed for PK10571 
using a validated analytical method. Appropriate pharmacokinetic parameters will be 
calculated for each formulation using non-compartmental methods.  
Subjects will be housed at the clinical research site for observation until Day 9 
(48 hours after the last dose) and return to the clinical research site for safety evaluation 
and pharmacokinetic blood collection on Days 10, 14, and 35. 
3.3 
Safety Review Team 
A Safety Review Committee consisting of the Principal Investigator or designee (e.g., a 
medically qualified sub-investigator) and Sponsor representatives with appropriate 
expertise will meet and review, at minimum, the 24-hour safety data for the sentinel 
group of each cohort in Part A prior to dosing the remainder of the cohort.  
The Safety Review Committee will review the safety and pharmacokinetic data from 
each cohort in Part A. Dose escalation to the next level will occur only after review of 
the 24-hour pharmacokinetic data, and safety data up to and including Day 11 from the 
preceding cohort(s). The factors to be used in determining the next incremental dose are 
described in Section 3.4. There will be at least 2 weeks between dosing of each cohort. 
The Safety Review Committee will review the safety and pharmacokinetic data of 
Part A before starting Part B. The pharmacokinetic data from the first 24 hours of 
Part B, Cohort 1 up to and including Day 7, and the safety data up to and including 
Day 14 will be reviewed prior to dosing of Part B, Cohort 2.  
All available safety data will be assessed prior to each dose escalation, including but 
not limited to the following: 
• All adverse events (AEs) 
• Safety laboratory tests (i.e., hematology, chemistry and urinalysis) 
• Coagulation tests 
• Vital signs 
• Physical examinations  
• ECGs (12-lead) 
• Pulmonary function tests (spirometry) 
If the initial dose administered to Cohort 1 is not tolerated, a lower dose cohort may be 
allowed.  
In subsequent cohorts, the dose may be decreased from the planned dose depending on 
results of safety and pharmacokinetic data. 
 
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3.4 
Dose Escalation 
Dose escalation will proceed after the review of all available safety data from subjects 
in the preceding cohort(s) is completed, the assessment has determined that the prior 
dose(s) is/are safe, and escalation to the next dose level is recommended. 
The following factors will be considered for determining the next incremental dose:  
1. Observation of clinical adverse effects based on symptoms and signs; 
2. Observed abnormalities in clinical chemistries, complete blood count (CBC), liver 
function tests, or coagulation tests;  
3. Pharmacokinetic parameters: maximum concentration (Cmax) and area under the 
plasma versus concentration curve (AUC). 
4. For Part A, if no adverse effects are observed at the starting dose 
, 
the next dose will be 
 the third dose will be 
 (2 times the second dose), the fourth dose will be up to 
 
(up to two times the third dose), and the fifth dose will be up to 
 (one 
and a half times the fourth dose).  
5. For Part B, if no adverse effects are observed at the starting dose regimen 
(whether QD, BID, or TID), then the next dose will be a mid-dose to be 
determined by the Safety Review Committee, and if no adverse effects are seen at 
the mid-dose, then the next dose will be higher dose to be determined by the 
Safety Review Committee. In the event of adverse effects at a given dose the 
Safety Review Committee may recommend a decrease in dose for the next dosing 
cohort. 
3.5 
Stopping Rules for Dose Escalation 
The following will result in a decision not to continue dose escalation if judged by the 
Safety Review Committee to be related to study drug:  
1. Onset of respiratory symptoms postdose suspected to be related to study 
medication including but not limited to bronchospasm (wheezing), stridor, 
clinically significant moderate dyspnea, oxygen desaturation with dyspnea, 
evidence of significant airflow obstruction on spirometry in at least 2 subjects. 
2. Three-fold increase in aspartate transaminase (AST) or alanine transaminase 
(ALT) above the upper limit of normal in at least 2 subjects; 
3. Two-fold increase in creatinine in at least 2 subjects;  
4. Gastrointestinal (GI) bleed in at least 1 subject;  
 
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5. New onset atrial fibrillation in at least 1 subject in which case the Safety Review 
Committee  will determine if dose escalation can be undertaken with additional 
monitoring (such as telemetry)  
6. Clinically significant decrease in hemoglobin in at least 2 subjects;  
7. Platelet count drop to less than 60,000 in at least 2 subjects;  
8. Fifty percent drop in total white blood cell (WBC) count in at least 2 subjects; or 
9. Two-fold increase in International Normalized Ratio (INR) in at least 2 subjects. 
3.6 
Stopping Rules for Study Discontinuation 
The study will be discontinued if a serious adverse event (SAE) occurs that is deemed 
directly related to study drug by the Safety Review Committee. In the event of an SAE 
the safety committee will meet to determine if a stopping rule for study termination has 
been met and if so will stop the study before any other subjects are dosed. 
Serious adverse events include: death, respiratory distress requiring hospitalization 
(acute respiratory distress syndrome [ARDS], pulmonary edema, pulmonary embolus, 
hemoptysis), GI bleed requiring blood transfusion, intracranial hemorrhage or stroke, 
renal failure requiring dialysis, MI, heart failure, ventricular tachycardia (torsades), 
heart block requiring temporary or permanent pacemaker, anaphylaxis, exfoliative 
dermatitis. 
4 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
All volunteers must satisfy the following criteria to be considered for study 
participation. 
1. 
Male or female.  
a) Female subjects must not be of childbearing potential. Women are not 
considered of childbearing potential if one of the following is reported and 
documented on the medical history: 
• Postmenopausal with spontaneous amenorrhea for at least 1 year, or 
spontaneous amenorrhea for less than 1 year with serum follicle-stimulating 
hormone (FSH) levels >40mIU/ml; or 
• Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral 
oophorectomy) at least 6 months prior to Screening. 
b) Male subjects must have a history of vasectomy greater than 6 months, or use a 
double-barrier local contraception (i.e., spermicidal gel plus condom) when 
 
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engaging in sexual activity with women of childbearing potential while on study 
medication and for 28 days after the last dose of study medication. 
2. 
Subject must be between 18 and 55 years of age (inclusive). 
3. 
Subject’s body mass index (BMI) must be between 18 and 32 kg/m2 (inclusive), 
and subject must weigh a minimum of 50 kg (110 lbs).  
4. 
Subject must voluntarily consent to participate in this study and provide their 
written informed consent prior to start of any study-specific procedures. 
5. 
Subject is willing and able to remain in the study unit for the entire duration of the 
confinement period (or periods) and return for outpatient visits. 
6. 
Subject must be a non-smoker. 
7. 
Subject must demonstrate ability to use a dry powder inhaler effectively. 
4.2 
Exclusion Criteria 
Subjects will be excluded for any of the following. 
1. Hospitalization within the 6 months prior to the first dose of study treatment. 
2. History or presence of clinically significant cardiovascular, pulmonary, hepatic, 
renal, hematologic, GI, endocrine, immunologic, dermatologic, neurologic, 
oncologic, or psychiatric disease or any other condition that, in the opinion of the 
Investigator, would jeopardize the safety of the subject or the validity of the study 
results. 
3. History or presence of active lung disease (i.e., asthma, chronic obstructive 
pulmonary disease [COPD], pulmonary fibrosis, hemoptysis, bronchiectasis) or 
prior intubation. 
4. Currently uses an inhaler. 
5. History or presence of heart disease (i.e., prior myocardial infarction [MI], 
coronary artery disease, heart failure, hypertension, pulmonary hypertension, 
valve disease, atrial fibrillation, other arrhythmia, or prolonged QT syndrome). 
6. History or presence of cancer (with the exception of basal cell skin cancer that has 
been effectively treated). 
7. History of diabetes mellitus. 
8. History of thyroid disease other than hypothyroidism control with levothyroxine 
and documented normal thyroid-stimulating hormone (TSH). 
9. History of tuberculosis, Lyme disease, or other chronic or opportunistic infection. 
 
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10. History of positive purified protein derivative (PPD) skin test, or positive PPD 
test at screening. 
11. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or human 
immunodeficiency virus (HIV) at screening or has been previously treated for 
hepatitis B, hepatitis C, or HIV infection. 
12. 
History of smoking within the past 15 years. 
13. Is a female with a positive pregnancy test result, or who has the ability to become 
pregnant, or who is lactating. 
14. Has forced expiratory volume in 1 second (FEV1) less than 80% predicted, forced 
vital capacity (FVC) ˂80% predicted, or resting oxygen saturation less than 97% 
on room air at screening or baseline.  
15. Upper respiratory infection within the 3 months prior to the first dose of 
medication. 
16. History of major bleeding or major surgical procedure of any type within 
6 months prior to the first dose of medication. 
17. History of minor bleeding disorders such as epistaxis, rectal bleeding (spots of 
blood on toilet paper), and gingival bleeding within 3 months before the study 
treatment. 
18. History of bleeding disorder or coagulopathy. 
19. Females with history of dysfunctional uterine bleeding, including history of 
menorrhagia or metrorrhagia, unless subject has had a hysterectomy. 
20. 
History of GI bleed. 
21. Has used any over-the-counter (OTC) medication, nutritional or dietary 
supplements, herbal preparations, or vitamins within 7 days prior to the first dose 
of medication. 
22. Has used any antiplatelet agents such as acetylsalicylic acid (ASA), nonsteroidal 
anti-inflammatory drugs (NSAIDs), clopidogrel (or similar agent) or anti-
coagulants within 7 days prior to the first dose of medication. 
23. Has used any prescription medication, except female hormonal replacement 
therapy, within 14 days prior to the first dose of study medication.  
24. Has been treated with any known drugs that are moderate or strong 
inhibitors/inducers of CYP enzymes such as barbiturates, phenothiazines, 
cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study 
 
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medication and that in the Investigator’s judgment may impact subject safety or 
the validity of the study results. 
25. 
History of peripheral vascular disease. 
26. 
History of autoimmune or collagen vascular disease. 
27. 
History of sleep apnea. 
28. 
History of clinically significant allergy to medications.  
29. 
History of anaphylaxis. 
30. 
History of liver disease 
31. 
History of alcohol or drug abuse. 
32. Prolonged QTc on 12-lead ECG (i.e., QTc corrected using Fridericia’s formula 
[QTcF] ˃450 msec), PR >210 msec, or QRS >110 msec at screening. 
33. Evidence of prior MI on ECG; presence of atrial fibrillation on ECG; presence of 
pre-excitation, 2nd or 3rd degree heart block, or abnormal waveform morphology 
that would preclude accurate measurement of the QT interval duration or other 
clinically significant abnormalities. 
34. Chest x-ray reveals presence of infiltrate or other abnormality (mass, granuloma, 
fibrosis, pulmonary thickening, pleural effusion, pulmonary edema, wide 
mediastinum, cardiomegaly, or clinically significant increased interstitial 
markings). 
35. History of neurologic disorder (i.e., multiple sclerosis, amyotrophic lateral 
sclerosis [ALS], cerebrovascular accident [CVA], transient ischemic attach [TIA]) 
36. 
History of deep vein thrombosis or pulmonary embolus.  
37. 
History of clotting disorder. 
38. 
History of mental illness requiring drug treatment or hospitalization. 
39. History of renal failure or proteinuria (defined as 2+ proteinuria: ≥100 mg/dL on 
isolated urinalysis). 
40. Test results greater than the upper limit of normal (ULN) for AST, ALT, or total 
bilirubin 
41. Test results greater than the upper limit of normal on the following coagulation 
tests: INR, prothrombin time (PT), or partial thromboplastin time (PTT). 
42. Total cholesterol >250 mg/dL or triglycerides >300 mg/dL at screening (based on 
fasting lipid profile). 
 
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43. Estimated creatinine clearance less than 60 mL/min at the screening visit using 
the Modification of Diet in Renal Disease (MDRD) equation. 
44. Hemoglobin at screening of <11.5 g/dl (if female subject) or <12.5 g/dl (if male 
subject). 
45. Has a clinically significant abnormal finding on the physical exam, medical 
history, electrocardiogram (ECG), or clinical laboratory results at screening. Note: 
Subjects with abnormal laboratory results not specifically excluded by this 
protocol may be enrolled if the Investigator deems the out-of-range values as not 
clinically significant. 
46. History of treatment with a kinase inhibitor. 
47. Has been on a significantly abnormal diet during the 4 weeks preceding the first 
dose of study medication. 
48. Has donated blood or plasma within 30 days prior to the first dose of study 
medication. 
49. Has participated in another clinical trial (randomized subjects only) within 
30 days prior to the first dose of study medication. 
50. Has a positive urine screen for drugs of abuse (amphetamines, barbiturates, 
benzodiazepines, cocaine, cannabinoids, opiates) or cotinine. 
51. Vital signs (measured sitting after 3 minutes rest) at screening that are not within 
the following ranges (inclusive): heart rate: 40–100 beats per minute [bpm]; 
systolic blood pressure (BP): 90–145 mmHg; diastolic BP: 50–95 mmHg. Out-of-
range vital signs may be repeated once. Blood pressure will be measured in both 
arms at screening, with a 3-minute rest between each measurement. Predose vital 
signs will be assessed by the Principal Investigator or designee (e.g., a medically 
qualified sub-investigator) prior to study drug administration. The Principal 
Investigator or designee will verify the eligibility of each subject with out-of-
range vital signs and document approval prior to dosing.  
52. Significant difference (i.e., greater than 15 mmHg) between the systolic blood 
pressure in each arm at screening. 
53. History of lactose intolerance. 
4.3 
Restrictions 
1. Subject must not take any OTC medication, nutritional or dietary supplements, 
herbal preparations, or vitamins within 7 days prior to the first dose of study 
medication until the end of study visit without evaluation and approval by the 
Investigator.  
 
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2. Has used any antiplatelet agents such as ASA, NSAIDs, or anti-coagulants within 
7 days prior to the first dose of medication until the end-of-study visit without 
evaluation and approval by the Investigator. 
3. Subject must not take any prescription medication, with the exception of female 
hormone replacement therapy, from 14 days prior to the first dose of study 
medication until the end-of-study visit without evaluation and approval by the 
Investigator.  
4. Subject must not consume beverages and foods containing alcohol, grapefruit, or 
caffeine/xanthine from 48 hours prior to the first dose of study medication until 
the end-of-study visit. Subjects will be instructed not to consume any of the above 
products; however, allowance for an isolated single incidental consumption may 
be evaluated and approved by the Investigator based on the potential for 
interaction with the study drug. 
5. Subject must not donate blood or plasma from 30 days prior to the first dose of 
study medication until the end-of-study visit. It is recommended that 
blood/plasma donations not be made for at least 30 days after the end-of-study 
visit. 
6. Subjects must not use tobacco or any products that contain tobacco or nicotine at 
any time during the study until after the end-of-study study visit. 
7. Subject must not engage in strenuous exercise from 48 hours prior to the first dose 
of study medication until after the end-of-study visit. 
8. Male subjects must refrain from sperm donations while on study drug, for the 
entire duration of the study, and for 30 days after the last dose of study drug.   
4.4 
Screening 
The informed consent document will be discussed with each potential participant, and 
each individual will sign an informed consent document for the study prior to any 
study-specific procedures being performed. Each potential study participant will have 
the following assessments by the Investigator or designee within 28 days prior to study 
start:  
• Medical and medication history 
• Demographic data, including: sex, age, race, ethnicity, body weight (kg), 
height (cm), BMI (kg/m2), and smoking habits 
• Physical examination 
• Vital signs measurements: blood pressure, pulse rate, respiration rate, temperature, 
and pulse oximetry 
 
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• ECG performed after subject has been in supine position for a minimum of 
5 minutes 
• Clinical laboratory tests: hematology, serum chemistry, and urinalysis 
• Serology testing: hepatitis B, hepatitis C, and HIV 
• Fasting glucose 
• Fasting lipid profile 
• Coagulation tests (PT, INR, and PTT) 
• Urine drug, alcohol, and cotinine screen tests. 
• Serum pregnancy tests (all female subjects) 
• FSH tests (female subjects claiming post-menopausal status for less than 1 year) 
• Pulmonary function tests: spirometry, including FVC and FEV1 
• Chest X-ray (posteroanterior [PA] and lateral) 
• PPD test (will be evaluated 48 to 72 hours post placement) 
Only medically healthy subjects with clinically acceptable laboratory profiles and 
ECGs will be enrolled in the study.  
A positive test result for pregnancy, HIV, hepatitis B, hepatitis C, or urine drug/cotinine 
screen will end the screening process. 
4.5 
Laboratory Tests 
A Clinical Laboratory Improvement Amendments (CLIA) certified laboratory will 
perform the following clinical laboratory tests for this study. Tests will be performed at 
the times noted in the Events Schedule (Section 12). 
Hematology: The following will be evaluated: hemoglobin, hematocrit, total and 
differential leukocyte count, red blood cell count (RBC), and platelet count. 
Serum Chemistry: The following will be evaluated: albumin, blood urea nitrogen 
(BUN), creatinine, total bilirubin, alkaline phosphatase (ALP), aspartate transaminase 
(AST), alanine transaminase (ALT), sodium (Na+), potassium (K+), chloride (Cl-), 
lactate dehydrogenase (LDH), calcium (Ca), uric acid, total cholesterol, triglycerides, 
globulin, and fasting glucose. 
Thyroid-stimulating hormone (TSH): The following will be evaluated: TSH at the times 
indicated. 
 
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Lipid profile: The following will be evaluated: fasting total cholesterol, high-density 
lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and 
triglycerides  
Serology: Blood will be tested for hepatitis B surface antigen, hepatitis C antibody, and 
human immunodeficiency virus (HIV). 
Coagulation: The following will be evaluated: INR, PT, and PTT. 
Platelet aggregation: The following will be evaluated: collagen-induced platelet 
aggregation 
Urinalysis: The following will be evaluated by an automated or manual urine 
“dipstick” method: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, 
nitrite, leukocyte esterase, and urobilinogen. If protein, occult blood, nitrite, or 
leukocyte esterase values are out of range, a microscopic examination will be 
performed. 
Urine Drug, Cotinine, and Alcohol Screens: Urine samples will be tested for drugs of 
abuse (amphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, opiates), 
alcohol, and cotinine.  
Pregnancy Test (Female Subjects Only): Serum pregnancy test will be performed on all 
female subjects at screening. A urine pregnancy test will be performed on all female 
subjects at check-in. 
Follicle-Stimulating Hormone: Female subjects claiming post-menopausal status for 
less than 2 years must have FSH test results equal to or greater than 40.0 mIU/mL at 
screening. 
5 
STUDY PROCEDURES 
5.1 
Subject Assignment 
Up to 40 subjects will be dosed in Part A of this study.  
Up to 24 subjects will be dosed in Part B of this study. 
The sample size is not based on statistical considerations. The number of subjects 
planned for enrollment is considered sufficient to achieve the study objectives. 
The maximum duration of the study from screening to study exit for each subject will 
be approximately 39 days for subjects enrolled in Part A and 63 days for subjects 
enrolled in Part B. 
Each subject will receive an assigned treatment based on the randomization schedule 
prepared by the clinical site. In order to achieve gender distribution with a minimum of 
 
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4 females per cohort, and 2 females per active dose group, subjects will be randomized 
in blocks of 4 by gender.  
Subjects who successfully qualified for the study but did not dose (for example, backup 
subjects) may be enrolled in a subsequent cohort if they continue to meet all of the 
inclusion requirements and none of the exclusion requirements in the timeframe 
specified. 
5.2 
Blinding 
The study will be conducted under double-blind conditions at the Clinical Site. An 
unblinded pharmacist will be required at the Clinical Site to comply with the study’s 
randomization and blinding requirements. At the Clinical Site, prior to study initiation, 
the Principal Investigator will be responsible for designating a qualified pharmacist to 
serve as the unblinded pharmacist in the study. At his/her discretion, the Principal 
Investigator may also designate a back-up unblinded pharmacist.  
Throughout the study, the unblinded pharmacist will be responsible for all drug 
accountability issues, including preparing, labeling, and dispensing study drug 
according to the randomization code provided, yet remain independent of all subject 
assessments.   
The unblinded pharmacist will be trained on the requirements of the study and the 
contents of the Pharmacy Manual. Specific topics covered in the training will include 
the randomization procedure, drug dispensing procedures, and drug accountability 
guidelines. 
Randomization codes will be provided to the unblinded pharmacist. Confirmation of 
receipt of the randomization code will be required by the Sponsor. The unblinded 
pharmacist will be responsible for maintaining the blind, consistent with protocol 
design, throughout the study. All documentation is to be filed in the Pharmacy Manual. 
Access to this manual by study personnel will be restricted to the unblinded pharmacist 
and back-up pharmacist (if applicable).  
The subjects, Principal Investigator, and all other clinical personnel involved with 
subject assessments will remain blinded to the actual treatment assignments of the 
subjects (active drug or placebo). The Principal Investigator will be ultimately 
responsible for ensuring that the integrity of the blind is maintained throughout the 
study and will be required to notify the Sponsor in the event of any breaking of the 
blind for any reason.  
5.2.1 
Staff 
All observers who evaluate any reported adverse event, laboratory abnormalities, 
ECGs, and changes in the ECGs will be blinded as to whether the subject is being 
dosed with active drug or placebo. 
 
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The bioanalytical laboratory and pharmacokineticist will be unblinded to allow for 
interim analysis between cohorts. 
5.2.2 
Subjects 
All subjects will be blinded as to treatment with active drug or placebo.  In order to 
maintain the blind of the study, on the designated dosing days, all subjects will be 
administered an oral inhalation dose of a study medication.  
5.2.3 
Unblinding Procedures 
The treatment assignment should be unblinded to the Principal Investigator or clinical 
staff prior to completion of the study only in the case of an emergency, when 
knowledge of the study drug assignment is absolutely necessary for the clinical 
management or welfare of the subject. Breaking of the blind under any other 
circumstances will be considered a protocol violation.  
The Investigator is strongly encouraged to contact the Sponsor before unblinding the 
study drug assignment prior to the scheduled assessment of tolerance and safety data.  
If the blind is broken for any reason, the Investigator must notify the Sponsor within 
one business day, and an SAE form must be completed, if appropriate.  In addition, the 
Investigator will record the date and reason for revealing the blinded study drug 
assignment for that subject in the source documents and appropriate CRF page(s). 
5.3 
Check-In Procedures 
Subjects will be admitted to the research facility on the day prior to study drug 
administration.  The following procedures will be completed following admission to the 
unit: 
• All subjects will be asked to affirm that the exclusion criteria and restrictions 
have not been violated since the screening. 
• Review concomitant medications 
• Assess for adverse events 
• Collect blood for serum chemistry, hematology (complete blood count), and 
coagulation testing 
• Collect urine for urinalysis 
• Collect urine for drug, alcohol, and cotinine testing 
• Spirometry 
• Collect urine for pregnancy testing (female subjects only) 
 
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If at any time the drug, cotinine, alcohol, or pregnancy test is positive, the subject will 
be discontinued from study participation. 
All subjects will be trained in the use of the dry powder inhaler. Instructions for 
training subjects will be provided in the Pharmacy Manual. 
5.4 
Confinement 
All subjects will check-in at an appropriate time the day before dosing to allow time for 
predose procedures, training in the use of the dry powder inhaler, and to fast overnight 
for at least 10 hours. 
Part A: Subjects will remain in the research center for observation until Day 3 and will 
be followed up by phone daily for the next 7 days (Days 4-10). Subjects will return to 
the clinical research site for a safety evaluation on study Day 11. 
Part B: Subjects will be released from the research center on Day 9 and return for 
outpatient visits on study Days 10, 14, and 35. 
5.5 
Fasting/Meals/Beverages 
5.5.1 
Fasting/Meals  
Part A (SAD) 
Optional meals may be provided the day of check-in. All subjects will then be required 
to fast for at least 10 hours prior to dosing. The subjects will fast for 4 hours thereafter. 
Standard meals will be provided at approximately 4 and 10 hours after drug 
administration and at appropriate times thereafter. Meal/snack menus will be the same 
for all SAD cohorts. 
Part B (MAD) 
 
Optional meals may be provided the day of check-in. All subjects will then be required 
to fast for at least 10 hours prior to dosing. 
For QD dosing, each dose will be administered following a 10-hour overnight fast. 
After dosing on Day 1 and Day 7, no food will be allowed until 4 hours postdose. On 
other dosing days (Days 2–6), subjects will have nothing to eat for at least 1 hour 
postdose.  
For BID dosing, the first dose of the day will be administered in the morning following 
a 10-hour overnight fast. After the morning dose on Day 1 and Day 7, no food will be 
allowed until 4 hours postdose. On other dosing days (Days 2–6), no food will be 
allowed for at least 1 hour after the morning dose. Subjects will have nothing to eat for 
at least 2 hours before the second dose of each day and for at least 1 hour after the 
second dose. 
 
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For TID dosing, the first dose of the day will be administered in the morning following 
a 10-hour overnight fast. On Day 1 and Day 7, no food will be allowed until 4 hours 
after the first dose of the day. On other dosing days (Days 2–6), no food will be 
allowed for at least 1 hour after the first dose of the day. Subjects will fast for at least 
1.5 hours before the second and third doses of each day.  
Meal/snack menus will be the same for all MAD cohorts. 
5.5.2 
Beverages 
Water will be allowed ad lib up to 1 hour prior to study treatment administration. Each 
subject will given 60 mL of water with which to rinse their mouths after dosing. 
Subjects will swish the water in their mouths and then spit it out. 
After 1 hour postdose, subjects will be encouraged to drink water ad lib.  
5.6 
Drug Administration 
Worldwide Clinical Trials pharmacy staff will package and dispense the study 
treatment. Prior to dosing, subjects will receive training in use of the oral inhalation 
device as indicated in the Events Schedules (Section 12) or as needed if additional 
training is determined. 
Details for dose preparation, device training, and dose administration will be provided 
in a separate pharmacy manual. 
Each subject will receive an oral inhalation dose of the assigned treatment (active drug 
or placebo). All doses of investigational product will be administered under the 
supervision of clinical study personnel. 
For QD dosing, the subjects will remain seated, except as otherwise required for study 
procedures or personal needs, for the first 4 hours after dosing. Subjects will not be 
allowed to lie down, except as directed by clinical staff secondary to adverse events 
(AEs), for the first 4 hours after dosing. 
For BID and TID dosing, the subjects will remain seated, except as otherwise required 
for study procedures or personal needs, for the first 4 hours after the first morning dose 
on Day 1 and Day 7. For other doses, subjects will remain seated for at least 1 hour 
after dosing. During the times when subjects are to remain seated, they will not be 
allowed to lie down, except as directed by clinical staff secondary to adverse events 
(AEs). 
5.7 
Blood Sampling, Processing and Shipment 
Pharmacokinetic blood samples will be collected as detailed in Appendix I, 
Pharmacokinetic Sample Collection, Processing, and Shipment Instructions. 
 
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Part A 
A total of 84 mL (14 x 6 mL samples) will be collected from each subject in Part A for 
pharmacokinetic analysis.  
In addition, approximately 114 mL of blood will be collected for laboratory 
evaluations. The total volume of blood collected from each subject will not exceed 
approximately 198 mL. Additional blood may be collected if necessary for repeat 
laboratory evaluations or AE follow up. 
Blood samples collected up to and including 24 hours postdose within ± 2 minutes of 
scheduled time will not be considered deviations. Blood samples collected after 
24 hours through 48 hours within ± 5 minutes of scheduled time will not be considered 
deviations. Blood samples collected after 48 hours postdose within ± 10 minutes of 
scheduled time will not be considered deviations. 
Table 4 
Total Amount of Blood to be Collected for Testing in Part A 
Reason for Collection 
Number of 
Samples 
Volume per 
Sample (mL) 
Total Volume (mL) 
Clinical labs at screening 
1 
25 
25 
Clinical labs during study (check-in, 24 and 
48 hours postdose) 
3 
15 
45 
Clinical labs at end-of-study 
1 
15 
15 
Platelet aggregation 
2 
6.5 
13 
Buffy coat samples 
2 
8 
16 
Pharmacokinetic analysis 
14 
6 
84 
Total 
198 
Part B 
Note: The information in this section applies to QD dosing only. The blood sample 
volumes for BID and TID dosing are provided in Appendix 4 and 5, respectively. 
A total of 204 mL (34 x 6 mL samples) will be collected from each subject in Part B for 
pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for laboratory 
evaluations. The total volume of blood collected from each subject will not exceed 
approximately 377.5 mL. Additional blood may be collected if necessary for repeat 
laboratory evaluations or AE follow up. 
Blood samples collected up to and including 24 hours postdose within ± 2 minutes of 
scheduled time will not be considered deviations. Blood samples collected after 
 
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24 hours through 48 hours after the last dose within ± 5 minutes of scheduled time will 
not be considered deviations, with the following exception: when blood collection is 
scheduled for the same time as dose administration (at times other than the first dose 
administration) samples collected within -5 minutes of scheduled time will not be 
considered deviations. Blood samples collected after 48 hours postdose after the last 
dose within ± 10 minutes of scheduled time will not be considered deviations.  
Table 5 
Total Amount of Blood to be Collected for Testing in Part B 
Reason for Collection 
Number of 
Samples 
Volume per 
Sample (mL) 
Total Volume (mL) 
Clinical labs at screening 
1 
25 
25 
Clinical labs during study (check-in, Days 2, 
4, 7, 9, and 14) 
6 
15 
90 
Clinical labs end-of-study 
1 
15 
15 
Platelet aggregation 
3 
6.5 
19.5 
Buffy coat samples 
3 
8  
24 
Pharmacokinetic analysis 
34 
6  
204 
Total 
377.5 
 
5.8 
Urine Sampling, Processing and Shipment 
Pharmacokinetic urine samples will be collected as detailed in Appendix II, Urine 
Sample Collection, Processing, and Shipment Instructions. 
Urine will be collected predose (spot collection) and for 24 hours postdose for the 
determination of drug levels. 
5.9 
End-of-Study/Early Termination Procedures 
End-of-study procedures will be performed on Day 11 of Part A and on Day 35 of 
Part B.  
The following procedures and assessments will be performed: 
• Concomitant medications review 
• Vital signs measurements (blood pressure, pulse rate, respiration rate, pulse 
oximetry, and temperature).  
• Physical examination 
• ECG 
 
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• Chest X-ray (PA and lateral) (required for Part A; at the Investigator’s 
discretion for Part B) 
• Spirometry 
• Clinical laboratory tests 
• Coagulation tests 
• Urinalysis 
• Pregnancy testing (female subjects) 
• Adverse event assessment 
When possible, end-of-study procedures will be performed in the event of a subject’s 
early termination from the study. 
5.10 
Safety Monitoring and Procedures 
5.10.1 
Vital Signs 
A full set of vital signs (blood pressure, pulse rate, respiration rate, temperature, and 
pulse oximetry) will be measured at screening, at 0 hour (predose), and at the end-of-
the study visit (Day 11 of Part A and Day 35 of Part B).  
In Part A, blood pressure, pulse rate, and pulse oximetry will be measured at the 
following times:  
• 10 minutes and 1, 2, 4, 8, 12, 16, 24, and 48 hours postdose 
Note: The information in this section for Part B applies to QD dosing only. The timing 
of vital sign measurements for BID and TID dosing are provided in Appendix 4 and 5, 
respectively. 
In Part B, blood pressure, pulse rate, and pulse oximetry will be measured at the 
following times:  
• 10 minutes and 1, 2, 4, 8, 12, 16, and 24 hours after Dose 1 
• 1, 2, and 4 hours after Doses 2-6  
• 10 minutes and 1, 2, 4, 8, 12, 16, 24 hours after Dose 7 
• Day 9 (prior to discharge) 
• Day 10 
• Day 14 
At the screening visit, each subject will have blood pressure measured in both arms. If 
there is no significant difference (i.e., greater than 15 mmHg) between the systolic 
 
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blood pressure in each arm at screening, then at other times the subject may have blood 
pressure measured in the dominant arm. Should one set of blood pressure 
measurements be out of range, the blood pressure reading will be repeated in the same 
arm. 
For purposes of qualifying any given subject for study participation, out-of-range vital 
signs may be repeated once.  
Additional vital signs measurements may be performed as deemed medically necessary 
by research personnel. All vital signs measurements will be taken after the subject has 
completed a minimum 3-minute sit.  
5.10.2 
Pulmonary Function Tests (Spirometry) 
Part A: Pulmonary function tests (FEV1 and FVC; best of 3 reproducible maneuvers) 
will be performed at screening, check-in, at 1, 8, and 24 hours after dose 
administration, and at the end of the study (Day 11). 
Part B: In the case of QD dosing, pulmonary function tests (FEV1 and FVC; best of 
3 reproducible maneuvers) will be performed at screening, check-in, at 1, 4, 8, and 
23 hours after administration of the first and last morning doses (Day 1 and Day 7), 
1 hour after dosing on Day 4, on Day 14, and at the end of the study (Day 35). 
In the case of BID dosing, pulmonary function tests (FEV1 and FVC; best of 
3 reproducible maneuvers) will be performed at screening, check-in, at 1, 4, 8, and 
23 hours after administration of the first morning dose on Day 1 and Day 7, at least 
1 hour after the first dose on Day 4, on Day 14, and at the end of the study (Day 35). 
In the case of TID dosing, pulmonary function tests (FEV1 and FVC; best of 
3 reproducible maneuvers) will be performed at screening, check-in, and at 1 hour after 
the first morning dose on Day 1, Day 4, and Day 7, at least 1 hour before second dose 
on Day 1 and Day 7, 23 hours after the first morning dose on Day 1 and Day 7, on Day 
14 and at the end of the study (Day 35).  
Repeat spirometry will be allowed at the Investigator’s discretion. 
5.10.3 
Physical Examination 
Part A: Physical examinations will be conducted for all subjects at screening, predose, 
daily while confined in the clinical research unit, and at the end of the study (Day 11). 
Part B: Physical examinations will be conducted for all subjects at screening, predose 
on Day 1, on Days 2, 4, 7, 9, 14, and at the end of the study (Day 35). 
Assessments will include: physical exam for general appearance; head, ears, eyes, nose 
and throat; thyroid; lymph nodes; back and neck; heart; chest; lungs; abdomen; skin; 
and extremities, musculoskeletal and neurological. 
 
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5.10.4 
Electrocardiograms 
All subjects will have ECGs performed at screening. All ECGs will be performed after 
subject has been in supine position for at least 5 minutes. 
In Part A ECGs will be performed at the following times: predose, 10 minutes 
postdose, 2, 4, 8, and 24 hours postdose, and at the end of the study.  
In Part B, ECGs will be performed at the following times (relative to the first dose): 
predose, 10 minutes postdose, 2, 4, 8, and 24 hours postdose, Day 9 (prior to 
check-out), Day 14, and at the end of the study. 
5.10.5 
Chest X-Ray 
All subjects will undergo chest X-rays (PA and lateral) at screening and on Day 11 of 
Part A and Day 9 of Part B. Additionally, subjects in Part B may undergo chest X-rays 
on Day 35 if clinically indicated, as determined by the Investigator. 
5.10.6 
PPD Test 
PPD: A PPD skin test will be performed at screening to assess for exposure to 
tuberculosis. The test site will be evaluated 48 to 72 hours after placement. 
5.10.7 
Other 
Subjects will be closely monitored during the confinement period in the research 
facility. Subjects will remain seated, except as otherwise required for study procedures 
or personal needs, for the first 4 hours after dosing. Should the need to move about 
occur during the first 4 hours after dose administration (or after the first dose in Part B), 
subjects may be escorted to such procedures or activities by research personnel as 
deemed medically necessary. 
Following dose administration, each subject will be queried periodically about changes 
in their health. Responses will be transcribed in each subject’s source documentation.  
Subjects will be instructed to inform the study physician and/or research personnel of 
any AEs that occur at any time during the study. 
Procedures will be completed as specified in this protocol unless contraindicated due to 
a reported AE. 
Medical emergency personnel trained in advanced cardiac life support will be on site to 
monitor subjects during the confinement period in the research center. Emergency 
medical equipment including but not limited to intubation equipment, pulse oximetry, 
crash cart, and defibrillator shall be maintained on site to administer appropriate 
medical care should it be required. A physician will remain on site for a minimum of 
4 hours after dose administration and will be available immediately by cell phone or 
pager thereafter. 
 
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6 
ADVERSE EVENTS 
Subjects will be monitored for any AEs from the beginning of confinement until the 
end-of-study visit. The Investigator or a medically qualified designee will review each 
event. The Investigator or a Sub-Investigator will assess its relationship to the study 
drug. Each sign or symptom will be graded for severity, and the date and time of onset, 
cessation and resolution will be recorded. Treatment of any adverse reactions will be 
evaluated and managed by a physician, either at the study site or at a nearby hospital 
emergency room, as appropriate. All non-serious AEs will be reported on a regular 
basis or as specified by the Sponsor. 
6.1 
Definitions 
6.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. 
An AE can be any unfavorable and unintended sign (eg, an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without 
judgment to causality. An AE can arise from any use of the drug (eg, use in 
combinations with another drug) and from any route of administration, formulation, or 
dose, including an overdose. 
6.1.2 
Serious Adverse Event/Serious Suspected Adverse Reaction  
A serious AE (SAE) or serious suspected adverse reaction, in the view of either the 
investigator or Sponsor, results in any of the following outcomes: Death, a life-
threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
6.1.3 
Life-Threatening Adverse Event/Life-Threatening Suspected Adverse Reaction 
A life-threatening AE/life-threatening suspected adverse reaction, in the view of either 
the Investigator or Sponsor, places the patient or subject at immediate risk of death. It 
does not include an adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
 
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6.1.4 
Unexpected Adverse Event/Unexpected Suspected Adverse Reaction  
An unexpected AE/unexpected suspected adverse reaction is an AE or suspected 
adverse reaction that is not listed in the investigator brochure or is not listed at the 
specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended.  
6.2 
Serious Adverse Event Reporting 
The Investigator or designee will notify the appropriate sponsor contact immediately 
after the SAE detection, observation, or report of occurrence (regardless of the 
relationship to test article). The sponsor contact information for SAE reporting is 
provided below: 
Lawrence S. Zisman, MD 
CEO 
Gossamer Bio, Inc. 
3013 Science Park Rd. Ste. 200 
San Diego CA 92121 
Phone: 518.472.0952 
24-hour contact number: 518.573.8315 
Email: lzisman@gossamerbio.com 
These SAE reports must contain the following information: 
A. Study name/number (for EU also the Eudract number) 
B. Study drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Subject number 
E. Subject initials 
F. Subject demographics 
G. Clinical event 
1) Description 
2) Date of onset 
3) Treatment (drug, dose, dosage form) 
4) AE relationship to study drug 
5) Action taken regarding study drug in direct relationship to the AE 
H. If the AE was fatal or life-threatening 
I. Cause of death (whether or not the death was related to study drug) 
J. Autopsy findings (if available) 
 
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Any new SAE that occurs within one month after the study period and is considered to 
be possibly related to the Investigational Medicinal Product (IMP) should be recorded 
and reported immediately to the Sponsor.    
The person responsible for the study shall take care that the study has been carried out 
in accordance with pharmacovigilance local regulations. 
All serious event reporting will adhere to 21 CFR 312.32 for IND drugs and 
21 CFR 314.80 for marketed drugs (15-day alerts). The Institutional Review Board 
(IRB) will be notified of the alert reports per FDA regulations. 
All AEs, including SAEs, will be followed to resolution when possible. All AEs and 
treatment administered will be recorded on the case report form (CRF). 
The Sponsor will be responsible for reporting and processing any SAEs to the FDA or 
other applicable regulatory agency. 
6.3 
Relationship to Study Treatment 
The relationship between the AE and the investigational product will be determined by 
the Principal Investigator or Sub-Investigator on the basis of his/her clinical judgment 
and the following definitions: 
Related: 
The AE follows a reasonable temporal sequence from the study product administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, or concomitant medications). 
The AE follows a reasonable temporal sequence from the study product administration, 
and represents a known reaction to the drug under study or other drugs in its class, or is 
predicted by the known pharmacological properties of the drug. 
The AE resolves with discontinuation of the investigational product and/or recurs with 
rechallenge, if applicable. 
Possibly Related: 
An AE may be considered possibly related if or when (at least two of the following):  
• It follows a reasonable temporal sequence from administration of the study product;  
• It could not readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject. 
• It follows a known pattern of response to the study product. 
 
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Not Related: 
The AE does not follow a reasonable temporal sequence from study product 
administration, or can be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications). 
6.4 
Pregnancies 
Any pregnancy will be considered a protocol violation. Pregnancies will not be 
documented or reported as AEs unless directed to do so by the Sponsor. However, if at 
any time the pregnancy falls under the scope and definition of an SAE, it will then be 
reported as such.  
7 
GENERAL CONSIDERATIONS 
7.1 
Basic Principles 
This research will be carried out in accordance with the protocol, the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH), Guideline for Good Clinical Practice: Consolidated Guidance (E6), and 
applicable regulatory requirements(s) including clinical research guidelines established 
by the Basic Principles defined in the U.S. 21 CFR Parts 50, 56, and 312 and the 
principles enunciated in the Declaration of Helsinki (revised version Fortaleza 2013). 
7.2 
Institutional Review Board 
This protocol will be reviewed by an appropriate IRB and study enrollment will not 
commence until the Board has approved the protocol or a modification thereof. The 
Board is constituted and operates in accordance with the principles and requirements 
described in the U.S. Code of Federal Regulations (21 CFR Part 56). 
7.3 
Informed Consent 
Written informed consent will be obtained from each subject prior to performing any 
baseline study-specific evaluations. The informed consent document is prepared by the 
Investigator or designee, subject to review and approval by the Sponsor, and forwarded 
to a qualified IRB for final review and approval. The IRB-approved document must 
contain, at minimum, the eight basic elements of informed consent. Only the most 
recently IRB-approved Informed Consent Document must be used to consent 
prospective study subjects. One copy of the signed and dated informed consent 
document will be given to the subject and the original retained by the Investigator/site. 
7.4 
Indications for Subject Withdrawal 
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn 
if necessary, to protect their health and safety or the integrity of the study data.  
 
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The final report will include reasons for withdrawals. In the event of an early 
termination, subjects will undergo the procedures described in Section 5.9. 
7.5 
Termination of the Study 
The Principal Investigator reserves the right to terminate the study in the interest of 
subject safety and welfare. The Sponsor reserves the right to terminate the study at any 
time for administrative reasons. 
7.6 
Documentation 
All documents pertaining to the study, including a copy of the approved protocol, copy 
of the informed consent document and Health Insurance Portability and Accountability 
Act (HIPAA) documents, completed CRFs (where applicable), drug accountability and 
retention records, and other study related documents will be retained in the permanent 
archives of the study site. These will be available for inspection at any time by the 
Sponsor or the FDA. Per 21 CFR 312, record retention for this study is required for a 
period of two years following the date on which this study agent is approved by the 
FDA for the marketing purposes that were the subject of this investigation; or, if no 
application is to be filed or if the application is not approved for such indication, until 
two years following the date on which the entire study (not merely the Investigator’s 
portion of the study, if it involved more than one investigator) is completed, terminated, 
or discontinued, and the FDA is notified. 
Subject records will be kept private except when ordered by law. The following 
individuals will have access to study subject records: Principal Investigator and 
designees, study Sponsor, monitors, and auditors, the FDA, other government offices, 
and the IRB. 
7.7 
Trial Monitoring 
Sponsor personnel (or designees) will be responsible for monitoring the study to ensure 
compliance with the protocol and Good Clinical Practice (GCP). Compliance may be 
verified by one or more of the following methods: on-site visits, frequent 
communication with the Investigator, and/or review of CRFs and source documents. 
The Investigator agrees to permit such monitoring as well as audits or reviews by 
regulatory authorities and the IRB. 
7.8 
Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement 
on terms agreed upon by the parties. 
 
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8 
PHARMACOKINETIC ANALYSIS 
8.1 
Analytical Methodology  
Plasma and urine samples will be analyzed for PK10571 using validated assays. The 
samples from all evaluable subjects who complete their study period will be analyzed.  
8.2 
Pharmacokinetic Analysis 
Pharmacokinetic parameters for PK10571will be calculated using non-compartmental 
analysis. The following pharmacokinetic parameters will be determined: 
The maximum plasma concentration (Cmax) and time to Cmax (Tmax) will be taken 
directly from the data. The elimination rate constant, λz, will be calculated as the 
negative of the slope of the terminal log-linear segment of the plasma concentration-
time curve; the range of data to be used will be determined by visual inspection of a 
semi-logarithmic plot of concentration vs. time. Elimination half-life (T½) will be 
calculated according to the following equation: 
T½ = 0.693 / λZ 
Area under the curve to the final sample with a concentration greater than the limit of 
quantitation (LOQ), (AUClast), will be calculated using the log trapezoidal method and 
extrapolated to infinity using: 
AUCinf = AUClast + Clast/ λZ 
where Clast is the final concentration ≥LOQ. 
All evaluable subjects will be included in the pharmacokinetic analysis. 
Pharmacokinetic calculations will be performed using appropriate software, e.g. 
Phoenix™ WinNonlin® (Version 6.3 or higher, Pharsight Corporation) and/or SAS® 
(Version 9.3 or higher, SAS Institute Inc.). 
8.3 
Statistical Analysis 
Comparison of the log-transformed pharmacokinetic parameters Cmax, AUClast, and 
AUCinf for PK10571across treatments will be performed using an ANOVA model and 
the two one-sided t-tests procedure. The ANOVA model will include factors for 
subject, treatment, and cohort. The ratios of the geometric means and 90% confidence 
intervals will be reported. Statistical analyses will be performed using appropriate 
software, e.g. Phoenix™ WinNonlin® (Version 6.3 or higher, Pharsight Corporation) 
and/or SAS® (Version 9.4 or higher, SAS Institute Inc.). Additional details regarding 
statistical analysis will be provided separately in the statistical analysis plan (SAP). 
 
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9 
FACILITIES 
CLINICAL TRIAL SITE 
Worldwide Clinical Trials Early Phase Services, LLC 
2455 N.E. Loop 410, Suite 150 
San Antonio, Texas 78217 
Telephone: 210.635.1500 
Fax: 210.635.1646 
CLINICAL LABORATORY 
Worldwide Clinical Trials Early Phase Services, LLC 
2455 N.E. Loop 410, Suite 150 
San Antonio, Texas 78217 
Telephone: 210.635.1500 
Fax: 210.635.1646 
ANALYTICAL LABORATORY 
Worldwide Clinical Trials Early Phase Services/Bioanalytical Sciences, Inc.  
8609 Cross Park Drive 
Austin, Texas 78754 
Telephone: 512.834.7766 
DATA MANAGEMENT  
Worldwide Clinical Trials, Ltd 
1st Floor, Waterfront House 
Beeston Business Park 
Beeston, Nottingham  
NG9 1LA, UK 
Telephone: +44(0)115.956.7711 
Fax: +44(0)115.922.0960 
10 
DRUG SUPPLIES 
Gossamer Bio, Inc. will supply sufficient quantities of the study drug formulation, 
capsules, closures, desiccants, and monodose inhalers to allow completion of this study. 
Study drug formulations of PK10571 for oral inhalation and placebo for oral inhalation 
will be shipped to Worldwide Clinical Trials Early Phase Services, LLC pursuant to 
site standard operating procedures (SOPs). Upon receipt of the study drug products, the 
supplies will be inventoried and stored in the appropriately designated environmentally 
controlled and secure, limited access area. The lot numbers of the PK10571 or placebo 
powder along with the retest dates will be recorded and copies of the Certificate of 
 
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Analysis (where available) will be maintained on file. Records will be maintained of 
the receipt and dispensation of the drugs supplied.  
 
 
 
 
 
At the conclusion of the study, any unused 
study drug will be returned to Gossamer Bio, Inc. or destroyed by the site pursuant to 
written authorization by the sponsor and applicable federal and state regulations.  
11 
ADMINISTRATIVE ISSUES 
The Investigator is referred to the Investigator Brochure, information provided during 
the study initiation visit, information provided by the study monitor, and ICH 
Guidelines for Good Clinical Practice for information regarding the study drug, details, 
or general considerations to be followed during the course of this study.  
 
 
 
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12 
EVENTS SCHEDULES  
Table 6 
Part A Events Schedule 
Part A 
Day -28 
to Day -1 
Day -1 
Day 1 
Day 
2 
Day 
3 
Days 
4-10 
Day 
11/ 
End-
of-
Study 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
hr 
Serial 
time-
points 
10 
min 
20 
min 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
10 
hr 
12 
hr 
16 
hr 
20 
hr 
24 
hrs 
48 
hrs 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication histories 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs and pulse 
oximetrya 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Physical 
examinationb 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
12-lead ECGc 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
X 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pulmonary function 
testsd 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
TSH, HIV, 
hepatitis B and C, 
PPDe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
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Part A 
Day -28 
to Day -1 
Day -1 
Day 1 
Day 
2 
Day 
3 
Days 
4-10 
Day 
11/ 
End-
of-
Study 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
hr 
Serial 
time-
points 
10 
min 
20 
min 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
10 
hr 
12 
hr 
16 
hr 
20 
hr 
24 
hrs 
48 
hrs 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Coagulation (PT, 
PTT, INR) 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Platelet aggregationf 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for 
buffy coat analysisf 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
female subjects)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (female 
subjects only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Urine 
drug/alcohol/cotinine 
screens  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meals 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Dose inhalation 
training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for 
PK analysisg 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Urine collection for 
PK analysish 
 
 
X 
 
X 
X 
 
 
 
Confinementi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Phone callsj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Part A 
Day -28 
to Day -1 
Day -1 
Day 1 
Day 
2 
Day 
3 
Days 
4-10 
Day 
11/ 
End-
of-
Study 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
hr 
Serial 
time-
points 
10 
min 
20 
min 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
10 
hr 
12 
hr 
16 
hr 
20 
hr 
24 
hrs 
48 
hrs 
Outpatient visitsk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse event 
assessmentl 
 
X 
BUN = blood urea nitrogen; CR = creatinine; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = 
human immunodeficiency virus; INR = international normalized ratio; PK = pharmacokinetic; PPD = positive purified 
protein derivative skin test; PT = prothrombin time; PTT = partial thromboplastin time; Tmax = time of maximum 
concentration; TSH = thyroid stimulating hormone 
a) A full set of vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse oximetry) will be 
measured at screening, at 0 hour (predose), and at the end-of-the study visit (Day 11). Blood pressure, pulse rate, 
and pulse oximetry will be measured at 10 minutes postdose and at the following hours postdose: 1, 2, 4, 8, 12, 16, 
24, and 48. At the screening visit, each subject will have blood pressure measured in both arms. If there is no 
significant difference (i.e., greater than 15 mmHg) between the systolic blood pressure in each arm at screening, 
then at other times the subject may have blood pressure measured in one arm. 
b) Physical examinations will be conducted for all subjects at screening, predose, daily while confined in the clinical 
research unit, and at the end-of-study visit on Day 11. 
c) All subjects will have ECGs at screening, predose, 20 minutes postdose, 2, 4, 8, and 24 hours postdose, and at the 
end-of-study visit on Day 11. All ECGs will be performed after subject has been in supine position for at least 5 
minutes. 
d) Pulmonary function tests (FEV1 and FVC; best of 3 reproducible maneuvers) to be performed using spirometry. 
Repeat spirometry will be allowed at the Investigator’s discretion. 
e) PPD test to be read 48-72 hours after placement. 
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f) To be performed 10 minutes after dosing of Cohort 1; for subsequent cohorts, to be performed at Tmax, based on 
analysis from previous cohort(s). 
g) Blood samples for pharmacokinetic analysis will be collected at 0 hour (predose), and then at 3, 10, 20, 30, 40 
minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after the start of study treatment administration. Exception: For 
multi-capsule administrations (if required to achieve the dose), the first postdose blood collection will be performed 
5 minutes after the start of study treatment administration. 
h) Urine samples for pharmacokinetic analysis will be collected predose (spot collection) and for the first 24 hours after 
dosing. 
i) Subjects will remain in the research center for observation for 3 days after dosing (Days 1-3). 
j) Subjects will be followed up by phone daily on Days 4-10.  
k) Subjects will return to the clinical research site for a safety evaluation on Day 11. 
l) Subjects will be monitored for adverse events from the beginning of confinement until the end-of-study visit. 
 
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Table 7 
Part B Events Schedule (Once Daily [QD] Dosing) 
 
Part B 
Study Day(s) 
-28 to  -1 
-1 
 
1 
2 
3 
to 
6 
7 
8 
9 
10 14 35 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
hr 
3/5 
min 
10 
min 
20 
min 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
10 
hr 
12 
hr 
16 
hr 
20 
hr 
24 
hr 
36 
hr 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and smoking 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication 
histories 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Vital signs and 
pulse oximetrya 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationb 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xb 
X 
 
X 
 
X 
X 
12-lead ECGc  
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Chest X-ray 
X 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X
O 
Pulmonary 
function testsd 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
 
 
X
e 
X
e 
 
 
X 
X 
PPDf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV, hepatitis B 
and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol 4004002 V.5.3 Final 
 
 
Part B 
Study Day(s) 
-28 to  -1 
-1 
 
1 
2 
3 
to 
6 
7 
8 
9 
10 14 35 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
hr 
3/5 
min 
10 
min 
20 
min 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
10 
hr 
12 
hr 
16 
hr 
20 
hr 
24 
hr 
36 
hr 
Fasting lipid 
panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum 
chemistryg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Hematologyg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Urinalysisg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Coagulation 
(PT, PTT, INR)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Platelet 
aggregationh 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Buffy coati 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
FSH 
(postmenopausa
l female 
subjects)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
(females 
subjects only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine 
drug/alcohol/ 
cotinine screens  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meals 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
Dose inhalation 
training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dose 
administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
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Protocol 4004002 V.5.3 Final 
Part B 
Study Day(s) 
-28 to  -1 
-1 
1 
2 
3 
to 
6 
7 
8 
9 
10 14 35 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
hr 
3/5 
min 
10 
min 
20 
min 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
10 
hr 
12 
hr 
16 
hr 
20 
hr 
24 
hr 
36 
hr 
Blood collection 
for PK analysisj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection 
for PK analysisk 
X 
X 
Confinementl 
X 
X 
X 
X 
X 
X 
X 
Outpatient 
visitsm 
X 
X 
X 
X 
Adverse event 
assessmentn 
X 
BUN = blood urea nitrogen; CR = creatinine; ECG = electrocardiogram; FSH = follicle-stimulating hormone; hr = 
hours; HIV = human immunodeficiency virus; INR = international normalized ratio; min = minutes; PK = 
pharmacokinetic; PPD = positive purified protein derivative skin test; PT = prothrombin time; PTT = partial 
thromboplastin time; Tmax = time of maximum concentration; TSH = thyroid stimulating hormone 
a) A full set of vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse oximetry) will be
measured at screening, at 0 hour (predose), and at the end-of-the study visit on Day 35. Blood pressure, pulse
rate, and pulse oximetry will be measured 10 minutes after the first dose and at the following hours after the
first dose: 1, 4, 8, 12, 16, 24, then daily on Days 3-9 (48, 72, 96, 120, 144, 168, 192, and 216 hours postdose)
and at the outpatient visits on Day 10 and 14. At the screening visit, each subject will have blood pressure
measured in both arms. If there is no significant difference (i.e., greater than 15 mmHg) between the systolic
blood pressure in each arm at screening, then at other times the subject may have blood pressure measured in
one arm.
b) Physical examinations will be conducted for all subjects at screening, predose on Day 1, and on Days 2, 4, 7, 9,
14, and 35.
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c) All subjects will have ECGs performed at screening and at the following times (relative to the first dose): 
predose, 20 minutes postdose, 2, 4, 8, and 24 hours postdose, Day 9 (prior to check-out), Day 14, and at the end 
of the study. 
d) Pulmonary function tests (FEV1 and FVC; best of 3 reproducible maneuvers) to be performed using spirometry. 
Repeat spirometry will be allowed at the Investigator’s discretion. 
e) To be performed at 1, 8, and 24 hours post Day 7 dose. 
f) PPD test to be read 48-72 hours after placement. 
g) Safety labs (chemistry, hematology, coagulation, and urinalysis) will be collected at the following time points: 
screening, check-in, Day 2, Day 4, Day 7, Day 9, Day 14, and Day 35 (end of study) 
h) To be performed on Day 1 predose and 10 minutes postdose (or Tmax, based on analysis from previous cohort) 
and on Day 7 at 10 minutes postdose (or Tmax, based on analysis from previous cohort). 
i) To be performed predose on Day 1 and 5 minutes postdose (or Tmax, based on analysis from previous cohort) on 
Day 1 and Day 7. 
j) Blood samples for pharmacokinetic evaluation will be obtained prior to the first dose administration (predose) 
on Day 1 and Day 7, and at the following times: Day 1 and Day 7 at 3, 10, 20, 30, and 40 minutes and 1, 2, 4, 8, 
12, 24, and 36 hours after dosing; predose on Days 3-6, and on Day 8, Day 9, Day 10, Day 14, and Day 35 
(total of 34 samples). For multi-dose administrations, the 3-minute blood collection will be performed after 
dosing procedures are complete. Exception: For multi-capsule administrations (if required to achieve the dose), 
the first postdose blood collection will be performed 5 minutes after the start of study treatment administration. 
k) Urine samples for pharmacokinetic analysis will be collected predose (spot collection) and for the first 24 hours 
after dosing. 
l) Subjects will remain in the research center for observation until 48 hours after the last dose (Day 9). 
m) Subjects will return to the clinical research site for a safety evaluation and PK blood draws on Days 10, 14, and 
35. 
n) Subjects will be monitored for adverse events from the beginning of confinement until the end-of-study visit. 
o) Subjects may undergo a chest x-ray on Day 35 if clinically indicated as determined by the investigator.
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Protocol 4004002 V.5.3 Final 
 
 
13 
REFERENCES 
1. Investigational Brochure PK10571, A PDGF Receptor Kinase Inhibitor Formulated 
for Inhalation as a Dry Powder to Treat Pulmonary Arterial Hypertension, Date: 
28 May 2017 
2. “Guidance For Industry: Bioavailability and Bioequivalence Studies for Orally 
Administered Drug Products-General Considerations” U.S. Department of Health 
and Human Services Food and Drug Administration Center for Drug Evaluation 
and Research (CDER) March 2003. 
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                          31 Jul 2018 
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Protocol 4004002 V.5.3 Final 
 
 
APPENDIX 1 PHARMACOKINETIC BLOOD SAMPLE COLLECTION, 
PROCESSING, AND SHIPMENT INSTRUCTIONS 
A. 
Collection and Processing 
A more detailed description of plasma sample preparation requirements may be provided by the 
analytical laboratory. If such a description is provided, the method of sample preparation 
provided by the laboratory shall supersede those provided in this protocol and appropriate 
documentation shall be placed in the investigator site file. 
Processing Instructions 
1 
Blood samples will be collected into 6 mL Vacutainer tube(s) containing K2-EDTA. 
The time and date of collection for each sample will be recorded. Samples will be 
placed on ice after collection and remain on ice throughout processing. 
2A 
PART A: Samples will be collected at 0 hour (predose) and then at 3, 10, 20, 30, 40 
minutes, and 1, 2, 4, 8, 12, 24, 36, and 48 hours after study treatment administration.  
(Note: The predose sample will be collected within 150 minutes of dose 
administration. Predose blood samples obtained from backup subjects who are 
randomized into the study may exceed the predose collection window.)  
2B 
PART B: If QD dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose) on Day 1 and Day 7, and at 
the following times: Day 1 and Day 7 at 3, 10, 20, 30, and 40 minutes and 1, 2, 4, 8, 
12, 24, and 36 hours after dosing; predose on Days 3-6, and on Day 8, Day 9, Day 10, 
Day 14, and Day 35 (total 34 samples). 
If BID dosing: Blood samples for pharmacokinetic evaluation will be obtained prior 
to the first dose administration (predose) on Day 1 and Day 7 and at the following 
times after each dose (2 per day) on Day 1 and Day 7: 3 and 30 minutes and 2, 8, and 
12 hours. Blood samples will also be collected before the first dose on Days 3-6, and 
on Day 8, Day 9, Day 10, Day 14, and Day 35 (total of 30 samples). 
If TID dosing: Blood samples for pharmacokinetic evaluation will be obtained prior 
to the first dose administration (predose) on Day 1 and Day 7, and at the following 
times after each dose (3 per day) on Day 1 and Day 7: 3 and 40 minutes and 6 hours. 
An additional sample will be obtained on Day 2 (12 hours after the 3rd dose on 
Day 1). Blood samples will also be collected before the first dose on Days 2-6, and on 
Day 8 (6 hours and 12 hours after the 3rd dose on Day 7), Day 9, Day 10, Day 14, and 
Day 35 (total of 30 samples). For multi-capsule administrations (if required to 
achieve the dose), the first postdose blood collection will be performed 5 minutes 
after the start of study treatment administration. 
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3 
The predose sample on Day 1 will be collected within 150 minutes of dose 
administration. Predose blood samples obtained from backup subjects who are 
randomized into the study may exceed the predose collection window. 
4 
Blood samples will be centrifuged at approximately 3000 rpm for 10 minutes at 
4 degrees Centigrade.  
5 
The resulting plasma samples will be harvested and transferred in approximately 
equal aliquots into two appropriately labeled polypropylene screw-cap tubes. 
6 
Samples will be placed in an upright position in a freezer at 
approximately -20 degrees Centigrade within 60 minutes of collection. 
6 
Samples will remain frozen until assayed. 
 
Part A Sample Collection Summary 
Number 
of 
Subjects 
Number of 
time points 
per period 
Number 
of Periods 
Sample type 
Tube type 
Number of tubes 
per sample 
Up to 40 
14 
1 
Collection 
6 mL K2EDTA 
Vacutainer 
1 
Aliquot 
3 mL Polypropylene 
screw Cap 
2 
 
 
Part B Sample Collection Summary 
Number 
of 
Subjects 
Number of 
time points 
per period 
Number 
of Periods 
Sample type 
Tube type 
Number of tubes 
per sample 
Up to 24 
34 (if QD) 
30 (if BID) 
30 (if TID) 
1 
Collection 
6 mL K2EDTA 
Vacutainer 
1 
Aliquot 
3 mL Polypropylene 
screw Cap 
2 
 
B. Labeling of aliquot tubes 
1. Labels will contain at least the following information: 
a. Sponsor study number 
b. Subject identification 
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c. Study Part; sampling time 
d. Aliquot number (1 or 2)  
C. Shipment 
1. 
The samples will be transferred to the analytical laboratory after completion of the 
study or at mutually agreed upon time points during the clinical conduct of the study. 
The second set of samples will be shipped after the bioanalytical laboratory confirms 
receipt of the first set of samples. 
2. 
Samples will be packaged into separate bags and sorted by subject. 
3. 
Prior to shipment, the samples will be appropriately packed in a cooler containing dry 
ice. Sufficient dry ice will be added to ensure that the samples will remain frozen for at 
least 72 hours.  
4. 
The shipment will be accompanied by documentation containing the following 
information: name of the study drug product, protocol number, number of subjects, 
and number of samples included in the shipment. Expected samples that are not 
present will be identified. 
5. 
All frozen pharmacokinetic plasma samples will be transferred with accompanying 
documentation to: 
Worldwide Clinical Trials Early Phase Services/Bioanalytical Sciences, Inc. 
8609 Cross Park Drive 
Austin, Texas 78754 
Telephone: 512.834.7766 
  
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Protocol 4004002 V.5.3 Final 
 
 
APPENDIX 2 
PHARMACOKINETIC URINE SAMPLE COLLECTION, 
PROCESSING, AND SHIPMENT INSTRUCTIONS 
A. 
Collection and Processing 
Processing Instructions 
Note 
A more detailed description of urine sample preparation requirements will be 
provided by the analytical laboratory. The method of sample preparation provided by 
the laboratory shall supersede those provided in this protocol and appropriate 
documentation shall be placed in the investigator site file. 
2 
PART A: A urine sample will be collected predose (spot collection). A 24-hour urine 
collection will begin after dose administration. 
PART B: A urine sample will be collected predose (spot collection). A 24-hour urine 
collection will begin after the first dose administration on Day 1. 
 
B. 
Labeling of aliquot tubes 
1. Labels will contain at least the following information: 
a) Sponsor study number 
b) Subject identification 
c) Study Part; sampling time 
d) Aliquot number (1 or 2)  
C. 
Shipment 
1. The samples will be transferred to the analytical laboratory after completion of the study or at 
mutually agreed upon time points during the clinical conduct of the study. The second set of 
samples will be shipped after the bioanalytical laboratory confirms receipt of the first set of 
samples. 
2. Samples will be packaged into separate containers and sorted by subject. 
3. Prior to shipment, the samples will be appropriately packed in a cooler containing dry ice. 
Sufficient dry ice will be added to ensure that the samples will remain frozen for at least 
72 hours.  
4. The shipment will be accompanied by documentation containing the following information: 
name of the study drug product, protocol number, number of subjects, and number of 
samples included in the shipment. Expected samples that are not present will be identified. 
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Protocol 4004002 V.5.3 Final 
 
 
5. All frozen pharmacokinetic urine samples will be transferred with accompanying 
documentation to: 
Worldwide Clinical Trials Early Phase Services/Bioanalytical Sciences, Inc. 
8609 Cross Park Drive 
Austin, Texas 78754 
Telephone: 512.834.7766 
 
 
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Protocol 4004002 V.5.3 Final 
 
 
APPENDIX 3 
BUFFY COAT SAMPLE COLLECTION, PROCESSING, AND 
SHIPMENT INSTRUCTIONS 
 
A more detailed description of buffy coat sample preparation requirements may be provided by 
the analytical laboratory. If such a description is provided, the method of sample preparation 
provided by the laboratory shall supersede those provided in this protocol and appropriate 
documentation shall be placed in the investigator site file. 
EQUIPMENT AND MATERIALS: 
BD Vacutainer® Blood Collection Set (BD Cat#367352)  
BD Vaucatainer Cell preparation tube (CPT) with sodium citrate (BD Cat#362761) 
Pasteur Pipettes 
15ml conical tubes 
1 x PBS with 0.5% v/v Phosphatase inhibitor cocktail (Sigma #P0044) 
Centrifuge – capable of producing ~10,000 x g 
 
PROCEDURES: 
A) Collection of Blood in BD Vacutainer® CPT with sodium citrate (cat# 362761)  
NOTE: Gloves should be worn for venipuncture procedure.  
1. Open the blood collection needle package (BD Cat#367352) but do not remove needle shield.  
2. Insert blood collection tube (BD Vacutainer CPT with sodium citrate; Cat#362761) into 
holder. (Do not in puncture the diaphragm of the stopper of CPT tube). 
3. Select site for venipuncture.   
4. Apply tourniquet. Prepare venipuncture site with an appropriate antiseptic. 
5. Remove needle shield. Perform venipuncture with patient’s arm in a downward position and 
tube stopper uppermost. This reduces the risk of backflow of any anticoagulant into the 
patient's circulation.   
6. Push the CPT tube onto needle of the holder, puncturing diaphragm of stopper.   
7. Remove tourniquet as soon as blood appears in the tube.   
8. Draw ~8 ml of blood in the BD Vacutainer CPT, remove the tube from the holder. 
9. If a multiple sample needle is being used, remove the tube and place a new tube into the 
holder.   
10. If the second tube does not draw, remove needle and discard in appropriate disposal device. 
Repeat procedure from step 1.   
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11. Remove needle from vein. Apply pressure to puncture site with dry, sterile gauze until 
bleeding stops.   
12. Apply bandage, if desired.    
13. After collection, dispose of needle using an appropriate disposal device. Do not reshield. 
14. Invert the blood-filled tube 8 to 10 times to mix anticoagulant additive with blood. Do not 
shake. Vigorous mixing can cause hemolysis.    
B) Isolation of Buffy Coat Cells (Peripheral Blood Mononuclear Cells (PBMCs)) 
1. Centrifuge the sample tubes at 1500 x g for 20 minutes at 18-25 °C. (Note: It is critical to 
centrifuge the sample tubes within 5 minutes, as waiting for a longer period of time may 
cause red blood cell lysis as well as affect the phosphorylation state of protein)  
2. After centrifugation, the buffy coat of mononuclear cells will be visible just under the plasma 
layer. Aspirate approximately half of the plasma without disturbing the buffy coat cell layer 
using a Pasteur pipette. Collect buffy coat cell layer with a Pasteur pipette and transfer to a 
15 mL size conical centrifuge tube with cap. (6-8 ml of blood will give a yield of ~3ml of 
buffy coat) 
3. Add 10 ml of 1 x PBS containing 0.5% Phosphatase Inhibitor cocktail (Sigma; Cat#P0044). 
Mix cells by inverting tube 5 times.  
4. Centrifuge for 15 minutes at 300 RCF. Aspirate as much supernatant as possible without 
disturbing cell pellet. 
5. Immediately after step 4 (within 1 minutes), freeze on dry ice, then store the cell pellet 
at -80°C until shipped. 
6.  Ship on Dry Ice (a sufficient amount to last at least 4 days) by overnight courier to Sponsor 
after full cohort collection complete. Communicate with sponsor before shipment to pre-
arrange shipment date. 
All frozen pharmacokinetic buffy coat samples will be transferred with accompanying 
documentation to: 
Attn: Ravikumar Sitapara, Ph.D. 
Pulmokine Inc. 
7 University Place, Room B127B 
Rensselaer NY 12144 
Phone: 518-472-0952 
 
 
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Protocol 4004002 V.5.3 Final 
 
 
 
APPENDIX 4 
PART B: MAD TWICE DAILY (BID) DOSING 
 
The Safety Review Committee will review the safety data (including local irritation) and 
pharmacokinetic data from the SAD protocol (Part A) to determine the starting dose for the first 
MAD cohort and if the first cohort of the MAD protocol should be dosed QD (once daily), BID 
(twice daily; once every 12 hours), or TID (three times daily; 6 hours between each dose for a 
given day of dosing).  
If the decision is made to start dosing in the MAD protocol at BID, then the Safety Review 
Committee will review the safety data (including local irritation) and PK data from the first 
MAD cohort to determine if BID dosing should continue, if dosing should be reduced to QD, or 
if dosing should be increased to TID for the next cohort.  
Blood Sampling, Processing and Shipment 
A total of 180 mL (30 x 6 mL samples) will be collected from each subject in Part B for 
pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for laboratory evaluations. The 
total volume of blood collected from each subject will not exceed approximately 353.5 mL. 
Additional blood may be collected if necessary for repeat laboratory evaluations or AE follow 
up. 
Blood samples collected up to and including 24 hours postdose within ± 2 minutes of scheduled 
time will not be considered deviations. Blood samples collected after 24 hours through 48 hours 
after the last dose within ± 5 minutes of scheduled time will not be considered deviations. Blood 
samples collected after 48 hours postdose after the last dose within ± 10 minutes of scheduled 
time will not be considered deviations.  
Table 8 
Total Amount of Blood to be Collected for Testing in Part B (BID Dosing) 
Reason for Collection 
Number of 
Samples 
Volume per 
Sample (mL) 
Total Volume (mL) 
Clinical labs at screening 
1 
25 
25 
Clinical labs during study (check-in, Days 2, 
4, 7, 9, and 14) 
6 
15 
90 
Clinical labs end-of-study 
1 
15 
15 
Platelet aggregation 
3 
6.5 
19.5 
Buffy coat samples 
3 
8  
24 
Pharmacokinetic analysis 
30 
6  
180 
Total 
353.5 
 
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Protocol 4004002 V.5.3 Final 
 
 
 
 
Table 9 
Part B Events Schedule (BID) 
Part B - BID 
Study Day(s) 
-28 to -1 
-1 
1 
2 
3 
to 
6 
7 
8 
9 
1
0 
1
4 
3
5 
Procedure 
Screening 
Check
-in 
Pre-
dose 
0 
hr 
3/5 
mi
n 
10 
mi
n 
20 
mi
n 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
1
0 
hr 
1
2 
hr 
1
6 
hr 
2
0 
hr 
23 
hr 
2
4 
hr 
 
36 
hr 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and smoking 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication 
histories 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Vital signs and 
pulse oximetrya 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationb 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xb 
X 
 
X 
 
X 
X 
12-lead ECGc  
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Chest X-ray 
X 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Xd 
Pulmonary 
function testse 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
X 
PPDf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Protocol 4004002 V.5.3 Final 
 
 
Part B - BID 
Study Day(s) 
-28 to -1 
-1 
1 
2 
3 
to 
6 
7 
8 
9 
1
0 
1
4 
3
5 
Procedure 
Screening 
Check
-in 
Pre-
dose 
0 
hr 
3/5 
mi
n 
10 
mi
n 
20 
mi
n 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
1
0 
hr 
1
2 
hr 
1
6 
hr 
2
0 
hr 
23 
hr 
2
4 
hr 
 
36 
hr 
HIV, hepatitis B 
and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid 
panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum 
chemistryg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Hematologyg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Urinalysisg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Coagulation 
(PT, PTT, INR) 
g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Platelet 
aggregationh 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Buffy coati 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
FSH 
(postmenopausal 
female subjects)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
(females 
subjects only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine 
drug/alcohol/ 
cotinine screens  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mealsj 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
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Protocol 4004002 V.5.3 Final 
 
 
Part B - BID 
Study Day(s) 
-28 to -1 
-1 
1 
2 
3 
to 
6 
7 
8 
9 
1
0 
1
4 
3
5 
Procedure 
Screening 
Check
-in 
Pre-
dose 
0 
hr 
3/5 
mi
n 
10 
mi
n 
20 
mi
n 
1 
hr 
2 
hr 
4 
hr 
8 
hr 
1
0 
hr 
1
2 
hr 
1
6 
hr 
2
0 
hr 
23 
hr 
2
4 
hr 
 
36 
hr 
Dose inhalation 
training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dose 
administration 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Blood collection 
for PK analysisk 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urine collection 
for PK analysisl 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
Confinementm 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
Outpatient 
visitsn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Adverse event 
assessmento 
 
 
           X 
 
BUN = blood urea nitrogen; CR = creatinine; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = 
human immunodeficiency virus; INR = international normalized ratio; PK = pharmacokinetic; PPD = positive purified 
protein derivative skin test; PT = prothrombin time; PTT = partial thromboplastin time; Tmax = time of maximum 
concentration; TSH = thyroid stimulating hormone 
a: A full set of vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse oximetry) will be 
measured at screening, predose on Day 1, and at the end-of-the study visit on Day 35. Blood pressure, pulse 
rate, and pulse oximetry will be measured on Day 1 and Day 7 (times relative to the first dose of the day) at 
10 minutes and 1, 4, 8, 12, 16, and 24 hours postdose, daily (predose) on Days 3-6 and 7-9, and at the outpatient 
visits on Day 10 and 14. At the screening visit, each subject will have blood pressure measured in both arms. If 
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there is no significant difference (i.e., greater than 15 mmHg) between the systolic blood pressure in each arm at 
screening, then at other times the subject may have blood pressure measured in one arm. 
b: Physical examinations will be conducted for all subjects at screening, before the first dose on Day 1, and on 
Days 2, 4, 7, 9, 14, and 35. 
c: All subjects will have ECGs performed at screening and at the following times on Day 1 and Day 7 (times 
relative to the first dose of the day): predose, 20 minutes postdose, 2, 4, 8, and 24 hours postdose, Day 9 (prior 
to check-out), Day 14, and at the end of the study. 
d: Chest x-ray will be performed on Day 35 if clinically indicated as determined by the Investigator. 
e: Pulmonary function tests (FEV1 and FVC; best of 3 reproducible maneuvers) using spirometry will be 
performed at screening, check-in, at 1, 4, 8, and 23 hours after administration of the first and last morning doses 
(Day 1 and Day 7), at least 1 hour after the first dose on Day 4, on Day 14, and at the end of the study (Day 35). 
Repeat spirometry will be allowed at the Investigator’s discretion. 
f: PPD test to be read 48-72 hours after placement. 
g: Safety labs (chemistry, hematology, coagulation, and urinalysis) will be collected at the following time points: 
screening, check-in, Day 2, Day 4, Day 7, Day 9, Day 14 and Day 35 (end of study) 
h: To be performed before the first dose of the day on Day 1 and 10 minutes after the first dose of the day (or 
Tmax, based on analysis from previous cohort) on Day 1 and Day 7. 
i: To be performed before the first dose of the day on Day 1 and 5 minutes after the first dose of the day (or Tmax, 
based on analysis from previous cohort) on Day 1 and Day 7. 
j: Optional meals may be provided the day of check-in. Subjects will fast overnight for at least 10-hours before 
the first dose of each day. After the morning dose on Day 1 and Day 7, no food will be allowed until 4 hours 
postdose. On other dosing days (Days 2–6), no food will be allowed for at least 1 hour after the morning dose. 
Subjects will nothing to eat for at least 2 hours before the second dose of each day and for at least 1 hour after 
the second dose. 
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k: Blood samples for pharmacokinetic evaluation will be obtained prior to the first dose administration (predose) 
on Day 1 and Day 7 and at the following times after each dose (2 per day) on Day 1 and Day 7: 3 and 
30 minutes and 2, 8, and 12 hours. Blood samples will also be collected before the first dose on Days 3-6, and 
on Day 8, Day 9, Day 10, Day 14, and Day 35 (total of 30 samples). Exception: For multi-capsule 
administrations (if required to achieve the dose), the first postdose blood collection will be performed 5 minutes 
after the start of study treatment administration. 
l: Urine samples for pharmacokinetic analysis will be collected on Day 1 and Day 7 (times relative to the first 
dose of the day) predose (spot collection) and for the first 24 hours after dosing. 
m: Subjects will remain in the research center for observation until 48 hours after the last dose (Day 9). 
n: Subjects will return to the clinical research site for a safety evaluation and PK blood draws on Days 10, 14, and 
35. 
o: Subjects will be monitored for adverse events from the beginning of confinement until the end-of-study visit. 
 
 
 
 
 
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APPENDIX 5 
PART B: MAD THREE TIMES DAILY (TID) DOSING 
The Safety Review Committee will review the safety data (including local irritation) and 
pharmacokinetic data from the SAD protocol (Part A) to determine the starting dose for the first 
MAD cohort, and if the first cohort of the MAD protocol should be dosed QD (once daily), BID 
(twice daily; once every 12 hours), or TID (three times daily; 6 hours between each dose).  
If the decision is made to start dosing in the MAD protocol at TID, then the Safety Review 
Committee will review the safety data (including local irritation) and PK data from the first 
MAD cohort to determine if TID dosing should continue, if dosing should be reduced to BID or 
QD for the next cohort. Similarly, if the starting dose in the MAD protocol is BID, then the 
Safety Review Committee will review the safety data (including local irritation) and PK data 
from the first MAD cohort to determine if BID dosing should continue, or if dosing should be 
changed to QD or TID for the next cohort. 
Blood Sampling, Processing and Shipment 
A total of 180 mL (30 x 6 mL samples) will be collected from each subject in Part B for 
pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for laboratory evaluations. The 
total volume of blood collected from each subject will not exceed approximately 353.5 mL. 
Additional blood may be collected if necessary for repeat laboratory evaluations or AE follow 
up. 
Blood samples collected up to and including 24 hours postdose within ± 2 minutes of scheduled 
time will not be considered deviations. Blood samples collected after 24 hours through 48 hours 
after the last dose within ± 5 minutes of scheduled time will not be considered deviations. Blood 
samples collected after 48 hours postdose after the last dose within ± 10 minutes of scheduled 
time will not be considered deviations.  
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Table 10 Total Amount of Blood to be Collected for Testing in Part B (TID Dosing) 
Reason for Collection 
Number of 
Samples 
Volume per 
Sample (mL) 
Total Volume (mL) 
Clinical labs at screening 
1 
25 
25 
Clinical labs during study (check-in, Days 2, 
4, 7, 9, and 14) 
6 
15 
90 
Clinical labs end-of-study 
1 
15 
15 
Platelet aggregation 
3 
6.5 
19.5 
Buffy coat samples 
3 
8 
24 
Pharmacokinetic analysis 
30 
6 
180 
Total 
353.5 
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Table 11 Part B Events Schedule (TID Dosing) 
Part B - TID 
Study Day(s) 
-28 to -1 
-1 
 
1 
2 
3 
to 
6 
7 
8 
9 10 14 35 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
h 
3/5 
min 
10 
m 
20 
m 
1 
h 
2 
h 
4 
h 
5 
h 
6 
h 
8 
h 
10 
h 
12 
h 
16 
h 
20 
h 
23 
h 
24 
h 
36 
h 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and smoking 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication 
histories 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Vital signs and 
pulse oximetrya 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationb 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xb 
X 
 
X 
 
X 
X 
12-lead ECGc  
X 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
Chest X-ray 
X 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Xd 
Pulmonary 
function testse 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
X 
X 
PPDf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV, hepatitis B 
and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part B - TID 
Study Day(s) 
-28 to -1 
-1 
 
1 
2 
3 
to 
6 
7 
8 
9 10 14 35 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
h 
3/5 
min 
10 
m 
20 
m 
1 
h 
2 
h 
4 
h 
5 
h 
6 
h 
8 
h 
10 
h 
12 
h 
16 
h 
20 
h 
23 
h 
24 
h 
36 
h 
 
 
 
 
 
 
 
Fasting lipid 
panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum 
chemistryg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Hematologyg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Urinalysisg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Coagulation 
(PT, PTT, INR)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Platelet 
aggregationh 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Buffy coati 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
FSH 
(postmenopausal 
female subjects)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
(females 
subjects only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine 
drug/alcohol/ 
cotinine screens  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mealsj 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Dose inhalation 
training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dose 
administration 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
tid 
tid 
tid 
 
 
 
 
 
Blood collection 
for PK analysisk 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
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Part B - TID 
Study Day(s) 
-28 to -1 
-1 
 
1 
2 
3 
to 
6 
7 
8 
9 10 14 35 
Procedure 
Screening Check-
in 
Pre-
dose 
0 
h 
3/5 
min 
10 
m 
20 
m 
1 
h 
2 
h 
4 
h 
5 
h 
6 
h 
8 
h 
10 
h 
12 
h 
16 
h 
20 
h 
23 
h 
24 
h 
36 
h 
 
 
 
 
 
 
 
Urine collection 
for PK analysisl 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Confinementm 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Outpatient 
visitsn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Adverse event 
assessmento 
 
 
     X 
BUN = blood urea nitrogen; CR = creatinine; ECG = electrocardiogram; FSH = follicle-stimulating hormone; h = hour; 
HIV = human immunodeficiency virus; INR = international normalized ratio; m = minute; PK = pharmacokinetic; PPD 
= positive purified protein derivative skin test; PT = prothrombin time; PTT = partial thromboplastin time; Tmax = time 
of maximum concentration; tid = three doses per day; each dose will be separated by 6 horus; TSH = thyroid 
stimulating hormone 
a) A full set of vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse oximetry) will be 
measured at screening, predose on Day 1, and at the end-of-the study visit on Day 35. Blood pressure, pulse rate, 
and pulse oximetry will be measured on Day 1 and Day 7 (times relative to the first dose of the day) at 10 minutes 
and 1, 4, 8, 12, 16, and 24 hours postdose, daily (predose) on Days 3-6 and 7-9, and at the outpatient visits on Day 
10 and 14. At the screening visit, each subject will have blood pressure measured in both arms. If there is no 
significant difference (i.e., greater than 15 mmHg) between the systolic blood pressure in each arm at screening, 
then at other times the subject may have blood pressure measured in one arm. 
b) Physical examinations will be conducted for all subjects at screening, before the first dose on Day 1, and on Days 2, 
4, 7, 9, 14, and 35. 
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c) All subjects will have ECGs performed at screening and at the following times on Day 1 and Day 7 (times relative 
to the first dose of the day): predose, 20 minutes postdose, 2, 4, 8, and 24 hours postdose, Day 9 (prior to 
check-out), Day 14, and at the end of the study. 
d) Chest x-ray will be performed on Day 35 if clinically indicated as determined by the Investigator. 
 e) Pulmonary function tests (FEV1 and FVC; best of 3 reproducible maneuvers) will be performed at screening, 
check-in, and at 1 hour after the first morning dose on Day 1, Day 4, and Day 7, at least 1 hour before second dose 
on Day 1 and Day 7, 23 hours after the first morning dose on Day 1 and Day 7, on Day 14 and at the end of the 
study (Day 35). Repeat spirometry will be allowed at the Investigator’s discretion. 
f) PPD test to be read 48-72 hours after placement. 
g) Safety labs (chemistry, hematology, coagulation, and urinalysis) will be collected at the following time points: 
screening, check-in, Day 2, Day 4, Day 7, Day 9, Day 14 and Day 35 (end of study). 
h) To be performed before the first dose of the day on Day 1 and 10 minutes after the first dose of the day (or Tmax, 
based on analysis from previous cohort) on Day 1 and  Day 7. 
i) To be performed before the first dose of the day on Day 1 and 5 minutes after the first dose of the day (or Tmax, 
based on analysis from previous cohort) on Day 1 and Day 7. 
j) Optional meals may be provided the day of check-in. Subjects will fast overnight for at least 10-hours before the 
first dose of each day. On Day 1 and Day 7, no food will be allowed until 4 hours after the first dose of the day. On 
other dosing days (Days 2–6), no food will be allowed for at least 1 hour after the first dose of the day. Subjects 
will fast for at least 1.5 hours before the second and third doses of each day. 
k) Blood samples for pharmacokinetic evaluation will be obtained prior to the first dose administration (predose) on 
Day 1 and Day 7, and at the following times after each dose (3 per day) on Day 1 and Day 7: 3 and 40 minutes and 
6 hours. An additional blood sample will be collected on Day 2 (12 hours after the 3rd dose on Day 1). Blood 
samples will also be collected before the first dose on Days 2-6, and on Day 8 (6 hours and 12 hours after the 3rd 
dose on Day 7), Day 9, Day 10, Day 14 and Day 35 (total of 30 samples). Exception: For multi-capsule 
administrations (if required to achieve the dose), the first postdose blood collection will be performed 5 minutes 
after the start of study treatment administration. 
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l) Urine samples for pharmacokinetic analysis will be collected on Day 1 and Day 7 (times relative to the first dose of 
the day) predose (spot collection) and for the first 24 hours after dosing. 
m) Subjects will remain in the research center for observation until 48 hours after the last dose (Day 9). 
n) Subjects will return to the clinical research site for a safety evaluation and PK blood draws on Days 10, 14, and 35. 
o) Subjects will be monitored for adverse events from the beginning of confinement until the end-of-study visit.
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APPENDIX 6 
SUMMARY OF CHANGES 
The purpose of this protocol amendment (protocol version.5.3, dated 31 July 2018) is to make the 
following revisions to protocol version 5.0 dated 29 Jun 2018: 
The primary purposes of this amendment are to: 
• Revise the sample collection times for buffy coat and platelet aggregation in Part B of the study
• Clarify that blood samples will be collected for PK analysis on Day 7 (predose) and on Day 9
during Part B of the study
• Add a PK blood sample collection on Day 2 (predose) and Day 8 (12 hours after the third dose on
Day 7) of Part 2, TID dosing
• Clarify timing of dose inhalation training on Table 11
This amendment also incorporates the following change from clarification letter 6 dated 12 Jul 2018: 
• Clarify the pharmacokinetic sample collection window
The sections of protocol version 5.0 affected by the protocol revisions are noted in the following table. 
Section 
Number 
Section Title 
Description of Change (s) 
3.2 
Part B 
From: 
Blood samples for pharmacokinetic evaluation will be obtained before 
the first dose of the day on Day 1 and at selected times through 36 
hours after the first dose on Day 1, before the first dose on Days 3-6, 
through 36 hours after the first dose on Day 7, and on Day 10, Day 
14, and Day 35. 
For QD dosing, a total of 33 pharmacokinetic blood samples will be 
collected from each subject in Part B. 
For BID dosing, a total of 29 pharmacokinetic blood samples will be 
collected from each subject in Part B. 
For TID dosing, a total of 27 pharmacokinetic blood samples will be 
collected from each subject in Part B.  
To: 
Blood samples for pharmacokinetic evaluation will be obtained before 
the first dose of the day on Day 1 and Day 7 and at selected times 
through 36 hours after the first dose on Day 1, before the first dose on 
Days 3-6, through 36 hours after the first dose on Day 7, and on Day 
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Section 
Number 
Section Title 
Description of Change (s) 
9, Day 10, Day 14, and Day 35. 
For QD dosing, a total of 34 pharmacokinetic blood samples will be 
collected from each subject in Part B. 
For BID dosing, a total of 30 pharmacokinetic blood samples will be 
collected from each subject in Part B. 
For TID dosing, a total of 30 pharmacokinetic blood samples will be 
collected from each subject in Part B.  
5.7 
Blood Sampling, 
Processing and 
Shipment 
The following applies to QD dosing, Change from: 
A total of 192 mL (32 x 6 mL samples) will be collected from each 
subject in Part B for pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for 
laboratory evaluations. The total volume of blood collected from each 
subject will not exceed approximately 365.5 mL. Additional blood 
may be collected if necessary for repeat laboratory evaluations or AE 
follow up. 
Blood samples collected up to and including 24 hours postdose within 
± 2 minutes of scheduled time will not be considered deviations. 
Blood samples collected after 24 hours through 48 hours after the last 
dose within ± 5 minutes of scheduled time will not be considered 
deviations. Blood samples collected after 48 hours postdose after the 
last dose within ± 10 minutes of scheduled time will not be considered 
deviations. 
To: 
A total of 204 mL (34 x 6 mL samples) will be collected from each 
subject in Part B for pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for 
laboratory evaluations. The total volume of blood collected from each 
subject will not exceed approximately 377.5 mL. Additional blood 
may be collected if necessary for repeat laboratory evaluations or AE 
follow up. 
Blood samples collected up to and including 24 hours postdose within 
± 2 minutes of scheduled time will not be considered deviations. 
Blood samples collected after 24 hours through 48 hours after the last 
dose within ± 5 minutes of scheduled time will not be considered 
deviations, with the following exception: when blood collection is 
scheduled for the same time as dose administration (at times other 
than the first dose administration) samples collected 
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Section 
Number 
Section Title 
Description of Change (s) 
within -5 minutes of scheduled time will not be considered 
deviations. Blood samples collected after 48 hours postdose after the 
last dose within ± 10 minutes of scheduled time will not be considered 
deviations. 
5.7 
Table 5, Total 
Amount of Blood to 
be Collected for 
Testing in Part B 
(QD) 
 
From: 
Pharmacokinetic 
analysis 
32 
6  
192 
Total 
365.5 
To: 
Pharmacokinetic 
analysis 
34 
6  
204 
Total 
377.5 
12 
Table 7 Part B Events 
Schedule (Once Daily 
[QD] Dosing) 
Footnotes “h” and “i” 
 
Footnotes “h” and “i”, Change from: 
h: To be performed on Day 1 predose and 10 minutes postdose (or 
Tmax, based on analysis from previous cohort) and on Day 7 at 
10 minutes postdose (or Tmax, based on analysis from previous 
cohort). 
i: To be performed on Day 1 predose and 10 minutes postdose (or 
Tmax, based on analysis from previous cohort) and on Day 7 at 
10 minutes postdose (or Tmax, based on analysis from previous 
cohort). 
To: 
h: To be performed on Day 1 predose and 5 minutes postdose (or 
Tmax, based on analysis from previous cohort); and on Day 7 at 
10 minutes postdose (or Tmax, based on analysis from previous 
cohort). 
To be performed on Day 1 predose and 5 minutes postdose (or Tmax, 
based on analysis from previous cohort) and on Day 7 at 5 minutes 
postdose (or Tmax, based on analysis from previous cohort). 
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Section 
Number 
Section Title 
Description of Change (s) 
12 
Table 7 Part B Events 
Schedule (Once Daily 
[QD] Dosing) 
 
Footnote “j”, change from: 
Blood samples for pharmacokinetic evaluation will be obtained prior 
to the first dose administration (predose on Day 1) and at the 
following times: Day 1 and Day 7 at 3, 10, 20, 30, and 40 minutes and 
1, 2, 4, 8, 12, 24, and 36 hours after dosing; predose on Days 3-6, and 
on Day 10, Day 14, and Day 35. For multi-dose administrations, the 
1-minute blood collection will be performed after dosing procedures 
are complete. Exception: For multi-capsule administrations (if 
required to achieve the dose), the first postdose blood collection will 
be performed 5 minutes after the start of study treatment 
administration. 
To: 
Blood samples for pharmacokinetic evaluation will be obtained prior 
to the first dose administration (predose) on Day 1 and Day 7, and at 
the following times: Day 1 and Day 7 at 3, 10, 20, 30, and 40 minutes 
and 1, 2, 4, 8, 12, 24, and 36 hours after dosing; predose on Days 3-6, 
and on Day 8, Day 9, Day 10, Day 14, and Day 35 (total of 34 
samples). For multi-dose administrations, the 3-minute blood 
collection will be performed after dosing procedures are complete. 
Exception: For multi-capsule administrations (if required to achieve 
the dose), the first postdose blood collection will be performed 5 
minutes after the start of study treatment administration. 
Appendix 
1 
Pharmacokinetic 
Blood Sample 
Collection, 
Processing, And 
Shipment Instructions 
Part B, Row 2B, change from: 
If QD dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose on Day 1) and 
at the following times: Day 1 and Day 7 at 3, 10, 20, 30, and 40 
minutes and 1, 2, 4, 8, 12, 24, and 36 hours after dosing; predose on 
Days 3-6, and on Day 10, Day 14, and Day 35 (total 32 samples). 
For multi-capsule administrations (if required to achieve the dose), the 
3-minute blood collection will be performed after inhalation 
procedures for a given dose are complete. 
If BID dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose) on Day 1 and 
Day 7 and at the following times after each dose (2 per day) on Day 1 
and Day 7: 3 and 30 minutes and 2, 8, and 12 hours. Blood samples 
will also be collected before the first dose on Days 3-6, Day 10, Day 
14, and Day 35 (total of 29 samples). 
If TID dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose) on Day 1 and 
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Section 
Number 
Section Title 
Description of Change (s) 
Day 7, and at the following times after each dose (3 per day) on Day 1 
and Day 7: 3 and 40 minutes and 6 hours. Blood samples will also be 
collected before the first dose on Days 3-6, and on Day 10, Day 14 
and Day 35 (total of 27 samples). 
To: 
If QD dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose on Day 1 and 
Day 7) and at the following times: Day 1 and Day 7 at 3, 10, 20, 30, 
and 40 minutes and 1, 2, 4, 8, 12, 24, and 36 hours after dosing; 
predose on Days 3-6, and on Day 9, Day 10, Day 14, and Day 35 
(total 34 samples). 
If BID dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose) on Day 1 and 
Day 7 and at the following times after each dose (2 per day) on Day 1 
and Day 7: 3 and 30 minutes and 2, 8, and 12 hours. Blood samples 
will also be collected before the first dose on Days 3-6, and on Day 8, 
Day 9, Day 10, Day 14, and Day 35 (total of 30 samples). 
If TID dosing: Blood samples for pharmacokinetic evaluation will be 
obtained prior to the first dose administration (predose) on Day 1 and 
Day 7, and at the following times after each dose (3 per day) on Day 1 
and Day 7: 3 and 40 minutes and 6 hours. An additional sample will 
be obtained on Day 2 (12 hours after the 3rd dose on Day 1). Blood 
samples will also be collected before the first dose on Days 2-6, and 
on Day 8 (6 hours and 12 hours after the 3rd dose on Day 7), Day 
9, Day 10, Day 14 and Day 35 (total of 30 samples). 
For multi-capsule administrations (if required to achieve the 
dose), the first postdose blood collection will be performed 
5 minutes after the start of study treatment administration. 
Appendix 
1 
Part B Sample 
Collection Summary 
Change the number of time points per period from 32 to 34 if QD. 
Change the number of time points per period from 29 to 30 if BID. 
Change number of time points per period from 27 to 30 if TID. 
Appendix 
4 
Part B: MAD Twice 
Daily (BID) Dosing 
Blood Sample Processing and Shipment, Change from: 
A total of 174 mL (29 x 6 mL samples) will be collected from each 
subject in Part B for pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for 
laboratory evaluations. The total volume of blood collected from each 
subject will not exceed approximately 347.5 mL. Additional blood 
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Section 
Number 
Section Title 
Description of Change (s) 
may be collected if necessary for repeat laboratory evaluations or AE 
follow up. 
To: 
A total of 180 mL (30 x 6 mL samples) will be collected from each 
subject in Part B for pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for 
laboratory evaluations. The total volume of blood collected from each 
subject will not exceed approximately 353.5 mL. Additional blood 
may be collected if necessary for repeat laboratory evaluations or AE 
follow up. 
Appendix 
4 
Part B: MAD Twice 
Daily (BID) Dosing 
Total Amount of Blood to be Collected for Testing in Part B (BID 
Dosing), change from: 
 
Pharmacokinetic analysis 
29 
6  
174 
Total 
347.5 
To: 
Pharmacokinetic analysis 
30 
6  
180 
Total 
353.5 
Appendix 
4 
Part B Events 
Schedule (BID) 
Footnotes “h”, “I”, and “k”, change from: 
h: To be performed before the first dose of the day on Day 1 and 10 
minutes after the first dose of the day (or Tmax, based on analysis 
from previous cohort) on Day 1 and Day 7. 
i: To be performed before the first dose of the day on Day 1 and 10 
minutes after the first dose of the day (or Tmax, based on analysis 
from previous cohort) on Day 1 and Day 7. 
k: Blood samples for pharmacokinetic evaluation will be obtained 
prior to the first dose administration (predose) on Day 1 and Day 7 
and at the following times after each dose (2 per day) on Day 1 and 
Day 7: 3 and 30 minutes and 2, 8, and 12 hours. Blood samples will 
also be collected before the first dose on Days 3-6, Day 10, Day 14, 
and Day 35 (total of 29 samples). Exception: For multi-capsule 
administrations (if required to achieve the dose), the first postdose 
blood collection will be performed 5 minutes after the start of study 
treatment administration. 
To: 
h: To be performed before the first dose of the day on Day 1 and 5 
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Section 
Number 
Section Title 
Description of Change (s) 
minutes after the first dose of the day (or Tmax, based on analysis 
from previous cohort) on Day 1; and 5 minutes after the first dose 
on Day 7. 
i: To be performed before the first dose of the day on Day 1 and 5 
minutes after the first dose of the day (or Tmax, based on analysis 
from previous cohort) on Day 1 and Day 7. 
k: Blood samples for pharmacokinetic evaluation will be obtained 
prior to the first dose administration (predose) on Day 1 and Day 7 
and at the following times after each dose (2 per day) on Day 1 and 
Day 7: 3 and 30 minutes and 2, 8, and 12 hours. Blood samples will 
also be collected before the first dose on Days 3-6, and on Day 8, 
Day 9, Day 10, Day 14, and Day 35 (total of 30 samples). Exception: 
For multi-capsule administrations (if required to achieve the dose), the 
first postdose blood collection will be performed 5 minutes after the 
start of study treatment administration 
Appendix 
5 
Part B: MAD Three 
Times Daily (TID) 
Dosing 
Blood Sampling, Processing, and Shipment, change from: 
A total of 162 mL (27 x 6 mL samples) will be collected from each 
subject in Part B for pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for 
laboratory evaluations. The total volume of blood collected from 
each subject will not exceed approximately 335.5 mL. Additional 
blood may be collected if necessary for repeat laboratory evaluations 
or AE follow up. 
To: 
A total of 180 mL (30 x 6 mL samples) will be collected from each 
subject in Part B for pharmacokinetic analysis.  
In addition, approximately 173.5 mL of blood will be collected for 
laboratory evaluations. The total volume of blood collected from 
each subject will not exceed approximately 353.5 mL. Additional 
blood may be collected if necessary for repeat laboratory evaluations 
or AE follow up. 
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Protocol 4004002 V.5.3 Final 
 
 
Section 
Number 
Section Title 
Description of Change (s) 
Appendix 
5 
Part B: MAD Three 
Times Daily (TID) 
Dosing 
Total Amount of Blood to be Collected for Testing in Part B (TID 
Dosing), change from: 
Pharmacokinetic analysis 
27 
6  
162 
Total 
335.5 
To: 
Pharmacokinetic analysis 
30 
6  
180 
Total 
353.5 
Appendix 
5 
Part B: MAD Three 
Times Daily (TID) 
Dosing 
Table 11, Dose Inhalation Training 
Place “X” under 24 hours 
Footnotes “h”, “I”, and “k”, change from: 
h: To be performed before the first dose of the day on Day 1 and 10 
minutes after the first dose of the day (or Tmax, based on analysis 
from previous cohort) on Day 1 and Day 7. 
i: 
To be performed before the first dose of the day on Day 1 and 10 
minutes after the first dose of the day (or Tmax, based on analysis 
from previous cohort) on Day 1 and Day 7. 
k: Blood samples for pharmacokinetic evaluation will be obtained 
prior to the first dose administration (predose) on Day 1 and Day 
7, and at the following times after each dose (3 per day) on Day 1 
and Day 7: 3 and 40 minutes and 6 hours. Blood samples will also 
be collected before the first dose on Days 3-6, and on Day 10, 
Day 14 and Day 35 (total of 27 samples). Exception: For multi-
capsule administrations (if required to achieve the dose), the first 
postdose blood collection will be performed 5 minutes after the 
start of study treatment administration. 
To: 
h: To be performed before the first dose of the day on Day 1 and 5 
minutes after the first dose of the day (or Tmax, based on 
analysis from previous cohort) on Day 1; and 5 minutes after the 
first dose on Day 7. 
i: 
To be performed before the first dose of the day on Day 1 and 5 
minutes after the first dose of the day (or Tmax, based on 
analysis from previous cohort) on Day 1 and Day 7. 
k: Blood samples for pharmacokinetic evaluation will be obtained 
prior to the first dose administration (predose) on Day 1 and Day 
7, and at the following times after each dose (3 per day) on Day 1 
and Day 7: 3 and 40 minutes and 6 hours. An additional sample 
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Protocol 4004002 V.5.3 Final 
 
 
Section 
Number 
Section Title 
Description of Change (s) 
will be obtained on Day 2 (12 hours after the 3rd dose on Day 
1). Blood samples will also be collected before the first dose 
on Days 2-6, and on Day 8 (6 hours and 12 hours after the 3rd 
dose on Day 7), Day 9, Day 10, Day 14 and Day 35 (total of 30 
samples). Exception: For multi-capsule administrations (if 
required to achieve the dose), the first postdose blood collection 
will be performed 5 minutes after the start of study treatment 
administration. 
 
 
 
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SAP_001.pdf: 
Cover Page 
 
GB002, Inc. 
Gossamer Bio, Inc. 
CONFIDENTIAL 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
A Phase 1A Single Ascending Dose and Multiple Ascending Dose 
Double-Blind, Placebo-Controlled, Randomized Trial of Oral Inhalation 
PK10571 in Healthy Adult Subjects 
Protocol Number: 4004002 
 
VERSION 1.0  
DATE: 16 Aug 2018 
 
 
 
NCT NUMBER:  NCT03473236