Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Arterial Hypertension Treprostinil Palmitil Inhalation Powder Treprostinil Palmitil
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 1
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of single dose of treprostinil palmitil inhalation powder (TPIP) in participants with pulmonary arterial hypertension (PAH).

Detailed description:

Arms:
arm 1: Participant received a single dose of TPIP 112.5 micrograms (μg) via oral inhalation on Day 1. The participant then entered into a 16-week Extended Use Treatment (EUT) Period during which TPIP, administered via oral inhalation, was titrated up to a mean daily dose of 320 μg.

Interventions: intervention 1: Treprostinil Palmitil
Intervention descriptions: intervention 1: Administered by oral inhalation using a Plastiape capsule-based dry powder inhaler

Protocol document:
Prot_000.pdf: 
Official Title: 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation 
Powder in 
Participants with Pulmonary Arterial Hypertension 
NCT Number: 
NCT04791514 
Document Date: 
Protocol Version 4: 03 June 2022
Protocol Version 3: 03 March 2022
Protocol Version 2: 06 October 2021
Protocol Version 1: 02 November 2020


Clinical Study Report INS1009-201 
16.1 Study Information 
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APPENDIX 16.1 STUDY INFORMATION 
16.1.1 
Protocol and Amendments 
Protocol/Amendment 
Version 
Date 
Amendment 3 
Version 4 
03 June 2022 
Amendment 2 
Version 3 
03 March 2022 
Amendment 1 
Version 2 
06 October 2021 
Protocol 
Version 1 
02 November 2020 


Signature Page for INS1009-201 Protocol Amendment No. 3
Approve
03-Jun-2022 21:25:26 GMT+0000


Treprostinil Palmitil Inhalation Powder (TPIP) 
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Clinical Trial Protocol INS1009-201 
Version 4.0, 03 JUN 2022 
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give this document or any copy of it or reveal any proprietary information contained in it to any third party (other 
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CLINICAL STUDY PROTOCOL 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation Powder in Participants with 
Pulmonary Arterial Hypertension 
Protocol Number: INS1009-201 
Version Number: 4.0 
Amendment Number: 3 
Compound: Treprostinil Palmitil Inhalation Powder (TPIP) 
Study Phase: 2a 
Sponsor Name: Insmed Incorporated 
Legal Registered Address:  
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
USA 
Regulatory Agency Identifier Number(s) 
IND: 147264 
EudraCT: 2022-000839-23 
NCT: NCT04791514 
Date: 03 JUN 2022 




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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................9 
ABBREVIATIONS .......................................................................................................................10 
1.
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Protocol Amendment Summary of Changes ..............................................................14 
1.2. 
Synopsis ......................................................................................................................16 
1.3. 
Schema ........................................................................................................................19 
1.3.1. 
Participant Progression Through the Study ................................................................19 
1.3.1.1. 
Screening Period .........................................................................................................19 
1.3.1.2. 
Inpatient Treatment Period .........................................................................................19 
1.3.1.3. 
Follow-up Period ........................................................................................................19 
1.3.1.4. 
Optional Extended Use Treatment Period ..................................................................20 
1.3.1.5. 
Extended Use Follow-up Period .................................................................................21 
1.3.2. 
Dose Selection ............................................................................................................21 
1.3.2.1. 
Inpatient Treatment Period Dose Selection ................................................................21 
1.3.2.2. 
Optional Extended Use Treatment Period ..................................................................22 
1.4. 
Schedule of Activities (SoA) ......................................................................................23 
2.
INTRODUCTION ......................................................................................................33 
2.1. 
Study Rationale ...........................................................................................................34 
2.2. 
Background .................................................................................................................34 
2.3. 
Benefit/Risk Assessment ............................................................................................35 
2.3.1. 
Risk Assessment .........................................................................................................35 
2.3.2. 
Benefit Assessment .....................................................................................................36 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................36 
3.
OBJECTIVES AND ENDPOINTS ............................................................................38 
3.1. 
Exploratory Objectives and Endpoints for the Optional Extended Use 
Treatment Period ........................................................................................................40 
4.
STUDY DESIGN .......................................................................................................41 


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4.1. 
Overall Design ............................................................................................................41 
4.1.1. 
Screening Period .........................................................................................................41 
4.1.2. 
Inpatient Treatment Period .........................................................................................42 
4.1.2.1. 
Baseline Procedures and Assessments ........................................................................42 
4.1.2.2. 
Post-TPIP Administration ...........................................................................................43 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up .................43 
4.1.3. 
Safety Follow-up ........................................................................................................43 
4.1.4. 
Optional Extended Use Treatment Period ..................................................................43 
4.1.5. 
Open-label Extension Study .......................................................................................44 
4.2. 
Scientific Rationale for Study Design ........................................................................44 
4.3. 
Justification for Dose ..................................................................................................44 
4.3.1. 
Inpatient Treatment Period (Single-dose) ...................................................................44 
4.3.2. 
Optional Extended Use Treatment Period ..................................................................45 
4.4. 
Study Completion .......................................................................................................46 
5.
STUDY POPULATION .............................................................................................47 
5.1. 
Inclusion Criteria ........................................................................................................47 
5.2. 
Exclusion Criteria .......................................................................................................48 
5.3. 
Lifestyle Considerations .............................................................................................50 
5.4. 
Screen Failures ............................................................................................................50 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period ..................................50 
6.
STUDY IMP AND CONCOMITANT THERAPY ...................................................52 
6.1. 
Study IMP Administered ............................................................................................52 
6.1.1. 
Inpatient Treatment Period (Single Dose) ..................................................................52 
6.1.2. 
Optional Extended Use Treatment Period ..................................................................52 
6.1.3. 
Medical Devices .........................................................................................................53 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................53 
6.2.1. 
Inpatient Treatment Period (Single-dose) ...................................................................53 
6.2.2. 
Optional Extended Use Treatment Period ..................................................................54 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................54 
6.4. 
Study Intervention Compliance ..................................................................................54 
6.4.1. 
Inpatient Treatment Period (Single Dose) ..................................................................54 


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6.4.2. 
Optional Extended Use Treatment Period ..................................................................54 
6.5. 
Dose Modification ......................................................................................................55 
6.6. 
Continued Access to Study Intervention After the End of the Study .........................55 
6.7. 
Treatment of Overdose ...............................................................................................55 
6.8. 
Concomitant Therapy .................................................................................................56 
6.8.1. 
CYP2C8 Inhibitors .....................................................................................................56 
7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................57 
7.1. 
Discontinuation of Study IMP ....................................................................................57 
7.1.1. 
Single-dose Period ......................................................................................................57 
7.1.2. 
Optional Extended Use Treatment Period ..................................................................57 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................57 
7.3. 
Lost to Follow Up .......................................................................................................57 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................59 
8.1. 
Pharmacodynamic Assessments .................................................................................59 
8.1.1. 
Required PD Assessments with RHC .........................................................................60 
8.1.2. 
Required Non-invasive PD Assessments ....................................................................60 
8.1.3. 
Nitric Oxide Challenge ...............................................................................................60 
8.1.4. 
Resting Respiratory Gas Exchange Assessments .......................................................60 
8.1.5. 
Transthoracic Echocardiogram Assessments .............................................................60 
8.1.6. 
Pulmonary CT Scan ....................................................................................................60 
8.1.6.1. 
Single-dose Period ......................................................................................................60 
8.1.6.2. 
Optional Extended Use Treatment Period ..................................................................61 
8.2. 
Safety Assessments .....................................................................................................61 
8.2.1. 
Physical Examinations ................................................................................................61 
8.2.2. 
Vital Signs ..................................................................................................................61 
8.2.2.1. 
Single-dose Period ......................................................................................................61 
8.2.2.2. 
Optional Extended Use Treatment Period ..................................................................61 
8.2.3. 
Electrocardiograms .....................................................................................................62 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................62 
8.2.5. 
Pregnancy Testing ......................................................................................................62 
8.2.5.1. 
Single-dose Period ......................................................................................................62 


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8.2.5.2. 
Optional Extended Use Treatment Period ..................................................................63 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................63 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................63 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................64 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................64 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................64 
8.3.5. 
Pregnancy ...................................................................................................................65 
8.3.6. 
Adverse Events of Special Interest (AESI) ................................................................65 
8.3.7. 
Medical Device Deficiencies ......................................................................................65 
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies ...........................................65 
8.3.7.2. 
Follow-Up of Medical Device Deficiencies ...............................................................66 
8.3.7.3. 
Prompt Reporting of Device Deficiencies to Insmed .................................................66 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies ...................................66 
8.4. 
Pharmacokinetic Assessments ....................................................................................66 
8.4.1. 
PK Sample Collection .................................................................................................66 
8.4.2. 
PK Analysis ................................................................................................................66 
8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations ................................................67 
8.5. 
Genetics / Pharmacogenomics ....................................................................................67 
8.6. 
Biomarkers ..................................................................................................................67 
8.7. 
Medical Resource Utilization and Health Economics ................................................67 
8.8. 
Immunogenicity Assessments ....................................................................................67 
9. 
STATISTICAL CONSIDERATIONS .......................................................................68 
9.1. 
Statistical Hypotheses .................................................................................................68 
9.2. 
Sample Size Determination ........................................................................................68 
9.3. 
Analysis Sets ...............................................................................................................68 
9.4. 
Statistical Analyses .....................................................................................................68 
9.4.1. 
General Considerations ...............................................................................................68 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values ...........................................................69 
9.5. 
Interim Analysis ..........................................................................................................69 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................70 


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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................70 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................70 
10.1.2. 
Protocol Deviations ....................................................................................................70 
10.1.3. 
Public Health Emergency Situations ..........................................................................71 
10.1.3.1. 
Continuation or Suspension of the Study ...................................................................71 
10.1.4. 
Financial Disclosure ...................................................................................................72 
10.1.5. 
Informed Consent Process ..........................................................................................72 
10.1.6. 
Protection of Participant Identification and Confidentiality .......................................73 
10.1.7. 
Committee Structure ...................................................................................................73 
10.1.8. 
Dissemination of Clinical Study Data ........................................................................73 
10.1.9. 
Data Quality Assurance ..............................................................................................74 
10.1.9.1. 
Data Collection ...........................................................................................................74 
10.1.9.2. 
Study Monitoring ........................................................................................................74 
10.1.9.3. 
Audits and Inspections ................................................................................................74 
10.1.9.4. 
Study Record Retention ..............................................................................................75 
10.1.9.5. 
Source Documents ......................................................................................................75 
10.1.10. 
Study Files and Materials ...........................................................................................75 
10.1.11. 
Use of Stored Samples and Data ................................................................................76 
10.1.12. 
Disposition of Stored Samples and Data ....................................................................76 
10.1.13. 
Study and Site Start and Closure ................................................................................77 
10.1.13.1. First Act of Recruitment .............................................................................................77 
10.1.13.2. Study/Site Termination ...............................................................................................77 
10.1.14. 
Protocol Amendments ................................................................................................77 
10.1.15. 
Financing and Insurance .............................................................................................78 
10.1.15.1. Finances ......................................................................................................................78 
10.1.15.2. Reimbursement, Indemnity, and Insurance ................................................................78 
10.1.15.3. Participant Reimbursement, Liability and Insurance ..................................................78 
10.1.16. 
Publication Policy .......................................................................................................78 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................80 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................81 
10.3.1. 
Definition of AE .........................................................................................................81 


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10.3.2. 
Definition of SAE .......................................................................................................82 
10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................83 
10.3.4. 
Reporting of SAEs ......................................................................................................84 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................85 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ..............86 
10.6. 
Appendix 6 Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies ............................89 
10.6.1. 
Definition of Medical Device AE and ADE ...............................................................89 
10.6.2. 
Definition of Medical Device SAE, SADE and USADE ...........................................89 
10.6.3. 
Definition of Device Deficiency .................................................................................90 
10.6.4. 
Recording and Follow-up of AE and/or SAE and Device Deficiencies .....................90 
10.6.5. 
Reporting of SAEs ......................................................................................................92 
10.6.6. 
Reporting of SADEs ...................................................................................................92 
11. 
REFERENCES ...........................................................................................................94 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Screening and Follow up, Single-Dose Period, 
INS1009-201 ...............................................................................................................24 
Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 .......................26 
Table 3: 
PK and PD Biomarker Sampling Schedule, Single-Dose Period, INS1009-
201 ..............................................................................................................................28 
Table 4: 
Schedule for Optional Procedures and Assessments, Inpatient Treatment 
Period, INS1009-201 ..................................................................................................29 
Table 5: 
Schedule of Activities for Screening and Follow-up, Extended Use 
Treatment Period, INS1009-201 .................................................................................30 
Table 6: 
Schedule of Activities for the Optional Extended Use Treatment Period, 
INS1009-201 ...............................................................................................................31 
Table 7: 
Windows for CYP2C8 Inhibitor Medications ............................................................56 
Table 8: 
Protocol-Required Safety Laboratory Tests, INS1009-201 ........................................80 
 


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LIST OF FIGURES 
Figure 1: 
Participant Progression Through INS1009-201 Studya ..............................................20 
Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period ..........................................................................................................................21 
Figure 3: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 ..........22 
Figure 4: 
Guideline for Optimal 3-Week Planned Titration Schedule (Optional 
Extended Use Treatment Period) ................................................................................23 


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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine amino transferase 
AST 
aspartate amino transferase 
AUC 
area under the concentration-time curve 
AUC0–∞ 
area under the concentration-time curve from time zero to infinity 
AUCt1–t2 
area under the plasma concentration-time curve from time zero to time of 
last measurable concentration 
CL/F 
apparent total clearance of drug from plasma after extravascular 
administration 
Cmax 
maximum (peak) plasma concentration of the drug 
CO 
cardiac output 
CRF 
case report form 
CRO 
contract research organization 
CT 
computerized tomography 
DILI 
drug induced liver injury 
DPI 
dry powder inhalation 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
end of study 
ERS/ERC 
European Respiratory Society/European Society for Cardiology 
EUT 
extended use treatment 
FDA 
Food and Drug Administration 


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FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HL 
Hy’s Law 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IMP 
investigational medicinal product 
IRB 
investigational review board 
IV 
intravenous 
MAD 
multiple ascending dose 
mPAP 
mean pulmonary arterial pressure 
MVO2 
mixed venous oxygen saturation 
NO 
nitric oxide 
NOAEL 
No observed adverse effect level 
NT-pro-BNP 
N-terminal (NT)-pro hormone brain natriuretic peptide 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary arterial pressure 
PCWP 
pulmonary capillary wedge pressure 
PD 
pharmacodynamic(s) 
PH 
pulmonary hypertension 
PHL 
potential Hy’s Law 
PI 
principal investigator 
PK 
pharmacokinetic(s) 


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PVR 
pulmonary vascular resistance 
QD 
once daily 
QID 
four times daily 
RAP 
right atrial pressure 
RHC 
right heart catheter 
RVP 
right ventricular pressure 
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS CoV 2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SoA 
schedule of activities/assessments 
SUSAR 
suspected unexpected serious adverse reaction 
SRC 
Safety Review Committee 
t1/2 
elimination half-life 
TBL 
total bilirubin 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment emergent adverse event 
tmax 
time to maximum (peak) plasma concentration following drug administration 
TPIP 
treprostinil palmitil inhalation powder 
TPIS 
treprostinil palmitil inhalation suspension 
TRE 
treprostinil 
TP 
treprostinil palmitil 
TVR 
tricuspid valve regurgitation 


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ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
Vd/F 
apparent volume of distribution at terminal phase 
WHO 
World Health Organization 
WOCBP 
woman of child-bearing potential 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Amendment Summary of Changes 
Amendment 3 (03 JUN 2022) 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment: 
The primary driver for the changes in the protocol amendment is to better assure the potential for 
vascular reactivity of participants. To that end, there is the addition of a nitric oxide (NO) 
challenge, as well as refinement and clarification of inclusion/exclusion criteria.  
Grammatical and typographical errors were corrected throughout the document.  
A summary of major changes compared to the current global amendment is shown in the table 
below. 
Revision 
Rationale 
Location of Revision 
Updated the Schedule of 
Activities 
To include an NO challenge, 
post-NO PD assessment, add 
assessments at 12 hours, and to 
clarify that PCWP is not only 
collected at Baseline (Table 2); 
To remove NT-pro-BNP and 
6MWD test requirements for 
screening or baseline in the 
Extended Use Treatment Period 
(Table 5, Table 6); 
To clarify that historical values 
for NT-pro-BNP (or BNP) and 
6MWD, within 3 months of first 
site visit or values at Baseline 
prior to RHC, are permitted; 
6MWD is optional upon 
discussion with Medical 
Monitor (Table 2) 
• 
Figure 1  
• 
Table 1  
• 
Table 2  
• 
Table 5  
• 
Table 6  
 
Updated Inclusion Criterion #3 
To include newly diagnosed 
participants 
• 
Section 5.1 
Updated Inclusion Criterion #4 
(previously Inclusion 
Criterion #5) 
To clarify requirement for stable 
therapy 
• 
Section 5.1 


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Revision 
Rationale 
Location of Revision 
Removed previous Inclusion 
Criterion #4 
To remove functional class 
requirements 
•
Section 5.1
Removed previous Exclusion 
Criterion #18 and added 
guidance on concomitant 
therapy 
To include washout guidance 
table and specify guidelines for 
handling CYP2C8 inhibitors  
•
Section 5.1
•
Section 6.8.1
Updated Inclusion Criterion #2 
To reduce redundancy with 
Inclusion Criterion #7 
•
Section 5.1
Removed previous Inclusion 
Criterion #6 
To include participants with 
recent changes in diuretics  
•
Section 5.1
Updated Inclusion Criterion #5 
(Previously Inclusion 
Criterion #7) 
To adjust timing for documented 
predicted FVC requirement 
•
Section 5.1
Updated Inclusion Criterion #6 
(Previously Inclusion 
Criterion #7) 
To include Investigator 
assessment of low or 
intermediate risk participant 
•
Section 5.1
Removed previous Inclusion 
Criterion #10 
To include participants with a 
wider range of BMI values  
•
Section 5.1
Clarified exploratory endpoint 
for 6MWD 
Changed baseline from EUT 
baseline to study baseline 
•
Section 3.1
Clarified dosing that 112.5 µg 
dose will only be used in first 
participant 
To clarify that only the first 
participant in the study will 
receive a dose containing 
112.5 µg; subsequent 
participants will receive 80 µg, 
or a combination of capsules 
containing 80 µg, 160 µg, and 
320 µg of TP, based on SRC 
recommendations.  
•
Section 1.3.2.1
•
Figure 3
•
Section 4.1
•
Section 4.3.1
•
Section 6.1.1
•
Section 6.2
Added an exploratory endpoint 
To evaluate the effect of NO 
challenge 
•
Section 3


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Document History 
Document 
Version 
Date 
Global Amendment 3 
4.0 
03 JUN 2022 
Global Amendment 2 
3.0 
03 MAR 2022 
Global Amendment 1 
2.0 
06 OCT 2021 
Original Protocol 
1.0 
02 NOV 2020 
1.2. 
Synopsis 
Protocol Title: 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of 
Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension 
Rationale: 
Treprostinil palmitil (TP) is an inactive prodrug of treprostinil (TRE), which is widely used in 
the treatment of pulmonary hypertension (PH). Treprostinil palmitil inhalation powder (TPIP) is 
a dry powder for inhalation formulation of TP. TPIP is being developed for the treatment of 
pulmonary arterial hypertension (PAH; World Health Organization (WHO) Group 1 PH). TPIP 
is expected to provide extended release of TRE in the lung with the goals of less frequent and 
more convenient and consistent dosing while reducing the frequency and severity of dose-
limiting side effects associated with the currently approved forms of TRE. No studies of TP or 
TPIP have been conducted in participants with PAH. The purpose of this study is to evaluate the 
safety, pharmacokinetics (PK), and pharmacodynamic (PD) effects of a single dose of TPIP in 
participants with PAH. 
The starting and planned doses for this study are primarily based on the safety and tolerability of 
treprostinil palmitil inhalation suspension (TPIS) in healthy participants following single 
inhalation at 85 to 340 µg (Study INS1009-101) and TPIP in healthy participants in a SAD/MAD 
study (Study INS1009-102). In INS1009-101, the systemic exposure for TRE at 340 µg was low 
(AUC < 2.5 ng*h/mL) with an elimination t1/2 of approximately 7 hours. In rats, the PK profile 
of TP inhalation solution was similar to that of TP inhalation powder. In INS1009-102, single 
doses of up to 675 μg and multiple doses of up to 225 μg for 7 days were administered to healthy 
participants. Overall, TP was well tolerated, with largely mild TEAEs and an adverse effect 
profile consistent with that of inhaled prostacyclin analogs. Treprostinil exposures increased 
approximately dose-proportionately, were similar between TPIS and TPIP, and showed no 
accumulation with once daily (QD) dosing.  




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Brief Summary: 
The study is designed to investigate the safety and acute pharmacokinetic (PK) and 
pharmacodynamic (PD) effects of a single dose of treprostinil palmitil inhalation powder (TPIP) 
in participants with pulmonary arterial hypertension (PAH). Intensive monitoring of pulmonary 
vascular resistance, cardiac output, right ventricular pressure, pulmonary arterial pressure, 
hemoglobin, right atrial pressure, and mixed venous oxygen saturation via right heart catheter in 
an appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate dose- and PK-effect relationships. Some assessments and study 
activities (resting respiratory gas exchange assessment, transthoracic echocardiogram, pulmonary 
computerized tomography scan) for exploratory endpoints are optionally left to the discretion of 
the individual Investigator, based on participant safety and study site capabilities. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 48 hours post TPIP 
dose will extend into Study Day 3. A remote safety follow-up visit (telephone visit) is scheduled 
for Study Day 30 (± 2 days). An optional extended treatment period of 16 weeks will be 
available to participants who have completed the single-dose inpatient treatment period. There 
will be a second safety follow-up visit 30 days (± 3 days) after extended use treatment (EUT) 
Week 16 for participants who elect to enter the extended use treatment period. If the initial 
remote safety follow-up visit overlaps with the start of the extended treatment period, the initial 
remote safety visit will be shortened and conducted just prior to administration of IMP in the 
extended treatment period.  
Number of Participants: 
Approximately 6 to 10 evaluable participants are planned. Evaluable participants for safety are 
those who receive a single dose of TPIP; evaluable participants for PD and PK endpoints are 
those who receive a single dose of TPIP and have at least 1 post-TPIP administration PK or PD 
datapoint. 
Treatment Groups and Duration: 
This is a multi-center, open-label, non-randomized study. There are no predefined treatment 
groups. The dose determination for each participant will be made based on all available PK, PD, 
and safety data at the time of the participant’s entry into the study. An optional extended use 
treatment period of 16 weeks will be available to all participants.  
Safety Review Committee:  
A Safety Review Committee (SRC) will be responsible for monitoring safety data. The SRC will 
comprise all Investigators and key members of the Insmed Study Team (including but not limited 
to Medical Monitor, Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, 
Clinical Pharmacologist) and external expert consultants. The SRC will continuously monitor all 
available safety, PD and PK data for each participant and will obtain consensus regarding the 
safety of continuing the study, the next TPIP dose, and clinical care of the next participant. 
Expert consultants may be invited to review and interpret participant data. With any safety 
findings, a decision will be made, based on the review, as to whether enrollment in the study will 


Treprostinil Palmitil Inhalation Powder (TPIP) 
Insmed Incorporated 
Clinical Trial Protocol INS1009-201 
Version 4.0, 03 JUN 2022 
 
Confidential 
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be allowed to continue. Decisions regarding final database values for PD parameters may be 
adjudicated by the SRC. 
1.3. 
Schema 
1.3.1. 
Participant Progression Through the Study 
The main study comprises an outpatient screening period, an inpatient treatment period, and an 
outpatient follow-up period. Participant progression through the study is shown in Figure 1. An 
optional EUT period is shown in Figure 2. 
1.3.1.1. 
Screening Period 
The outpatient screening period will last up to 30 days. After participants complete screening and 
have met the study eligibility criteria, the right heart catheter (RHC) procedure and inpatient 
treatment period should be scheduled without delay. 
1.3.1.2. 
Inpatient Treatment Period 
The inpatient treatment period will start on Study Day 1 and extend overnight into Study Day 2. 
Because the study requires an inpatient treatment period, institutional requirements for elective 
inpatient admissions, which may vary from site to site, will be followed. The participant may be 
required to undergo pre-admission assessments required by the institution for elective admission, 
for example testing for common infectious pathogens. Signature of elective admission 
documents and other consents may be required by the institution. An RHC will be placed. 
Following completion of Baseline assessments, a single dose of TPIP will be administered via a 
dry powder inhaler. Safety, PD, and PK assessments will continue at scheduled intervals through 
24 hours following TPIP administration. Following the final assessments at 24 hours, the RHC 
will be removed and the participant will be discharged from the inpatient setting when deemed 
safe for the participant.  
1.3.1.3. 
Follow-up Period 
PK blood draw at 48 (± 4) hours after TPIP dosing will be done on an outpatient basis as 
arranged by the site. The 48-hour post-TPIP visit will also include safety assessments including 
physical examination, clinical laboratory evaluations, ECG, AE collection and vital signs. An 
additional safety follow-up will be conducted by telephone call or telemedicine on Study Day 30 
(± 2 days) unless the participant elects to enter the EUT period prior to this follow-up visit. If the 
initial remote safety follow-up visit overlaps with the start of the extended treatment period, the 
initial remote safety visit will be shortened and conducted just prior to administration of 
investigational medicinal product (IMP) in the extended treatment period.  


Treprostinil Palmitil Inhalation Powder (TPIP) 
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Figure 1: 
Participant Progression Through INS1009-201 Studya  
 
NO=nitric oxide; PD-pharmacodynamic assessments; PK=pharmacokinetic assessments; h=hours; d=days 
a Does not include optional extended use treatment period; the 30 day follow-up visit will be shortened and 
conducted just prior to administration of IMP in the extended treatment period if the visit overlaps with the start 
of the extended treatment period. 
1.3.1.4. 
Optional Extended Use Treatment Period 
All participants will be allowed to enter the optional 16 week EUT period after the completion of 
the inpatient treatment period and final PK sample collection. Entry into the optional EUT period 
will be at participant and Investigator discretion. A gap between the inpatient treatment period 
and EUT period is expected, but not required, and can be up to 6 months.  
After collection of the final PK sample, all participants will be allowed optional continued access 
to IMP for 16 weeks (includes a 3-week titration period) from first administration in the EUT 
period. At the Investigator’s discretion, participants may undergo a study drug taper for up to 
2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug. 
Participants will be screened to ensure they meet inclusion and exclusion criteria if they enter the 
EUT period more than 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period) (Table 5).  
Participant in-clinic study visits will be scheduled for EUT at Baseline (EUT Day 1), EUT 
Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16. 


Treprostinil Palmitil Inhalation Powder (TPIP) 
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Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period 
 
a 
The 30 day follow-up visit from the single dose period will occur on EU Day 1 if the visit overlaps with the start 
of the extended treatment period. 
b At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks after the Week 16 
visit. 
c  The follow-up telephone call or visit will be 30 days after the Week 16 visit.  
EU = Extended Use; QD = once daily; EOT = end of treatment 
1.3.1.5. 
Extended Use Follow-up Period 
There will be a second remote safety follow-up visit 30 days (± 3 days) after EUT Week 16 
administration for participants who elect to enter the EUT period. 
1.3.2. 
Dose Selection 
1.3.2.1. 
Inpatient Treatment Period Dose Selection 
Each participant will enter the study in a serial fashion, following review of available safety, PK, 
and PD data from all previous participants by the Safety Review Committee (SRC). Each 
participant will receive a single-dose administration of TPIP via a dry powder inhaler. TPIP will 
be administered to only one participant at a time, with full evaluation of all available data prior to 
dosing the next participant. 
The first participant will receive a dose of TPIP containing 112.5 µg. Subsequent participants 
will receive 80 µg, or a combination of capsules containing 80 µg, 160 µg, and 320 µg of TP, 


Treprostinil Palmitil Inhalation Powder (TPIP) 
Insmed Incorporated 
Clinical Trial Protocol INS1009-201 
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based on SRC recommendations. After the first participant, the SRC will review all available 
safety, PD, and PK data including data from the first participant and select the TPIP dose and 
any changes to the assessments for the second participant. Then, following review of all 
available data including that from the first and second participants, the SRC will select the dose 
for the third participant. Similarly, all available data from previous studies and participants will 
be assessed prior to determining the dose for the next participant, until such a time as the SRC 
believes the study must conclude. Figure 3 describes the planned dose-selection and study 
continuation process. 
Figure 3: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 
     
 
SRC=Safety Review Committee 
1.3.2.2. 
Optional Extended Use Treatment Period 
Entrance into the optional EUT period is at participants’ and Investigators’ discretion and begins 
with a titration. The guideline for the optimal 3-week planned titration schedule is provided in 
Figure 4. The target TPIP dose will be achieved with a combination of dry powder capsules 
containing 80 µg, 160 µg, and 320 µg of TP. 
During the titration period (EUT Days 1 to 21), each participant’s dose will be up-titrated to the 
highest tolerated dose for that individual. Participants will start open-label study drug with 
1 capsule (80 μg TPIP) QD. If this dose is well tolerated, the dose should be up-titrated until 
reaching the participant’s highest tolerable dose as described by the dosing schedule in Figure 4. 
During this titration period, participants must stay on study drug for the minimum number of 
cumulative days required for each dose (e.g., 2 days at 80 µg, 160 µg, or 240 µg; 3 days at 
320 µg; or 4 days at 400 µg or 480 µg) prior to titrating to the next higher dose. Study drug 
titration may occur slower, but not faster, than described in Figure 4. If a dose is not tolerated, 
study drug may be decreased to the previous dose level. At the Investigator’s discretion, 
up-titration may resume (as described in Figure 4) until the participant’s highest tolerated dose is 
achieved at EUT Day 21.  
All dose adjustments must be preceded by contact with the Investigator or study site personnel. 
In addition, the Investigator and/or study site personnel will be in contact with participants 
during the dose adjustment period to assess the tolerability to study drug as measured by the AEs 
commonly observed with other prostacyclin receptor agonists, which include headache, flushing, 
nausea, cough, and muscle pain. The decision to up-titrate to the next TPIP dose will be based on 
safety and tolerance data (e.g., AEs) as reported by the participant and assessed by the 
Investigator.  


Treprostinil Palmitil Inhalation Powder (TPIP) 
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At the Investigator’s discretion, based on tolerability, the study drug dose may be increased by 
1 dose level (as described in Figure 4) at the EUT Week 5 in-clinic visit for participants who 
have not achieved the 640 μg dose. The increase in dose will be administered under clinical 
observation at the study site to ensure tolerability and correct dosing and self-administration of 
study drug. The participant’s highest dose tolerated is expected to continue for the remainder of 
the study after the EUT Week 5 visit.  
At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks 
after the EUT Week 16 visit to help facilitate a safe withdrawal from study drug. The 
Investigator and/or study site personnel will be in contact with participants during the study drug 
taper to assess the tolerability to study drug. 
Figure 4: 
Guideline for Optimal 3-Week Planned Titration Schedule (Optional 
Extended Use Treatment Period) 
 
1.4. 
Schedule of Activities (SoA) 
The SoA is divided into the following tables:  
• Screening and follow-up activities in the single-dose period 
• SoA in the inpatient treatment period  


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• PK and PD biomarker blood sampling schedule 
• Optional procedures and assessments in the inpatient treatment period 
• Screening and follow-up activities in the EUT period 
• SoA in the EUT period 
The single-dose period refers to the combination of the inpatient treatment period (Study Day 1 
to Study Day 2), the PK/PD sampling period, and the 30 day follow-up period.  
 
Table 1: 
Schedule of Activities for Screening and Follow up, Single-Dose Period, 
INS1009-201 
Procedure 
Screening 
Follow-up 
 
Up to 30 
Days 
48 h post 
TPIP dosea 
Study Day 30 
(± 2 days)b 
Informed Consent 
X 
-- 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
-- 
Demographics and Medical History 
X 
-- 
-- 
Smoking Status 
X 
-- 
-- 
Height, Weight 
X 
-- 
-- 
Prior/Concomitant Medications 
X 
X 
X 
Serology (HBsAg, HIV antibody, HCV 
antibody) 
X 
-- 
-- 
Serum Pregnancy Test (WOCBP only) 
X 
 
 
Urine Pregnancy Test (WOCBP only) 
-- 
 
X 
Hematology, Clinical Chemistry (Table 8) 
X 
X 
-- 
Coagulation Profile (Table 8) 
X 
-- 
-- 
12-lead ECG 
X 
X 
-- 
Physical Examination 
X 
X 
-- 
Vital Signs 
X 
X 
-- 
Pulmonary Function Testing (if needed, 
(Section 5.1) 
X 
-- 
-- 
Adverse Eventsc 
X 
X 
X  
a 48 h safety follow-up assessments are to be conducted at the time of the visit for the 48h PK blood draw (Table 3). 
b Follow-up visit will be shortened and conducted just prior to administration of IMP in the extended treatment 
period if the visit overlaps with the start of the extended treatment period. 


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c AE collection is from the time of signing the informed consent through the Day 30 safety follow-up. Events 
between ICF signing and TPIP dosing that are serious will be recorded as SAE; non-serious events during this 
period must be recorded as medical history. 
BMI = body mass index; ECG = electrocardiogram WOCBP = woman of childbearing potential 
Note:  Additional safety follow-ups may be conducted at any time per the investigator’s discretion to ensure 
participant safety. The reason for any additional safety follow-up must be reported as an AE. 


Treprostinil Palmitil Inhalation Powder (TPIP) 
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Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 
 
Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP Administration 
TPIP Administration 
Post-TPIP Administration 
Procedure 
Day 1 
Baseline  
NO 
valuea 
Post-NO 
Baselinea 
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
12 h 
24 h 
24 h to 
discharge 
Hematology, clinical 
chemistry, coagulation 
profile blood drawb 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
-- 
Urine pregnancy test 
(WOCBP only) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12-lead ECG 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Cardiac telemetry per 
institutional protocolc 
X 
 
Physical Exam 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signsd 
X 
-- 
-- 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
Adverse events 
collection 
X 
 
Place right heart catheter 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
NT-pro-BNP or BNPe 
X 
-- 
-- 
 
 
 
 
 
 
 
 
 
 
 
6MWDe 
X 
-- 
-- 
 
 
 
 
 
 
 
 
 
 
 
PD assessments: PVR, 
MVO2, Hgb, RVP, PAP 
CO, PVR, RAP, oxygen 
consumption, PCWP, 
heart rate, SpO2, 
systemic blood pressuref  
X 
-- 
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
X 
-- 
NO Challenge 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 


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Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP Administration 
TPIP Administration 
Post-TPIP Administration 
Procedure 
Day 1 
Baseline  
NO 
value 
Post-NO 
Baseline 
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
12 h 
24 h 
24 h to 
discharge 
Administer TPIP 
-- 
-- 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Remove RHC 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Discharge/Safety 
Follow-up Instructions 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
a Exception to NO challenge and post-NO Baseline assessment is allowed for sites without the technical ability/equipment to effectively carry out the 
assessment, as determined by the Sponsor. 
b See Section 10.2, Table 8 for specific laboratory tests. 
c Routine cardiac telemetry readings will not be collected as study data unless they pertain to a relevant adverse event. 
d Heart rate, systemic blood pressure, and SpO2 are required PD measurements and will be collected as scheduled. They may be measured with pulse oximetry 
for heart rate and SpO2 and an automated inflatable arm cuff for blood pressure. Temperature and respiratory rate may be measured per institutional inpatient 
protocol. Respiratory rate will be measured as part of pulmonary gas exchange testing, if performed. 
e Historical values for Baseline NT-pro-BNP and 6MWD are permitted up to 3 months before Baseline visit. If the tests are performed at the Baseline visit, they 
must be performed prior to RHC. The 6MWD test is optional if discussed with the Medical Monitor. 
f Systemic blood pressure must include 3 values:  systolic, diastolic, and mean arterial pressure.  
CO = cardiac output; Hgb = hemoglobin; MVO2 = mixed venous oxygen saturation; NO = nitric oxide; PAP = pulmonary arterial pressure; PVR=pulmonary 
vascular resistance; RAP = right atrial pressure; RVP = right ventricular pressure; SpO2 = arterial blood oxygen saturation; WOCBP = woman of childbearing 
potential 
 
 


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Table 3: 
PK and PD Biomarker Sampling Schedule, Single-Dose Period, INS1009-201 
-- 
Baseline 
Pre-TPIP 
Administration 
TPIP 
administration 
Post-TPIP Administration 
Time  
-- 
0 
30 (± 10) mins 
60 (± 10) mins 
2 h (± 20) mins 
4 (± 1) h 
8 (± 2) h 
24 (± 2) h 
48 (± 4) h 
PK samplinga 
X 
-- 
X 
X 
X 
X 
X 
X 
X 
Biomarker 
samplingb 
X 
-- 
-- 
-- 
-- 
X 
X 
-- 
-- 
a PK sampling for treprostinil palmitil and treprostinil; each PK sample will be approximately 10 mL. 
b Each biomarker sample will be approximately 5 to 7 mL. 
 
 
 


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Table 4: 
Schedule for Optional Procedures and Assessments, Inpatient Treatment Period, INS1009-201 
Inpatient Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
Post-TPIP 
Administration 
Procedure 
Study Day 
1 Baseline  
Time 0 
2-8 hr 
4-8 hr 
Transthoracic 
echocardiogram 
(LVEF,TVR maximum 
velocity, TAPSE, end 
diastolic right ventricular 
volume)  
X 
-- 
X 
-- 
Pulmonary CT scan (total 
blood volume, blood 
volume in vessels < 5 
mm2)  
X 
-- 
-- 
X 
-- 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
-- 
-- 
Study Day 
1 Baseline 
Time 0 
30 mins 
60 mins 
90 mins 
2 h 
3 h 
4 h 
8 h 
24 h 
Resting respiratory gas 
exchange assessmenta 
(respiratory rate, minute 
ventilation, VCO2, ETO2, 
ETCO2, SpO2  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
a Resting respiratory gas assessment parameters are collected at the same time points as RHC parameters with the exception of the 12 h timepoint. 
NOTE:  Parameters to be measured for each procedure are in parentheses. 
CT=computerized tomography; ETCO2 =end tidal carbon dioxide concentration; ETO2,=end tidal oxygen concentration; LVEF=left ventricular ejection fraction; 
SpO2=arterial blood oxygen saturation; TAPSE=tricuspid annular plane systolic excursion; TVR=tricuspid valve regurgitation; VCO2,=carbon dioxide 
production  


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Table 5: 
Schedule of Activities for Screening and Follow-up, Extended Use Treatment Period, INS1009-201 
Procedure 
Screeninga 
Follow-up 
 
EUT Study Day 1 
(± 3 days) 
EUT Study Day 142 
(± 3 days) 
Informed Consent 
X 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
Demographics 
X 
-- 
Smoking Status 
X 
-- 
Height, Weight 
X 
-- 
Prior/Concomitant Medications 
X 
X 
Urine Pregnancy Test (WOCBP only) 
X 
X 
Hematology, Clinical Chemistry (Table 8) 
X 
-- 
12-lead ECG 
X 
-- 
Vital Signs 
X 
-- 
Adverse Eventsb 
X 
X  
a Participants will only be screened at EUT Day 1 if they enter the EUT period beyond 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period). 
b AEs for the period from the Study Day 30 follow-up until the enrollment in the EUT period will be collected during participants’ screening for the EUT. 
BMI = Body Mass Index; EUT = extended use treatment; WOCBP = woman of childbearing potential 
 
 
 
 
 


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Table 6: 
Schedule of Activities for the Optional Extended Use Treatment Period, INS1009-201 
 
Period 
Extended Use Treatment Period 
Follow-Up 
E/Da 
Week 
EUT W1 
EUT W2  
EUT W3 
EUT W5 
EUT W10 
EUT W16 
EUT W20b 
 
Day 
EUT D1 
(Screeningc and 
Baseline)  
EUT D10 
(± 3 days) 
EUT D21 
(± 3 days) 
EUT D35d 
(± 3 days) 
EUT D70 
(± 3 days) 
EUT 
D112 
(± 3 days) 
EUT D142 
(± 3 days) 
 
Visit 
EUT V1 
EUT V2 
EUT V3 
EUT V4 
EUT V5 
EUT V6 
EUT V7 
 
Inclusion/exclusion 
Xc 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Prior/concomitant 
medications 
 
Pregnancy test 
(WOCBP only)e 
Xc 
 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
-- 
X 
6MWD test 
-- 
-- 
-- 
-- 
-- 
X 
-- 
-- 
Hematology, clinical 
chemistry g 
Xc 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12-lead ECG 
Xc 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
NT-pro-BNP (or BNP) 
Sample 
-- 
-- 
-- 
-- 
-- 
X 
-- 
-- 
Optional pulmonary CT 
scan (total blood 
volume, blood volume in 
vessels < 5 mm2) 
X 
-- 
-- 
-- 
-- 
X 
-- 
-- 
Study drug distributionh 
X 
X 
X 
X 
X 
X 
-- 
-- 
Study drug 
self-administration 
re-assessmenti 
-- 
X 
X 
X 
X 
X 
-- 
-- 
Targeted physical 
examinationj   
X 
-- 
X 
X 
X 
-- 
-- 
-- 
Study drug 
accountabilityk 
-- 
X 
X 
X 
X 
X 
Xl 
-- 


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Period 
Extended Use Treatment Period 
Follow-Up 
E/Da 
Week 
EUT W1 
EUT W2  
EUT W3 
EUT W5 
EUT W10 
EUT W16 
EUT W20b 
 
Day 
EUT D1 
(Screeningc and 
Baseline)  
EUT D10 
(± 3 days) 
EUT D21 
(± 3 days) 
EUT D35d 
(± 3 days) 
EUT D70 
(± 3 days) 
EUT 
D112 
(± 3 days) 
EUT D142 
(± 3 days) 
 
Visit 
EUT V1 
EUT V2 
EUT V3 
EUT V4 
EUT V5 
EUT V6 
EUT V7 
 
Dosing diary 
 
-- 
-- 
Adverse eventsm 
 
a Participants who enroll in the optional EUT period and discontinue before the end of study will be classified as early discontinuations.  
b Follow-up telephone call or visit will be 30 days after the EUT Week 16 visit.  
c Participants will undergo assessments for screening at EUT Day 1 if they enter the EUT period beyond 30 days after beginning the single dose period (e.g., 
beyond the initial 30 day follow-up period). 
d At the Investigator’s discretion, an increase of 1 dose level may be allowed at EUT Week 5 if the participant has not achieved the 640 µg dose.  
e Pregnancy test: Urine pregnancy tests will be performed in-clinic at EUT Baseline (EUT Day 1) in WOCBP. WOCBP will be provided home pregnancy test 
kits with instructions to conduct the pregnancy tests every 30 days or more if required during the treatment and follow-up periods. Study site personnel will 
contact the participant every 30 days by telephone and record the pregnancy test results. An additional on-site urine test must be performed prior to starting any 
procedure that requires the use of ionizing radiation. 
f Vital signs: Includes body temperature (°C), pulse rate (bpm), respiratory rate (breaths/min), blood pressure (systolic, diastolic, and mean arterial [mmHg]), and 
SpO2. Vital signs will be measured at EUT Screening/Baseline (EUT Day 1), EUT Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16 and 
at the Early Discontinuation visit, if appropriate.  
g See Table 8 for additional information. 
h Participants will receive study drug supply on EUT Day 1 and at EUT Week 2, EUT Week 3, EUT Week 5, and EUT Week 10 visits. Participants who undergo 
a study drug taper will receive study drug supply at the EUT Week 16 visit. A telephone call from study personnel or the Investigator will be placed to 
participants assigned to a study drug taper to check on the participant’s well-being; timing of the telephone call will be based on the Investigator’s discretion, 
and any adverse events will be captured on the CRF. 
i  Assessment of study drug self-administration: Study drug self-administration will be overseen by study site personnel at all in-clinic visits.  
j The targeted physical examination will be performed at Week 3, Week 5, and Week 10 prior to study drug administration. The targeted physical exam includes 
cardiovascular (cardiac auscultation, assessment of peripheral pulses and edema) and pulmonary assessments (pulmonary auscultation).  
k Participants will return unused capsules and used capsules and devices to the study site at the Week 2, Week 3, Week 5, Week 10, and Week 16 visits.  
l Participants who undergo a study drug taper will return unused capsules and used capsules and devices to the study site at a follow-up visit. 
m AE collection from the 30 day follow-up period in the single-dose period to enrollment in the EUT period will be queried during EUT screening; All other AEs 
and SAEs will be collected from EUT Day 1 and followed up as described in Section 8.3.3.  
6MWD = 6-minute walk distance; CT = computerized tomography; CRF = case report form; D = day; E/D = early discontinuation; EUT = extended use 
treatment; NT-pro-BNP = N-terminal pro B-type natriuretic peptide; W = week; WOCBP = woman of childbearing potential; V = Visit


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2. 
INTRODUCTION 
Pulmonary hypertension (PH), a hemodynamic state characterized by resting mean 
PAP > 20 mmHg per updated guidelines (Simonneau et al., 2019), is generally classified into 5 
groups based on the underlying pathology: Group 1 is PH due to pulmonary vascular disease, 
also known as pulmonary arterial hypertension (PAH); Group 2 is PH due to left heart disease; 
Group 3 is PH due to lung disease or hypoxia; Group 4 is PH due to chronic thromboembolic 
disease or other pulmonary vasculature obstruction; Group 5 is miscellaneous PH syndromes 
caused by a variety of disorders such as hemolytic anemias and sarcoidosis (Thenappan et al., 
2018). 
In Group 1 PH (PAH), the resting mean PAP > 20 mmHg occurs in the setting of normal 
pulmonary arterial wedge pressure of ≤15 mm Hg with PVR of ≥3 Wood Units (WU) 
(McLaughlin et al., 2009). In PAH the pulmonary vasculature is affected by vasoconstriction, 
vascular remodeling, increased rigidity of vessel walls and vascular fibrosis. These vascular 
anomalies increase PVR, which leads to increases in right ventricular afterload, and a cascade of 
maladaptive changes to the heart including right ventricular hypertrophy, ischemia and fibrosis, 
reducing right ventricular function and eventually leading to right ventricular failure and death 
(Thenappan et al., 2018). The pulmonary vascular lesions of PAH may be idiopathic, hereditary, 
or occur as a complication of drug use (e.g., anorexigens), connective tissue disease, portal 
hypertension, congenital cardiac malformations or HIV infection (Hoeper et al., 2017). 
Data from PAH registries around the world (Thenappan et al., 2018) estimate a global incidence 
ranging from 2.0 to 7.6 cases per million adults per year, with a prevalence of 11 to 26 cases per 
million adults; the incidence in females is approximately 4 times that in males. Most registries 
report a mean age of onset ranging from approximately 36 to 53 years. While overall median 
survival has improved from 2.8 years in the 1980’s to 6 years currently, mortality is high, with 
1 year survival ranging from 68% to 93% and 5 year survival ranging from 21% to 65%. Nearly 
half of the patients in these registries have PAH of idiopathic, heritable or anorexigen-induced 
origin.  
PAH is a debilitating progressive disease that causes a wide range of non-specific symptoms 
including, dyspnea, shortness of breath, chest pain, fatigue, generalized weakness and exertional 
syncope (Delcroix and Howard, 2015), severely affecting the patient’s physical mobility, 
emotional and social well-being, ability to perform activities of daily living and overall quality of 
life. Pharmacological treatments are available to mitigate disease symptoms and slow disease 
progression, but treatment-related AEs, inconvenience and side effects can be treatment-limiting 
and negatively influence the patient’s daily life (Delcroix and Howard, 2015). 
The currently available pharmacologic treatments for PAH include calcium channel blockers, 
guanylate cyclase stimulators, endothelin receptor antagonists, phosphodiesterase type 5 
inhibitors, and prostanoids and prostacyclin agonists. Prostanoids, such as TRE, are among the 
most effective medications for the treatment of PAH. However, they are limited by the need for 
inconvenient and frequent drug administration and dose-limiting side effects (Thenappan et al., 
2018). 


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2.1. 
Study Rationale 
Treprostinil palmitil (TP) is an inactive prodrug of treprostinil (TRE). TPIP is a dry powder for 
inhalation formulation of TP. TPIP is being developed for the treatment of PAH. TPIP is 
expected to provide extended release of TRE in the lung with the goals of less frequent and more 
convenient and consistent dosing while reducing the frequency and severity of dose-limiting side 
effects associated with the currently approved forms of TRE. TP has been previously studied in 
healthy volunteers as an inhalation suspension (treprostinil palmitil inhalation suspension, TPIS), 
in single doses up to 340 µg (Study INS1009-101), and TPIP has been previously studied in a 
single ascending dose/multiple ascending dose (SAD/MAD) study in healthy volunteers (Study 
INS1009-102). 
No studies of TP or TPIP have been conducted in participants with PAH. Study INS1009-201 is 
an open label, non-randomized, single- dose study designed to evaluate the safety, 
pharmacokinetics (PK), and pharmacodynamic (PD) effects of a single dose of TPIP in 
participants with PAH. An optional EUT period was added to maximize participant convenience 
and accessibility.   
2.2. 
Background 
Treprostinil is a tricyclic benzidene analogue of prostacyclin. As such, TRE has vasodilatory and 
anti-platelet activity within the pulmonary vascular system, thereby reducing blood flow 
resistance and improving the clinical state, functional class, exercise capacity, and quality of life 
of patients with PAH (Vachiery and Naeije, 2004). 
Treprostinil has a high potency but is short-lived in the body and must be administered by 
continuous IV or SC infusion, or given multiple times per day by inhaled or oral routes. At 
present, TRE is available in the United States in formulations of IV or SC infusion (Remodulin 
Package Insert, 2018), oral extended-release tablets (Orenitram Package Insert, 2019), and 
inhalation solution (Tyvaso Package Insert, 2017) to treat PAH. The clinical experience with 
TRE suggests that most of the AEs experienced are related to its effects on prostanoid 
metabolism (e.g., headache, nausea, diarrhea, flushing, bleeding, and hypotension). Dose-
limiting side effects correlate to systemic plasma concentrations of TRE.  
Treprostinil palmitil is a hexadecyl ester prodrug of TRE. In the lung, TP is hydrolyzed by 
esterase to TRE and hexadecanol. TPIP is a dry powder formulation of TP designed to provide 
sustained release of TRE in the lung over a prolonged period, thus providing prolonged 
vasodilation in the lung vasculature. This effect was demonstrated in a rat acute hypoxia model 
that showed a maximal reduction in PAP through the 3-hour monitoring limit with TP, while the 
effect of inhaled TRE started to diminish by 1 hour and was completely gone after approximately 
2.5 hours. The prolonged lung exposure and pharmacological action of TRE achieved with 
sustained release from the prodrug TP aims to reduce both dosing frequency and side effects 
driven by fluctuations of plasma levels of TRE. 
Treprostinil palmitil was well tolerated in rats and dogs following 16-week once-daily inhalation. 
At no observed adverse effect level (NOAEL) doses, the plasma Cmax and AUC of TRE at steady 


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state in rats (2000 μg/kg/day) were 11 ng/mL and 73 ng*h/mL, respectively, and in dogs (250 
μg/kg/day) were 1.2 ng/mL and 13 ng*h/mL, respectively. 
Thus far, TP has been studied in 2 Phase 1 studies of healthy participants: An SAD study of 
TPIS (Study INS1009-101) and an SAD/MAD study of TPIP (Study INS1009-102). Single 
doses of up to 675 μg and multiple doses of up to 225 μg for 7 days were administered to healthy 
participants. Overall, TP was well tolerated, with largely mild treatment-emergent adverse events 
(TEAEs) and an adverse effect profile consistent with that of inhaled prostacyclin analogs. 
Treprostinil exposures increased approximately dose-proportionately, were similar between TPIS 
and TPIP, and showed no accumulation with QD dosing. Doses of TP achieved were several-fold 
higher than label-indicated target dose of inhaled treprostinil (54 μg). When comparing TPIS to 
inhaled treprostinil, TP had a 10-fold lower maximum plasma concentration (89.0 pg/mL vs. 
958 pg/mL) and a markedly longer half-life (5.69 hours vs. 0.485 hours) than inhaled treprostinil 
at the molar equivalent dose. Half-life of TP was even longer with TPIP, ranging from 8.67 to 
11.6 hours. These differential PK of TP may offer therapeutic advantages over treprostinil with 
the need for less frequent administration (QD vs QID), fewer adverse effects, and potentially 
improved efficacy with higher tolerated dose.  
Additional information regarding the results of non-clinical and clinical studies of TP are 
provided in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
TEAEs for TPIP from clinical and non-clinical studies may be found in the Investigator’s 
Brochure.  
2.3.1. 
Risk Assessment 
There is no TPIP experience in participants with PAH; however, the active component, TRE, 
like other prostanoids and their agonists, has a well-characterized safety profile. This will help 
enable participants to be adequately monitored during the study. 
Insmed has conducted a SAD study of TPIS in healthy volunteer participants, with safety and 
tolerability findings similar to those of other prostanoids (Study INS1009-101). In this study, 
32 TEAEs were reported for 11 of 18 participant who received TPIS. No fatal TEAEs were 
reported and no TEAEs led to the withdrawal of participants. One participant who received a 
single dose of TPIS containing 340 µg of TP experienced several interrelated AEs that 
culminated in 2 TEAEs of severe and life-threatening intensity, as judged by the Investigator. 
The Investigator believed a severe TEAE of micturition syncope was precipitated by a TEAE of 
chest pain, which was assessed as probably related to the study IMP and increased vagal tone 
during micturition. Follow-up evaluation by an external cardiologist reveled that the participant 
had Tachy-Brady syndrome. A serious adverse event (SAE) of cardiac pause/nodal arrhythmia 
was reported for this participant and assessed as probably related to TPIS. Beyond this event, 
7 TEAEs were assessed as being of moderate intensity and 23 TEAEs to be of mild intensity. 
The most frequently reported TEAEs among participants receiving TPIS were cough (5 events 
for 5 participants), dyspnea (4 events for 4 participants), and throat irritation (4 events for 


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4 participants). Other TEAEs reported for more than 1 participant receiving TPIS included 
nausea (3 events for 3 participants) and headache (2 events for 2 participants). 
There was a dose-related trend in the incidence of TEAE reporting with increasing dose levels of 
TPIS: 5 TEAEs were reported for 2 participants after receiving a single TPIS dose containing 
85 µg of TP, 7 TEAEs were reported for 4 participants after receiving a single TPIS dose 
containing 170 µg of TP, and 20 TEAEs were reported for 5 participants after receiving a single 
TPIS dose containing 340 µg of TP. 
Safety results from a recently conducted SAD/MAD study of TPIP in healthy volunteer 
participants (Study INS1009-102) support the TPIP dosing and management of participant safety 
for this study. In this study, TPIP was generally safe and well tolerated. TEAEs reported with 
TPIP were consistent to those seen with other inhaled prostanoid therapies. The majority of 
TEAEs were judged by the Investigator to be of mild intensity; there were few moderate TEAEs 
and no severe TEAEs across the study. No participants reported AEs of severe intensity, and no 
SAEs were reported. There was 1 participant in the MAD panel who discontinued after 2 doses. 
TEAEs were more frequent with increasing TPIP doses. In the MAD panel, participants titrated 
from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 
225 µg QD at treatment initiation, and all TEAEs were of mild severity. 
Nonserious adverse events (AEs) observed in clinical studies to date are known for the 
pharmacological class of prostacyclin vasodilators and are considered expected for TPIP. No 
serious adverse reactions are considered expected for TPIP. Please refer to the Reference Safety 
Information in Section 6.1 of the Investigator’s Brochure. 
Risks inherent in study procedures and in the inpatient treatment period will be managed per 
Investigator and institutional processes. It is possible that the RHC-dependent Baseline 
parameters may indicate that the participant does not meet study inclusion criteria, may meet 
exclusion criteria, or is otherwise not suitable for study participation; in this case the Investigator 
may end the RHC procedure and not administer TPIP. 
In general, an RHC is left in place for 30 to 60 minutes to take necessary measurements. This 
study requires the RHC to be in place for approximately 24 hours. Excess risks with prolonged 
placement of the RHC may include but not be limited to dislodging of the RHC, infection, 
bleeding, clot formation, and participant discomfort. 
2.3.2. 
Benefit Assessment 
TPIP is being developed for the treatment of PAH. TPIP may or may not result in beneficial 
effects for participants with PAH by providing extended release of TRE in the lung with less 
frequent and more convenient dosing.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Although participants may or may not benefit individually from this study, risks to their well-
being will be carefully monitored and managed throughout their participation. Insmed considers 
the risks to be appropriate to the value of the knowledge gained in this study about the 
characteristics of this promising therapy. The well-characterized safety profile of TRE and the 


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continued safety monitoring by both the Investigator and SRC (in the inpatient treatment period, 
observation period, and optional EUT period, if applicable) will minimize risk to participants. 
Most TEAEs observed with exposure to this drug are events known to be associated with 
prostanoids and their agonists. Study inclusion and exclusion criteria will help to ensure that only 
appropriate participants are enrolled. Risks involved with study procedures and settings will be 
managed by the relevant Investigator and institutional processes. 
 




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• To evaluate changes in clinical 
laboratory parameters in participants 
with PAH after TPIP administration 
• Clinically relevant change from 
Baseline in hematology, coagulation, 
and clinical chemistry parameters 
(Section 10.2, Table 8) 
• To evaluate the PK of TP in 
participants with PAH 
 
• To evaluate the PK of TRE in 
participants with PAH 
• Plasma PK parameters of TP, such as 
Cmax, tmax, AUCt1–t2, AUC0–∞, t1/2, 
CL/F and Vd/F 
• Plasma PK parameters of TRE, such 
as Cmax, tmax, AUCt1–t2, AUC0–∞, t1/2, 
CL/F and Vd/F 
• To evaluate the effects of TPIP on 
resting respiratory gas exchange in 
participants with PAHa 
• Change from Baseline in respiratory 
rate, minute ventilation, VCO2, ETO2, 
ETCO2, SpO2 over 24 hours after 
TPIP administration 
• To evaluate the effects of TPIP on 
parameters of right ventricular 
function in participants with PAH as 
measured by transthoracic 
echocardiogramb 
• Change from Baseline in LVEF, TVR 
maximum velocity, TAPSE, and end 
diastolic right ventricular volume at 2 
to 8 hours after TPIP administration 
• To evaluate the effects of TPIP on 
pulmonary vasculature and blood flow 
parameters in participants with PAH 
as measured by pulmonary CT scanc 
• Change from Baseline in total blood 
volume, blood volume in 
vessels < 5mm2 at 4 to 8 hours after 
TPIP administration 
a Respiratory gas exchange testing optional at Investigator discretion 
b Echocardiogram optional at Investigator discretion 
c Pulmonary CT scan optional at Investigator discretion 
AUC0–∞ = area under the concentration time curve from time zero to infinity; AUCt1-t2 = area under the concentration 
time  curve from time zero to last sampling time point with measurable concentration; Cmax = maximum observed 
concentration after drug administration; CL/F = apparent total clearance; CO = cardiac output; CT = computerized 
tomography; ETCO2 = end tidal carbon dioxide concentration; ETO2 = end tidal oxygen concentration; LVEF = left 
ventricular ejection fraction; MVO2 = mixed venous oxygen saturation; PAH = pulmonary arterial hypertension; 
PAP = pulmonary arterial pressure; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PVR = pulmonary 
vascular resistance; SpO2 = arterial blood oxygen saturation; TAPSE = tricuspid annular plane systolic excursion; 
TEAE = treatment emergent adverse event; TP = treprostinil palmitil; TPIP = treprostinil palmitil inhalation powder; 
TRE = treprostinil; TVR = tricuspid valve regurgitation; tmax = time of maximum observed concentration following 
drug administration;  t1/2 = elimination half-life; Vd/F = apparent volume of distribution at terminal phase; 
VCO2 = carbon dioxide production  
 




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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2a, open label, non-randomized study to assess the safety, tolerability, PD effects 
and PK of TPIP administered to participants with WHO Group 1 PH (PAH). This is the first 
patient study of TPIP. Each participant will receive a single dose of TPIP. The first participant 
will receive a dose containing 112.5 µg. Subsequent participants will receive 80 µg, or a 
combination of capsules containing 80 µg, 160 µg, and 320 µg of TP, based on SRC 
recommendations. The TP dose level for each subsequent participant will be determined 
following review and adjudication of all available safety, PK, and PD data from the previous 
participant(s) by the SRC (Section 10.1.7). There is an optional extended-use period for 16 
weeks in participants who have completed the core, single-dose period.  
This is a “proof of mechanism” study designed to investigate the following: 
1. The safety and tolerability of TPIP in participants with PAH, 
2. The relationship between the PK and PD effects of TPIP in participants with PAH, and 
3. The duration of the PD effects of a single dose of TPIP in participants with PAH. 
The cardiopulmonary and overall functional status of participants with PAH can be labile and 
medical instability can develop quickly. The study is designed to provide maximal safety and 
minimal risk to participants. As such, there considerable flexibility built into the protocol to 
allow Investigator discretion with the frequency, timing, and/or conduct of PD and PK 
assessments to ensure participant safety. Because the study requires an overnight inpatient 
treatment period, institutional requirements for elective inpatient admissions, which may vary 
from site to site, will be followed. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 48 (± 4) hours post 
TPIP dose will extend into Study Day 3. A remote safety follow-up visit is scheduled for Study 
Day 30 (± 2 days). The 48 hour PK visit will also include safety assessments including ECG, 
clinical laboratory evaluations, vital signs, physical examination, and AE collection (Table 1). 
The safety follow-up period will conclude with a remote (telephone or telemedicine) visit on 
Study Day 30 (± 2 days). The screening, treatment, and follow-up periods for the core, 
single-dose portion of the study are expected to be 62 days or less. An EUT period of 16 weeks 
will be optional for participants that complete the single-dose period, followed by a 30 day 
follow-up (± 3 days). This extends study participation to 142 days after enrollment in the EUT 
period.  
4.1.1. 
Screening Period 
The initial screening period will be up to 30 days. Required screening assessments are shown in 
Table 1. Participants who fail one or more screening assessments may be re-screened twice at the 
Investigator’s discretion in order to meet study entry criteria. See Section 5.4 for additional 
information regarding participants who fail screening and/or are re-screened. 


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Participants who enter the optional EUT period more than 30 days after beginning the 
single-dose period (e.g., beyond the initial 30 day follow-up period) will be screened to ensure 
they continue to satisfy inclusion and exclusion criteria. Extended use treatment period screening 
assessments are shown in Table 5. 
4.1.2. 
Inpatient Treatment Period 
4.1.2.1. 
Baseline Procedures and Assessments 
The inpatient treatment period will be on Study Days 1 and 2. The participant may be required to 
undergo pre-admission assessments required by the Institution for elective admission, for 
example testing for common infectious pathogens. Signature of institutional elective admission 
documents and consents to procedures may be required. Data from required institutional 
assessments and consents will not be routinely collected as part of study data unless they pertain 
to a relevant AE or study endpoint. 
Participants will be admitted to an inpatient care setting such as an ICU, cardiac catheterization 
laboratory or other similar setting. They will have Baseline laboratory and safety assessments as 
shown in Table 2.  A nitric oxide challenge will be performed to screen for vasoreactivity of 
pulmonary vasculature. An RHC will be placed for Baseline assessment of cardiopulmonary 
hemodynamics prior to TPIP administration and intermittent assessments of cardiopulmonary 
hemodynamics for 24 hours following TPIP administration. Institutional procedures and 
protocols for placement, care, monitoring, and removal of the RHC will be carried out but will 
not be collected as study data unless relevant. 
Some procedures and assessments for exploratory endpoints may not be offered at all sites. 
Participants will be asked to give informed consent only to those procedures that are being 
conducted by their Investigator at their site. These procedures include the following: 
• Transthoracic echocardiogram at Baseline and during a 2 to 8 hour window after TPIP 
administration (Table 4). 
• Pulmonary computerized tomography (CT) scan at Baseline and during a 4 to 8 hour 
window after TPIP administration (Table 4). 
• Resting respiratory gas exchange assessment at Baseline and intermittently after TPIP 
administration for up to 24 hours (Table 4). Resting respiratory gas exchange assessments 
will be standardized, with all participating investigators using similar equipment and 
procedures. 
For example, an Investigator who is doing only RHC and resting respiratory gas exchange 
assessments for this study will obtain informed consent for those procedures only and will not 
offer or ask the participant for informed consent for transthoracic echocardiogram or pulmonary 
CT scan as part of this study. 
Following completion of all Baseline assessments, including Baseline blood draws for PK and 
PD biomarkers (Table 3), the prescribed single dose of TPIP will be administered (Table 2).  


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4.1.2.2. 
Post-TPIP Administration 
Following TPIP administration, participants will have intermittent safety, clinical laboratory, PK, 
and PD assessments, as specified in the SoA (Table 2, Table 3, and Table 4). The study is 
designed to allow maximum flexibility for interventions and assessments at the discretion of the 
Investigator and institutional policies and procedures to ensure participant safety. At any time, 
the Investigator has the option to discontinue assessments for participant safety or tolerability 
reasons. Additional laboratory and/or hemodynamic assessments may be performed as deemed 
necessary for participant safety. Following completion of scheduled events, the Investigator has 
the option of continued laboratory and/or hemodynamic monitoring as deemed appropriate for 
participant safety.  
If, in the interest of participant safety, the Investigator omits scheduled assessments/procedures 
or performs additional assessments/procedures, the reason for doing so must be reported on the 
CRF as an AE in order to avoid a protocol violation.  
Following completion of protocol-required assessments and removal of the RHC, the participant 
will be discharged from the inpatient setting when deemed safe by the Investigator. Investigator 
and institutional usual care protocols for participant discharge and follow-up for an RHC 
procedure will apply. 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up 
The participant will be required to return as an outpatient for the 48 (± 4) hour post-TPIP 
administration PK sample. Additional safety assessments such as ECG, physical examination, 
vital signs, AE collection, and clinical laboratory evaluations will be completed at the 48 hour 
visit. Female participants who are women of child-bearing potential (WOCBP) will be given a 
self-administered pregnancy test kit with instructions to self-administer the test and report the 
results on the day of the Study Day 30 safety follow-up visit (Section 4.1.3). 
4.1.3. 
Safety Follow-up 
A remote (telephone call or telemedicine) safety follow-up visit is scheduled for Study Day 30, 
at which time participants who are WOCBP will also be asked to report the results of the self-
administered pregnancy test they were given at the 48 hour post-TPIP follow-up visit 
(Section 4.1.2.3, Table 1). 
4.1.4. 
Optional Extended Use Treatment Period 
All participants will be allowed to enter the optional 16 week EUT period after the completion of 
the inpatient treatment period and final PK sample collection. Entry into the optional EUT period 
will be at participant and Investigator discretion. A gap between the inpatient treatment period 
and EUT period is expected, but not required, and can be up to 6 months.  
After collection of the final PK sample, all participants will be allowed optional continued access 
to IMP for 16 weeks (includes a 3-week titration period) from first administration in the EUT 
period. At the Investigator’s discretion, participants may undergo a study drug taper for up to 
2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug. 


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Participants will be screened to ensure they meet inclusion and exclusion criteria if they enter the 
EUT period more than 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period) (Table 5).  
Participant in-clinic study visits will be scheduled for EUT Baseline (EUT Day 1), EUT Week 2, 
EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16. 
The CT scan will be performed according to instructions provided by the CT scan vendor. 
There will be a second safety follow-up visit 30 days (± 3 days) after EUT Week 16 for 
participants who elect to enter the EUT period. 
4.1.5. 
Open-label Extension Study  
When available, participants may be eligible to enroll in a separate OLE study that will have a 
duration of approximately 2 years. Details of the planned OLE study will be provided in a 
separate protocol. 
4.2. 
Scientific Rationale for Study Design 
The study is designed to understand the safety and acute PK and PD effects of TPIP in 
participants with PAH, the intended patient population. Intensive monitoring via RHC in an 
appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate relationships between dose, PK, and PD effects. Some 
assessments and study activities for exploratory endpoints are considered optional depending on 
Investigator preference and/or based on study site capabilities and procedures (Table 4). 
4.3. 
Justification for Dose 
4.3.1. 
Inpatient Treatment Period (Single-dose) 
Treprostinil palmitil has been previously studied in healthy volunteer participants as a liquid 
suspension for inhalation (TPIS) and has now been formulated as a dry powder for oral 
inhalation (TPIP). Data from pre-clinical pharmacology and safety studies supported the 
initiation of human studies with TPIS. Preclinical studies in rats and dogs showed that the plasma 
kinetics of TRE and TP after dosing with TPIP are similar to those of TPIS. Additional clinical 
PK and safety data from healthy participants after SAD and MAD dosing with TPIP supported 
the chosen study design and dose. For further information on the non-clinical pharmacology and 
safety studies of TPIS and TPIP, please refer to the Investigator’s Brochure.  
The current study utilizes the clinical experience of TPIS from Study INS1009-101 in healthy 
volunteer participants and the INS1009-102 SAD/MAD study of TPIP in healthy volunteer 
participants. In Study INS1009-101, doses of TPIS were administered in multiples of 85 µg TP 
to include 170 µg (2 × 85 µg) and 340 µg (4 × 85 µg) of TP. The systemic exposure for TRE at 
340 µg TP was low (AUC < 2.5 ng*h/mL) with an elimination t1/2 of approximately 7 hours.  
Data from the INS1009-102 SAD/MAD study of TPIP reinforced the study design and informed 
maximum dosage for the optional extended use portion of the study (Section 4.3.2). In the first 
SAD portion of INS1009-102 (SAD1), 18 participants were randomized to 1 of 3 TP dose levels 


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of TPIP: 112.5 μg, 225 μg, or 450 μg of TP (6 participants at each dose). Treprostinil peak 
concentrations in the SAD portion were attained at 1.5 to 3 hours post-dose; Cmax and AUC were 
dose-dependent and approximately proportional to the increase of dose; and elimination t1/2 was 
8.7 to 11.6 hours. Total treprostinil exposure (AUC) of treprostinil was found to be dose 
proportional following a single administration of TPIP across the dose range of 112.5 μg to 
675 μg.  
Based on this Phase 1 study experience, the first participant will be dosed with 112.5 µg of TP.  
Subsequent participants will receive 80 µg of TP, or a combination of capsules containing 80 µg, 
160 µg, and 320 µg of TP, based on SRC recommendations. Additional details on these doses 
may be found in Section 4.3.2. Single doses of up to 90 µg of Tyvaso have been administered in 
clinical studies of healthy volunteer participants (Tyvaso Package Insert, 2017).  
Each participant will receive a single dose administration of TPIP. All available data (PD, PK, 
safety) from the first participant will be assessed and evaluated by the SRC. Following this 
evaluation, the SRC will determine if it is safe to continue the study, the TPIP dose level and any 
changes to safety PD and PK assessments for the second participant (Figure 3). This process will 
be repeated using the total accrued data of all completed participants prior to determining the 
TPIP dose for each subsequent participant. There will be no simultaneous dosing of inpatient 
participants; each participant will be treated as an individual case for evaluation. The TP dose 
level for each subsequent participant may be increased, held stable or lowered, depending on the 
accumulating data from previous participants up to a maximum of 640 µg. TPIP dosing may also 
be stopped at any dose level as determined by the SRC. 
4.3.2. 
Optional Extended Use Treatment Period 
Selection of once-daily inhalation of TPIP at 80 – 640 µg was based on clinical PK and safety 
data from healthy participants, predicted efficacious dose levels using pre-clinical data, safety 
margin from rat and dog NOAEL doses, and Tyvaso® clinical experience.  
In Phase 1 studies, TRE PK was linear, and the systemic exposure was dose proportional. Single 
doses of up to 675 µg and multiple doses of up to 225 µg TPIP QD for 7 days were generally 
well tolerated. Most AEs observed were mild in severity and consistent with the safety profile of 
other prostanoid therapies.  
Based on exposures following a single dose of TPIP 675 µg in Study INS1009-102, TRE 
exposures in this study are not anticipated to exceed those following administration of the 
currently approved treprostinil product, Remodulin®. Treprostinil exposures following a 
continuous IV infusion of 10 ng/kg/min Remodulin (Cmax 1,470 pg/mL; AUC 25,690 pg*h/mL) 
are reported to be 2.1-fold and 4.7-fold higher, respectively, than those observed following 
administration of TPIP 675 μg (Cmax 717 pg/mL; AUC 5,480 pg*h/mL) (Laliberte et al., 2004). 
Minimal accumulation was observed following repeat doses of TPIP 225 μg QD for 7 days, and 
since a lower maximum dose (640 μg) will be used in this study, TRE exposures are expected to 
be lower than those observed following single doses of TPIP 675 μg in Study INS1009-102. 
Based on the findings above, the TPIP dose will range from 80 µg to 640 µg QD in this 
treatment period.  


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4.4. 
Study Completion 
A participant will be considered to have completed the study if he/she has completed the 
Study Day 30 safety follow-up (shown in Table 1) and has not elected to enter the optional EUT 
period. A participant who has entered the optional EUT period will be considered to have 
completed the study if he/she has completed the EUT period safety follow-up (EUT Day 142). 
The study will be considered completed on the date of the last safety follow-up of the last 
participant in the study.  
 


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5. 
STUDY POPULATION 
The study is expected to recruit approximately 6 to 10 participants at up to 12 centers with 
appropriate inpatient facilities. Eligible participants must have clinically stable disease, and 
participants may not be taking more than 2 medications from the following classes: 
• Endothelin receptor antagonists (eg ambrisentan, bosentan, macitentan), 
• Phosphodiesterase type 5 inhibitors (eg sildenafil, tadalafil) 
• Guanylate cyclase stimulator (eg riociguat) 
It is expected that the site will recruit appropriate potential participants according to the criteria 
in Section 5.1 and Section 5.2.  
 
The study inclusion and exclusion criteria include thresholds of selected RHC and ECG 
parameters that must be met at Baseline or the participant will not be considered eligible for the 
study. In this case, the participant is to be reported as a Screen Failure (Section 5.4). 
5.1. 
Inclusion Criteria 
 
Participants are eligible to be included in the study only if they meet all of the following criteriaa: 
Age:  
1. Participant must be ≥ 18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants must have a diagnosis of WHO Group 1 PH (PAH) with etiology of 
idiopathic, heritable, drug/toxin-induced or connective tissue disease (CTD)-
related PAH (Galie et al., 2016). 
3. Prior PAH diagnosis, or diagnosis at Baseline if participant has not had a prior 
right heart catherization. 
4. No change in pulmonary hypertension medications (e.g., ambrisentan, bosentan, 
macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to 
Screening. 
5. Documented predicted percent forced vital capacity (FVC) > 70% within 3 years 
of Screening. If not available, pulmonary function testing will be performed at 
Screening (Table 1). 
6. Low or Intermediate risk, as per Investigator assessment of the European Respiratory 
Society/European Society for Cardiology (ERS/ESC) criteria (Galie et al., 2016). 
7. Right heart catheterization at Baseline with the following hemodynamic findings: 
a. Mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest,  
b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
c. Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 


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Sex and Contraceptive/Barrier Requirements 
8. Male participants:  Male participants and their female partners of childbearing 
potential must agree to use highly effective contraception from Study Day 1 to at 
least 90 days after dosing. 
9. Female participants:  Women of child-bearing potential (WOCPB, defined as 
premenopausal, not surgically sterile for at least 3 months prior to Screening) must 
use a highly effective contraception method and agree to be tested for pregnancy 
from at Screening, Baseline, and 30 days after dosing. 
See Section 10.4 for contraceptive guidance. 
Informed Consent 
10. Capable of giving signed informed consent as described in Section 10.1.5 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
a Please note that participants who enroll in the optional EUT period beyond the initial 30 day follow-up period will 
be screened to confirm that they still meet inclusion/exclusion criteria. Please refer to Table 5.  
 
5.2. 
Exclusion Criteria  
 
Participants are excluded from the study if they meet any of the following criteriaa: 
Medical Conditions 
1. Any PH other than idiopathic, hereditary, drug/toxin-induced, or connective tissue 
disease (CTD) associated PAH (e.g., congenital heart disease-associated PAH, 
portal hypertension-associated PAH, PH belonging to Groups 2 through 5) 
2. Allergy, or documented hypersensitivity or contraindication, to the ingredients of 
treprostinil palmitil inhalation powder (TPIP) or treprostinil (TRE). 
3. Previous intolerance to prostacyclin analogs or receptor agonists (e.g., selexipag) 
per Investigator discretion 
4. History of anaphylaxis or previously documented hypersensitivity reaction to any 
drug per Investigator discretion 
5. QTcF interval > 480 ms on resting ECG at Baseline 
6. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% 
or clinically significant valvular, constrictive, or atherosclerotic heart disease 
(myocardial infarction, etc) 
7. Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) 
at Screening. 
8. Active liver disease or hepatic dysfunction manifested as: 


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a. Elevated liver function test results (ALT or AST > 2 × ULN) at Screening 
b. Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable 
if bilirubin is fractionated and direct bilirubin < 35%) at Screening. 
c. Known hepatic or biliary abnormalities, not including Gilbert's syndrome or 
asymptomatic gallstones at Screening.  
9. History of HIV infection/positive HIV serology test result at Screening. 
10. History of active/chronic Hepatitis B or C/ positive hepatitis B or C serology test 
result at Screening 
11. History of abnormal bleeding or bruising. 
12. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or 
otherwise recurrent infections of abnormal frequency, or prolonged infections 
suggesting an immune-compromised status, as judged by the Investigator. 
13. Active and current symptomatic infection by SARS CoV 2. Additional COVID 19 
restrictions per institutional guidelines (See also Section 10.1.3.1.3) 
14. Participants with current or recent (past 4 weeks) lower respiratory tract infection 
(may be re-screened at appropriate time (Section 5.4) 
15. History of malignancy in the past 5 years, with exception of completely treated in 
situ carcinoma of the cervix and completely treated non-metastatic squamous or 
basal cell carcinoma of the skin. 
Concomitant Therapy 
16. Participants receiving triple combination therapy for PAH consisting of endothelin 
receptor agonists, phosphodiesterase type 5 inhibitors, and guanylate cyclase 
stimulators (riociguat). 
17. Participants receiving prostanoids/prostacyclin agonists 
18. Other prior/concomitant therapies are allowed/disallowed at the Investigator’s 
discretion 
Prior/Concurrent Clinical Study Experience 
19. Have participated in any other interventional clinical studies within 30 days of 
Baseline 
Diagnostic assessments 
20. Any clinically significant abnormal laboratory, value, test result, or physical 
examination finding at Screening; diseases or diagnoses/disorders that, in the 


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opinion of the Investigator, may put the participant or others at risk by participating 
in the study, interfere with the participant's treatment and assessment, or influence 
the results of the study; or have compliance issues with the study. 
Other Exclusions 
21. Current or history of substance and/or alcohol abuse per Investigator assessment 
22. Current user of cigarettes or e-cigarettes 
23. Pregnant or breastfeeding. 
a Please note that participants who enroll in the optional EUT period beyond the initial 30 day follow-up period will 
be screened to confirm that they still meet inclusion/exclusion criteria. Please refer to Table 5.  
 
 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study because they did not meet all inclusion criteria or meet one 
or more exclusion criteria. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened twice at the Investigator’s discretion. If a participant can be rescreened, the PI is to 
consult with the Medical Monitor to determine whether some or all of the screening assessments 
must be repeated. Rescreened participants will sign a new ICF and will be assigned a new 
participant number. 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period 
Following successful screening and meeting of study eligibility criteria, the inpatient treatment 
period and RHC procedure must be scheduled without delay.  
 
The scheduled treatment period may be temporarily delayed no longer than 28 days by the 
Investigator in consultation with the Medical Monitor for valid reasons. Examples of valid 
reasons for delaying the treatment period may include such things as a life event for the 
participant (eg death in the family), local public health emergency (e.g., COVID 19 outbreak), 
site facility issues (e.g., catheterization lab or ICU bed availability), or pending TPIP dosing 
directives from the SRC. 
 
A temporary delay in the scheduled inpatient treatment period for a valid reason may result in 
previously met Inclusion Criteria that rely on a time window to be not met. This is not 
considered to be a Screen Failure. In this case, the Investigator should consult with the Medical 


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Monitor to identify which screening tests need to be conducted or repeated to ensure that the 
participant meets study inclusion criteria and can safely participate in the study.  
 
Deterioration of the participant’s medical condition is not a valid reason to delay start of the 
inpatient treatment period. In some cases, delaying the inpatient treatment period may cause the 
participant to meet one or more exclusion criteria (e.g., participant develops a lower respiratory 
infection). In this case the participant should be considered a Screen Failure and Section 5.4 
applies. 


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6. 
STUDY IMP AND CONCOMITANT THERAPY 
Study IMP is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study IMP Administered 
6.1.1. 
Inpatient Treatment Period (Single Dose) 
A single dose of TPIP will be used in the inpatient treatment period, as listed below. A dose may 
consist of a single capsule or of multiple capsules administered in succession. 
Name of 
Treatment 
Dose 
Supplied 
Formulation 
Route and 
Frequency of 
Administration 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or more single actuation 
capsules  
First study 
participant only: 
Single actuation 
capsules containing 
112.5 µg TP per 7.5 
mg powder 
Inhalation; single 
dose after Baseline 
assessments 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or more actuation capsules 
(80 µg, 160 µg, 240 µg, 320 µg, 
400 µg, 480 µg, or 640 µg) 
Dry powder single 
actuation capsules 
containing 
80 µg, 160 µg, or 
320 μg 
Inhalation; single 
dose after Baseline 
assessments 
QD = once daily 
6.1.2. 
Optional Extended Use Treatment Period 
The IMP used in the EUT period will be capsules containing 1 of 3 dosage strengths of TPIP 
(80 µg, 160 µg, or 320 µg). IMP should be taken around the same time every day. 
Administration of IMP will be via inhalational dry powder packaged in single actuation capsules. 
One or 2 capsules will be administered for each dose. Administration of 2 capsules should be 
done sequentially. Each TPIP capsule contains 8 mg, 16 mg, or 32 mg of dry powder containing 
80 µg, 160 µg, or 320 µg of the TP prodrug, respectively.  
 
Name of 
Treatment 
Dose 
Supplied Formulation 
Route of Administration 
Treprostinil 
palmitil 
inhalation 
powder (TPIP) 
One or two single 
actuation capsules 
(80 µg, 160 µg, 240 µg, 
320 µg, 400 µg, 480 µg 
or 640 µg QD) 
Dry powder single 
actuation capsules 
containing 
80 µg, 160 µg, or 320 μg 
Inhalation (QD) 
QD = once daily 


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6.1.3. 
Medical Devices 
In the planned clinical study, the TPIP will be administered by oral inhalation using a Plastiape 
capsule-based Dry Powder Inhaler (RS 01 Mod 7). A Type III Drug Master File is filed at the US 
FDA and the RS01 inhaler is classified as a Class I medical device. The Instructions for Use of 
the device document is provided separately as an Appendix to the Pharmacy Manual. 
 
All device deficiencies (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the Investigator throughout the clinical investigation (Section 8.3.7) 
and appropriately managed by Insmed. 
6.2. 
Preparation/Handling/Storage/Accountability 
Insmed Incorporated will provide the Investigator and clinical unit with adequate quantities of 
TPIP capsules. For 80 µg, 160 µg, and 320 µg doses, HDPE bottles will be closed with the 
desiccant placed inside the bottle, and induction sealed. The powder will be administered by oral 
inhalation using a Plastiape capsule-based Dry Powder Inhaler. 
6.2.1. 
Inpatient Treatment Period (Single-dose) 
Directions for preparation and administration of the TPIP dose to the participant are provided in 
a separate document as an Appendix to the Pharmacy Manual for the single-dose Inpatient 
Period. 
All study IMP must be stored according to the labeled instructions in a secure cabinet or room 
with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. Current stability 
data supports the shelf life assigned to TPIP when stored at 2 to 8 °C. 
• The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study IMP received and any discrepancies are 
reported and resolved before use of the study IMP. 
• Only participants enrolled in the study may receive TPIP and only authorized site 
staff may supply or administer it. All TPIP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
• The Investigator, institution, and/or pharmacist or designee is responsible for study 
IMP and dosing devices accountability, reconciliation, and record maintenance (e.g., 
receipt, reconciliation, and final disposition records). 
• Study IMP and dosing device accountability records will be maintained for all clinical 
supplies. All transactions will be recorded on the drug and dosing device 
accountability records including shipment receipts and study participant doses. All 
transactions will be recorded on a real-time basis. 
• The Investigator/site will maintain detailed documentation of the number and 
identification of bottles and dispensing units of TPIP with copies of these documents 


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to be provided to Insmed at the end of the study. All used and unused study IMP and 
dosing devices will be maintained by the site until inventoried by the study monitor. 
Upon completion of the study IMP and dosing device inventory by the study monitor, 
used and any unused study IMP and dosing devices will be disposed of in accordance 
with instructions provided to sites and according to site destruction policies. 
Documentation of destruction must be provided to Insmed. 
• Further guidance and information for the final disposition of unused study IMP 
supplies can be obtained from Insmed. 
6.2.2. 
Optional Extended Use Treatment Period 
Directions for preparation and administration of IMP to the participant in-clinic are provided in 
the Pharmacy Manual for the optional EUT period. Directions for preparation and administration 
of IMP for home use will be provided to the participants. 
Only participants enrolled in the study may receive IMP, and only authorized study personnel 
may supply IMP. All IMP must be stored according to the labeled instructions with access 
restricted to necessary clinic personnel. The site will be required to keep a temperature log to 
establish a record of compliance with storage conditions. Refer to the Pharmacy Manual for the 
optional EUT period for shelf-life and storage conditions. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP and dosing devices accountability, reconciliation, and record maintenance 
(e.g., receipt, reconciliation, and final disposition records). Directions for storage, handling, 
accountability, and destruction are provided in the Pharmacy Manual for the optional EUT. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 
6.4. 
Study Intervention Compliance 
6.4.1. 
Inpatient Treatment Period (Single Dose) 
Study participants will receive the TPIP dose directly from the Investigator or designee, under 
medical supervision, in an appropriate inpatient setting. The date and time of the dose 
administered will be recorded in the source documents. The dose of TPIP and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the TPIP. 
6.4.2. 
Optional Extended Use Treatment Period 
At each in-clinic visit, participants will be dispensed adequate IMP to allow for daily dosing. 
When participants are dosed at the site, IMP administration will be overseen by study site 
personnel. The date and time of each dose self-administered in the clinic will be recorded in the 
source documents. The dose of IMP and study participant identification will be confirmed at the 
time of dosing by a member of the study site personnel. 


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When participants administer IMP at home, compliance with IMP will be assessed at each 
in-clinic visit. Participants will record their daily dose on paper dosing diaries. Compliance will 
be assessed by direct questioning, review of participant dosing diaries, and counting of returned 
capsules during the site visits. Participants will return unused capsules and used study capsules 
and devices to the study site at each in-clinic visit. Participants who undergo a study drug taper 
will return unused capsules and used capsules and devices to the study site at a follow-up visit. 
Unused capsules should be returned in the bottle they were dispensed in. Deviation(s) from the 
prescribed dosage regimen should be recorded.  
A record of the quantity of capsules dispensed to and administered by each participant must be 
maintained and reconciled with study drug logs and participant dosing diaries. Study drug start 
and stop dates, including dates for study drug interruptions and/or dose reductions will also be 
recorded. 
6.5. 
Dose Modification 
Dose modification is part of the study design and is described in detail in Section 4.3 and 
Section 1.3.2. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
An overdose is defined as the participant receiving any TPIP in excess of their assigned dose as 
predetermined by the SRC (Section 4.3). An overdose itself is not an AE. However, if the 
overdose results in clinical signs and symptoms, it requires expedited reporting as if it is an SAE. 
The Investigators must refer to the relevant documents for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the study 
IMP. Such documents may include, but are not limited to, the Investigator’s brochure. 
In the event of an overdose, the Investigator must: 
• Contact the Medical Monitor within 24 hours. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, how to 
proceed with treatment period procedures and assessments. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until TP or 
TRE is likely to be sufficiently metabolized and/or excreted and/or can no longer be 
detected systemically. The frequency and duration of plasma sampling from the last dose 
of TPIP must be determined by the Investigator in conjunction with the study team and 
Medical Monitor. 
• The overdose must be fully documented (e.g., quantity of the excess dose, duration of the 
overdose, how it happened) in the CRF. 


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6.8. 
Concomitant Therapy 
Any medications, treatments, or therapies that the participant is receiving at Baseline 
(Study Day 1) or receives during the study (Study Day 1 through end of study [EOS]) are 
considered concomitant therapy and will be collected and documented in the study CRF.  
Documentation includes the name of the therapy, with the reason for use, the dates of 
administration including start and end dates, and dosage information including dose and 
frequency.  
Prior medications are those medications taken before the first dose of study IMP. A medication 
that starts prior to first dose but continues after the first dose of study IMP is classified both in 
prior and concomitant medications. Any procedures performed from Day 1 through EOS are 
considered concomitant procedures and will be collected and documented in the study CRF. 
The Medical Monitor must be contacted if there are any questions regarding concomitant or prior 
therapy. 
For participants who enroll in the EUT period, new concomitant therapy for the period from the 
single-dose Study Day 30 follow-up until the enrollment in the EUT will be collected during 
participant’s screening for the EUT. 
6.8.1. 
CYP2C8 Inhibitors 
Use of CYP2C8 inhibitors may increase the systemic exposure to TRE and should be avoided 
prior to initiation of study drug administration. Should the use of any of these medications within 
the specified pre-Baseline window or during the study be considered essential, the Investigator 
should consult the study Medical Monitor prior to dosing. 
Table 7: 
Windows for CYP2C8 Inhibitor Medications 
Medication 
Minimal Time from Last Dose to Baseline 
Gemfibrozil 
1 day 
Trimethoprim 
1 week 
Montelukast 
3 days 
Clopidogrel  
3 days 


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7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study IMP 
7.1.1. 
Single-dose Period 
This is a single dose period; not applicable. 
7.1.2. 
Optional Extended Use Treatment Period 
If study drug is permanently discontinued, the participant will be encouraged to participate in 
their remaining study visits. See Table 6 for data to be collected at the time of discontinuation of 
IMP and follow-up. If a participant discontinues the study and needs to be started on another 
PAH medication, the Investigator should contact the Medical Monitor.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or compliance 
reasons.  
At the time of discontinuing from the study after study drug administration, if possible, an early 
discontinuation evaluation should be conducted to maximize participant safety. This final 
evaluation and the reason for participant withdrawal must be documented in the CRF.  
The participant will be permanently discontinued both from the study drug and from the study at 
that time. 
If the participant is discontinued from the study due to an SAE, the Investigator will follow the 
participant until the Investigator deems that the SAE has resolved or stabilized.  
The Investigator may withdraw the participant from the study due to absence of a PD response to 
TPIP. Lack of expected pharmacological action per se will not be reported as an AE or SAE. 
Such instances will be captured in the PK and PD assessments. 
If the participant withdraws consent for disclosure of future information, Insmed may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled follow-up visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of 


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maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
must be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered 
lost to follow-up and to have withdrawn from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants, 
including those who did not get study IMP. Public sources may be searched 
for vital status information.  If vital status is determined as deceased, this will 
be documented and the participant will not be considered lost to follow-up. 
Insmed personnel will not be involved in any attempts to collect vital status 
information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.13.2). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Table 1, Table 2, Table 3, Table 4, Table 5, 
Table 6.  
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet eligibility criteria prior to scheduling the study RHC procedure and inpatient admission. 
The RHC procedure and inpatient admission must be scheduled for as soon as possible once the 
participant’s eligibility for the study is confirmed by screening. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., previous 
RHC, previous echocardiogram, previous 6MWD test) and obtained before signing of the ICF 
may be utilized for screening or Baseline purposes provided the procedures meet the protocol-
specified criteria and were performed within the time frames defined either in the inclusion and 
exclusion criteria in Section 5 or in the SoA (Section 1.4).  
For participants who do not elect to enter the EUT period, the maximum amount of blood 
collected from each participant over the duration of the study, including any extra assessments 
that may be required is expected to be approximately 140 mL and will not exceed 200 mL. 
Approximately 80 mL will be required for PK sampling over 48 hours and approximately 20 mL 
for biomarker sampling. Safety and screening blood samples will require 
approximately 20 to 30 mL. Blood loss from the RHC procedure is anticipated to be negligible. 
For participants who do elect to enter the optional EUT period within the 30 day follow-up 
window in the single-dose period, there is no anticipated blood collection. For participants who 
elect to enter the optional EUT period after the 30 day follow-up in the single-dose period, 
Safety and screening blood samples will require approximately 20 to 30 mL. Blood loss from the 
RHC procedures is anticipated to be negligible.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples at the Investigator’s discretion. 
At any time, the Investigator has the option to discontinue assessments for participant safety or 
tolerability reasons. Additional laboratory, PK, and/or hemodynamic assessments may be 
performed as deemed necessary for participant safety. Following completion of scheduled 
events, the Investigator has the option of continued laboratory and/or hemodynamic monitoring 
as deemed appropriate for participant safety. If, in the interest of participant safety, the 
Investigator omits scheduled assessments/procedures or performs additional 
assessments/procedures, the reason for doing so must be reported on the CRF as an AE in order 
to avoid a protocol violation. 
8.1. 
Pharmacodynamic Assessments 
The results of each individual participant’s PD assessments will contribute to the dosing decision 
for the next participant (Section 4.3).  


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8.1.1. 
Required PD Assessments with RHC 
PVR, CO, PAP (mean), RAP (mean), RVP, hemoglobin, and MVO2 will be measured via the 
RHC at the time points indicated in the SoA (Table 2). Oxygen consumption is part of the MVO2 
calculation and may be measured or estimated at 125 mL O2 per square meter (m2) of body 
surface area (BSA). These or other parameters may be optionally measured at other time points 
or omitted to ensure participant safety at the Investigator’s discretion. If measurements are 
missed, or additional measurements are taken for safety purposes, the reason must be 
documented as an AE in the CRF. 
Institutional procedures for insertion, care, monitoring, and removal of the RHC will be 
followed. Specific technique and procedures for measurement of PVR, CO, PAP, RAP, RVP, 
hemoglobin, oxygen consumption, and MVO2 are provided in a separate Procedure Guide. 
8.1.2. 
Required Non-invasive PD Assessments 
Systemic blood pressure (mmHg) may be measured by inflatable cuff. Systemic blood pressure 
must include 3 values:  systolic, diastolic, and mean arterial pressure. Arterial oxygen saturation 
(SpO2, %) and heart rate (beats per minute) may be measured by pulse oximeter.  
8.1.3. 
Nitric Oxide Challenge 
NO challenge is to be performed after Baseline and before post-NO Baseline. Specific 
instructions for procedures and measurements are provided in a separate Procedure Guide.  
8.1.4. 
Resting Respiratory Gas Exchange Assessments 
Specific measurements for resting respiratory gas exchange assessment include changes from 
Baseline in respiratory rate (breaths per minute), minute ventilation (mL per minute), carbon 
dioxide production (VCO2, mL per minute), end tidal oxygen concentration (ETO2, %), and end 
tidal carbon dioxide concentration (ETCO2, %). The gas exchange parameters will be monitored 
at the same time points as the PD assessments in Section 8.1.1 (Table 2, Table 4) with the 
exception of the 12 h assessment. Specific instructions for resting respiratory gas exchange 
assessment procedures and measurements are provided in a separate Procedure Guide. 
8.1.5. 
Transthoracic Echocardiogram Assessments 
Transthoracic echocardiogram is to be performed at Baseline and during a 2-8 hour window 
following TPIP administration (Table 4). Specific instructions for echocardiographic procedures 
and measurements are provided in a separate Procedure Guide. 
8.1.6. 
Pulmonary CT Scan 
8.1.6.1. 
Single-dose Period 
Pulmonary CT scanning to assess pulmonary vasculature and blood flow is scheduled for 
Baseline and during a 4-8 hour window following TPIP administration (Table 4). Specific 
requirements and instructions for pulmonary CT scanning and required parameters are provided 
in a separate Procedure Guide. 


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8.1.6.2. 
Optional Extended Use Treatment Period 
An optional pulmonary CT scan may be performed at first visit (±3 days) and at EUT Week 16 
(±3 days) in the optional EUT period, as indicated in Table 6. The CT scan will be performed 
according to instructions provided by the CT scan vendor. 
8.2. 
Safety Assessments 
 
Evaluation of the safety and tolerability of single doses of TPIP in participants with PAH is the 
primary objective of this study. Planned time points for all safety assessments are provided in 
Table 1 and Table 2. The results of the individual participant’s safety assessments during and 
after TPIP administration will contribute to the dosing decision for the next participant 
(Section 1.3.2). Participants who elect to enter the optional EUT period will also be monitored 
for safety, as listed in Table 6.  
8.2.1. 
Physical Examinations 
Screening: The physical examination must focus on those areas that determine the individual 
participant’s eligibility to participate in the study and do so safely at the Investigator’s discretion 
and will be documented accordingly.  
Baseline:  The physical examination must focus on the participant’s fitness for the study 
procedures and TPIP administration.  
Discharge:  The physical examination must focus on the participant’s fitness to be safely 
discharged to home from the inpatient setting.  Special attention must be paid to assessment of 
any new or ongoing AEs. 
Follow-up: The in-person physical examination must focus on participant safety and assessment 
of AEs that were ongoing at discharge or have occurred since discharge. 
8.2.2. 
Vital Signs 
8.2.2.1. 
Single-dose Period 
Temperature, heart rate, respiratory rate, and blood pressure at screening and 48 hour post-TPIP 
administration follow-up will be per the Investigator’s usual outpatient practice and documented 
accordingly. 
Baseline and post-TPIP administration:  Changes from Baseline in heart rate, respiratory rate, 
and systemic blood pressure are PD endpoints as well as safety variables and must be measured 
as specified (Section 8.1). Vital signs outside of PD endpoints will be monitored per the inpatient 
unit’s usual practices. 
8.2.2.2. 
Optional Extended Use Treatment Period 
Changes in heart rate, respiratory rate, body temperature, and systemic blood pressure will be 
monitored as described in Table 6. Vital signs will be measured at Extended Use 


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Screening/Baseline (EUT Day 1), EUT Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and 
EUT Week 16 and at the Early Discontinuation visit, if appropriate. 
8.2.3. 
Electrocardiograms 
Screening:  a single 12-lead ECG will be conducted per the Investigator’s usual practice 
Baseline: A single 12-lead ECG will be performed to ensure the participant’s eligibility for the 
study (Section 5.2). Inpatient telemetry monitoring will be utilized per the unit’s usual practice 
until the participant is discharged from the inpatient setting, but routine telemetry readings will 
not be collected as study data unless they pertain to a relevant AE. 
48 hours post-TPIP administration follow-up:  a single 12-lead ECG will be conducted per the 
Investigator’s usual practice. 
8.2.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 (Table 8) for the list of clinical laboratory tests to be performed and the SoA 
(Table 1, Table 2, Table 5, Table 6) for the timing and frequency. All clinical laboratory tests 
will be performed locally by the study site. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 7 days after TPIP dosing must be repeated at the Investigator’s discretion, 
consistent with the participant’s level of disease until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator or Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology must be identified, and Insmed 
notified.] 
• All protocol-required laboratory tests, as defined in Section 10, Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.4). 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.5. 
Pregnancy Testing 
8.2.5.1. 
Single-dose Period 
Willingness of WOCBP to undergo serum or urine pregnancy testing is a study eligibility 
criterion. Pregnancy tests will be conducted at screening, baseline, and Study Day 30. WOCBP 


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participants will be provided a home pregnancy test kit with instructions to conduct and report 
test results at the Study Day 30 follow-up visit which is scheduled to be by telephone call or 
telemedicine. If the participant elects to enter the optional EUT period and the remote safety 
follow-up visit overlaps with the start of the EUT period, the results of a urine pregnancy test 
will be recorded at the first visit in the extended treatment period.  
8.2.5.2. 
Optional Extended Use Treatment Period 
Urine pregnancy tests will be performed in-clinic at EUT Baseline (EUT Day 1) in WOCBP. 
WOCBP participants will be provided home pregnancy test kits with instructions to conduct the 
pregnancy tests every 30 days or more if required during the treatment and follow-up periods. 
Study site personnel will contact the participant every 30 days by telephone and record the 
pregnancy test results. An additional on-site urine test must be performed prior to starting any 
procedure that requires the use of ionizing radiation. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). AEs may be solicited or unsolicited. Solicited and 
unsolicited AEs are defined in Section 10.3. 
The Investigator is responsible for detecting, documenting, and recording events that meet the 
definition of an AE or SAE as provided in the protocol and remain responsible for following up 
all AEs. 
The Investigator should proactively follow participants with AEs until the EOS for each 
participant. At the EOS visit, the Investigator will record the AE status (stable or not stable) in 
the electronic CRF. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs (serious and non-serious) for the core, single-dose period will be collected from the 
signing of the ICF until the Study Day 30 follow-up visit at the time points specified in the SoA 
(Table 1, Table 2). Medical occurrences that begin after obtaining informed consent but before 
TPIP administration will be recorded as Medical History/Current Medical Conditions, not as 
AEs. 
SAEs that occur after signing the ICF but before study IMP starts must be recorded and reported 
as SAEs. Non-serious medical occurrences that begin after obtaining informed consent but 
before TPIP administration will be recorded as Medical History/Current Medical Conditions, not 
as AEs. 


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For participants who enroll in the EUT period, AEs for the period from the single-dose Study 
Day 30 follow-up until the enrollment in the EUT will be collected during participant’s screening 
for the optional EUT period. All AEs and SAEs for participants who choose to enroll in the 
optional EUT period will be recorded at the time points specified in the SoA (Table 5, Table 6).  
All SAEs will be recorded and reported to Insmed or designee immediately and under no 
circumstance must this exceed 24 hours, as indicated in Appendix 3, (Section 10.3). The 
Investigator will submit any updated SAE data to Insmed within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IMP or study participation, the Investigator must promptly notify 
Insmed. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. The Investigator should proactively follow participants 
with AEs until the EOS for each participant. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool has been 
taken offline due to study completion, then the site can report this information to the Medical 
Monitor by email or telephone. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to Insmed of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
Insmed has a legal responsibility to notify relevant health authorities and regulatory agencies 
about the safety of a study drug under clinical investigation. This study is being conducted in the 
USA only; regulatory requirements relating to safety reporting to the US FDA, IRBs, and 
investigators will be followed. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from Insmed will review and then file it 
along with other study documents and will notify the IRB, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Insmed policy and forwarded to Investigators as necessary. No serious adverse 


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reactions are considered expected for TPIP. Please refer to the Reference Safety Information in 
Section 6.1 of the Investigator’s Brochure. 
8.3.5. 
Pregnancy 
Details of all pregnancies that occur in WOCBP participants within 30 days after TPIP 
administration will be collected. Male participants with WOCBP partners must continue to use 
contraception for 90 days after TPIP administration and report any pregnancies that occur within 
that time period.  
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to Insmed within 24 hours of learning of the pregnancy in a female participant 
or female partner of male participant and after obtaining the necessary signed informed consent 
from the female partner. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from the study. 
8.3.6. 
Adverse Events of Special Interest (AESI) 
There are no AESIs for TPIP that require special collection and rapid communication by the 
Investigator. 
8.3.7. 
Medical Device Deficiencies 
A medical device, the Plastiape capsule based Dry Powder Inhaler is being provided for use in 
this study to administer TPIP. To fulfill regulatory reporting obligations worldwide, the 
Investigator is responsible for the detection and documentation of events meeting the definitions 
of device deficiency that occur during the study with such devices. 
The definition of a Medical Device deficiency and reporting requirements and procedures for 
device deficiencies and AEs/SAEs resulting from device deficiencies can be found in 
Section 10.6.  
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• If the Investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 
related to a medical device provided for the study, the Investigator will promptly 
notify Insmed. 
The method of documenting Medical Device Deficiency is provided in Section 10.6. 


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8.3.7.2. 
Follow-Up of Medical Device Deficiencies 
Follow-up applies to all participants who experienced a device deficiency. 
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the Investigator. 
8.3.7.3. 
Prompt Reporting of Device Deficiencies to Insmed 
Device deficiencies will be reported to Insmed within 24 hours after the Investigator determines 
that the event meets the protocol definition of a medical device deficiency. 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies 
The Investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for Insmed to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
The Investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB. 
8.4. 
Pharmacokinetic Assessments 
The schedule for PK assessments and sampling windows during the single-dose period is shown 
in Table 3. The 48 (± 4) hour post-TPIP administration blood draw is expected to be done on an 
outpatient basis. 
8.4.1. 
PK Sample Collection 
Plasma blood samples of approximately 10 mL each will be collected for measurement of plasma 
concentrations of TP and TRE as specified in the SoA (Section 1.4).  
A maximum of 2 samples may be collected at additional time points during the study if an SAE 
occurs or at early termination.  
Each PK plasma sample will be divided into 2 aliquots (1 each for PK analysis and the other for 
backup. All samples will be stored frozen (-70°C or -20°C) until shipment and then stored at -
70°C until analysis. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Full instructions for the collection and handling of PK samples will be provided by Insmed in a 
separate Laboratory Manual.  
8.4.2. 
PK Analysis 
Individual PK parameters of TRE and TP will be determined using non-compartmental analysis 
for the following parameters: Cmax, tmax, AUCt1–t2, AUC0–∞, CL/F, Vd/F, and t1/2. 


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8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Relationships between PK (TP dose and TRE exposure) and PD effects and safety will be 
explored and reported separately. 
8.5. 
Genetics / Pharmacogenomics 
Genetic and/or pharmacogenomic analyses are not included in this study. 
8.6. 
Biomarkers 
A blood sample for NT-pro-BNP will be taken at screening or Baseline if no historical value 
within 3 months of Baseline visit is available.  
Blood samples (5-7 mL per time point) will be collected for biomarker measurement at Baseline 
and at 4 and 8 hours after TPIP administration. The plasma generated from the blood samples 
will be stored frozen (-70 C or lower is preferred) until shipment and analysis. 
Full instructions for the collection and handling of biomarker samples will be provided by 
Insmed in a separate Laboratory Manual. 
8.7. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity assessments do not apply to this study of a small molecule. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be evaluated in this study. 
9.2. 
Sample Size Determination 
The sample size for this study is not based on statistical power calculations. The planned number 
of evaluable participants to complete the study is approximately 6-10.  
9.3. 
Analysis Sets 
The analysis sets comprise participants who are considered evaluable for the parameters under 
consideration.  
All participants who receive a single dose of TPIP will be considered evaluable for safety and 
included in the safety population. 
All participants who receive a single dose of TPIP and have a least one measurable post-dose 
plasma TP/TRE concentration will be considered evaluable for PK and included in the PK 
population. 
All participants who receive a single dose of TPIP and have a Baseline datapoint and at least one 
measurable post-dose PD datapoint will be considered evaluable for PD and included in the PD 
population. 
All participants who receive a single dose of TPIP and have at least 1 measurable post-dose 
biomarker datapoint will be considered evaluable for biomarkers and included in the biomarker 
population. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to Database Lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1. 
General Considerations 
There is no hypothesis-testing in this study and no inferential statistical analyses will be 
conducted. There will be no proxy values for missing data. Participant PK, PD, and biomarker 
data will be presented individually in listings and graphs as appropriate for each variable.  
The frequency of TEAEs is the primary endpoint for this study. All safety analyses will be 
performed on the safety population. AE listings as required by ICH E3 guidelines will be 
produced. TEAEs, SAEs, AEs leading to treatment and/or study withdrawal, and AESIs will be 
listed for each participant along with outcome, severity, and relatedness to study IMP. Ad hoc 
summaries of TEAEs may be prepared if the volume of data allow.  
PK and PD values for secondary endpoints will be listed and graphed if appropriate for each 
evaluable participant. 


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PK and PD values for exploratory endpoints will be listed and graphed as appropriate for each 
participant. 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values 
ECG data will be listed for each participant. Vital signs data that are not considered part of a PD 
assessment (Section 8.1) will be listed for each participant. Clinical laboratory values will be 
listed for each participant. 
9.5. 
Interim Analysis 
All available safety, PK, and PD data from each participant will be evaluated by the SRC prior to 
the next participant in order to determine the value of proceeding with the study and the TPIP 
dose for each subsequent participant (Section 4.3). 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
a. Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
b. Applicable ICH Good Clinical Practice (GCP) Guidelines 
c. Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, Instructions for Use of the 
Plastiape capsule based Dry Powder Inhaler, and other relevant documents must be 
submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
d. Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
e. Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
f. Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
10.1.2. 
Protocol Deviations 
The Investigator must conduct the study in compliance with the protocol as agreed to by Insmed 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRB. 
The Investigator must notify the IRB of deviations from the protocol in accordance with IRB 
reporting requirements.  
As of May 2020, due to concern regarding COVID-19, there may be restrictions to participant 
attendance at in-clinic visits or elective inpatient admissions. In the event participants are 
restricted to attend in-clinic visits, or if the participant has concern regarding travel and attending 
in-clinic visits (due to potential public health concerns), the site must contact Insmed on how to 


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conduct the scheduled assessments, and decisions must be documented in the source 
documentation. Where necessary, in-clinic visits may be conducted via telemedicine link and 
home health care visits. 
10.1.3. 
Public Health Emergency Situations 
During the COVID-19 public health emergency, Insmed, IRBs, and Investigators shall follow the 
most current version of local guidance to assure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. The continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms, 
which will remain in effect only for the duration of the local public health emergency. Examples 
of such mechanisms may include, but are not limited to, any of the following: telephone contact, 
virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use 
of local clinic or laboratory locations, and home visits by skilled staff. The site must contact 
Insmed on how and when to implement temporary and/or alternative mechanism of scheduled 
assessments, and all decisions taken must be documented in the source documentation. 
Additionally, all temporary mechanisms utilized, and the resulting deviations from planned study 
procedures are to be documented as being related to COVID-19. 
In a situation where local health authorities declare a public health emergency while the study is 
ongoing, the suggested guidance in the following subsections must be followed. 
10.1.3.1. Continuation or Suspension of the Study 
Ensuring the safety of trial participants is paramount. Insmed (Insmed Incorporated), in 
consultation with clinical Investigators and IRB, will determine if the protection of a 
participant’s safety, welfare, and rights are best served by continuing or stopping the trial at the 
specific site. Such decision will depend on specific circumstances, including the ability to 
conduct appropriate safety monitoring, the potential impact on the investigational product supply 
chain, and other considerations. 
If the decision is to continue the study, the following considerations will be taken into account: 
10.1.3.1.1. Study Recruitment 
Insmed will communicate to the sites the decision on whether to continue or suspend recruitment 
after considering the specific circumstances of each site, recommendation by the IRB, and its 
local health authority mandates. If, due to COVID-19, study discontinuation exceeds the 
assumed rate, Insmed may allow enrollment past the assumed sample size. 
10.1.3.1.2. Participants Already Enrolled in the Study 
If the decision is to continue the participation of participants already enrolled, the following steps 
must be taken:  
• If a participant is not able to complete a protocol specified study visit, it may be 
necessary to adjust the visit schedule, convert in-clinic visits to telemedicine visits, 
and/or postpone study procedures until the next available in-clinic study visit. If there 
is information available from previous visits (e.g., laboratory assessments) that 


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requires follow-up procedures or other safety assessments, the Investigator will 
decide if an on-site visit or home healthcare visit is required or whether the 
participant’s safety can be preserved by other means. 
10.1.3.1.3. Participants Infected by COVID-19 
If a participant has had a past documented mild to moderate COVID-19 infection prior to 
enrollment in the trial but the participant has recovered and the current diagnostic tests are 
negative (negative antigen by any diagnostic laboratory kit), the participant can be screened, at 
the Investigator’s discretion. Participants who experienced hospitalization, severe disease, and/or 
COVID-19 acute respiratory distress syndrome (ARDS) must be excluded. 
If a participant has a documented infection by COVID-19 while in the trial, the event will be 
reported as an AE or SAE, depending on the criteria. The Investigator will follow the guidance 
provided by health authorities in the treatment of those participants. 
10.1.4. 
Financial Disclosure 
The disclosed financial interest of the Investigator/sub-investigator must be collected before 
screening of the first participant, following study completion at the Investigator site and 1 year 
following overall study completion. The Investigator/sub-investigator must promptly update this 
information if any relevant changes occur during this period. 
10.1.5. 
Informed Consent Process 
Before a participant’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the participant or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any study IMPs are administered. 
A legally acceptable representative is an individual or other body authorized under applicable 
law to consent, on behalf of a prospective participant, to the participant’s participation in the 
clinical study. An informed consent document that includes both information about the study and 
the consent form will be prepared and given to the participant. This document will contain all the 
elements required by the ICH E6 (R2) Guideline for GCP and any additional elements required 
by local regulations. The written ICF must be prepared in the local language(s) of the potential 
participant population. 
 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirements, and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) must be 
approved by the IRB prior to being provided to potential participants. 
 
The participant’s written informed consent (written or electronic) must be obtained prior to 
his/her participation in the study, and must be documented in the participant’s medical records, 
as required by applicable regulations. The ICF must be signed and personally dated by the 
participant or a legally acceptable representative, and by the person who conducted the informed 
consent discussion (not necessarily the Investigator). The signed ICF must be retained in 
accordance with institutional policy, and a copy of the signed consent form must be provided to 


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the participant or legal representative. The date and time that informed consent was given must 
be recorded in the CRF.  
Participants who are rescreened are required to sign a new ICF. 
10.1.6. 
Protection of Participant Identification and Confidentiality 
The Investigators and Insmed will preserve the confidentiality of all participants taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the participant’s anonymity is maintained. On the CRF or other 
documents submitted to Insmed, participants must be identified by a unique participant identifier 
as designated by Insmed. Documents that are not for submission to Insmed (e.g., signed ICFs) 
must be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB direct 
access to review the participant’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the participant that his/her study-
related records will be reviewed by the above-named representatives without violating the 
confidentiality of the participant. 
Participant names will not be supplied to Insmed. A participant number will be recorded in the 
CRF, and if the participant name appears on any other document (e.g., laboratory report), it must 
be obliterated on the copy of the document to be supplied to Insmed. All records will be kept 
confidential to the extent provided by federal, state, and local laws. The participants will be 
informed that representatives of Insmed, IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
The Investigator will maintain a personal participant identification list (participant numbers with 
the corresponding participant names) to enable records to be identified. 
10.1.7. 
Committee Structure 
An SRC will be responsible for monitoring safety data. The SRC will comprise all Investigators 
and key members of the Insmed Study Team (including but not limited to Medical Monitor, 
Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, Clinical Pharmacologist) 
and external expert consultants. The SRC will continuously monitor all available safety, PD and 
PK data for each participant and will obtain consensus regarding the safety of continuing the 
study, the next TPIP dose, and clinical care of the next participant. Expert consultants may be 
invited to review and interpret participant data. With any safety findings, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to continue. 
Decisions regarding final database values for PD parameters may be adjudicated by the SRC. 
10.1.8. 
Dissemination of Clinical Study Data 
Insmed will provide study information for inclusion in national registries according to 
national/local regulatory requirements. 


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Results of this study will be disclosed according to the relevant national regulatory requirements. 
10.1.9. 
Data Quality Assurance 
The Investigator/investigational site will permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
10.1.9.1. Data Collection 
All data obtained for this study will be entered into a 21 CFR Part 11 compliant Data 
Management System provided by Insmed or its designee. These data will be recorded with an 
EDC system using CRFs. The Investigator will ensure the accuracy and completeness of the data 
reported to Insmed. All data entry, modification or deletion will be recorded automatically in an 
electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
Insmed to verify the proper transcription of data. Data reported in the CRFs must be consistent 
with and substantiated by the participant’s medical record and original source documents. The 
CRF data will be monitored by Insmed or designee. The final, completed CRF Casebook for 
each participant must be electronically signed and dated by the PI within the EDC system to 
signify that the Investigator has reviewed the CRF and certifies it to be complete and accurate. 
Insmed will retain the final CRF data and audit trail. A copy of all completed CRFs will be 
provided to the Investigator. 
10.1.9.2. Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, an Insmed 
representative will review the protocol, CRF, Investigator Brochure, and any study-related 
materials with the Investigators and their staff. During the study, Insmed study monitor or its 
designee will visit the site regularly to check the completeness of participant records, the 
accuracy of entries on the CRFs, adherence to the protocol, adherence to ICH GCP and 
applicable regulatory requirements, the progress of enrollment, and also to ensure that study IMP 
is being stored, dispensed, and accounted for according to specifications. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the CRF entries. Participant confidentiality will be maintained by the 
study center. Insmed monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording 
of primary activity and safety variables. Additional checks of the consistency of the source data 
with the CRFs are performed according to the study specific monitoring plan. 
10.1.9.3. Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB, and an auditor authorized by Insmed may 
request access to all source documents, CRFs, and other study documentation for onsite audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 


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provide support at all times for these activities. Medical records and other study documents may 
be copied during audit or inspection provided that participant names are obliterated on the copies 
to ensure confidentiality. 
If an inspection is requested by a regulatory authority, the Investigator will inform Insmed, 
immediately that this request has been made. 
10.1.9.4. Study Record Retention 
Study documents must be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents must be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of Insmed. It is the responsibility of Insmed to inform the Investigator when 
these documents no longer need to be retained. 
10.1.9.5. Source Documents 
Source documentation is the point of initial recording of a piece of data. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. Source documents 
provide evidence for the existence of the participant and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study Files and Materials 
Before the start of any study related procedures, all initial documents required by ICH GCP, 
Good Pharmacoepidemiology Practice, and applicable local regulations must be available in the 
relevant files maintained by Insmed (or delegate) and the Investigator. An Investigator Study File 
prepared by Insmed (or delegate), containing all applicable documents for use at the study site, 
will be made available to the Investigator before the start of the study. A list of personnel and 
organizations responsible for conduct of the study as well as the list of Investigator-delegates 
(e.g., sub-investigator) at each site will be included in the Investigator Study File. The respective 
files will be kept and updated by Insmed (or delegate) and the Investigator, as applicable. 


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All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by Insmed’s study monitor (or delegate) to determine that all 
required documentation is present and correct. 
The study may be audited by qualified delegates from Insmed or a competent regulatory 
authority. 
10.1.11. 
Use of Stored Samples and Data 
Clinical samples may be stored for 5 years or longer after completion of the study. The 
information already collected, including biological samples, will continue to be used to evaluate 
the study results and in future medical and pharmaceutical research activities. However, the 
stored samples will not be used for genetic evaluation unless stated in a separate consent 
document. 
Stored samples will be labeled with study and participant information and secured with limited 
access and retained per protocol requirements and in accordance with the laboratory's operating 
procedures. Electronic data will be kept in password protected computers at the laboratory and 
then transferred to Insmed or CRO, as applicable, for data analysis. Samples and corresponding 
data will be tracked using the laboratory’s specimen tracking system. 
Prior Insmed and IRB approval are required before using or sharing study samples or data in 
ways not specifically specified in the study protocol during conduct of this study. 
Any loss or unanticipated destruction of samples (e.g., freezer malfunction) or data (e.g., loss of 
a data sheet with individually identifiable information) that violates or compromises the 
scientific integrity of study data must be reported to Insmed and the IRB. 
At any time, participants may inform the Investigator in writing that they do not wish to have 
their samples stored beyond the completion (termination) of the study. In this case, the 
Investigator will request that all known remaining samples be destroyed and report the 
disposition of samples to the requesting participants and the IRB. 
10.1.12. 
Disposition of Stored Samples and Data 
Participant samples will be secured with limited access and retained per protocol requirements 
and in accordance with the laboratory's operating procedures. Samples stored by the central 
laboratories will be labeled with the participant’s study identification information. Data will be 
kept in password protected computers at the laboratory and then transferred to the vendor for 
data analysis. Samples and corresponding data acquired will be tracked using the laboratory’s 
specimen tracking system. 
In the future, if other Investigators may wish to study these samples and/or data, they need to 
obtain Insmed approval and participant consent before any sharing of samples and/or data.  
Any loss or unanticipated destruction of samples (e.g., due to freezer malfunction) or data (e.g., 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to Insmed 
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Additionally, participants may withdraw authorization in writing to decline their sample storage 
for a period of up to 2 years beyond the duration of the study. In this case, the PI will request the 
destruction of all known remaining samples and report what was done to both the participant and 
to the IRB. This decision will not affect the individual’s participation in the study. 
10.1.13. 
Study and Site Start and Closure 
Before the start of the study at each study site, Insmed’s study monitor (or delegate) shall 
confirm adequacy of the facilities by study site visit or other acceptable methods. 
The Investigator may not enroll any participant into the study before Insmed has received written 
approval or a favorable opinion from the IRB for conducting the study and a formal meeting has 
been conducted by Insmed’s study monitor (or delegate) to initiate the study. This meeting will 
include a detailed review of the study plan, and completion of the CRF. 
10.1.13.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first participant screened for participation in the study is considered the first act 
of recruitment. 
10.1.13.2. Study/Site Termination 
Insmed or designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of Insmed. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Insmed or Investigator may include but are not 
limited to: 
For study termination: 
Discontinuation of further study IMP development 
For site termination: 
Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, Insmed's procedures, or GCP guidelines 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, Insmed shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and must assure appropriate participant 
therapy and/or follow-up. 
10.1.14. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by Insmed, before implementation. Amendments significantly affecting the 


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safety of participants, the scope of the investigation, or the scientific quality of the study, require 
additional approval by the applicable regulatory authority(ies) and IRBs. Copies of the 
applicable written approvals must be filed in Insmed files and investigator site files. 
The requirements for approval must in no way prevent any immediate action from being taken 
by the Investigator or by Insmed in the interests of preserving the safety of all participants 
included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, Insmed or its agent must be 
notified and the applicable regulatory authority(ies)/IRBs must be informed as soon as possible. 
Any other regional reporting requirements must be adhered to. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/IRB approval, but the regulatory authority(ies)/IRBs must 
be kept informed of such administrative changes in accordance with country specific 
requirements. 
10.1.15. 
Financing and Insurance 
10.1.15.1. Finances 
Prior to starting the study, the Investigator and/or institution will sign a clinical study agreement 
with Insmed. This agreement will include the financial information agreed upon by the parties. 
10.1.15.2. Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.15.3. Participant Reimbursement, Liability and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
Insmed will provide insurance to the Investigator if required by the applicable regulatory and 
legal requirement(s). 
If required by local law, participants taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
10.1.16. 
Publication Policy 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel of Insmed. Authorship will 
be determined by mutual agreement. For multi-center studies, it is mandatory that the first 
publication be based on data from all centers, analyzed as stipulated in the protocol by Insmed 
and statisticians, and not by the Investigators themselves. Investigators participating in multi 
center studies agree not to present data gathered from a single center or a small group of centers 


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before the full, initial publication, unless formally agreed to by all other Investigators and 
Insmed. 
Insmed must receive copies of any intended communication in advance of publication (at least 
15 working days for an abstract or oral presentation and 45 working days for a journal 
submission). Insmed will review the communications for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), verify that confidential information is 
not being inadvertently divulged, and to provide any relevant supplementary information. 
Authorship of communications arising from pooled data may include members from each of the 
contributing centers as well as Insmed personnel. 
At the conclusion of the study, after the data are analyzed, the results of study will be reported in 
a clinical study report. 
 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 8 will be performed by the local laboratory. If local laboratory results 
are used to make a study IMP decision or response evaluation, the results must be recorded. 
Protocol-specific clinical laboratory requirements for the inclusion or exclusion of participants 
are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 8: 
Protocol-Required Safety Laboratory Tests, INS1009-201 
Category 
Laboratory Parameters 
Clinical 
Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, 
phosphate, total bilirubin (with direct and indirect fractionation, if total 
bilirubin is elevated >2 ULN), alkaline phosphatase, LDH, AST, ALT, 
CPK, albumin, total protein, creatinine, urea-nitrogen, uric acid, estimated 
glomerular filtration rate  
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, leukocytes, 
differential blood count of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and platelets 
Coagulationa 
PT, PTT, INR 
Serologya 
HIV antibody, hepatitis B surface antigen [HBsAg], Hepatitis C virus 
antibody 
Pregnancy test 
Highly sensitive serum or urine hCG 
a Not included in EUT screening for participants enrolling in the extended use treatment period. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CO2 = carbon dioxide; CPK = creatine 
phosphokinase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin 
time; ULN = upper limit of normal 
Investigators must document their review of each laboratory safety report. 
 
 












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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Insmed clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than Drug-Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN and total 
bilirubin (TBL) ≥2×ULN at any point during the study irrespective of an increase in alkaline 
phosphatase (ALP). The elevations do not have to occur at the same time or within a specified 
time frame. 
Hy’s Law (HL) 
AST or ALT ≥3× ULN and TBL ≥2×ULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral 
hepatitis, another drug. The elevations do not have to occur at the same time or within a specified 
time frame. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any participant who meets any of the following identification criteria in isolation or in 
combination: 
1. ALT ≥ 3xULN 
2. AST ≥ 3xULN 
3. TBL ≥ 2xULN 
The Investigator will review without delay each new laboratory report and if the identification 
criteria are met will: 
1. Notify Insmed representative  
2. Determine whether the participant meets PHL criteria (see DEFINITIONS of this 
Appendix) by reviewing laboratory reports from all previous visits 


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3. Promptly enter the laboratory data into the laboratory CRF 
FOLLOW-UP 
POTENTIAL HY’S LAW CRITERIA NOT MET 
1. If the participant does not meet PHL criteria the Investigator will: 
2. Inform Insmed representative that the participant has not met PHL criteria. 
3. Perform follow-up on subsequent laboratory results according to the guidance provided 
in the clinical study protocol 
POTENTIAL HY’S LAW CRITERIA MET 
If the participant does meet PHL criteria the Investigator will: 
• Notify Insmed representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
• Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or Baseline levels, or as long as medically indicated 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
• Complete the 3 Liver CRF Modules as information becomes available 
• If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section must be followed for all cases where PHL criteria were met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than drug-induced liver injury caused 
by the IMP. The Insmed Medical Science Director and Global Safety Physician will also be 
involved in this review together with other participant matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
• If there is an agreed alternative explanation for the ALT or AST and TBL 
elevations, a determination of whether the alternative explanation is an AE will be 
made and subsequently whether the AE meets the criteria for a SAE 
• If the alternative explanation is not an AE, record the alternative explanation on 
the appropriate CRF 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow Insmed standard processes. 


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• Report an SAE (report term ‘Hy’s Law’) according to Insmed standard processes. 
• The ‘Medically Important’ serious criterion must be used if no other serious criteria apply 
• As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
must be assigned. 
If there is an unavoidable delay, of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review 
 
 
 










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Any device deficiency that is associated with an SAE must be reported to Insmed within 
24 hours after the Investigator determines that the event meets the definition of a 
device deficiency. 
Insmed will review all device deficiencies and determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs as required by national regulations. 
 
 
 


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11. 
REFERENCES 
Delcroix M, Howard L. Pulmonary arterial hypertension: the burden of disease and impact on 
quality of life. Eur Respir Rev. 2015;24(138):621-9. 
 
Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk 
Noordegraaf A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension 
of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): 
Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-
119. 
 
Hoeper MM, Ghofrani HA, Grunig E, Klose H, Olschewski H, Rosenkranz S. Pulmonary 
Hypertension. Dtsch Arztebl Int. 2017;114(5):73-84. 
Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state 
bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and 
subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004 Aug;44(2):209-14.  
McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, Kim NH, 
Oudiz RJ, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll 
Cardiol. 2009;54(1 Suppl):S97-107. 
 
Orenitram Package Insert.  2019. Accessed on: 23 October 2020.  
https://www.orenitram.com/pdf/Orenitram Full Prescribing Information.pdf 
 
Remodulin Package Insert.  2018. Accessed on: 23 October 2020.  
https://www.remodulinpro.com/files/remodulin-pi.pdf 
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical 
classification of pulmonary hypertension. Eur Respir J. 2019; 53(1):1801913. 
Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis 
and clinical management. BMJ. 2018;360:j5492. 
 
Tyvaso Package Insert.  2017. Accessed on: 23 October 2020.  
https://www.tyvaso.com/hcp/pdf/Tyvaso-PI.pdf?v=102017 
 
US Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers.  2005. Accessed on: 23 Oct 2020.  
https://www.fda.gov/media/72309/download 
 
Vachiery JL, Naeije R. Treprostinil for pulmonary hypertension. Expert Rev Cardiovasc Ther. 
2004;2(2):183-91. 


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CLINICAL STUDY PROTOCOL 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation Powder in Participants with 
Pulmonary Arterial Hypertension 
Protocol Number: INS1009-201 
Version Number: 3.0 
Amendment Number: 2 
Compound: Treprostinil Palmitil Inhalation Powder (TPIP) 
Study Phase: 2a 
Sponsor Name: Insmed Incorporated 
Legal Registered Address:  
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
USA 
Regulatory Agency Identifier Number(s) 
IND: 147264 
EudraCT: 2022-000839-23 
Date: 03 MAR 2022 




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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
ABBREVIATIONS .......................................................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Protocol Amendment Summary of Changes ..............................................................14 
1.2. 
Synopsis ......................................................................................................................15 
1.3. 
Schema ........................................................................................................................18 
1.3.1. 
Participant Progression Through the Study ................................................................18 
1.3.1.1. 
Screening Period .........................................................................................................18 
1.3.1.2. 
Inpatient Treatment Period .........................................................................................18 
1.3.1.3. 
Follow-up Period ........................................................................................................18 
1.3.1.4. 
Optional Extended Use Treatment Period ..................................................................19 
1.3.1.5. 
Extended Use Follow-up Period .................................................................................20 
1.3.2. 
Dose Selection ............................................................................................................20 
1.3.2.1. 
Inpatient Treatment Period Dose Selection ................................................................20 
1.3.2.2. 
Optional Extended Use Treatment Period ..................................................................22 
1.4. 
Schedule of Activities (SoA) ......................................................................................23 
2. 
INTRODUCTION ......................................................................................................31 
2.1. 
Study Rationale ...........................................................................................................32 
2.2. 
Background .................................................................................................................32 
2.3. 
Benefit/Risk Assessment ............................................................................................33 
2.3.1. 
Risk Assessment .........................................................................................................33 
2.3.2. 
Benefit Assessment .....................................................................................................34 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................34 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................36 
3.1. 
Exploratory Objectives and Endpoints for the Optional Extended Use 
Treatment Period ........................................................................................................37 
4. 
STUDY DESIGN .......................................................................................................39 


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4.1. 
Overall Design ............................................................................................................39 
4.1.1. 
Screening Period .........................................................................................................39 
4.1.2. 
Inpatient Treatment Period .........................................................................................40 
4.1.2.1. 
Baseline Procedures and Assessments ........................................................................40 
4.1.2.2. 
Post-TPIP Administration ...........................................................................................41 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up .................41 
4.1.3. 
Safety Follow-up ........................................................................................................41 
4.1.4. 
Optional Extended Use Treatment Period ..................................................................41 
4.1.5. 
Open-label Extension Study .......................................................................................42 
4.2. 
Scientific Rationale for Study Design ........................................................................42 
4.3. 
Justification for Dose ..................................................................................................42 
4.3.1. 
Inpatient Treatment Period (Single-dose) ...................................................................42 
4.3.2. 
Optional Extended Use Treatment Period ..................................................................43 
4.4. 
Study Completion .......................................................................................................44 
5. 
STUDY POPULATION .............................................................................................45 
5.1. 
Inclusion Criteria ........................................................................................................45 
5.2. 
Exclusion Criteria .......................................................................................................47 
5.3. 
Lifestyle Considerations .............................................................................................48 
5.4. 
Screen Failures ............................................................................................................49 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period ..................................49 
6. 
STUDY IMP AND CONCOMITANT THERAPY ...................................................50 
6.1. 
Study IMP Administered ............................................................................................50 
6.1.1. 
Inpatient Treatment Period (Single Dose) ..................................................................50 
6.1.2. 
Optional Extended Use Treatment Period ..................................................................50 
6.1.3. 
Medical Devices .........................................................................................................51 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................51 
6.2.1. 
Inpatient Treatment Period (Single-dose) ...................................................................51 
6.2.2. 
Optional Extended Use Treatment Period ..................................................................52 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................52 
6.4. 
Study Intervention Compliance ..................................................................................52 
6.4.1. 
Inpatient Treatment Period (Single Dose) ..................................................................52 


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6.4.2. 
Optional Extended Use Treatment Period ..................................................................52 
6.5. 
Dose Modification ......................................................................................................53 
6.6. 
Continued Access to Study Intervention After the End of the Study .........................53 
6.7. 
Treatment of Overdose ...............................................................................................53 
6.8. 
Concomitant Therapy .................................................................................................54 
7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................55 
7.1. 
Discontinuation of Study IMP ....................................................................................55 
7.1.1. 
Single-dose Period ......................................................................................................55 
7.1.2. 
Optional Extended Use Treatment Period ..................................................................55 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................55 
7.3. 
Lost to Follow Up .......................................................................................................55 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................57 
8.1. 
Pharmacodynamic Assessments .................................................................................57 
8.1.1. 
Required PD Assessments with RHC .........................................................................58 
8.1.2. 
Required Non-invasive PD Assessments ....................................................................58 
8.1.3. 
Resting Respiratory Gas Exchange Assessments .......................................................58 
8.1.4. 
Transthoracic Echocardiogram Assessments .............................................................58 
8.1.5. 
Pulmonary CT Scan ....................................................................................................58 
8.1.5.1. 
Single-dose Period ......................................................................................................58 
8.1.5.2. 
Optional Extended Use Treatment Period ..................................................................59 
8.2. 
Safety Assessments .....................................................................................................59 
8.2.1. 
Physical Examinations ................................................................................................59 
8.2.2. 
Vital Signs ..................................................................................................................59 
8.2.2.1. 
Single-dose Period ......................................................................................................59 
8.2.2.2. 
Optional Extended Use Treatment Period ..................................................................59 
8.2.3. 
Electrocardiograms .....................................................................................................60 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................60 
8.2.5. 
Pregnancy Testing ......................................................................................................60 
8.2.5.1. 
Single-dose Period ......................................................................................................60 
8.2.5.2. 
Optional Extended Use Treatment Period ..................................................................61 


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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................61 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................61 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................62 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................62 
8.3.5. 
Pregnancy ...................................................................................................................63 
8.3.6. 
Adverse Events of Special Interest (AESI) ................................................................63 
8.3.7. 
Medical Device Deficiencies ......................................................................................63 
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies ...........................................63 
8.3.7.2. 
Follow-Up of Medical Device Deficiencies ...............................................................64 
8.3.7.3. 
Prompt Reporting of Device Deficiencies to Insmed .................................................64 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies ...................................64 
8.4. 
Pharmacokinetic Assessments ....................................................................................64 
8.4.1. 
PK Sample Collection .................................................................................................64 
8.4.2. 
PK Analysis ................................................................................................................64 
8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations ................................................65 
8.5. 
Genetics / Pharmacogenomics ....................................................................................65 
8.6. 
Biomarkers ..................................................................................................................65 
8.7. 
Medical Resource Utilization and Health Economics ................................................65 
8.8. 
Immunogenicity Assessments ....................................................................................65 
9. 
STATISTICAL CONSIDERATIONS .......................................................................66 
9.1. 
Statistical Hypotheses .................................................................................................66 
9.2. 
Sample Size Determination ........................................................................................66 
9.3. 
Analysis Sets ...............................................................................................................66 
9.4. 
Statistical Analyses .....................................................................................................66 
9.4.1. 
General Considerations ...............................................................................................66 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values ...........................................................67 
9.5. 
Interim Analysis ..........................................................................................................67 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................68 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................68 


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10.1.1. 
Regulatory and Ethical Considerations ......................................................................68 
10.1.2. 
Protocol Deviations ....................................................................................................68 
10.1.3. 
Public Health Emergency Situations ..........................................................................69 
10.1.3.1. 
Continuation or Suspension of the Study ...................................................................69 
10.1.4. 
Financial Disclosure ...................................................................................................70 
10.1.5. 
Informed Consent Process ..........................................................................................70 
10.1.6. 
Protection of Participant Identification and Confidentiality .......................................71 
10.1.7. 
Committee Structure ...................................................................................................71 
10.1.8. 
Dissemination of Clinical Study Data ........................................................................71 
10.1.9. 
Data Quality Assurance ..............................................................................................72 
10.1.9.1. 
Data Collection ...........................................................................................................72 
10.1.9.2. 
Study Monitoring ........................................................................................................72 
10.1.9.3. 
Audits and Inspections ................................................................................................72 
10.1.9.4. 
Study Record Retention ..............................................................................................73 
10.1.9.5. 
Source Documents ......................................................................................................73 
10.1.10. 
Study Files and Materials ...........................................................................................73 
10.1.11. 
Use of Stored Samples and Data ................................................................................74 
10.1.12. 
Disposition of Stored Samples and Data ....................................................................74 
10.1.13. 
Study and Site Start and Closure ................................................................................75 
10.1.13.1. First Act of Recruitment .............................................................................................75 
10.1.13.2. Study/Site Termination ...............................................................................................75 
10.1.14. 
Protocol Amendments ................................................................................................75 
10.1.15. 
Financing and Insurance .............................................................................................76 
10.1.15.1. Finances ......................................................................................................................76 
10.1.15.2. Reimbursement, Indemnity, and Insurance ................................................................76 
10.1.15.3. Participant Reimbursement, Liability and Insurance ..................................................76 
10.1.16. 
Publication Policy .......................................................................................................76 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................78 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................79 
10.3.1. 
Definition of AE .........................................................................................................79 
10.3.2. 
Definition of SAE .......................................................................................................80 


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10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................81 
10.3.4. 
Reporting of SAEs ......................................................................................................82 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................83 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ..............84 
10.6. 
Appendix 6 Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies ............................87 
10.6.1. 
Definition of Medical Device AE and ADE ...............................................................87 
10.6.2. 
Definition of Medical Device SAE, SADE and USADE ...........................................87 
10.6.3. 
Definition of Device Deficiency .................................................................................88 
10.6.4. 
Recording and Follow-up of AE and/or SAE and Device Deficiencies .....................88 
10.6.5. 
Reporting of SAEs ......................................................................................................90 
10.6.6. 
Reporting of SADEs ...................................................................................................90 
11. 
REFERENCES ...........................................................................................................92 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Screening and Follow up, Single-Dose Period, 
INS1009-201 ...............................................................................................................24 
Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 .......................25 
Table 3: 
PK and PD Biomarker Sampling Schedule, Single-Dose Period, INS1009-
201 ..............................................................................................................................26 
Table 4: 
Schedule for Optional Procedures and Assessments, Inpatient Treatment 
Period, INS1009-201 ..................................................................................................27 
Table 5: 
Schedule of Activities for Screening and Follow-up, Extended Use 
Treatment Period, INS1009-201 .................................................................................28 
Table 6: 
Schedule of Activities for the Optional Extended Use Treatment Period, 
INS1009-201 ...............................................................................................................29 
Table 7: 
Protocol-Required Safety Laboratory Tests, INS1009-201 ........................................78 
 
LIST OF FIGURES 
Figure 1: 
Participant Progression Through INS1009-201 Studya ..............................................19 


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Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period ..........................................................................................................................20 
Figure 3: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 ..........21 
Figure 4: 
Guideline for Optimal 3-Week Planned Titration Schedule (Optional 
Extended Use Treatment Period) ................................................................................23 
 
 
 


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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine amino transferase 
AST 
aspartate amino transferase 
AUC 
area under the concentration-time curve 
AUC0–∞ 
area under the concentration-time curve from time zero to infinity 
AUCt1–t2 
area under the plasma concentration-time curve from time zero to time of 
last measurable concentration 
CL/F 
apparent total clearance of drug from plasma after extravascular 
administration 
Cmax 
maximum (peak) plasma concentration of the drug 
CO 
cardiac output 
CRF 
case report form 
CRO 
contract research organization 
CT 
computerized tomography 
DILI 
drug induced liver injury 
DPI 
dry powder inhalation 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
end of study 
EUT 
extended use treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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HIV 
Human Immunodeficiency Virus 
HL 
Hy’s Law 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IMP 
investigational medicinal product 
IRB 
investigational review board 
IV 
intravenous 
MAD 
multiple ascending dose 
mPAP 
mean pulmonary arterial pressure 
MVO2 
mixed venous oxygen saturation 
NOAEL 
No observed adverse effect level 
NT-pro-BNP 
N-terminal (NT)-pro hormone brain natriuretic peptide 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary arterial pressure 
PD 
pharmacodynamic(s) 
PH 
pulmonary hypertension 
PHL 
potential Hy’s Law 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PVR 
pulmonary vascular resistance 
QD 
Once daily 
QID 
four times daily 
RAP 
right atrial pressure 


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RHC 
right heart catheter 
RVP 
right ventricular pressure  
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS CoV 2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SoA 
schedule of activities/assessments 
SUSAR 
suspected unexpected serious adverse reaction 
SRC 
Safety Review Committee 
t1/2 
elimination half-life 
TBL 
total bilirubin 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment emergent adverse event 
tmax 
time to maximum (peak) plasma concentration following drug administration 
TPIP 
treprostinil palmitil inhalation powder 
TPIS 
treprostinil palmitil inhalation suspension 
TRE 
treprostinil 
TP 
treprostinil palmitil 
TVR 
tricuspid valve regurgitation 
ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
Vd/F 
apparent volume of distribution at terminal phase 


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WHO 
World Health Organization 
WOCBP 
woman of child-bearing potential 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Amendment Summary of Changes 
Amendment 2 (03 MAR 2022) 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment: 
The primary driver for the changes in the protocol amendment is to account for the proper drug 
product availability and to incorporate the 80 µg formulation earlier in the dosing schema.  
Grammatical and typographical errors were corrected throughout the document.  
A summary of major changes in this amendment, compared to the original protocol, is shown in 
the table below. 
Revision 
Rationale 
Location of Revision 
Updated description of first dose 
to include the 80 µg formulation  
To account for the proper drug 
product availability  
• 
Section 1.3.2.1   
• 
Section 4.1  
• 
Section 4.3.1  
• 
Section 6.1.1  
Updated Inclusion Criterion #2 
To eliminate the time constraint 
on right heart catherization 
history 
• 
Section 5.1 
Updated Inclusion Criterion #10 
To reduce the required BMI 
from “19.0” to “18.0” 
• 
Section 5.1  
Updated Schedule of 
Assessments 
To include 12-lead ECG, 
Inclusion/Exclusion criteria, 
targeted physical examination, 
and study drug accountability 
• 
Table 6  
Included “bleeding” as a risk 
with TRE 
To be complete in the list of 
example effects of TRE on 
prostanoid metabolism 
• 
Section 2.2   
 






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hemodynamics and to elucidate dose- and PK-effect relationships. Some assessments and study 
activities (resting respiratory gas exchange assessment, transthoracic echocardiogram, pulmonary 
computerized tomography scan) for exploratory endpoints are optionally left to the discretion of 
the individual Investigator, based on participant safety and study site capabilities. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 48 hours post TPIP 
dose will extend into Study Day 3. A remote safety follow-up visit (telephone visit) is scheduled 
for Study Day 30 (± 2 days). An optional extended treatment period of 16 weeks will be 
available to participants who have completed the single-dose inpatient treatment period. There 
will be a second safety follow-up visit 30 days (± 3 days) after extended use treatment (EUT) 
Week 16 for participants who elect to enter the extended use treatment period. If the initial 
remote safety follow-up visit overlaps with the start of the extended treatment period, the initial 
remote safety visit will be shortened and conducted just prior to administration of IMP in the 
extended treatment period.  
Number of Participants: 
Approximately 6 to 10 evaluable participants are planned. Evaluable participants for safety are 
those who receive a single dose of TPIP; evaluable participants for PD and PK endpoints are 
those who receive a single dose of TPIP and have at least 1 post-TPIP administration PK or PD 
datapoint. 
Treatment Groups and Duration: 
This is a multi-center, open-label, non-randomized study. There are no predefined treatment 
groups. The dose determination for each participant will be made based on all available PK, PD, 
and safety data at the time of the participant’s entry into the study. An optional extended use 
treatment period of 16 weeks will be available to all participants.  
Safety Review Committee:  
A Safety Review Committee (SRC) will be responsible for monitoring safety data. The SRC will 
comprise all Investigators and key members of the Insmed Study Team (including but not limited 
to Medical Monitor, Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, 
Clinical Pharmacologist) and external expert consultants. The SRC will continuously monitor all 
available safety, PD and PK data for each participant and will obtain consensus regarding the 
safety of continuing the study, the next TPIP dose, and clinical care of the next participant. 
Expert consultants may be invited to review and interpret participant data. With any safety 
findings, a decision will be made, based on the review, as to whether enrollment in the study will 
be allowed to continue. Decisions regarding final database values for PD parameters may be 
adjudicated by the SRC. 


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1.3. 
Schema 
1.3.1. 
Participant Progression Through the Study 
The main study comprises an outpatient screening period, an inpatient treatment period, and an 
outpatient follow-up period. Participant progression through the study is shown in Figure 1. An 
optional EUT period is shown in Figure 2. 
1.3.1.1. 
Screening Period 
The outpatient screening period will last up to 30 days. After participants complete screening and 
have met the study eligibility criteria, the right heart catheter (RHC) procedure and inpatient 
treatment period should be scheduled without delay. 
1.3.1.2. 
Inpatient Treatment Period 
The inpatient treatment period will start on Study Day 1 and extend overnight into Study Day 2. 
Because the study requires an inpatient treatment period, institutional requirements for elective 
inpatient admissions, which may vary from site to site, will be followed. The participant may be 
required to undergo pre-admission assessments required by the institution for elective admission, 
for example testing for common infectious pathogens. Signature of elective admission 
documents and other consents may be required by the institution. An RHC will be placed. 
Following completion of Baseline assessments, a single dose of TPIP will be administered via a 
dry powder inhaler. Safety, PD, and PK assessments will continue at scheduled intervals through 
24 hours following TPIP administration. Following the final assessments at 24 hours, the RHC 
will be removed and the participant will be discharged from the inpatient setting when deemed 
safe for the participant.  
1.3.1.3. 
Follow-up Period 
PK blood draw at 48 (± 4) hours after TPIP dosing will be done on an outpatient basis as 
arranged by the site. The 48-hour post-TPIP visit will also include safety assessments including 
physical examination, clinical laboratory evaluations, ECG, AE collection and vital signs. An 
additional safety follow-up will be conducted by telephone call or telemedicine on Study Day 30 
(± 2 days) unless the participant elects to enter the EUT period prior to this follow-up visit. If the 
initial remote safety follow-up visit overlaps with the start of the extended treatment period, the 
initial remote safety visit will be shortened and conducted just prior to administration of 
investigational medicinal product (IMP) in the extended treatment period.  


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Figure 1: 
Participant Progression Through INS1009-201 Studya  
 
PD-pharmacodynamic assessments; PK=pharmacokinetic assessments; h=hours; d=days 
a Does not include optional extended use treatment period; the 30 day follow-up visit will be shortened and 
conducted just prior to administration of IMP in the extended treatment period if the visit overlaps with the start 
of the extended treatment period. 
1.3.1.4. 
Optional Extended Use Treatment Period 
All participants will be allowed to enter the optional 16 week EUT period after the completion of 
the inpatient treatment period and final PK sample collection. Entry into the optional EUT period 
will be at participant and Investigator discretion. A gap between the inpatient treatment period 
and EUT period is expected, but not required, and can be up to 6 months.  
After collection of the final PK sample, all participants will be allowed optional continued access 
to IMP for 16 weeks (includes a 3-week titration period) from first administration in the EUT 
period. At the Investigator’s discretion, participants may undergo a study drug taper for up to 
2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug. 
Participants will be screened to ensure they meet inclusion and exclusion criteria if they enter the 
EUT period more than 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period) (Table 5).  
Participant in-clinic study visits will be scheduled for EUT at Baseline (EUT Day 1), EUT 
Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16. 


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Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period 
 
a 
The 30 day follow-up visit from the single dose period will occur on EU Day 1 if the visit overlaps with the start 
of the extended treatment period. 
b At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks after the Week 16 
visit. 
c  The follow-up telephone call or visit will be 30 days after the Week 16 visit.  
EU = Extended Use; QD = once daily; EOT = end of treatment 
1.3.1.5. 
Extended Use Follow-up Period 
There will be a second remote safety follow-up visit 30 days (± 3 days) after EUT Week 16 
administration for participants who elect to enter the EUT period. 
1.3.2. 
Dose Selection 
1.3.2.1. 
Inpatient Treatment Period Dose Selection 
Each participant will enter the study in a serial fashion, following review of available safety, PK, 
and PD data from all previous participants by the Safety Review Committee (SRC). Each 
participant will receive a single-dose administration of TPIP via a dry powder inhaler. TPIP will 
be administered to only one participant at a time, with full evaluation of all available data prior to 
dosing the next participant. 
The first participant should receive a dose of TPIP containing 112.5 µg; if the 112.5 µg 
formulation is not available due to expiration date, it is acceptable to use the 80 µg formulation. 


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The SRC will then review all available safety, PD, and PK data including data from the first 
participant and select the TPIP dose and any changes to the assessments for the second 
participant. Then, following review of all available data including that from the first and second 
participants, the SRC will select the dose for the third participant. Similarly, all available data 
from previous studies and participants will be assessed prior to determining the dose for the next 
participant, until such a time as the SRC believes the study must conclude. Figure 3 describes the 
planned dose-selection and study continuation process. 
Figure 3: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 
   
 
SRC=Safety Review Committee 
 
 


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1.3.2.2. 
Optional Extended Use Treatment Period 
Entrance into the optional EUT period is at participants’ and Investigators’ discretion and begins 
with a titration. The guideline for the optimal 3-week planned titration schedule is provided in 
Figure 4. The target TPIP dose will be achieved with a combination of dry powder capsules 
containing 80 µg, 160 µg, and 320 µg of TP. 
During the titration period (EUT Days 1 to 21), each participant’s dose will be up-titrated to the 
highest tolerated dose for that individual. Participants will start open-label study drug with 
1 capsule (80 μg TPIP) QD. If this dose is well tolerated, the dose should be up-titrated until 
reaching the participant’s highest tolerable dose as described by the dosing schedule in Figure 4. 
During this titration period, participants must stay on study drug for the minimum number of 
cumulative days required for each dose (e.g., 2 days at 80 µg, 160 µg, or 240 µg; 3 days at 
320 µg; or 4 days at 400 µg or 480 µg) prior to titrating to the next higher dose. Study drug 
titration may occur slower, but not faster, than described in Figure 4. If a dose is not tolerated, 
study drug may be decreased to the previous dose level. At the Investigator’s discretion, 
up-titration may resume (as described in Figure 4) until the participant’s highest tolerated dose is 
achieved at EUT Day 21.  
All dose adjustments must be preceded by contact with the Investigator or study site personnel. 
In addition, the Investigator and/or study site personnel will be in contact with participants 
during the dose adjustment period to assess the tolerability to study drug as measured by the AEs 
commonly observed with other prostacyclin receptor agonists, which include headache, flushing, 
nausea, cough, and muscle pain. The decision to up-titrate to the next TPIP dose will be based on 
safety and tolerance data (e.g., AEs) as reported by the participant and assessed by the 
Investigator.  
At the Investigator’s discretion, based on tolerability, the study drug dose may be increased by 
1 dose level (as described in Figure 4) at the EUT Week 5 in-clinic visit for participants who 
have not achieved the 640 μg dose. The increase in dose will be administered under clinical 
observation at the study site to ensure tolerability and correct dosing and self-administration of 
study drug. The participant’s highest dose tolerated is expected to continue for the remainder of 
the study after the EUT Week 5 visit.  
At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks 
after the EUT Week 16 visit to help facilitate a safe withdrawal from study drug. The 
Investigator and/or study site personnel will be in contact with participants during the study drug 
taper to assess the tolerability to study drug. 


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Figure 4: 
Guideline for Optimal 3-Week Planned Titration Schedule (Optional 
Extended Use Treatment Period) 
 
 
1.4. 
Schedule of Activities (SoA) 
The SoA is divided into the following tables:  
• Screening and follow-up activities in the single-dose period 
• SoA in the inpatient treatment period  
• PK and PD biomarker blood sampling schedule 
• Optional procedures and assessments in the inpatient treatment period 
• Screening and follow-up activities in the EUT period 
• SoA in the EUT period 
The single-dose period refers to the combination of the inpatient treatment period (Study Day 1 
to Study Day 2), the PK/PD sampling period, and the 30 day follow-up period.  
 


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Table 1: 
Schedule of Activities for Screening and Follow up, Single-Dose Period, 
INS1009-201 
Procedure 
Screening 
Follow-up 
 
Up to 30 
Days 
48 h post 
TPIP dosea 
Study Day 30 
(± 2 days)b 
Informed Consent 
X 
-- 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
-- 
Demographics and Medical History 
X 
-- 
-- 
Smoking Status 
X 
-- 
-- 
Height, Weight, BMI Calculation 
X 
-- 
-- 
Prior/Concomitant Medications 
X 
X 
X 
Serology (HBsAg, HIV antibody, HCV 
antibody) 
X 
-- 
-- 
Serum Pregnancy Test (WOCBP only) 
X 
 
 
Urine Pregnancy Test (WOCBP only) 
-- 
 
X 
Hematology, Clinical Chemistry (Table 7) 
X 
X 
-- 
Coagulation Profile (Table 7) 
X 
-- 
-- 
NT-pro-BNP Sample (if needed, Section 5.1) 
X 
-- 
-- 
12-lead ECG 
X 
X 
-- 
Physical Examination 
X 
X 
-- 
Vital Signs 
X 
X 
-- 
6 Minute Walking Distance Test (if needed, 
Section 5.1) 
X 
-- 
-- 
Pulmonary Function Testing (if needed, 
(Section 5.1) 
X 
-- 
-- 
Adverse Eventsc 
X 
X 
X  
a 48 h safety follow-up assessments are to be conducted at the time of the visit for the 48h PK blood draw (Table 3). 
b Follow-up visit will be shortened and conducted just prior to administration of IMP in the extended treatment 
period if the visit overlaps with the start of the extended treatment period. 
c AE collection is from the time of signing the informed consent through the Day 30 safety follow-up. Events 
between ICF signing and TPIP dosing that are serious will be recorded as SAE; non-serious events during this 
period must be recorded as medical history. 
Note:  Additional safety follow-ups may be conducted at any time per the investigator’s discretion to ensure 
participant safety. The reason for any additional safety follow-up must be reported as an AE. 
BMI = body mass index; ECG = electrocardiogram WOCBP = woman of childbearing potential  


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Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 
Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administration 
TPIP 
Administration 
Post-TPIP Administration 
Procedure 
Day 1 Baseline  
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
24 h 
24 h to 
discharge 
Hematology, clinical 
chemistry, coagulation 
profile blood drawa 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
-- 
Urine pregnancy test 
(WOCBP only) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12-lead ECG 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Cardiac telemetry per 
institutional protocolb 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signsc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
collection 
X 
 
 
 
 
 
 
 
 
 
 
Place right heart 
catheter 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
PD assessments: PVR, 
MVO2, Hgb, RVP, 
PAP CO, PVR, RAP, 
oxygen consumption, 
PCWP (Baseline 
only)d, heart rate, 
SpO2, systemic blood 
pressuree  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
-- 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administration 
TPIP 
Administration 
Post-TPIP Administration 
Procedure 
Day 1 Baseline  
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
24 h 
24 h to 
discharge 
Administer TPIP 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Remove RHC 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Discharge/Safety 
Follow-up Instructions 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
a See Section 10.2, Table 7 for specific laboratory tests. 
b Routine cardiac telemetry readings will not be collected as study data unless they pertain to a relevant adverse event. 
c Heart rate, systemic blood pressure, and SpO2 are required PD measurements and will be collected as scheduled. They may be measured with pulse oximetry 
for heart rate and SpO2 and an automated inflatable arm cuff for blood pressure. Temperature and respiratory rate may be measured per institutional inpatient 
protocol. Respiratory rate will be measured as part of pulmonary gas exchange testing, if performed. 
d PCWP is measured at Baseline only to ensure study eligibility (Section 5.1). 
e Systemic blood pressure must include 3 values:  systolic, diastolic, and mean arterial pressure.  
CO = cardiac output; Hgb = hemoglobin; MVO2 = mixed venous oxygen saturation; PAP = pulmonary arterial pressure; PVR=pulmonary vascular resistance; 
RAP = right atrial pressure; RVP = right ventricular pressure; SpO2 = arterial blood oxygen saturation; WOCBP = woman of childbearing potential 
 
Table 3: 
PK and PD Biomarker Sampling Schedule, Single-Dose Period, INS1009-201 
-- 
Baseline 
Pre-TPIP 
Administration 
TPIP 
administration 
Post-TPIP Administration 
Time  
-- 
0 
30 (± 10) mins 
60 (± 10) mins 
2 h (± 20) mins 
4 (± 1) h 
8 (± 2) h 
24 (± 2) h 
48 (± 4) h 
PK samplinga 
X 
-- 
X 
X 
X 
X 
X 
X 
X 
Biomarker 
samplingb 
X 
-- 
-- 
-- 
-- 
X 
X 
-- 
-- 
a PK sampling for treprostinil palmitil and treprostinil; each PK sample will be approximately 10 mL. 
b Each biomarker sample will be approximately 5 to 7 mL. 


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Table 4: 
Schedule for Optional Procedures and Assessments, Inpatient Treatment Period, INS1009-201 
Inpatient Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
Post-TPIP 
Administration 
Procedure 
Study Day 
1 Baseline  
Time 0 
2-8 hr 
4-8 hr 
Transthoracic 
echocardiogram 
(LVEF,TVR maximum 
velocity, TAPSE, end 
diastolic right ventricular 
volume)  
X 
-- 
X 
-- 
Pulmonary CT scan (total 
blood volume, blood 
volume in vessels < 5 
mm2)  
X 
-- 
-- 
X 
-- 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
-- 
-- 
Study Day 
1 Baseline 
Time 0 
30 mins 
60 mins 
90 mins 
2 h 
3 h 
4 h 
8 h 
24 h 
Resting respiratory gas 
exchange assessmenta 
(respiratory rate, minute 
ventilation, VCO2, ETO2, 
ETCO2, SpO2  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
a Resting respiratory gas assessment parameters are collected at the same time points as RHC parameters. 
NOTE:  Parameters to be measured for each procedure are in parentheses. 
CT=computerized tomography; ETCO2 =end tidal carbon dioxide concentration; ETO2,=end tidal oxygen concentration; LVEF=left ventricular ejection fraction; 
SpO2=arterial blood oxygen saturation; TAPSE=tricuspid annular plane systolic excursion; TVR=tricuspid valve regurgitation; VCO2,=carbon dioxide 
production  


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Table 5: 
Schedule of Activities for Screening and Follow-up, Extended Use Treatment Period, INS1009-201 
Procedure 
Screeninga 
Follow-up 
 
EUT Study Day 1 
(± 3 days) 
EUT Study Day 142 
(± 3 days) 
Informed Consent 
X 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
Demographics 
X 
-- 
Smoking Status 
X 
-- 
Height, Weight, BMI Calculation 
X 
-- 
Prior/Concomitant Medications 
X 
X 
Urine Pregnancy Test (WOCBP only) 
X 
X 
Hematology, Clinical Chemistry (Table 7) 
X 
-- 
NT-pro-BNP Sample (if needed, Section 5.1) 
X 
-- 
Vital Signs 
X 
-- 
6 Minute Walking Distance Test (if needed, 
Section 5.1) 
X 
-- 
Adverse Eventsb 
X 
X  
a Participants will only be screened at EUT Day 1 if they enter the EUT period beyond 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period). 
b AEs for the period from the Study Day 30 follow-up until the enrollment in the EUT period will be collected during participants’ screening for the EUT. 
BMI = Body Mass Index; EUT = extended use treatment; WOCBP = woman of childbearing potential 
 
 
 
 
 


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Table 6: 
Schedule of Activities for the Optional Extended Use Treatment Period, INS1009-201 
 
Period 
Extended Use Treatment Period 
Follow-Up 
E/Da 
Week 
EUT W1 
EUT W2  
EUT W3 
EUT W5 
EUT W10 
EUT W16 
EUT W20b 
 
Day 
EUT D1 
(Screeningc and 
Baseline)  
EUT D10 
(± 3 days) 
EUT D21 
(± 3 days) 
EUT D35d 
(± 3 days) 
EUT D70 
(± 3 days) 
EUT 
D112 
(± 3 days) 
EUT D142 
(± 3 days) 
 
Visit 
EUT V1 
EUT V2 
EUT V3 
EUT V4 
EUT V5 
EUT V6 
EUT V7 
 
Inclusion/exclusion 
Xc 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
 
Pregnancy test 
(WOCBP only)e 
Xc 
 
X 
Vital signsf 
Xc 
X 
X 
X 
X 
X 
 
X 
6MWD test 
X 
 
 
 
 
X 
 
 
Hematology, clinical 
chemistry g 
Xc 
 
 
 
 
 
 
 
12-lead ECG 
Xc 
 
 
 
 
 
 
 
NT-pro-BNP Sample 
X 
 
 
 
 
Xc 
 
 
Optional pulmonary CT 
scan (total blood 
volume, blood volume in 
vessels < 5 mm2) 
X 
 
 
 
 
X 
 
 
Study drug distributionh 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
self-administration 
re-assessmenti 
 
X 
X 
X 
X 
X 
 
 
Targeted physical 
examinationj 
X 
 
X 
X 
X 
 
 
 
Study drug 
accountabilityk 
 
X 
X 
X 
X 
X 
Xl 
 


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Period 
Extended Use Treatment Period 
Follow-Up 
E/Da 
Week 
EUT W1 
EUT W2  
EUT W3 
EUT W5 
EUT W10 
EUT W16 
EUT W20b 
 
Day 
EUT D1 
(Screeningc and 
Baseline)  
EUT D10 
(± 3 days) 
EUT D21 
(± 3 days) 
EUT D35d 
(± 3 days) 
EUT D70 
(± 3 days) 
EUT 
D112 
(± 3 days) 
EUT D142 
(± 3 days) 
 
Visit 
EUT V1 
EUT V2 
EUT V3 
EUT V4 
EUT V5 
EUT V6 
EUT V7 
 
Dosing diary 
 
 
 
Adverse eventsm 
 
a Participants who enroll in the optional EUT period and discontinue before the end of study will be classified as early discontinuations.  
b Follow-up telephone call or visit will be 30 days after the EUT Week 16 visit.  
c Participants will undergo assessments for screening at EUT Day 1 if they enter the EUT period beyond 30 days after beginning the single dose period (e.g., 
beyond the initial 30 day follow-up period). 
d At the Investigator’s discretion, an increase of 1 dose level may be allowed at EUT Week 5 if the participant has not achieved the 640 µg dose.  
e Pregnancy test: Urine pregnancy tests will be performed in-clinic at EUT Baseline (EUT Day 1) in WOCBP. WOCBP will be provided home pregnancy test 
kits with instructions to conduct the pregnancy tests every 30 days or more if required during the treatment and follow-up periods. Study site personnel will 
contact the participant every 30 days by telephone and record the pregnancy test results. An additional on-site urine test must be performed prior to starting any 
procedure that requires the use of ionizing radiation. 
f Vital signs: Includes body temperature (°C), pulse rate (bpm), respiratory rate (breaths/min), blood pressure (systolic, diastolic and mean arterial [mmHg]), and 
SpO2. Vital signs will be measured at EUT Screening/Baseline (EUT Day 1), EUT Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16 and 
at the Early Discontinuation visit, if appropriate.  
g See Table 7 for additional information. 
h Participants will receive study drug supply on EUT Day 1 and at EUT Week 2, EUT Week 3, EUT Week 5, and EUT Week 10 visits. Participants who undergo 
a study drug taper will receive study drug supply at the EUT Week 16 visit. A telephone call from study personnel or the Investigator will be placed to 
participants assigned to a study drug taper to check on the participant’s well-being; timing of the telephone call will be based on the Investigator’s discretion, 
and any adverse events will be captured on the CRF. 
i  Assessment of study drug self-administration: Study drug self-administration will be overseen by study site personnel at all in-clinic visits.  
j The targeted physical examination will be performed at Week 3, Week 5, and Week 10 prior to study drug administration. The targeted physical exam includes 
cardiovascular (cardiac auscultation, assessment of peripheral pulses and edema) and pulmonary assessments (pulmonary auscultation).  
k Participants will return unused capsules and used capsules and devices to the study site at the Week 2, Week 3, Week 5, Week 10, and Week 16 visits.  
l Participants who undergo a study drug taper will return unused capsules and used capsules and devices to the study site at a follow-up visit. 
m AE collection from the 30 day follow-up period in the single-dose period to enrollment in the EUT period will be queried during EUT screening; All other AEs 
and SAEs will be collected from EUT Day 1 and followed up as described in Section 8.3.3. 
6MWD = 6-minute walk distance; CT = computerized tomography; CRF = case report form; D = day; E/D = early discontinuation; EUT = extended use 
treatment; NT-pro-BNP = N-terminal pro B-type natriuretic peptide; W = week; WOCBP = woman of childbearing potential; V = Visit


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2. 
INTRODUCTION 
Pulmonary hypertension (PH), a hemodynamic state characterized by resting mean 
PAP > 20 mmHg per updated guidelines (Simonneau et al., 2019), is generally classified into 5 
groups based on the underlying pathology: Group 1 is PH due to pulmonary vascular disease, 
also known as pulmonary arterial hypertension (PAH); Group 2 is PH due to left heart disease; 
Group 3 is PH due to lung disease or hypoxia; Group 4 is PH due to chronic thromboembolic 
disease or other pulmonary vasculature obstruction; Group 5 is miscellaneous PH syndromes 
caused by a variety of disorders such as hemolytic anemias and sarcoidosis (Thenappan et al., 
2018). 
In Group 1 PH (PAH), the resting mean PAP > 20 mmHg occurs in the setting of normal 
pulmonary arterial wedge pressure of ≤15 mm Hg with PVR of ≥3 Wood Units (WU) 
(McLaughlin et al., 2009). In PAH the pulmonary vasculature is affected by vasoconstriction, 
vascular remodeling, increased rigidity of vessel walls and vascular fibrosis. These vascular 
anomalies increase PVR, which leads to increases in right ventricular afterload, and a cascade of 
maladaptive changes to the heart including right ventricular hypertrophy, ischemia and fibrosis, 
reducing right ventricular function and eventually leading to right ventricular failure and death 
(Thenappan et al., 2018). The pulmonary vascular lesions of PAH may be idiopathic, hereditary, 
or occur as a complication of drug use (e.g., anorexigens), connective tissue disease, portal 
hypertension, congenital cardiac malformations or HIV infection (Hoeper et al., 2017). 
Data from PAH registries around the world (Thenappan et al., 2018) estimate a global incidence 
ranging from 2.0 to 7.6 cases per million adults per year, with a prevalence of 11 to 26 cases per 
million adults; the incidence in females is approximately 4 times that in males. Most registries 
report a mean age of onset ranging from approximately 36 to 53 years. While overall median 
survival has improved from 2.8 years in the 1980’s to 6 years currently, mortality is high, with 
1 year survival ranging from 68% to 93% and 5 year survival ranging from 21% to 65%. Nearly 
half of the patients in these registries have PAH of idiopathic, heritable or anorexigen-induced 
origin.  
PAH is a debilitating progressive disease that causes a wide range of non-specific symptoms 
including, dyspnea, shortness of breath, chest pain, fatigue, generalized weakness and exertional 
syncope (Delcroix and Howard, 2015), severely affecting the patient’s physical mobility, 
emotional and social well-being, ability to perform activities of daily living and overall quality of 
life. Pharmacological treatments are available to mitigate disease symptoms and slow disease 
progression, but treatment-related AEs, inconvenience and side effects can be treatment-limiting 
and negatively influence the patient’s daily life (Delcroix and Howard, 2015). 
The currently available pharmacologic treatments for PAH include calcium channel blockers, 
guanylate cyclase stimulators, endothelin receptor antagonists, phosphoesterase type 5 inhibitors, 
and prostanoids and prostacyclin agonists. Prostanoids, such as TRE, are among the most 
effective medications for the treatment of PAH. However, they are limited by the need for 
inconvenient and frequent drug administration and dose-limiting side effects (Thenappan et al., 
2018). 


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2.1. 
Study Rationale 
Treprostinil palmitil (TP) is an inactive prodrug of treprostinil (TRE). TPIP is a dry powder for 
inhalation formulation of TP. TPIP is being developed for the treatment of PAH. TPIP is 
expected to provide extended release of TRE in the lung with the goals of less frequent and more 
convenient and consistent dosing while reducing the frequency and severity of dose-limiting side 
effects associated with the currently approved forms of TRE. TP has been previously studied in 
healthy volunteers as an inhalation suspension (treprostinil palmitil inhalation suspension, TPIS), 
in single doses up to 340 µg (Study INS1009-101), and TPIP has been previously studied in a 
single ascending dose/multiple ascending dose (SAD/MAD) study in healthy volunteers (Study 
INS1009-102). 
No studies of TP or TPIP have been conducted in participants with PAH. Study INS1009-201 is 
an open label, non-randomized, single- dose study designed to evaluate the safety, 
pharmacokinetics (PK), and pharmacodynamic (PD) effects of a single dose of TPIP in 
participants with PAH. An optional EUT period was added to maximize participant convenience 
and accessibility.   
2.2. 
Background 
Treprostinil is a tricyclic benzidene analogue of prostacyclin. As such, TRE has vasodilatory and 
anti-platelet activity within the pulmonary vascular system, thereby reducing blood flow 
resistance and improving the clinical state, functional class, exercise capacity, and quality of life 
of patients with PAH (Vachiery and Naeije, 2004). 
Treprostinil has a high potency but is short-lived in the body and must be administered by 
continuous IV or SC infusion, or given multiple times per day by inhaled or oral routes. At 
present, TRE is available in the United States in formulations of IV or SC infusion (Remodulin 
Package Insert, 2018), oral extended-release tablets (Orenitram Package Insert, 2019), and 
inhalation solution (Tyvaso Package Insert, 2017) to treat PAH. The clinical experience with 
TRE suggests that most of the AEs experienced are related to its effects on prostanoid 
metabolism (e.g., headache, nausea, diarrhea, flushing, bleeding, and hypotension). Dose-
limiting side effects correlate to systemic plasma concentrations of TRE.  
Treprostinil palmitil is a hexadecyl ester prodrug of TRE. In the lung, TP is hydrolyzed by 
esterase to TRE and hexadecanol. TPIP is a dry powder formulation of TP designed to provide 
sustained release of TRE in the lung over a prolonged period, thus providing prolonged 
vasodilation in the lung vasculature. This effect was demonstrated in a rat acute hypoxia model 
that showed a maximal reduction in PAP through the 3-hour monitoring limit with TP, while the 
effect of inhaled TRE started to diminish by 1 hour and was completely gone after approximately 
2.5 hours. The prolonged lung exposure and pharmacological action of TRE achieved with 
sustained release from the prodrug TP aims to reduce both dosing frequency and side effects 
driven by fluctuations of plasma levels of TRE. 
Treprostinil palmitil was well tolerated in rats and dogs following 16-week once-daily inhalation. 
At no observed adverse effect level (NOAEL) doses, the plasma Cmax and AUC of TRE at steady 


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state in rats (2000 μg/kg/day) were 11 ng/mL and 73 ng*h/mL, respectively, and in dogs (250 
μg/kg/day) were 1.2 ng/mL and 13 ng*h/mL, respectively. 
Thus far, TP has been studied in 2 Phase 1 studies of healthy participants: An SAD study of 
TPIS (Study INS1009-101) and an SAD/MAD study of TPIP (Study INS1009-102). Single 
doses of up to 675 μg and multiple doses of up to 225 μg for 7 days were administered to healthy 
participants. Overall, TP was well tolerated, with largely mild treatment-emergent adverse events 
(TEAEs) and an adverse effect profile consistent with that of inhaled prostacyclin analogs. 
Treprostinil exposures increased approximately dose-proportionately, were similar between TPIS 
and TPIP, and showed no accumulation with QD dosing. Doses of TP achieved were several-fold 
higher than label-indicated target dose of inhaled treprostinil (54 μg). When comparing TPIS to 
inhaled treprostinil, TP had a 10-fold lower maximum plasma concentration (89.0 pg/mL vs. 
958 pg/mL) and a markedly longer half-life (5.69 hours vs. 0.485 hours) than inhaled treprostinil 
at the molar equivalent dose. Half-life of TP was even longer with TPIP, ranging from 8.67 to 
11.6 hours. These differential PK of TP may offer therapeutic advantages over treprostinil with 
the need for less frequent administration (QD vs QID), fewer adverse effects, and potentially 
improved efficacy with higher tolerated dose.  
Additional information regarding the results of non-clinical and clinical studies of TP are 
provided in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
TEAEs for TPIP from clinical and non-clinical studies may be found in the Investigator’s 
Brochure.  
2.3.1. 
Risk Assessment 
There is no TPIP experience in participants with PAH; however, the active component, TRE, 
like other prostanoids and their agonists, has a well-characterized safety profile. This will help 
enable participants to be adequately monitored during the study. 
Insmed has conducted a SAD study of TPIS in healthy volunteer participants, with safety and 
tolerability findings similar to those of other prostanoids (Study INS1009-101). In this study, 
32 TEAEs were reported for 11 of 18 participant who received TPIS. No fatal TEAEs were 
reported and no TEAEs led to the withdrawal of participants. One participant who received a 
single dose of TPIS containing 340 µg of TP experienced several interrelated AEs that 
culminated in 2 TEAEs of severe and life-threatening intensity, as judged by the Investigator. 
The Investigator believed a severe TEAE of micturition syncope was precipitated by a TEAE of 
chest pain, which was assessed as probably related to the study IMP and increased vagal tone 
during micturition. Follow-up evaluation by an external cardiologist reveled that the participant 
had Tachy-Brady syndrome. A serious adverse event (SAE) of cardiac pause/nodal arrhythmia 
was reported for this participant and assessed as probably related to TPIS. Beyond this event, 
7 TEAEs were assessed as being of moderate intensity and 23 TEAEs to be of mild intensity. 
The most frequently reported TEAEs among participants receiving TPIS were cough (5 events 
for 5 participants), dyspnea (4 events for 4 participants), and throat irritation (4 events for 


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4 participants). Other TEAEs reported for more than 1 participant receiving TPIS included 
nausea (3 events for 3 participants) and headache (2 events for 2 participants). 
There was a dose-related trend in the incidence of TEAE reporting with increasing dose levels of 
TPIS: 5 TEAEs were reported for 2 participants after receiving a single TPIS dose containing 
85 µg of TP, 7 TEAEs were reported for 4 participants after receiving a single TPIS dose 
containing 170 µg of TP, and 20 TEAEs were reported for 5 participants after receiving a single 
TPIS dose containing 340 µg of TP. 
Safety results from a recently conducted SAD/MAD study of TPIP in healthy volunteer 
participants (Study INS1009-102) support the TPIP dosing and management of participant safety 
for this study. In this study, TPIP was generally safe and well tolerated. TEAEs reported with 
TPIP were consistent to those seen with other inhaled prostanoid therapies. The majority of 
TEAEs were judged by the Investigator to be of mild intensity; there were few moderate TEAEs 
and no severe TEAEs across the study. No participants reported AEs of severe intensity, and no 
SAEs were reported. There was 1 participant in the MAD panel who discontinued after 2 doses. 
TEAEs were more frequent with increasing TPIP doses. In the MAD panel, participants titrated 
from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 
225 µg QD at treatment initiation, and all TEAEs were of mild severity. 
Nonserious adverse events (AEs) observed in clinical studies to date are known for the 
pharmacological class of prostacyclin vasodilators and are considered expected for TPIP. No 
serious adverse reactions are considered expected for TPIP. Please refer to the Reference Safety 
Information in Section 6.1 of the Investigator’s Brochure. 
Risks inherent in study procedures and in the inpatient treatment period will be managed per 
Investigator and institutional processes. It is possible that the RHC-dependent Baseline 
parameters may indicate that the participant does not meet study inclusion criteria, may meet 
exclusion criteria, or is otherwise not suitable for study participation; in this case the Investigator 
may end the RHC procedure and not administer TPIP. 
In general, an RHC is left in place for 30 to 60 minutes to take necessary measurements. This 
study requires the RHC to be in place for approximately 24 hours. Excess risks with prolonged 
placement of the RHC may include but not be limited to dislodging of the RHC, infection, 
bleeding, clot formation, and participant discomfort. 
2.3.2. 
Benefit Assessment 
TPIP is being developed for the treatment of PAH. TPIP may or may not result in beneficial 
effects for participants with PAH by providing extended release of TRE in the lung with less 
frequent and more convenient dosing.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Although participants may or may not benefit individually from this study, risks to their well-
being will be carefully monitored and managed throughout their participation. Insmed considers 
the risks to be appropriate to the value of the knowledge gained in this study about the 
characteristics of this promising therapy. The well-characterized safety profile of TRE and the 


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continued safety monitoring by both the Investigator and SRC (in the inpatient treatment period, 
observation period, and optional EUT period, if applicable) will minimize risk to participants. 
Most TEAEs observed with exposure to this drug are events known to be associated with 
prostanoids and their agonists. Study inclusion and exclusion criteria will help to ensure that only 
appropriate participants are enrolled. Risks involved with study procedures and settings will be 
managed by the relevant Investigator and institutional processes. 
 






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• To assess the effect of TPIP on 
exercise capacity 
• Change from Baseline in 6MWD 
distance at EUT Baseline to EUT 
Week 16 
6MWD = 6-minute walk distance; EUT = extended use treatment period; PAH = pulmonary arterial hypertension; 
TEAE = treatment emergent adverse event; TPIP = treprostinil palmitil inhalation powder 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2a, open label, non-randomized study to assess the safety, tolerability, PD effects 
and PK of TPIP administered to participants with WHO Group 1 PH (PAH). This is the first 
patient study of TPIP. Each participant will receive a single dose of TPIP. The first participant 
should receive a dose containing 112.5 µg; if the 112.5 µg formulation is not available due to 
expiration date, the first participant may receive the 80 µg formulation. The TP dose level for 
each subsequent participant will be determined following review and adjudication of all available 
safety, PK, and PD data from the previous participant(s) by the SRC (Section 10.1.7). There is an 
optional extended-use period for 16 weeks in participants who have completed the core, single-
dose period.  
This is a “proof of mechanism” study designed to investigate the following: 
1. The safety and tolerability of TPIP in participants with PAH, 
2. The relationship between the PK and PD effects of TPIP in participants with PAH, and 
3. The duration of the PD effects of a single dose of TPIP in participants with PAH. 
The cardiopulmonary and overall functional status of participants with PAH can be labile and 
medical instability can develop quickly. The study is designed to provide maximal safety and 
minimal risk to participants. As such, there considerable flexibility built into the protocol to 
allow Investigator discretion with the frequency, timing, and/or conduct of PD and PK 
assessments to ensure participant safety. Because the study requires an overnight inpatient 
treatment period, institutional requirements for elective inpatient admissions, which may vary 
from site to site, will be followed. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 48 (± 4) hours post 
TPIP dose will extend into Study Day 3. A remote safety follow-up visit is scheduled for Study 
Day 30 (± 2 days). The 48 hour PK visit will also include safety assessments including ECG, 
clinical laboratory evaluations, vital signs, physical examination, and AE collection (Table 1). 
The safety follow-up period will conclude with a remote (telephone or telemedicine) visit on 
Study Day 30 (± 2 days). The screening, treatment, and follow-up periods for the core, 
single-dose portion of the study are expected to be 62 days or less. An EUT period of 16 weeks 
will be optional for participants that complete the single-dose period, followed by a 30 day 
follow-up (± 3 days). This extends study participation to 142 days after enrollment in the EUT 
period.  
4.1.1. 
Screening Period 
The initial screening period will be up to 30 days. Required screening assessments are shown in 
Table 1. Participants who fail one or more screening assessments may be re-screened twice at the 
Investigator’s discretion in order to meet study entry criteria. See Section 5.4 for additional 
information regarding participants who fail screening and/or are re-screened. 


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Participants who enter the optional EUT period more than 30 days after beginning the 
single-dose period (e.g., beyond the initial 30 day follow-up period) will be screened to ensure 
they continue to satisfy inclusion and exclusion criteria. Extended use treatment period screening 
assessments are shown in Table 5. 
4.1.2. 
Inpatient Treatment Period 
4.1.2.1. 
Baseline Procedures and Assessments 
The inpatient treatment period will be on Study Days 1 and 2. The participant may be required to 
undergo pre-admission assessments required by the Institution for elective admission, for 
example testing for common infectious pathogens. Signature of institutional elective admission 
documents and consents to procedures may be required. Data from required institutional 
assessments and consents will not be routinely collected as part of study data unless they pertain 
to a relevant AE or study endpoint. 
Participants will be admitted to an inpatient care setting such as an ICU, cardiac catheterization 
laboratory or other similar setting. They will have Baseline laboratory and safety assessments as 
shown in Table 2. An RHC will be placed for Baseline assessment of cardiopulmonary 
hemodynamics prior to TPIP administration and intermittent assessments of cardiopulmonary 
hemodynamics for 24 hours following TPIP administration. Institutional procedures and 
protocols for placement, care, monitoring, and removal of the RHC will be carried out but will 
not be collected as study data unless relevant. 
Some procedures and assessments for exploratory endpoints may not be offered at all sites. 
Participants will be asked to give informed consent only to those procedures that are being 
conducted by their Investigator at their site. These procedures include the following: 
• Transthoracic echocardiogram at Baseline and during a 2 to 8 hour window after TPIP 
administration (Table 4). 
• Pulmonary computerized tomography (CT) scan at Baseline and during a 4 to 8 hour 
window after TPIP administration (Table 4). 
• Resting respiratory gas exchange assessment at Baseline and intermittently after TPIP 
administration for up to 24 hours (Table 4). Resting respiratory gas exchange assessments 
will be standardized, with all participating investigators using similar equipment and 
procedures. 
For example, an Investigator who is doing only RHC and resting respiratory gas exchange 
assessments for this study will obtain informed consent for those procedures only and will not 
offer or ask the participant for informed consent for transthoracic echocardiogram or pulmonary 
CT scan as part of this study. 
Following completion of all Baseline assessments, including Baseline blood draws for PK and 
PD biomarkers (Table 3), the prescribed single dose of TPIP will be administered (Table 2).  


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4.1.2.2. 
Post-TPIP Administration 
Following TPIP administration, participants will have intermittent safety, clinical laboratory, PK, 
and PD assessments, as specified in the SoA (Table 2, Table 3, and Table 4). The study is 
designed to allow maximum flexibility for interventions and assessments at the discretion of the 
Investigator and institutional policies and procedures to ensure participant safety. At any time, 
the Investigator has the option to discontinue assessments for participant safety or tolerability 
reasons. Additional laboratory and/or hemodynamic assessments may be performed as deemed 
necessary for participant safety. Following completion of scheduled events, the Investigator has 
the option of continued laboratory and/or hemodynamic monitoring as deemed appropriate for 
participant safety.  
If, in the interest of participant safety, the Investigator omits scheduled assessments/procedures 
or performs additional assessments/procedures, the reason for doing so must be reported on the 
CRF as an AE in order to avoid a protocol violation.  
Following completion of protocol-required assessments and removal of the RHC, the participant 
will be discharged from the inpatient setting when deemed safe by the Investigator. Investigator 
and institutional usual care protocols for participant discharge and follow-up for an RHC 
procedure will apply. 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up 
The participant will be required to return as an outpatient for the 48 (± 4) hour post-TPIP 
administration PK sample. Additional safety assessments such as ECG, physical examination, 
vital signs, AE collection, and clinical laboratory evaluations will be completed at the 48 hour 
visit. Female participants who are women of child-bearing potential (WOCBP) will be given a 
self-administered pregnancy test kit with instructions to self-administer the test and report the 
results on the day of the Study Day 30 safety follow-up visit (Section 4.1.3). 
4.1.3. 
Safety Follow-up 
A remote (telephone call or telemedicine) safety follow-up visit is scheduled for Study Day 30, 
at which time participants who are WOCBP will also be asked to report the results of the self-
administered pregnancy test they were given at the 48 hour post-TPIP follow-up visit 
(Section 4.1.2.3, Table 1). 
4.1.4. 
Optional Extended Use Treatment Period 
All participants will be allowed to enter the optional 16 week EUT period after the completion of 
the inpatient treatment period and final PK sample collection. Entry into the optional EUT period 
will be at participant and Investigator discretion. A gap between the inpatient treatment period 
and EUT period is expected, but not required, and can be up to 6 months.  
After collection of the final PK sample, all participants will be allowed optional continued access 
to IMP for 16 weeks (includes a 3-week titration period) from first administration in the EUT 
period. At the Investigator’s discretion, participants may undergo a study drug taper for up to 
2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug. 


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Participants will be screened to ensure they meet inclusion and exclusion criteria if they enter the 
EUT period more than 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period) (Table 5).  
Participant in-clinic study visits will be scheduled for EUT Baseline (EUT Day 1), EUT Week 2, 
EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16. 
The CT scan will be performed according to instructions provided by the CT scan vendor. 
There will be a second safety follow-up visit 30 days (± 3 days) after EUT Week 16 for 
participants who elect to enter the EUT period. 
4.1.5. 
Open-label Extension Study  
When available, participants may be eligible to enroll in a separate OLE study that will have a 
duration of approximately 2 years. Details of the planned OLE study will be provided in a 
separate protocol. 
4.2. 
Scientific Rationale for Study Design 
The study is designed to understand the safety and acute PK and PD effects of TPIP in 
participants with PAH, the intended patient population. Intensive monitoring via RHC in an 
appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate relationships between dose, PK, and PD effects. Some 
assessments and study activities for exploratory endpoints are considered optional depending on 
Investigator preference and/or based on study site capabilities and procedures (Table 4). 
4.3. 
Justification for Dose 
4.3.1. 
Inpatient Treatment Period (Single-dose) 
Treprostinil palmitil has been previously studied in healthy volunteer participants as a liquid 
suspension for inhalation (TPIS) and has now been formulated as a dry powder for oral 
inhalation (TPIP). Data from pre-clinical pharmacology and safety studies supported the 
initiation of human studies with TPIS. Preclinical studies in rats and dogs showed that the plasma 
kinetics of TRE and TP after dosing with TPIP are similar to those of TPIS. Additional clinical 
PK and safety data from healthy participants after SAD and MAD dosing with TPIP supported 
the chosen study design and dose. For further information on the non-clinical pharmacology and 
safety studies of TPIS and TPIP, please refer to the Investigator’s Brochure.  
The current study utilizes the clinical experience of TPIS from Study INS1009-101 in healthy 
volunteer participants and the INS1009-102 SAD/MAD study of TPIP in healthy volunteer 
participants. In Study INS1009-101, doses of TPIS were administered in multiples of 85 µg TP 
to include 170 µg (2 × 85 µg) and 340 µg (4 × 85 µg) of TP. The systemic exposure for TRE at 
340 µg TP was low (AUC < 2.5 ng*h/mL) with an elimination t1/2 of approximately 7 hours.  
Data from the INS1009-102 SAD/MAD study of TPIP reinforced the study design and informed 
maximum dosage for the optional extended use portion of the study (Section 4.3.2). In the first 
SAD portion of INS1009-102 (SAD1), 18 participants were randomized to 1 of 3 TP dose levels 


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of TPIP: 112.5 μg, 225 μg, or 450 μg of TP (6 participants at each dose). Treprostinil peak 
concentrations in the SAD portion were attained at 1.5 to 3 hours post-dose; Cmax and AUC were 
dose-dependent and approximately proportional to the increase of dose; and elimination t1/2 was 
8.7 to 11.6 hours. Total treprostinil exposure (AUC) of treprostinil was found to be dose 
proportional following a single administration of TPIP across the dose range of 112.5 μg to 
675 μg.  
Based on this Phase 1 study experience, the first participant is expected to be dosed with 
112.5 µg of TP. However, if the 112.5 µg formulation is not available due to expiry, it is 
acceptable to use the 80 µg formulation (described in more detail in Section 4.3.2). 
Administration of TPIP will be via inhalational dry powder packaged in single actuation 
capsules. Each capsule with 112.5 µg of TP contains the molar equivalent of 71 µg of TRE and 
7.5 mg of dry powder. Approximately 85 µg of TP (54 µg of TRE equivalent) will be emitted 
from the dry powder inhalation device for this formulation. This is comparable to a single 
administration of Tyvaso for patients with PAH with the target dose being 54 µg QID. Single 
doses of up to 90 µg of Tyvaso have been administered in clinical studies of healthy volunteer 
participants (Tyvaso Package Insert, 2017).  
Each participant will receive a single dose administration of TPIP. A TPIP dose containing 
112.5 µg of TP (or 80 µg, depending on 112.5 µg expiry) will be given to the first participant in 
Study INS1009-201. All available data (PD, PK, safety) from the first participant will be 
assessed and evaluated by the SRC. Following this evaluation, the SRC will determine if it is 
safe to continue the study, the TPIP dose level and any changes to safety PD and PK assessments 
for the second participant (Figure 3). This process will be repeated using the total accrued data of 
all completed participants prior to determining the TPIP dose for each subsequent participant. 
There will be no simultaneous dosing of inpatient participants; each participant will be treated as 
an individual case for evaluation. The TP dose level for each subsequent participant may be 
increased, held stable or lowered, depending on the accumulating data from previous participants 
up to a maximum of 675 µg. TPIP dosing may also be stopped at any dose level as determined 
by the SRC. 
4.3.2. 
Optional Extended Use Treatment Period 
Selection of once-daily inhalation of TPIP at 80 – 640 µg was based on clinical PK and safety 
data from healthy participants, predicted efficacious dose levels using pre-clinical data, safety 
margin from rat and dog NOAEL doses, and Tyvaso® clinical experience.  
In Phase 1 studies, TRE PK was linear, and the systemic exposure was dose proportional. Single 
doses of up to 675 µg and multiple doses of up to 225 µg TPIP QD for 7 days were generally 
well tolerated. Most AEs observed were mild in severity and consistent with the safety profile of 
other prostanoid therapies.  
Based on exposures following a single dose of TPIP 675 µg in Study INS1009-102, TRE 
exposures in this study are not anticipated to exceed those following administration of the 
currently approved treprostinil product, Remodulin®. Treprostinil exposures following a 
continuous IV infusion of 10 ng/kg/min Remodulin (Cmax 1,470 pg/mL; AUC 25,690 pg*h/mL) 
are reported to be 2.1-fold and 4.7-fold higher, respectively, than those observed following 


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administration of TPIP 675 μg (Cmax 717 pg/mL; AUC 5,480 pg*h/mL) (Laliberte et al., 2004). 
Minimal accumulation was observed following repeat doses of TPIP 225 μg QD for 7 days, and 
since a lower maximum dose (640 μg) will be used in the extended use portion of this study, 
TRE exposures are expected to be lower than those observed following single doses of TPIP 
675 μg in Study INS1009-102. 
Based on the findings above, the TPIP dose will range from 80 µg to 640 µg QD in this 
treatment period.  
4.4. 
Study Completion 
A participant will be considered to have completed the study if he/she has completed the 
Study Day 30 safety follow-up (shown in Table 1) and has not elected to enter the optional EUT 
period. A participant who has entered the optional EUT period will be considered to have 
completed the study if he/she has completed the EUT period safety follow-up (EUT Day 142). 
The study will be considered completed on the date of the last safety follow-up of the last 
participant in the study.  
 


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5. 
STUDY POPULATION 
The study is expected to recruit approximately 6 to 10 participants at up to 12 centers with 
appropriate inpatient facilities. Eligible participants must have clinically stable disease of mild to 
moderate severity, with good to moderate functional status. Participants may not be taking more 
than 2 medications from the following classes: 
• Endothelin receptor antagonists (eg ambrisentan, bosentan, macitentan), 
• Phosphodiesterase type 5 inhibitors (eg sildenafil, tadalafil) 
• Guanylate cyclase stimulator (eg riociguat) 
It is expected that the site will recruit appropriate potential participants according to the criteria 
in Section 5.1 and Section 5.2.  
 
The study inclusion and exclusion criteria include thresholds of selected RHC and ECG 
parameters that must be met at Baseline or the participant will not be considered eligible for the 
study. In this case, the participant is to be reported as a Screen Failure (Section 5.4). 
5.1. 
Inclusion Criteria 
 
Participants are eligible to be included in the study only if they meet all of the following criteriaa: 
Age:  
1. Participant must be ≥ 18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants must have a diagnosis of WHO Group 1 PH (PAH) with the following 
characteristics (Galie et al., 2016): 
a. Etiology of idiopathic, heritable, drug/toxin-induced or connective tissue 
disease (CTD)-related PAH; 
b. Right heart catheterization with the following hemodynamic findings:  
- Mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest,  
- Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
- Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 
3. PAH diagnosis of at least 1 year 
4. New York Heart Association (NYHA)/WHO Functional capacity Class I-III 
5. No change in pulmonary hypertension medications (e.g., ambrisentan, bosentan, 
macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 90 days prior to 
Screening.  
6. No change in diuretic use or dosage for at least 30 days prior to Screening 


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7. Documented predicted percent forced vital capacity (FVC) > 70% within 1 year of 
Screening. If not available, pulmonary function testing will be performed at 
Screening (Table 1). 
8. At least 2 of the following European Respiratory Society/European Society for 
Cardiology (ERS/ESC) low risk criteria: 
a. NT-pro-BNP concentration < 300 ng/L within 6 months of Baseline (if not 
available will be obtained at Screening, Table 1). 
b. Historical documentation of 6- minute walk distance (6MWD) > 440 
meters within 6 months prior to Baseline. If not available will obtain 
6MWD test at Screening (Table 1). 
c. Right atrial pressure (RAP) < 8 mmHg within 1 year prior to Baseline 
d. Cardiac Index (CI) ≥ 2.5 L/min*m2 or mixed venous oxygen saturation 
(MVO2) > 65% within 1 year prior to Baseline 
9. Right heart catheterization at Baseline with the following hemodynamic findings: 
a. Mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest,  
b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
c. Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 
Weight 
10. Body mass index (BMI) within the range 18.0 - 32.0 kg/m2 (inclusive). 
Sex and Contraceptive/Barrier Requirements 
11. Male participants:  Male participants and their female partners of childbearing 
potential must agree to use highly effective contraception from Study Day 1 to at 
least 90 days after dosing. 
12. Female participants:  Women of child-bearing potential (WOCPB, defined as 
premenopausal, not surgically sterile for at least 3 months prior to Screening) must 
use a highly effective contraception method and agree to be tested for pregnancy 
from at Screening, Baseline, and 30 days after dosing. 
See Section 10.4 for contraceptive guidance. 
Informed Consent 
13. Capable of giving signed informed consent as described in Section 10.1.5 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
a Please note that participants who enroll in the optional EUT period beyond the initial 30 day follow-up period will 
be screened to confirm that they still meet inclusion/exclusion criteria. Please refer to Table 5.  
 


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5.2. 
Exclusion Criteria  
 
Participants are excluded from the study if they meet any of the following criteriaa: 
Medical Conditions 
1. Any PH other than idiopathic, hereditary, drug/toxin-induced, or connective tissue 
disease (CTD) associated PAH (e.g., congenital heart disease-associated PAH, 
portal hypertension-associated PAH, PH belonging to Groups 2 through 5) 
2. Allergy, or documented hypersensitivity or contraindication, to the ingredients of 
treprostinil palmitil inhalation powder (TPIP) or treprostinil (TRE). 
3. Previous intolerance to prostacyclin analogs or receptor agonists (e.g., selexipag) 
per Investigator discretion 
4. History of anaphylaxis or previously documented hypersensitivity reaction to any 
drug per Investigator discretion 
5. QTcF interval > 480 ms on resting ECG at Baseline 
6. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% 
or clinically significant valvular, constrictive, or atherosclerotic heart disease 
(myocardial infarction, etc) 
7. Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) 
at Screening. 
8. Active liver disease or hepatic dysfunction manifested as: 
a. Elevated liver function test results (ALT or AST > 2 × ULN) at Screening 
b. Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable 
if bilirubin is fractionated and direct bilirubin < 35%) at Screening. 
c. Known hepatic or biliary abnormalities, not including Gilbert's syndrome or 
asymptomatic gallstones at Screening.  
9. History of HIV infection/positive HIV serology test result at Screening. 
10. History of active/chronic Hepatitis B or C/ positive hepatitis B or C serology test 
result at Screening 
11. History of abnormal bleeding or bruising. 
12. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or 
otherwise recurrent infections of abnormal frequency, or prolonged infections 
suggesting an immune-compromised status, as judged by the Investigator. 


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13. Active and current symptomatic infection by SARS CoV 2. Additional COVID 19 
restrictions per institutional guidelines (See also Section 10.1.3.1.3) 
14. Participants with current or recent (past 4 weeks) lower respiratory tract infection 
(may be re-screened at appropriate time (Section 5.4) 
15. History of malignancy in the past 5 years, with exception of completely treated in 
situ carcinoma of the cervix and completely treated non-metastatic squamous or 
basal cell carcinoma of the skin. 
Concomitant Therapy 
16. Participants receiving triple combination therapy for PAH consisting of endothelin 
receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase 
stimulators (riociguat). 
17. Participants receiving prostanoids/prostacyclin agonists 
18. Participants receiving potent CYP2C8 inhibitors, such as gemfibrozil 
19. Other prior/concomitant therapies are allowed/disallowed at the Investigator’s 
discretion 
Prior/Concurrent Clinical Study Experience 
20. Have participated in any other interventional clinical studies within 30 days of 
Baseline 
Diagnostic assessments 
21. Any clinically significant abnormal laboratory, value, test result, or physical 
examination finding at Screening; diseases or diagnoses/disorders that, in the 
opinion of the Investigator, may put the participant or others at risk by participating 
in the study, interfere with the participant's treatment and assessment, or influence 
the results of the study; or have compliance issues with the study. 
Other Exclusions 
22. Current or history of substance and/or alcohol abuse per Investigator assessment 
23. Current user of cigarettes or e-cigarettes 
24. Pregnant or breastfeeding. 
a Please note that participants who enroll in the optional EUT period beyond the initial 30 day follow-up period will 
be screened to confirm that they still meet inclusion/exclusion criteria. Please refer to Table 5.  
 
 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are required. 


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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study because they did not meet all inclusion criteria or meet one 
or more exclusion criteria. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened twice at the Investigator’s discretion. If a participant can be rescreened, the PI is to 
consult with the Medical Monitor to determine whether some or all of the screening assessments 
must be repeated. Rescreened participants will sign a new ICF and will be assigned a new 
participant number. 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period 
Following successful screening and meeting of study eligibility criteria, the inpatient treatment 
period and RHC procedure must be scheduled without delay.  
 
The scheduled treatment period may be temporarily delayed no longer than 28 days by the 
Investigator in consultation with the Medical Monitor for valid reasons. Examples of valid 
reasons for delaying the treatment period may include such things as a life event for the 
participant (eg death in the family), local public health emergency (e.g., COVID 19 outbreak), 
site facility issues (e.g., catheterization lab or ICU bed availability), or pending TPIP dosing 
directives from the SRC. 
 
A temporary delay in the scheduled inpatient treatment period for a valid reason may result in 
previously met Inclusion Criteria that rely on a time window to be not met (e.g., 6MWD falls 
outside the 6 months prior to Baseline window). This is not considered to be a Screen Failure. In 
this case, the Investigator should consult with the Medical Monitor to identify which screening 
tests need to be conducted or repeated to ensure that the participant meets study inclusion criteria 
and can safely participate in the study.  
 
Deterioration of the participant’s medical condition is not a valid reason to delay start of the 
inpatient treatment period. In some cases, delaying the inpatient treatment period may cause the 
participant to meet one or more exclusion criteria (e.g., participant develops a lower respiratory 
infection). In this case the participant should be considered a Screen Failure and Section 5.4 
applies. 


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6. 
STUDY IMP AND CONCOMITANT THERAPY 
Study IMP is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study IMP Administered 
6.1.1. 
Inpatient Treatment Period (Single Dose) 
A single dose of TPIP will be used in the inpatient treatment period, as listed below. A dose may 
consist of a single capsule or of multiple capsules administered in succession. 
Name of 
Treatment 
Dose 
Supplied 
Formulation 
Route and 
Frequency of 
Administration 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or more single actuation 
capsules  
Single actuation 
capsules containing 
112.5 µg TP per 7.5 
mg powder 
Inhalation; single 
dose after Baseline 
assessments 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or more actuation capsules 
(80 µg, 160 µg, 240 µg, 320 µg, 
400 µg, 480 µg, or 640 µg) 
Dry powder single 
actuation capsules 
containing 
80 µg, 160 µg, or 
320 μg 
Inhalation; single 
dose after Baseline 
assessments 
QD = once daily 
6.1.2. 
Optional Extended Use Treatment Period 
The IMP used in the EUT period will be capsules containing 1 of 3 dosage strengths of TPIP (80 
µg, 160 µg, or 320 µg). IMP should be taken around the same time every day. Administration of 
IMP will be via inhalational dry powder packaged in single actuation capsules. One or 2 capsules 
will be administered for each dose. Administration of 2 capsules should be done sequentially. 
Each TPIP capsule contains 8 mg, 16 mg, or 32 mg of dry powder containing 80 µg, 160 µg, or 
320 µg of the TP prodrug, respectively.  
 
Name of 
Treatment 
Dose 
Supplied Formulation 
Route of Administration 
Treprostinil 
palmitil 
inhalation 
powder (TPIP) 
One or two single 
actuation capsules 
(80 µg, 160 µg, 240 µg, 
320 µg, 400 µg, 480 µg 
or 640 µg QD) 
Dry powder single 
actuation capsules 
containing 
80 µg, 160 µg, or 320 μg 
Inhalation (QD) 
QD = once daily 


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6.1.3. 
Medical Devices 
In the planned clinical study, the TPIP will be administered by oral inhalation using a Plastiape 
capsule-based Dry Powder Inhaler (RS 01 Mod 7). A Type III Drug Master File is filed at the US 
FDA and the RS01 inhaler is classified as a Class I medical device. The Instructions for Use of 
the device document is provided separately as an Appendix to the Pharmacy Manual. 
 
All device deficiencies (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the Investigator throughout the clinical investigation (Section 8.3.7) 
and appropriately managed by Insmed. 
6.2. 
Preparation/Handling/Storage/Accountability 
Insmed Incorporated will provide the Investigator and clinical unit with adequate quantities of 
TPIP capsules. For 112.5 µg doses, TPIP-filled HPMC capsules will be delivered in HDPE 
bottles overwrapped with an aluminum pouch, containing a sachet of desiccant to prevent 
moisture ingress. For 80 µg, 160 µg, and 320 µg doses, HDPE bottles will be closed with the 
desiccant placed inside the bottle, and induction sealed. The powder will be administered by oral 
inhalation using a Plastiape capsule-based Dry Powder Inhaler. 
6.2.1. 
Inpatient Treatment Period (Single-dose) 
Directions for preparation and administration of the TPIP dose to the participant are provided in 
a separate document as an Appendix to the Pharmacy Manual for the single-dose Inpatient 
Period. 
All study IMP must be stored according to the labeled instructions in a secure cabinet or room 
with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. Current stability 
data supports the shelf life assigned to TPIP when stored at 2 to 8 °C. 
• The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study IMP received and any discrepancies are 
reported and resolved before use of the study IMP. 
• Only participants enrolled in the study may receive TPIP and only authorized site 
staff may supply or administer it. All TPIP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
• The Investigator, institution, and/or pharmacist or designee is responsible for study 
IMP and dosing devices accountability, reconciliation, and record maintenance (e.g., 
receipt, reconciliation, and final disposition records). 
• Study IMP and dosing device accountability records will be maintained for all clinical 
supplies. All transactions will be recorded on the drug and dosing device 
accountability records including shipment receipts and study participant doses. All 
transactions will be recorded on a real-time basis. 


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• The Investigator/site will maintain detailed documentation of the number and 
identification of bottles and dispensing units of TPIP with copies of these documents 
to be provided to Insmed at the end of the study. All used and unused study IMP and 
dosing devices will be maintained by the site until inventoried by the study monitor. 
Upon completion of the study IMP and dosing device inventory by the study monitor, 
used and any unused study IMP and dosing devices will be disposed of in accordance 
with instructions provided to sites and according to site destruction policies. 
Documentation of destruction must be provided to Insmed. 
• Further guidance and information for the final disposition of unused study IMP 
supplies can be obtained from Insmed. 
6.2.2. 
Optional Extended Use Treatment Period 
Directions for preparation and administration of IMP to the participant in-clinic are provided in 
the Pharmacy Manual for the optional EUT period. Directions for preparation and administration 
of IMP for home use will be provided to the participants. 
Only participants enrolled in the study may receive IMP, and only authorized study personnel 
may supply IMP. All IMP must be stored according to the labeled instructions with access 
restricted to necessary clinic personnel. The site will be required to keep a temperature log to 
establish a record of compliance with storage conditions. Refer to the Pharmacy Manual for the 
optional EUT period for shelf-life and storage conditions. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP and dosing devices accountability, reconciliation, and record maintenance 
(e.g., receipt, reconciliation, and final disposition records). Directions for storage, handling, 
accountability, and destruction are provided in the Pharmacy Manual for the optional EUT. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 
6.4. 
Study Intervention Compliance 
6.4.1. 
Inpatient Treatment Period (Single Dose) 
Study participants will receive the TPIP dose directly from the Investigator or designee, under 
medical supervision, in an appropriate inpatient setting. The date and time of the dose 
administered will be recorded in the source documents. The dose of TPIP and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the TPIP. 
6.4.2. 
Optional Extended Use Treatment Period 
At each in-clinic visit, participants will be dispensed adequate IMP to allow for daily dosing. 
When participants are dosed at the site, IMP administration will be overseen by study site 
personnel. The date and time of each dose self-administered in the clinic will be recorded in the 


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source documents. The dose of IMP and study participant identification will be confirmed at the 
time of dosing by a member of the study site personnel. 
When participants administer IMP at home, compliance with IMP will be assessed at each 
in-clinic visit. Participants will record their daily dose on paper dosing diaries. Compliance will 
be assessed by direct questioning, review of participant dosing diaries, and counting of returned 
capsules during the site visits. Participants will return unused capsules and used study capsules 
and devices to the study site at each in-clinic visit. Participants who undergo a study drug taper 
will return unused capsules and used capsules and devices to the study site at a follow-up visit. 
Unused capsules should be returned in the bottle they were dispensed in. Deviation(s) from the 
prescribed dosage regimen should be recorded.  
A record of the quantity of capsules dispensed to and administered by each participant must be 
maintained and reconciled with study drug logs and participant dosing diaries. Study drug start 
and stop dates, including dates for study drug interruptions and/or dose reductions will also be 
recorded. 
6.5. 
Dose Modification 
Dose modification is part of the study design and is described in detail in Section 4.3 and 
Section 1.3.2. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
An overdose is defined as the participant receiving any TPIP in excess of their assigned dose as 
predetermined by the SRC (Section 4.3). An overdose itself is not an AE. However, if the 
overdose results in clinical signs and symptoms, it requires expedited reporting as if it is an SAE. 
The Investigators must refer to the relevant documents for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the study 
IMP. Such documents may include, but are not limited to, the Investigator’s brochure. 
In the event of an overdose, the Investigator must: 
• Contact the Medical Monitor within 24 hours. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, how to 
proceed with treatment period procedures and assessments. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until TP or 
TRE is likely to be sufficiently metabolized and/or excreted and/or can no longer be 
detected systemically. The frequency and duration of plasma sampling from the last dose 
of TPIP must be determined by the Investigator in conjunction with the study team and 
Medical Monitor. 
• The overdose must be fully documented (e.g., quantity of the excess dose, duration of the 
overdose, how it happened) in the CRF. 


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6.8. 
Concomitant Therapy 
Any medications, treatments, or therapies that the participant is receiving at Baseline 
(Study Day 1) or receives during the study (Study Day 1 through end of study [EOS]) are 
considered concomitant therapy and will be collected and documented in the study CRF.  
Documentation includes the name of the therapy, with the reason for use, the dates of 
administration including start and end dates, and dosage information including dose and 
frequency.  
Prior medications are those medications taken before the first dose of study IMP. A medication 
that starts prior to first dose but continues after the first dose of study IMP is classified both in 
prior and concomitant medications. Any procedures performed from Day 1 through EOS are 
considered concomitant procedures and will be collected and documented in the study CRF. 
The Medical Monitor must be contacted if there are any questions regarding concomitant or prior 
therapy. 
For participants who enroll in the EUT period, new concomitant therapy for the period from the 
single-dose Study Day 30 follow-up until the enrollment in the EUT will be collected during 
participant’s screening for the EUT. 


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7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study IMP 
7.1.1. 
Single-dose Period 
This is a single dose period; not applicable. 
7.1.2. 
Optional Extended Use Treatment Period 
If study drug is permanently discontinued, the participant will be encouraged to participate in 
their remaining study visits. See Table 6 for data to be collected at the time of discontinuation of 
IMP and follow-up. If a participant discontinues the study and needs to be started on another 
PAH medication, the Investigator should contact the Medical Monitor.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or compliance 
reasons.  
At the time of discontinuing from the study after study drug administration, if possible, an early 
discontinuation evaluation should be conducted to maximize participant safety. This final 
evaluation and the reason for participant withdrawal must be documented in the CRF.  
The participant will be permanently discontinued both from the study drug and from the study at 
that time. 
If the participant is discontinued from the study due to an SAE, the Investigator will follow the 
participant until the Investigator deems that the SAE has resolved or stabilized.  
The Investigator may withdraw the participant from the study due to absence of a PD response to 
TPIP. Lack of expected pharmacological action per se will not be reported as an AE or SAE. 
Such instances will be captured in the PK and PD assessments. 
If the participant withdraws consent for disclosure of future information, Insmed may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled follow-up visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of 


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maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
must be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered 
lost to follow-up and to have withdrawn from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants, 
including those who did not get study IMP. Public sources may be searched 
for vital status information.  If vital status is determined as deceased, this will 
be documented and the participant will not be considered lost to follow-up. 
Insmed personnel will not be involved in any attempts to collect vital status 
information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.13.2). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Table 1, Table 2, Table 3, Table 4, Table 5, 
Table 6.  
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet eligibility criteria prior to scheduling the study RHC procedure and inpatient admission. 
The RHC procedure and inpatient admission must be scheduled for as soon as possible once the 
participant’s eligibility for the study is confirmed by screening. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., previous 
RHC, previous echocardiogram, previous 6MWD test) and obtained before signing of the ICF 
may be utilized for screening or Baseline purposes provided the procedures meet the protocol-
specified criteria and were performed within the time frames defined in the inclusion and 
exclusion criteria in Section 5.  
For participants who do not elect to enter the EUT period, the maximum amount of blood 
collected from each participant over the duration of the study, including any extra assessments 
that may be required is expected to be approximately 140 mL and will not exceed 200 mL. 
Approximately 80 mL will be required for PK sampling over 48 hours and approximately 20 mL 
for biomarker sampling. Safety and screening blood samples will require 
approximately 20 to 30 mL. Blood loss from the RHC procedure is anticipated to be negligible. 
For participants who do elect to enter the optional EUT period within the 30 day follow-up 
window in the single-dose period, there is no anticipated blood collection. For participants who 
elect to enter the optional EUT period after the 30 day follow-up in the single-dose period, 
Safety and screening blood samples will require approximately 20 to 30 mL. Blood loss from the 
RHC procedures is anticipated to be negligible.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples at the Investigator’s discretion. 
At any time, the Investigator has the option to discontinue assessments for participant safety or 
tolerability reasons. Additional laboratory, PK, and/or hemodynamic assessments may be 
performed as deemed necessary for participant safety. Following completion of scheduled 
events, the Investigator has the option of continued laboratory and/or hemodynamic monitoring 
as deemed appropriate for participant safety. If, in the interest of participant safety, the 
Investigator omits scheduled assessments/procedures or performs additional 
assessments/procedures, the reason for doing so must be reported on the CRF as an AE in order 
to avoid a protocol violation. 
8.1. 
Pharmacodynamic Assessments 
The results of each individual participant’s PD assessments will contribute to the dosing decision 
for the next participant (Section 4.3).  


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8.1.1. 
Required PD Assessments with RHC 
PVR, CO, PAP (mean), RAP (mean), RVP, hemoglobin, and MVO2 will be measured via the 
RHC at the time points indicated in the SoA (Table 2). Oxygen consumption is part of the MVO2 
calculation and may be measured or estimated at 125 mL O2 per square meter (m2) of body 
surface area (BSA). These or other parameters may be optionally measured at other time points 
or omitted to ensure participant safety at the Investigator’s discretion. If measurements are 
missed, or additional measurements are taken for safety purposes, the reason must be 
documented as an AE in the CRF. 
Institutional procedures for insertion, care, monitoring, and removal of the RHC will be 
followed. Specific technique and procedures for measurement of PVR, CO, PAP, RAP, RVP, 
hemoglobin, oxygen consumption, and MVO2 are provided in a separate Procedure Guide. 
8.1.2. 
Required Non-invasive PD Assessments 
Systemic blood pressure (mmHg) may be measured by inflatable cuff. Systemic blood pressure 
must include 3 values:  systolic, diastolic, and mean arterial pressure. Arterial oxygen saturation 
(SpO2, %) and heart rate (beats per minute) may be measured by pulse oximeter.  
8.1.3. 
Resting Respiratory Gas Exchange Assessments 
Specific measurements for resting respiratory gas exchange assessment include changes from 
Baseline in respiratory rate (breaths per minute), minute ventilation (mL per minute), carbon 
dioxide production (VCO2, mL per minute), end tidal oxygen concentration (ETO2, %), and end 
tidal carbon dioxide concentration (ETCO2, %). The gas exchange parameters will be monitored 
at the same time points as the PD assessments in Section 8.1.1 (Table 2, Table 4). Specific 
instructions for resting respiratory gas exchange assessment procedures and measurements are 
provided in a separate Procedure Guide. 
8.1.4. 
Transthoracic Echocardiogram Assessments 
Transthoracic echocardiogram is to be performed at Baseline and during a 2-8 hour window 
following TPIP administration (Table 4). Specific instructions for echocardiographic procedures 
and measurements are provided in a separate Procedure Guide. 
8.1.5. 
Pulmonary CT Scan 
8.1.5.1. 
Single-dose Period 
Pulmonary CT scanning to assess pulmonary vasculature and blood flow is scheduled for 
Baseline and during a 4-8 hour window following TPIP administration (Table 4). Specific 
requirements and instructions for pulmonary CT scanning and required parameters are provided 
in a separate Procedure Guide. 


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8.1.5.2. 
Optional Extended Use Treatment Period 
An optional pulmonary CT scan may be performed at first visit (±3 days) and at EUT Week 16 
(±3 days) in the optional EUT period, as indicated in Table 6. The CT scan will be performed 
according to instructions provided by the CT scan vendor. 
8.2. 
Safety Assessments 
 
Evaluation of the safety and tolerability of single doses of TPIP in participants with PAH is the 
primary objective of this study. Planned time points for all safety assessments are provided in 
Table 1 and Table 2. The results of the individual participant’s safety assessments during and 
after TPIP administration will contribute to the dosing decision for the next participant 
(Section 1.3.2). Participants who elect to enter the optional EUT period will also be monitored 
for safety, as listed in Table 6.  
8.2.1. 
Physical Examinations 
Screening: The physical examination must focus on those areas that determine the individual 
participant’s eligibility to participate in the study and do so safely at the Investigator’s discretion 
and will be documented accordingly.  
Baseline:  The physical examination must focus on the participant’s fitness for the study 
procedures and TPIP administration.  
Discharge:  The physical examination must focus on the participant’s fitness to be safely 
discharged to home from the inpatient setting.  Special attention must be paid to assessment of 
any new or ongoing AEs. 
Follow-up: The in-person physical examination must focus on participant safety and assessment 
of AEs that were ongoing at discharge or have occurred since discharge. 
8.2.2. 
Vital Signs 
8.2.2.1. 
Single-dose Period 
Temperature, heart rate, respiratory rate, and blood pressure at screening and 48 hour post-TPIP 
administration follow-up will be per the Investigator’s usual outpatient practice and documented 
accordingly. 
Baseline and post-TPIP administration:  Changes from Baseline in heart rate, respiratory rate, 
and systemic blood pressure are PD endpoints as well as safety variables and must be measured 
as specified (Section 8.1). Vital signs outside of PD endpoints will be monitored per the inpatient 
unit’s usual practices. 
8.2.2.2. 
Optional Extended Use Treatment Period 
Changes in heart rate, respiratory rate, body temperature, and systemic blood pressure will be 
monitored as described in Table 6. Vital signs will be measured at Extended Use 


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Screening/Baseline (EUT Day 1), EUT Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and 
EUT Week 16 and at the Early Discontinuation visit, if appropriate. 
8.2.3. 
Electrocardiograms 
Screening:  a single 12-lead ECG will be conducted per the Investigator’s usual practice 
Baseline: A single 12-lead ECG will be performed to ensure the participant’s eligibility for the 
study (Section 5.2). Inpatient telemetry monitoring will be utilized per the unit’s usual practice 
until the participant is discharged from the inpatient setting, but routine telemetry readings will 
not be collected as study data unless they pertain to a relevant AE. 
48 hours post-TPIP administration follow-up:  a single 12-lead ECG will be conducted per the 
Investigator’s usual practice. 
8.2.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 (Table 7) for the list of clinical laboratory tests to be performed and the SoA 
(Table 1, Table 2, Table 5, Table 6) for the timing and frequency. All clinical laboratory tests 
will be performed locally by the study site. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 7 days after TPIP dosing must be repeated at the Investigator’s discretion, 
consistent with the participant’s level of disease until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator or Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology must be identified, and Insmed 
notified.] 
• All protocol-required laboratory tests, as defined in Section 10, Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.4). 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.5. 
Pregnancy Testing 
8.2.5.1. 
Single-dose Period 
Willingness of WOCBP to undergo serum or urine pregnancy testing is a study eligibility 
criterion. Pregnancy tests will be conducted at screening, baseline, and Study Day 30. WOCBP 


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participants will be provided a home pregnancy test kit with instructions to conduct and report 
test results at the Study Day 30 follow-up visit which is scheduled to be by telephone call or 
telemedicine. If the participant elects to enter the optional EUT period and the remote safety 
follow-up visit overlaps with the start of the EUT period, the results of a urine pregnancy test 
will be recorded at the first visit in the extended treatment period.  
8.2.5.2. 
Optional Extended Use Treatment Period 
Urine pregnancy tests will be performed in-clinic at EUT Baseline (EUT Day 1) in WOCBP. 
WOCBP participants will be provided home pregnancy test kits with instructions to conduct the 
pregnancy tests every 30 days or more if required during the treatment and follow-up periods. 
Study site personnel will contact the participant every 30 days by telephone and record the 
pregnancy test results. An additional on-site urine test must be performed prior to starting any 
procedure that requires the use of ionizing radiation. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). AEs may be solicited or unsolicited. Solicited and 
unsolicited AEs are defined in Section 10.3. 
The Investigator is responsible for detecting, documenting, and recording events that meet the 
definition of an AE or SAE as provided in the protocol and remain responsible for following up 
all AEs. 
The Investigator should proactively follow participants with AEs until the EOS for each 
participant. At the EOS visit, the Investigator will record the AE status (stable or not stable) in 
the electronic CRF. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs (serious and non-serious) for the core, single-dose period will be collected from the 
signing of the ICF until the Study Day 30 follow-up visit at the time points specified in the SoA 
(Table 1, Table 2). Medical occurrences that begin after obtaining informed consent but before 
TPIP administration will be recorded as Medical History/Current Medical Conditions, not as 
AEs. 
SAEs that occur after signing the ICF but before study IMP starts must be recorded and reported 
as SAEs. Non-serious medical occurrences that begin after obtaining informed consent but 
before TPIP administration will be recorded as Medical History/Current Medical Conditions, not 
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For participants who enroll in the EUT period, AEs for the period from the single-dose Study 
Day 30 follow-up until the enrollment in the EUT will be collected during participant’s screening 
for the optional EUT period. All AEs and SAEs for participants who choose to enroll in the 
optional EUT period will be recorded at the time points specified in the SoA (Table 5, Table 6).  
All SAEs will be recorded and reported to Insmed or designee immediately and under no 
circumstance must this exceed 24 hours, as indicated in Appendix 3, (Section 10.3). The 
Investigator will submit any updated SAE data to Insmed within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IMP or study participation, the Investigator must promptly notify 
Insmed. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. The Investigator should proactively follow participants 
with AEs until the EOS for each participant. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool has been 
taken offline due to study completion, then the site can report this information to the Medical 
Monitor by email or telephone. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to Insmed of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
Insmed has a legal responsibility to notify relevant health authorities and regulatory agencies 
about the safety of a study drug under clinical investigation. This study is being conducted in the 
USA only; regulatory requirements relating to safety reporting to the US FDA, IRBs, and 
investigators will be followed. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from Insmed will review and then file it 
along with other study documents and will notify the IRB, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Insmed policy and forwarded to Investigators as necessary. No serious adverse 


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reactions are considered expected for TPIP. Please refer to the Reference Safety Information in 
Section 6.1 of the Investigator’s Brochure. 
8.3.5. 
Pregnancy 
Details of all pregnancies that occur in WOCBP participants within 30 days after TPIP 
administration will be collected. Male participants with WOCBP partners must continue to use 
contraception for 90 days after TPIP administration and report any pregnancies that occur within 
that time period.  
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to Insmed within 24 hours of learning of the pregnancy in a female participant 
or female partner of male participant and after obtaining the necessary signed informed consent 
from the female partner. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from the study. 
8.3.6. 
Adverse Events of Special Interest (AESI) 
There are no AESIs for TPIP that require special collection and rapid communication by the 
Investigator. 
8.3.7. 
Medical Device Deficiencies 
A medical device, the Plastiape capsule based Dry Powder Inhaler is being provided for use in 
this study to administer TPIP. To fulfill regulatory reporting obligations worldwide, the 
Investigator is responsible for the detection and documentation of events meeting the definitions 
of device deficiency that occur during the study with such devices. 
The definition of a Medical Device deficiency and reporting requirements and procedures for 
device deficiencies and AEs/SAEs resulting from device deficiencies can be found in 
Section 10.6.  
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• If the Investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 
related to a medical device provided for the study, the Investigator will promptly 
notify Insmed. 
The method of documenting Medical Device Deficiency is provided in Section 10.6. 


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8.3.7.2. 
Follow-Up of Medical Device Deficiencies 
Follow-up applies to all participants who experienced a device deficiency. 
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the Investigator. 
8.3.7.3. 
Prompt Reporting of Device Deficiencies to Insmed 
Device deficiencies will be reported to Insmed within 24 hours after the Investigator determines 
that the event meets the protocol definition of a medical device deficiency. 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies 
The Investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for Insmed to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
The Investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB. 
8.4. 
Pharmacokinetic Assessments 
The schedule for PK assessments and sampling windows during the single-dose period is shown 
in Table 3. The 48 (± 4) hour post-TPIP administration blood draw is expected to be done on an 
outpatient basis. 
8.4.1. 
PK Sample Collection 
Plasma blood samples of approximately 10 mL each will be collected for measurement of plasma 
concentrations of TP and TRE as specified in the SoA (Section 1.4).  
A maximum of 2 samples may be collected at additional time points during the study if an SAE 
occurs or at early termination.  
Each PK plasma sample will be divided into 2 aliquots (1 each for PK analysis and the other for 
backup. All samples will be stored frozen (-70°C or -20°C) until shipment and then stored at -
70°C until analysis. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Full instructions for the collection and handling of PK samples will be provided by Insmed in a 
separate Laboratory Manual.  
8.4.2. 
PK Analysis 
Individual PK parameters of TRE and TP will be determined using non-compartmental analysis 
for the following parameters: Cmax, tmax, AUCt1–t2, AUC0–∞, CL/F, Vd/F, and t1/2. 


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8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Relationships between PK (TP dose and TRE exposure) and PD effects and safety will be 
explored and reported separately. 
8.5. 
Genetics / Pharmacogenomics 
Genetic and/or pharmacogenomic analyses are not included in this study. 
8.6. 
Biomarkers 
A blood sample for NT-pro-BNP will be taken at screening if needed as part of study inclusion 
criteria (Section 5.1).  
Blood samples (5-7 mL per time point) will be collected for biomarker measurement at Baseline 
and at 4 and 8 hours after TPIP administration. The plasma generated from the blood samples 
will be stored frozen (-70 C or lower is preferred) until shipment and analysis. 
Full instructions for the collection and handling of biomarker samples will be provided by 
Insmed in a separate Laboratory Manual. 
8.7. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity assessments do not apply to this study of a small molecule. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be evaluated in this study. 
9.2. 
Sample Size Determination 
The sample size for this study is not based on statistical power calculations. The planned number 
of evaluable participants to complete the study is approximately 6-10.  
9.3. 
Analysis Sets 
The analysis sets comprise participants who are considered evaluable for the parameters under 
consideration.  
All participants who receive a single dose of TPIP will be considered evaluable for safety and 
included in the safety population. 
All participants who receive a single dose of TPIP and have a least one measurable post-dose 
plasma TP/TRE concentration will be considered evaluable for PK and included in the PK 
population. 
All participants who receive a single dose of TPIP and have a Baseline datapoint and at least one 
measurable post-dose PD datapoint will be considered evaluable for PD and included in the PD 
population. 
All participants who receive a single dose of TPIP and have at least 1 measurable post-dose 
biomarker datapoint will be considered evaluable for biomarkers and included in the biomarker 
population. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to Database Lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1. 
General Considerations 
There is no hypothesis-testing in this study and no inferential statistical analyses will be 
conducted. There will be no proxy values for missing data. Participant PK, PD, and biomarker 
data will be presented individually in listings and graphs as appropriate for each variable.  
The frequency of TEAEs is the primary endpoint for this study. All safety analyses will be 
performed on the safety population. AE listings as required by ICH E3 guidelines will be 
produced. TEAEs, SAEs, AEs leading to treatment and/or study withdrawal, and AESIs will be 
listed for each participant along with outcome, severity, and relatedness to study IMP. Ad hoc 
summaries of TEAEs may be prepared if the volume of data allow.  
PK and PD values for secondary endpoints will be listed and graphed if appropriate for each 
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PK and PD values for exploratory endpoints will be listed and graphed as appropriate for each 
participant. 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values 
ECG data will be listed for each participant. Vital signs data that are not considered part of a PD 
assessment (Section 8.1) will be listed for each participant. Clinical laboratory values will be 
listed for each participant. 
9.5. 
Interim Analysis 
All available safety, PK, and PD data from each participant will be evaluated by the SRC prior to 
the next participant in order to determine the value of proceeding with the study and the TPIP 
dose for each subsequent participant (Section 4.3). 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
a. Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
b. Applicable ICH Good Clinical Practice (GCP) Guidelines 
c. Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, Instructions for Use of the 
Plastiape capsule based Dry Powder Inhaler, and other relevant documents must be 
submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
d. Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
e. Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
f. Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
10.1.2. 
Protocol Deviations 
The Investigator must conduct the study in compliance with the protocol as agreed to by Insmed 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRB. 
The Investigator must notify the IRB of deviations from the protocol in accordance with IRB 
reporting requirements.  
As of May 2020, due to concern regarding COVID-19, there may be restrictions to participant 
attendance at in-clinic visits or elective inpatient admissions. In the event participants are 
restricted to attend in-clinic visits, or if the participant has concern regarding travel and attending 
in-clinic visits (due to potential public health concerns), the site must contact Insmed on how to 


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conduct the scheduled assessments, and decisions must be documented in the source 
documentation. Where necessary, in-clinic visits may be conducted via telemedicine link and 
home health care visits. 
10.1.3. 
Public Health Emergency Situations 
During the COVID-19 public health emergency, Insmed, IRBs, and Investigators shall follow the 
most current version of local guidance to assure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. The continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms, 
which will remain in effect only for the duration of the local public health emergency. Examples 
of such mechanisms may include, but are not limited to, any of the following: telephone contact, 
virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use 
of local clinic or laboratory locations, and home visits by skilled staff. The site must contact 
Insmed on how and when to implement temporary and/or alternative mechanism of scheduled 
assessments, and all decisions taken must be documented in the source documentation. 
Additionally, all temporary mechanisms utilized, and the resulting deviations from planned study 
procedures are to be documented as being related to COVID-19. 
In a situation where local health authorities declare a public health emergency while the study is 
ongoing, the suggested guidance in the following subsections must be followed. 
10.1.3.1. Continuation or Suspension of the Study 
Ensuring the safety of trial participants is paramount. Insmed (Insmed Incorporated), in 
consultation with clinical Investigators and IRB, will determine if the protection of a 
participant’s safety, welfare, and rights are best served by continuing or stopping the trial at the 
specific site. Such decision will depend on specific circumstances, including the ability to 
conduct appropriate safety monitoring, the potential impact on the investigational product supply 
chain, and other considerations. 
If the decision is to continue the study, the following considerations will be taken into account: 
10.1.3.1.1. Study Recruitment 
Insmed will communicate to the sites the decision on whether to continue or suspend recruitment 
after considering the specific circumstances of each site, recommendation by the IRB, and its 
local health authority mandates. If, due to COVID-19, study discontinuation exceeds the 
assumed rate, Insmed may allow enrollment past the assumed sample size. 
10.1.3.1.2. Participants Already Enrolled in the Study 
If the decision is to continue the participation of participants already enrolled, the following steps 
must be taken:  
• If a participant is not able to complete a protocol specified study visit, it may be 
necessary to adjust the visit schedule, convert in-clinic visits to telemedicine visits, 
and/or postpone study procedures until the next available in-clinic study visit. If there 
is information available from previous visits (e.g., laboratory assessments) that 


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requires follow-up procedures or other safety assessments, the Investigator will 
decide if an on-site visit or home healthcare visit is required or whether the 
participant’s safety can be preserved by other means. 
10.1.3.1.3. Participants Infected by COVID-19 
If a participant has had a past documented mild to moderate COVID-19 infection prior to 
enrollment in the trial but the participant has recovered and the current diagnostic tests are 
negative (negative antigen by any diagnostic laboratory kit), the participant can be screened, at 
the Investigator’s discretion. Participants who experienced hospitalization, severe disease, and/or 
COVID-19 acute respiratory distress syndrome (ARDS) must be excluded. 
If a participant has a documented infection by COVID-19 while in the trial, the event will be 
reported as an AE or SAE, depending on the criteria. The Investigator will follow the guidance 
provided by health authorities in the treatment of those participants. 
10.1.4. 
Financial Disclosure 
The disclosed financial interest of the Investigator/sub-investigator must be collected before 
screening of the first participant, following study completion at the Investigator site and 1 year 
following overall study completion. The Investigator/sub-investigator must promptly update this 
information if any relevant changes occur during this period. 
10.1.5. 
Informed Consent Process 
Before a participant’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the participant or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any study IMPs are administered. 
A legally acceptable representative is an individual or other body authorized under applicable 
law to consent, on behalf of a prospective participant, to the participant’s participation in the 
clinical study. An informed consent document that includes both information about the study and 
the consent form will be prepared and given to the participant. This document will contain all the 
elements required by the ICH E6 (R2) Guideline for GCP and any additional elements required 
by local regulations. The written ICF must be prepared in the local language(s) of the potential 
participant population. 
 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirements, and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) must be 
approved by the IRB prior to being provided to potential participants. 
 
The participant’s written informed consent (written or electronic) must be obtained prior to 
his/her participation in the study, and must be documented in the participant’s medical records, 
as required by applicable regulations. The ICF must be signed and personally dated by the 
participant or a legally acceptable representative, and by the person who conducted the informed 
consent discussion (not necessarily the Investigator). The signed ICF must be retained in 
accordance with institutional policy, and a copy of the signed consent form must be provided to 


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the participant or legal representative. The date and time that informed consent was given must 
be recorded in the CRF.  
Participants who are rescreened are required to sign a new ICF. 
10.1.6. 
Protection of Participant Identification and Confidentiality 
The Investigators and Insmed will preserve the confidentiality of all participants taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the participant’s anonymity is maintained. On the CRF or other 
documents submitted to Insmed, participants must be identified by a unique participant identifier 
as designated by Insmed. Documents that are not for submission to Insmed (e.g., signed ICFs) 
must be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB direct 
access to review the participant’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the participant that his/her study-
related records will be reviewed by the above-named representatives without violating the 
confidentiality of the participant. 
Participant names will not be supplied to Insmed. A participant number will be recorded in the 
CRF, and if the participant name appears on any other document (e.g., laboratory report), it must 
be obliterated on the copy of the document to be supplied to Insmed. All records will be kept 
confidential to the extent provided by federal, state, and local laws. The participants will be 
informed that representatives of Insmed, IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
The Investigator will maintain a personal participant identification list (participant numbers with 
the corresponding participant names) to enable records to be identified. 
10.1.7. 
Committee Structure 
An SRC will be responsible for monitoring safety data. The SRC will comprise all Investigators 
and key members of the Insmed Study Team (including but not limited to Medical Monitor, 
Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, Clinical Pharmacologist) 
and external expert consultants. The SRC will continuously monitor all available safety, PD and 
PK data for each participant and will obtain consensus regarding the safety of continuing the 
study, the next TPIP dose, and clinical care of the next participant. Expert consultants may be 
invited to review and interpret participant data. With any safety findings, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to continue. 
Decisions regarding final database values for PD parameters may be adjudicated by the SRC. 
10.1.8. 
Dissemination of Clinical Study Data 
Insmed will provide study information for inclusion in national registries according to 
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Results of this study will be disclosed according to the relevant national regulatory requirements. 
10.1.9. 
Data Quality Assurance 
The Investigator/investigational site will permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
10.1.9.1. Data Collection 
All data obtained for this study will be entered into a 21 CFR Part 11 compliant Data 
Management System provided by Insmed or its designee. These data will be recorded with an 
EDC system using CRFs. The Investigator will ensure the accuracy and completeness of the data 
reported to Insmed. All data entry, modification or deletion will be recorded automatically in an 
electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
Insmed to verify the proper transcription of data. Data reported in the CRFs must be consistent 
with and substantiated by the participant’s medical record and original source documents. The 
CRF data will be monitored by Insmed or designee. The final, completed CRF Casebook for 
each participant must be electronically signed and dated by the PI within the EDC system to 
signify that the Investigator has reviewed the CRF and certifies it to be complete and accurate. 
Insmed will retain the final CRF data and audit trail. A copy of all completed CRFs will be 
provided to the Investigator. 
10.1.9.2. Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, an Insmed 
representative will review the protocol, CRF, Investigator Brochure, and any study-related 
materials with the Investigators and their staff. During the study, Insmed study monitor or its 
designee will visit the site regularly to check the completeness of participant records, the 
accuracy of entries on the CRFs, adherence to the protocol, adherence to ICH GCP and 
applicable regulatory requirements, the progress of enrollment, and also to ensure that study IMP 
is being stored, dispensed, and accounted for according to specifications. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the CRF entries. Participant confidentiality will be maintained by the 
study center. Insmed monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording 
of primary activity and safety variables. Additional checks of the consistency of the source data 
with the CRFs are performed according to the study specific monitoring plan. 
10.1.9.3. Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB, and an auditor authorized by Insmed may 
request access to all source documents, CRFs, and other study documentation for onsite audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 


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provide support at all times for these activities. Medical records and other study documents may 
be copied during audit or inspection provided that participant names are obliterated on the copies 
to ensure confidentiality. 
If an inspection is requested by a regulatory authority, the Investigator will inform Insmed, 
immediately that this request has been made. 
10.1.9.4. Study Record Retention 
Study documents must be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents must be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of Insmed. It is the responsibility of Insmed to inform the Investigator when 
these documents no longer need to be retained. 
10.1.9.5. Source Documents 
Source documentation is the point of initial recording of a piece of data. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. Source documents 
provide evidence for the existence of the participant and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study Files and Materials 
Before the start of any study related procedures, all initial documents required by ICH GCP, 
Good Pharmacoepidemiology Practice, and applicable local regulations must be available in the 
relevant files maintained by Insmed (or delegate) and the Investigator. An Investigator Study File 
prepared by Insmed (or delegate), containing all applicable documents for use at the study site, 
will be made available to the Investigator before the start of the study. A list of personnel and 
organizations responsible for conduct of the study as well as the list of Investigator-delegates 
(e.g., sub-investigator) at each site will be included in the Investigator Study File. The respective 
files will be kept and updated by Insmed (or delegate) and the Investigator, as applicable. 


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All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by Insmed’s study monitor (or delegate) to determine that all 
required documentation is present and correct. 
The study may be audited by qualified delegates from Insmed or a competent regulatory 
authority. 
10.1.11. 
Use of Stored Samples and Data 
Stored samples will be labeled with study and participant information and secured with limited 
access and retained per protocol requirements and in accordance with the laboratory's operating 
procedures. Electronic data will be kept in password protected computers at the laboratory and 
then transferred to Insmed or CRO, as applicable, for data analysis. Samples and corresponding 
data will be tracked using the laboratory’s specimen tracking system. 
Prior Insmed and IRB approval are required before using or sharing study samples or data in 
ways not specifically specified in the study protocol during conduct of this study. 
Any loss or unanticipated destruction of samples (e.g., freezer malfunction) or data (e.g., loss of 
a data sheet with individually identifiable information) that violates or compromises the 
scientific integrity of study data must be reported to Insmed and the IRB. 
At any time, participants may inform the Investigator in writing that they do not wish to have 
their samples stored beyond the completion (termination) of the study. In this case, the 
Investigator will request that all known remaining samples be destroyed and report the 
disposition of samples to the requesting participants and the IRB. 
10.1.12. 
Disposition of Stored Samples and Data 
Participant samples will be secured with limited access and retained per protocol requirements 
and in accordance with the laboratory's operating procedures. Samples stored by the central 
laboratories will be labeled with the participant’s study identification information. Data will be 
kept in password protected computers at the laboratory and then transferred to the vendor for 
data analysis. Samples and corresponding data acquired will be tracked using the laboratory’s 
specimen tracking system. 
In the future, if other Investigators may wish to study these samples and/or data, they need to 
obtain Insmed approval and participant consent before any sharing of samples and/or data.  
Any loss or unanticipated destruction of samples (e.g., due to freezer malfunction) or data (e.g., 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to Insmed 
and the IRB. 
Additionally, participants may withdraw authorization in writing to decline their sample storage 
for a period of up to 2 years beyond the duration of the study. In this case, the PI will request the 
destruction of all known remaining samples and report what was done to both the participant and 
to the IRB. This decision will not affect the individual’s participation in the study. 


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10.1.13. 
Study and Site Start and Closure 
Before the start of the study at each study site, Insmed’s study monitor (or delegate) shall 
confirm adequacy of the facilities by study site visit or other acceptable methods. 
The Investigator may not enroll any participant into the study before Insmed has received written 
approval or a favorable opinion from the IRB for conducting the study and a formal meeting has 
been conducted by Insmed’s study monitor (or delegate) to initiate the study. This meeting will 
include a detailed review of the study plan, and completion of the CRF. 
10.1.13.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first participant screened for participation in the study is considered the first act 
of recruitment. 
10.1.13.2. Study/Site Termination 
Insmed or designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of Insmed. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Insmed or Investigator may include but are not 
limited to: 
For study termination: 
Discontinuation of further study IMP development 
For site termination: 
Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, Insmed's procedures, or GCP guidelines 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, Insmed shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and must assure appropriate participant 
therapy and/or follow-up. 
10.1.14. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by Insmed, before implementation. Amendments significantly affecting the 
safety of participants, the scope of the investigation, or the scientific quality of the study, require 
additional approval by the applicable regulatory authority(ies) and IRBs. Copies of the 
applicable written approvals must be filed in Insmed files and investigator site files. 


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The requirements for approval must in no way prevent any immediate action from being taken 
by the Investigator or by Insmed in the interests of preserving the safety of all participants 
included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, Insmed or its agent must be 
notified and the applicable regulatory authority(ies)/IRBs must be informed as soon as possible. 
Any other regional reporting requirements must be adhered to. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/IRB approval, but the regulatory authority(ies)/IRBs must 
be kept informed of such administrative changes in accordance with country specific 
requirements. 
10.1.15. 
Financing and Insurance 
10.1.15.1. Finances 
Prior to starting the study, the Investigator and/or institution will sign a clinical study agreement 
with Insmed. This agreement will include the financial information agreed upon by the parties. 
10.1.15.2. Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.15.3. Participant Reimbursement, Liability and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
Insmed will provide insurance to the Investigator if required by the applicable regulatory and 
legal requirement(s). 
If required by local law, participants taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
10.1.16. 
Publication Policy 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel of Insmed. Authorship will 
be determined by mutual agreement. For multi-center studies, it is mandatory that the first 
publication be based on data from all centers, analyzed as stipulated in the protocol by Insmed 
and statisticians, and not by the Investigators themselves. Investigators participating in multi 
center studies agree not to present data gathered from a single center or a small group of centers 
before the full, initial publication, unless formally agreed to by all other Investigators and 
Insmed. 
Insmed must receive copies of any intended communication in advance of publication (at least 
15 working days for an abstract or oral presentation and 45 working days for a journal 


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submission). Insmed will review the communications for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), verify that confidential information is 
not being inadvertently divulged, and to provide any relevant supplementary information. 
Authorship of communications arising from pooled data may include members from each of the 
contributing centers as well as Insmed personnel. 
At the conclusion of the study, after the data are analyzed, the results of study will be reported in 
a clinical study report. 
 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 7 will be performed by the local laboratory. If local laboratory results 
are used to make a study IMP decision or response evaluation, the results must be recorded. 
Protocol-specific clinical laboratory requirements for the inclusion or exclusion of participants 
are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 7: 
Protocol-Required Safety Laboratory Tests, INS1009-201 
Category 
Laboratory Parameters 
Clinical 
Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, 
phosphate, total bilirubin (with direct and indirect fractionation, if total 
bilirubin is elevated >2 ULN), alkaline phosphatase, LDH, AST, ALT, 
CPK, albumin, total protein, creatinine, urea-nitrogen, uric acid, estimated 
glomerular filtration rate  
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, leukocytes, 
differential blood count of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and platelets 
Coagulationa 
PT, PTT, INR 
Serologya 
HIV antibody, hepatitis B surface antigen [HBsAg], Hepatitis C virus 
antibody 
Pregnancy test 
Highly sensitive serum or urine hCG 
a Not included in EUT screening for participants enrolling in the extended use treatment period. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CO2 = carbon dioxide; CPK = creatine 
phosphokinase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin 
time; ULN = upper limit of normal 
Investigators must document their review of each laboratory safety report. 
 
 












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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Insmed clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than Drug-Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN and total 
bilirubin (TBL) ≥2×ULN at any point during the study irrespective of an increase in alkaline 
phosphatase (ALP). The elevations do not have to occur at the same time or within a specified 
time frame. 
Hy’s Law (HL) 
AST or ALT ≥3× ULN and TBL ≥2×ULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral 
hepatitis, another drug. The elevations do not have to occur at the same time or within a specified 
time frame. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any participant who meets any of the following identification criteria in isolation or in 
combination: 
1. ALT ≥ 3xULN 
2. AST ≥ 3xULN 
3. TBL ≥ 2xULN 
The Investigator will review without delay each new laboratory report and if the identification 
criteria are met will: 
1. Notify Insmed representative  
2. Determine whether the participant meets PHL criteria (see DEFINITIONS of this 
Appendix) by reviewing laboratory reports from all previous visits 


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3. Promptly enter the laboratory data into the laboratory CRF 
FOLLOW-UP 
POTENTIAL HY’S LAW CRITERIA NOT MET 
1. If the participant does not meet PHL criteria the Investigator will: 
2. Inform Insmed representative that the participant has not met PHL criteria. 
3. Perform follow-up on subsequent laboratory results according to the guidance provided 
in the clinical study protocol 
POTENTIAL HY’S LAW CRITERIA MET 
If the participant does meet PHL criteria the Investigator will: 
• Notify Insmed representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
• Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or Baseline levels, or as long as medically indicated 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
• Complete the 3 Liver CRF Modules as information becomes available 
• If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section must be followed for all cases where PHL criteria were met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than drug-induced liver injury caused 
by the IMP. The Insmed Medical Science Director and Global Safety Physician will also be 
involved in this review together with other participant matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
• If there is an agreed alternative explanation for the ALT or AST and TBL 
elevations, a determination of whether the alternative explanation is an AE will be 
made and subsequently whether the AE meets the criteria for a SAE 
• If the alternative explanation is not an AE, record the alternative explanation on 
the appropriate CRF 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow Insmed standard processes. 


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
•Report an SAE (report term ‘Hy’s Law’) according to Insmed standard processes. 
• The ‘Medically Important’ serious criterion must be used if no other serious 
criteria apply 
• As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ must be assigned. 
If there is an unavoidable delay, of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review 
 
 
 










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Any device deficiency that is associated with an SAE must be reported to Insmed within 
24 hours after the Investigator determines that the event meets the definition of a 
device deficiency. 
Insmed will review all device deficiencies and determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs as required by national regulations. 
 
 
 


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11. 
REFERENCES 
Delcroix M, Howard L. Pulmonary arterial hypertension: the burden of disease and impact on 
quality of life. Eur Respir Rev. 2015;24(138):621-9. 
 
Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk 
Noordegraaf A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension 
of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): 
Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-
119. 
 
Hoeper MM, Ghofrani HA, Grunig E, Klose H, Olschewski H, Rosenkranz S. Pulmonary 
Hypertension. Dtsch Arztebl Int. 2017;114(5):73-84. 
Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state 
bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and 
subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004 Aug;44(2):209-14.  
McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, Kim NH, 
Oudiz RJ, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll 
Cardiol. 2009;54(1 Suppl):S97-107. 
 
Orenitram Package Insert.  2019. Accessed on: 23 October 2020.  
https://www.orenitram.com/pdf/Orenitram Full Prescribing Information.pdf 
 
Remodulin Package Insert.  2018. Accessed on: 23 October 2020.  
https://www.remodulinpro.com/files/remodulin-pi.pdf 
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical 
classification of pulmonary hypertension. Eur Respir J. 2019; 53(1):1801913. 
Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis 
and clinical management. BMJ. 2018;360:j5492. 
 
Tyvaso Package Insert.  2017. Accessed on: 23 October 2020.  
https://www.tyvaso.com/hcp/pdf/Tyvaso-PI.pdf?v=102017 
 
US Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers.  2005. Accessed on: 23 Oct 2020.  
https://www.fda.gov/media/72309/download 
 
Vachiery JL, Naeije R. Treprostinil for pulmonary hypertension. Expert Rev Cardiovasc Ther. 
2004;2(2):183-91. 


Signature Page for INS1009-201 Protocol Amendment No. 1
Approve
06-Oct-2021 23:02:59 GMT+0000


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CLINICAL STUDY PROTOCOL 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation Powder in Participants with 
Pulmonary Arterial Hypertension 
Protocol Number: INS1009-201 
Version Number: 2.0 
Amendment Number: 1 
Compound: Treprostinil Palmitil Inhalation Powder (TPIP) 
Study Phase: 2a 
Sponsor Name: Insmed Incorporated 
Legal Registered Address:  
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
USA 
Regulatory Agency Identifier Number(s) 
IND: 147264 
Date: 06 OCT 2021 




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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
ABBREVIATIONS .......................................................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Protocol Amendment Summary of Changes ..............................................................14 
1.2. 
Synopsis ......................................................................................................................17 
1.3. 
Schema ........................................................................................................................19 
1.3.1. 
Participant Progression Through the Study ................................................................19 
1.3.1.1. 
Screening Period .........................................................................................................20 
1.3.1.2. 
Inpatient Treatment Period .........................................................................................20 
1.3.1.3. 
Follow-up Period ........................................................................................................20 
1.3.1.4. 
Optional Extended Use Treatment Period ..................................................................21 
1.3.1.5. 
Extended Use Follow-up Period .................................................................................22 
1.3.2. 
Dose Selection ............................................................................................................22 
1.3.2.1. 
Inpatient Treatment Period Dose Selection ................................................................22 
1.3.2.2. 
Optional Extended Use Treatment Period ..................................................................23 
1.4. 
Schedule of Activities (SoA) ......................................................................................24 
2. 
INTRODUCTION ......................................................................................................32 
2.1. 
Study Rationale ...........................................................................................................33 
2.2. 
Background .................................................................................................................33 
2.3. 
Benefit/Risk Assessment ............................................................................................34 
2.3.1. 
Risk Assessment .........................................................................................................34 
2.3.2. 
Benefit Assessment .....................................................................................................35 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................35 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................37 
3.1. 
Exploratory Objectives and Endpoints for the Optional Extended Use 
Treatment Period ........................................................................................................38 
4. 
STUDY DESIGN .......................................................................................................40 


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4.1. 
Overall Design ............................................................................................................40 
4.1.1. 
Screening Period .........................................................................................................40 
4.1.2. 
Inpatient Treatment Period .........................................................................................41 
4.1.2.1. 
Baseline Procedures and Assessments ........................................................................41 
4.1.2.2. 
Post-TPIP Administration ...........................................................................................42 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up .................42 
4.1.3. 
Safety Follow-up ........................................................................................................42 
4.1.4. 
Optional Extended Use Treatment Period ..................................................................42 
4.1.5. 
Open-label Extension Study .......................................................................................43 
4.2. 
Scientific Rationale for Study Design ........................................................................43 
4.3. 
Justification for Dose ..................................................................................................43 
4.3.1. 
Inpatient Treatment Period (Single-dose) ...................................................................43 
4.3.2. 
Optional Extended Use Treatment Period ..................................................................44 
4.4. 
Study Completion .......................................................................................................45 
5. 
STUDY POPULATION .............................................................................................46 
5.1. 
Inclusion Criteria ........................................................................................................46 
5.2. 
Exclusion Criteria .......................................................................................................48 
5.3. 
Lifestyle Considerations .............................................................................................49 
5.4. 
Screen Failures ............................................................................................................50 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period ..................................50 
6. 
STUDY IMP AND CONCOMITANT THERAPY ...................................................51 
6.1. 
Study IMP Administered ............................................................................................51 
6.1.1. 
Inpatient Treatment Period (Single Dose) ..................................................................51 
6.1.2. 
Optional Extended Use Treatment Period ..................................................................51 
6.1.3. 
Medical Devices .........................................................................................................52 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................52 
6.2.1. 
Inpatient Treatment Period (Single-dose) ...................................................................52 
6.2.2. 
Optional Extended Use Treatment Period ..................................................................53 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................53 
6.4. 
Study Intervention Compliance ..................................................................................53 
6.4.1. 
Inpatient Treatment Period (Single Dose) ..................................................................53 


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6.4.2. 
Optional Extended Use Treatment Period ..................................................................53 
6.5. 
Dose Modification ......................................................................................................54 
6.6. 
Continued Access to Study Intervention After the End of the Study .........................54 
6.7. 
Treatment of Overdose ...............................................................................................54 
6.8. 
Concomitant Therapy .................................................................................................55 
7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................56 
7.1. 
Discontinuation of Study IMP ....................................................................................56 
7.1.1. 
Single-dose Period ......................................................................................................56 
7.1.2. 
Optional Extended Use Treatment Period ..................................................................56 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................56 
7.3. 
Lost to Follow Up .......................................................................................................56 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
8.1. 
Pharmacodynamic Assessments .................................................................................58 
8.1.1. 
Required PD Assessments with RHC .........................................................................59 
8.1.2. 
Required Non-invasive PD Assessments ....................................................................59 
8.1.3. 
Resting Respiratory Gas Exchange Assessments .......................................................59 
8.1.4. 
Transthoracic Echocardiogram Assessments .............................................................59 
8.1.5. 
Pulmonary CT Scan ....................................................................................................59 
8.1.5.1. 
Single-dose Period ......................................................................................................59 
8.1.5.2. 
Optional Extended Use Treatment Period ..................................................................60 
8.2. 
Safety Assessments .....................................................................................................60 
8.2.1. 
Physical Examinations ................................................................................................60 
8.2.2. 
Vital Signs ..................................................................................................................60 
8.2.2.1. 
Single-dose Period ......................................................................................................60 
8.2.2.2. 
Optional Extended Use Treatment Period ..................................................................60 
8.2.3. 
Electrocardiograms .....................................................................................................61 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................61 
8.2.5. 
Pregnancy Testing ......................................................................................................61 
8.2.5.1. 
Single-dose Period ......................................................................................................61 
8.2.5.2. 
Optional Extended Use Treatment Period ..................................................................62 


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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................62 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................62 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................63 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................63 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................63 
8.3.5. 
Pregnancy ...................................................................................................................64 
8.3.6. 
Adverse Events of Special Interest (AESI) ................................................................64 
8.3.7. 
Medical Device Deficiencies ......................................................................................64 
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies ...........................................64 
8.3.7.2. 
Follow-Up of Medical Device Deficiencies ...............................................................65 
8.3.7.3. 
Prompt Reporting of Device Deficiencies to Insmed .................................................65 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies ...................................65 
8.4. 
Pharmacokinetic Assessments ....................................................................................65 
8.4.1. 
PK Sample Collection .................................................................................................65 
8.4.2. 
PK Analysis ................................................................................................................65 
8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations ................................................66 
8.5. 
Genetics / Pharmacogenomics ....................................................................................66 
8.6. 
Biomarkers ..................................................................................................................66 
8.7. 
Medical Resource Utilization and Health Economics ................................................66 
8.8. 
Immunogenicity Assessments ....................................................................................66 
9. 
STATISTICAL CONSIDERATIONS .......................................................................67 
9.1. 
Statistical Hypotheses .................................................................................................67 
9.2. 
Sample Size Determination ........................................................................................67 
9.3. 
Analysis Sets ...............................................................................................................67 
9.4. 
Statistical Analyses .....................................................................................................67 
9.4.1. 
General Considerations ...............................................................................................67 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values ...........................................................68 
9.5. 
Interim Analysis ..........................................................................................................68 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................69 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................69 


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10.1.1. 
Regulatory and Ethical Considerations ......................................................................69 
10.1.2. 
Protocol Deviations ....................................................................................................69 
10.1.3. 
Public Health Emergency Situations ..........................................................................70 
10.1.3.1. 
Continuation or Suspension of the Study ...................................................................70 
10.1.4. 
Financial Disclosure ...................................................................................................71 
10.1.5. 
Informed Consent Process ..........................................................................................71 
10.1.6. 
Protection of Participant Identification and Confidentiality .......................................72 
10.1.7. 
Committee Structure ...................................................................................................72 
10.1.8. 
Dissemination of Clinical Study Data ........................................................................72 
10.1.9. 
Data Quality Assurance ..............................................................................................73 
10.1.9.1. 
Data Collection ...........................................................................................................73 
10.1.9.2. 
Study Monitoring ........................................................................................................73 
10.1.9.3. 
Audits and Inspections ................................................................................................73 
10.1.9.4. 
Study Record Retention ..............................................................................................74 
10.1.9.5. 
Source Documents ......................................................................................................74 
10.1.10. 
Study Files and Materials ...........................................................................................74 
10.1.11. 
Use of Stored Samples and Data ................................................................................75 
10.1.12. 
Disposition of Stored Samples and Data ....................................................................75 
10.1.13. 
Study and Site Start and Closure ................................................................................76 
10.1.13.1. First Act of Recruitment .............................................................................................76 
10.1.13.2. Study/Site Termination ...............................................................................................76 
10.1.14. 
Protocol Amendments ................................................................................................76 
10.1.15. 
Financing and Insurance .............................................................................................77 
10.1.15.1. Finances ......................................................................................................................77 
10.1.15.2. Reimbursement, Indemnity, and Insurance ................................................................77 
10.1.15.3. Participant Reimbursement, Liability and Insurance ..................................................77 
10.1.16. 
Publication Policy .......................................................................................................77 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................79 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................80 
10.3.1. 
Definition of AE .........................................................................................................80 
10.3.2. 
Definition of SAE .......................................................................................................81 


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10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................82 
10.3.4. 
Reporting of SAEs ......................................................................................................83 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................84 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ..............85 
10.6. 
Appendix 6 Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies ............................88 
10.6.1. 
Definition of Medical Device AE and ADE ...............................................................88 
10.6.2. 
Definition of Medical Device SAE, SADE and USADE ...........................................88 
10.6.3. 
Definition of Device Deficiency .................................................................................89 
10.6.4. 
Recording and Follow-up of AE and/or SAE and Device Deficiencies .....................89 
10.6.5. 
Reporting of SAEs ......................................................................................................91 
10.6.6. 
Reporting of SADEs ...................................................................................................91 
11. 
REFERENCES ...........................................................................................................93 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Screening and Follow up, Single-Dose Period, 
INS1009-201 ...............................................................................................................25 
Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 .......................26 
Table 3: 
PK and PD Biomarker Sampling Schedule, Single-Dose Period, INS1009-
201 ..............................................................................................................................27 
Table 4: 
Schedule for Optional Procedures and Assessments, Inpatient Treatment 
Period, INS1009-201 ..................................................................................................28 
Table 5: 
Schedule of Activities for Screening and Follow-up, Extended Use 
Treatment Period, INS1009-201 .................................................................................29 
Table 6: 
Schedule of Activities for the Optional Extended Use Treatment Period, 
INS1009-201 ...............................................................................................................30 
Table 7: 
Protocol-Required Safety Laboratory Tests, INS1009-201 ........................................79 
 
LIST OF FIGURES 
Figure 1: 
Participant Progression Through INS1009-201 Studya ..............................................20 


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Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period ..........................................................................................................................21 
Figure 3: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 ..........22 
Figure 4: 
Guideline for Optimal 3-Week Planned Titration Schedule (Optional 
Extended Use Treatment Period) ................................................................................24 
 
 
 


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ABBREVIATIONS  
AE  
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine amino transferase 
AST 
aspartate amino transferase 
AUC  
area under the concentration-time curve 
AUC0–∞ 
area under the concentration-time curve from time zero to infinity 
AUCt1–t2 
area under the plasma concentration-time curve from time zero to time of 
last measurable concentration 
CL/F 
apparent total clearance of drug from plasma after extravascular 
administration 
Cmax 
maximum (peak) plasma concentration of the drug 
CO 
cardiac output 
CRF 
case report form 
CRO 
contract research organization 
CT 
computerized tomography 
DILI 
drug induced liver injury 
DPI 
dry powder inhalation 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
end of study 
EUT 
extended use treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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HIV 
Human Immunodeficiency Virus 
HL 
Hy’s Law 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IMP 
investigational medicinal product 
IRB 
investigational review board 
IV 
intravenous 
MAD 
multiple ascending dose 
mPAP 
mean pulmonary arterial pressure 
MVO2 
mixed venous oxygen saturation 
NOAEL 
No observed adverse effect level 
NT-pro-BNP 
N-terminal (NT)-pro hormone brain natriuretic peptide 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary arterial pressure 
PD 
pharmacodynamic(s) 
PH 
pulmonary hypertension 
PHL 
potential Hy’s Law 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PVR 
pulmonary vascular resistance 
QD 
Once daily 
QID 
four times daily 
RAP 
right atrial pressure 


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RHC 
right heart catheter 
RVP 
right ventricular pressure  
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS CoV 2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SoA 
schedule of activities/assessments 
SUSAR 
suspected unexpected serious adverse reaction 
SRC 
Safety Review Committee 
t1/2 
elimination half-life 
TBL 
total bilirubin 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment emergent adverse event 
tmax 
time to maximum (peak) plasma concentration following drug administration 
TPIP 
treprostinil palmitil inhalation powder 
TPIS 
treprostinil palmitil inhalation suspension 
TRE 
treprostinil 
TP 
treprostinil palmitil 
TVR 
tricuspid valve regurgitation 
ULN 
upper limit of normal 
US 
United States 
VCO2 
carbon dioxide production 
Vd/F 
apparent volume of distribution at terminal phase 


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WHO 
World Health Organization 
WOCBP 
woman of child-bearing potential 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Amendment Summary of Changes 
Amendment 1 (06 OCT 2021) 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment: 
The primary driver for the changes in the protocol amendment is to provide extended access of 
investigational medicinal product (IMP) to the study participants.  
Grammatical and typographical errors were corrected throughout the document.  
A summary of major changes in this amendment, compared to the original protocol, is shown in 
the table below. 
Revision 
Rationale 
Location of Revision 
Updated overall design 
description 
To include and clarify the 
parameters of the optional 
extended use treatment (EUT) 
period; to add reference to a 
separate open-label extension 
study 
• 
Section 1.2  
• 
Section 2.1  
• 
Section 4.1  
• 
Section 4.1.4  
• 
Section 4.1.5  
• 
Section 5.1  
Updated the study schema 
To include and clarify the 
parameters of the optional EUT 
period 
• 
Section 1.3.1.3  
• 
Figure 1  
• 
Section 1.3.1.4  
• 
Section 1.3.1.5  
• 
Figure 3  
• 
Section 2.3.2  
• 
Section 2.3.3  
Updated the Schedule of 
Activities 
To include the optional EUT 
period and optional CT scans; to 
remove pharmacokinetic draw at 
36 hours 
• 
Section 1.3.1.3  
• 
Section 1.4  
• 
Section 4.1  
• 
Section 4.1.2  
• 
Section 7.1.2  
• 
Section 8.1.5.2  
• 
Section 8.4  


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Revision 
Rationale 
Location of Revision 
Updated the definition of study 
completion 
To add the optional EUT period 
to the definition of study 
completion 
• 
Section 4.4  
Addition of exploratory 
objectives 
To add corresponding 
exploratory objectives for the 
EUT period 
• 
Section 3.1  
Updated Inclusion Criterion #4 
To include participants with 
Functional Class I 
• 
Section 5.1  
Updated Inclusion Criterion #3 
To remove maximum length of 
time for pulmonary arterial 
hypertension (PAH) diagnosis 
• 
Section 5.1  
Added Inclusion Criterion #18 
To exclude participants 
receiving potent CYP2C8 
inhibitors 
• 
Section 5.2  
Updated study title 
Updated title of study to remove 
single-dose qualifier 
• 
Title 
• 
Section 1.2  
Updated cardiovascular and 
adverse events of special interest 
To remove unexpected or 
common events 
• 
Section 8.3.6  
Updated PAH definition 
To change mean pulmonary 
arterial pressure to > 20 mmHg 
in Inclusion Criterion #2, 
Inclusion Criterion #9, and 
generally across the document 
per updated guidelines 
• 
Section 5.1  
• 
Section 0  
Updated dose selection 
justification 
To add a subsection for the 
optional EUT period; to update 
original dose justification with 
additional data from Study 
INS1009-102 
• 
Section 1.3.2.2 
• 
Section 4.3.1 
• 
Section 4.3.2  
Added additional information 
regarding study IMP 
administered 
To add an additional section 
describing the study IMP that 
participants entering the 
optional EUT period would 
receive 
• 
Section 6.1.2  


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Revision 
Rationale 
Location of Revision 
Clarified screening/rescreening 
activities  
To verify participants enrolling 
in the optional EUT period after 
the initial follow-up visit still 
meet inclusion/exclusion criteria  
• 
Section 1.3.1.4  
• 
Section 1.4  
• 
Section 4.1.1  
• 
Section 4.1.4  
• 
Section 5.1  
• 
Section 5.2  
• 
Section 6.8  
• 
Section 8  
• 
Section 8.2.2.2 
• 
Section 8.2.5  
Updated the description of 
adverse event (AE) and serious 
adverse event (SAE) collection 
To add reference to AE and 
SAE collection for participants 
and clarify follow-up procedures  
• 
Section 7.2  
• 
Section 8.3  
• 
Section 8.3.1  
• 
Section 8.3.3  
Updated information from 
newly completed study 
To update background and 
safety information from Study 
INS1009-102 
• 
Section 2.2  
• 
Section 2.3.1  
Updated number of study 
centers 
To update to the most current 
estimation of study centers 
expected 
• 
Section 5  
Updated information regarding 
IMP preparation, handling, 
storage, and accountability 
To include information from the 
EUT period and use of updated 
dose 
• 
Section 6.2  
• 
Section 6.2.2  
Updated study intervention 
compliance description  
To include and clarify details for 
the EUT period  
• 
Section 6.4.2  
 
Document History 
Document 
Version 
Date 
Global Amendment 1 
2.0 
06 OCT 2021 
Original Protocol 
1.0 
02 NOV 2020 
 




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first 24 hours following 
administration  
 
• To evaluate the PK of TPIP as 
TRE in participants with PAH 
• Cmax, tmax, AUCt1–t2, AUC0–∞, t1/2 
of TRE in plasma 
TPIP=treprostinil palmitil inhalation powder; PAH=pulmonary arterial hypertension; TEAE=treatment emergent 
adverse event; PD=pharmacodynamic; PVR=pulmonary vascular resistance; PK=pharmacokinetics; TP=treprostinil 
palmitil; TRE=treprostinil; Cmax=maximum observed concentration; tmax=time to maximum concentration after drug 
administration; AUCt1–t2= area under the concentration time curve from time zero to last sampling time point with 
measurable concentration; AUC0–∞=area under the concentration time curve from time zero to infinity; 
t1/2=elimination half-life 
Overall Design: 
This is a Phase 2a open-label study to assess the safety, tolerability, PD effects, and PK of TPIP 
administered to participants with PAH. This is the first study of TPIP in participants with PAH. 
Each participant will receive a single dose of TPIP, which may vary from participant to 
participant, as determined by the Safety Review Committee (SRC) for the study. The study 
includes a 24-hour inpatient observation period following TPIP dosing, during which PK, PD, 
and safety parameters will be assessed. An optional extended treatment period of 16 weeks will 
be available to participants who have completed the single-dose inpatient treatment period. 
When available, participants may be eligible to enroll in a separate open-label extension study 
(OLE) study that will have a duration of approximately 2 years. Details of the planned OLE 
study will be provided in a separate protocol. The study is designed to ensure the safety of and 
maintain minimal risk to participants. The cardiopulmonary and overall functional status of 
participants with PAH can be labile and medical instability can develop quickly. As such, there 
is considerable flexibility built into the protocol to allow Investigator discretion with the 
frequency, timing, and/or conduct of PD and PK assessments to again ensure participants' safety. 
Brief Summary: 
The study is designed to investigate the safety and acute pharmacokinetic (PK) and 
pharmacodynamic (PD) effects of a single dose of treprostinil palmitil inhalation powder (TPIP) 
in participants with pulmonary arterial hypertension (PAH). Intensive monitoring of pulmonary 
vascular resistance, cardiac output, right ventricular pressure, pulmonary arterial pressure, 
hemoglobin, right atrial pressure, and mixed venous oxygen saturation via right heart catheter in 
an appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate dose- and PK-effect relationships. Some assessments and study 
activities (resting respiratory gas exchange assessment, transthoracic echocardiogram, pulmonary 
computerized tomography scan) for exploratory endpoints are optionally left to the discretion of 
the individual Investigator, based on participant safety and study site capabilities. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 


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overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 48 hours post TPIP 
dose will extend into Study Day 3. A remote safety follow-up visit (telephone visit) is scheduled 
for Study Day 30 (± 2 days). An optional extended treatment period of 16 weeks will be 
available to participants who have completed the single-dose inpatient treatment period. There 
will be a second safety follow-up visit 30 days (± 3 days) after extended use treatment (EUT) 
Week 16 for participants who elect to enter the extended use treatment period. If the initial 
remote safety follow-up visit overlaps with the start of the extended treatment period, the initial 
remote safety visit will be shortened and conducted just prior to administration of IMP in the 
extended treatment period.  
Number of Participants: 
Approximately 6 to 10 evaluable participants are planned. Evaluable participants for safety are 
those who receive a single dose of TPIP; evaluable participants for PD and PK endpoints are 
those who receive a single dose of TPIP and have at least 1 post-TPIP administration PK or PD 
datapoint. 
Treatment Groups and Duration: 
This is an open-label, non-randomized study. There are no predefined treatment groups. The 
dose determination for each participant will be made based on all available PK, PD, and safety 
data at the time of the participant’s entry into the study. An optional extended use treatment 
period of 16 weeks will be available to all participants.  
Safety Review Committee:  
A Safety Review Committee (SRC) will be responsible for monitoring safety data. The SRC will 
comprise all Investigators and key members of the Insmed Study Team (including but not limited 
to Medical Monitor, Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, 
Clinical Pharmacologist) and external expert consultants. The SRC will continuously monitor all 
available safety, PD and PK data for each participant and will obtain consensus regarding the 
safety of continuing the study, the next TPIP dose, and clinical care of the next participant. 
Expert consultants may be invited to review and interpret participant data. With any safety 
findings, a decision will be made, based on the review, as to whether enrollment in the study will 
be allowed to continue. Decisions regarding final database values for PD parameters may be 
adjudicated by the SRC. 
1.3. 
Schema 
1.3.1. 
Participant Progression Through the Study 
The main study comprises an outpatient screening period, an inpatient treatment period, and an 
outpatient follow-up period. Participant progression through the study is shown in Figure 1. An 
optional EUT period is shown in Figure 2. 


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1.3.1.1. 
Screening Period 
The outpatient screening period will last up to 30 days. After participants complete screening and 
have met the study eligibility criteria, the right heart catheter (RHC) procedure and inpatient 
treatment period should be scheduled without delay. 
1.3.1.2. 
Inpatient Treatment Period 
The inpatient treatment period will start on Study Day 1 and extend overnight into Study Day 2. 
Because the study requires an inpatient treatment period, institutional requirements for elective 
inpatient admissions, which may vary from site to site, will be followed. The participant may be 
required to undergo pre-admission assessments required by the institution for elective admission, 
for example testing for common infectious pathogens. Signature of elective admission 
documents and other consents may be required by the institution. An RHC will be placed. 
Following completion of Baseline assessments, a single dose of TPIP will be administered via a 
dry powder inhaler. Safety, PD, and PK assessments will continue at scheduled intervals through 
24 hours following TPIP administration. Following the final assessments at 24 hours, the RHC 
will be removed and the participant will be discharged from the inpatient setting when deemed 
safe for the participant.  
1.3.1.3. 
Follow-up Period 
PK blood draw at 48 (± 4) hours after TPIP dosing will be done on an outpatient basis as 
arranged by the site. The 48-hour post-TPIP visit will also include safety assessments including 
physical examination, clinical laboratory evaluations, ECG, AE collection and vital signs. An 
additional safety follow-up will be conducted by telephone call or telemedicine on Study Day 30 
(± 2 days) unless the participant elects to enter the EUT period prior to this follow-up visit. If the 
initial remote safety follow-up visit overlaps with the start of the extended treatment period, the 
initial remote safety visit will be shortened and conducted just prior to administration of 
investigational medicinal product (IMP) in the extended treatment period.  
Figure 1: 
Participant Progression Through INS1009-201 Studya  
 
PD-pharmacodynamic assessments; PK=pharmacokinetic assessments; h=hours; d=days 
a Does not include optional extended use treatment period; the 30 day follow-up visit will be shortened and 
conducted just prior to administration of IMP in the extended treatment period if the visit overlaps with the start 
of the extended treatment period. 


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1.3.1.4. 
Optional Extended Use Treatment Period 
All participants will be allowed to enter the optional 16 week EUT period after the completion of 
the inpatient treatment period and final PK sample collection. Entry into the optional EUT period 
will be at participant and Investigator discretion. A gap between the inpatient treatment period 
and EUT period is expected, but not required, and can be up to 6 months.  
After collection of the final PK sample, all participants will be allowed optional continued access 
to IMP for 16 weeks (includes a 3-week titration period) from first administration in the EUT 
period. At the Investigator’s discretion, participants may undergo a study drug taper for up to 
2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug. 
Participants will be screened to ensure they meet inclusion and exclusion criteria if they enter the 
EUT period more than 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period) (Table 5).  
Participant in-clinic study visits will be scheduled for EUT at Baseline (EUT Day 1), EUT 
Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16. 
Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period 
 
a 
The 30 day follow-up visit from the single dose period will occur on EU Day 1 if the visit overlaps with the start 
of the extended treatment period. 
b At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks after the Week 16 
visit. 
c  The follow-up telephone call or visit will be 30 days after the Week 16 visit.  
EU = Extended Use; QD = once daily; EOT = end of treatment 


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1.3.1.5. 
Extended Use Follow-up Period 
There will be a second remote safety follow-up visit 30 days (± 3 days) after EUT Week 16 
administration for participants who elect to enter the EUT period. 
1.3.2. 
Dose Selection 
1.3.2.1. 
Inpatient Treatment Period Dose Selection 
Each participant will enter the study in a serial fashion, following review of available safety, PK, 
and PD data from all previous participants by the Safety Review Committee (SRC). Each 
participant will receive a single-dose administration of TPIP via a dry powder inhaler. TPIP will 
be administered to only one participant at a time, with full evaluation of all available data prior to 
dosing the next participant. 
The first participant will receive a dose of TPIP containing 112.5 µg of TP. The SRC will then 
review all available safety, PD, and PK data including data from the first participant and select 
the TPIP dose and any changes to the assessments for the second participant. Then, following 
review of all available data including that from the first and second participants, the SRC will 
select the dose for the third participant. Similarly, all available data from previous studies and 
participants will be assessed prior to determining the dose for the next participant, until such a 
time as the SRC believes the study must conclude. Figure 3 describes the planned dose-selection 
and study continuation process. 
Figure 3: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 
 
SRC=Safety Review Committee 
 
 


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1.3.2.2. 
Optional Extended Use Treatment Period 
Entrance into the optional EUT period is at participants’ and Investigators’ discretion and begins 
with a titration. The guideline for the optimal 3-week planned titration schedule is provided in 
Figure 4. The target TPIP dose will be achieved with a combination of dry powder capsules 
containing 80 µg, 160 µg, and 320 µg of TP. 
During the titration period (EUT Days 1 to 21), each participant’s dose will be up-titrated to the 
highest tolerated dose for that individual. Participants will start open-label study drug with 
1 capsule (80 μg TPIP) QD. If this dose is well tolerated, the dose should be up-titrated until 
reaching the participant’s highest tolerable dose as described by the dosing schedule in Figure 4. 
During this titration period, participants must stay on study drug for the minimum number of 
cumulative days required for each dose (e.g, 2 days at 80 µg, 160 µg, or 240 µg; 3 days at 
320 µg; or 4 days at 400 µg or 480 µg) prior to titrating to the next higher dose. Study drug 
titration may occur slower, but not faster, than described in Figure 4. If a dose is not tolerated, 
study drug may be decreased to the previous dose level. At the Investigator’s discretion, 
up-titration may resume (as described in Figure 4) until the participant’s highest tolerated dose is 
achieved at EUT Day 21.  
All dose adjustments must be preceded by contact with the Investigator or study site personnel. 
In addition, the Investigator and/or study site personnel will be in contact with participants 
during the dose adjustment period to assess the tolerability to study drug as measured by the AEs 
commonly observed with other prostacyclin receptor agonists, which include headache, flushing, 
nausea, cough, and muscle pain. The decision to up-titrate to the next TPIP dose will be based on 
safety and tolerance data (e.g., AEs) as reported by the participant and assessed by the 
Investigator.  
At the Investigator’s discretion, based on tolerability, the study drug dose may be increased by 
1 dose level (as described in Figure 4) at the EUT Week 5 in-clinic visit for participants who 
have not achieved the 640 μg dose. The increase in dose will be administered under clinical 
observation at the study site to ensure tolerability and correct dosing and self-administration of 
study drug. The participant’s highest dose tolerated is expected to continue for the remainder of 
the study after the EUT Week 5 visit.  
At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks 
after the EUT Week 16 visit to help facilitate a safe withdrawal from study drug. The 
Investigator and/or study site personnel will be in contact with participants during the study drug 
taper to assess the tolerability to study drug. 


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Figure 4: 
Guideline for Optimal 3-Week Planned Titration Schedule (Optional 
Extended Use Treatment Period) 
 
 
1.4. 
Schedule of Activities (SoA) 
The SoA is divided into the following tables:  
• Screening and follow-up activities in the single-dose period 
• SoA in the inpatient treatment period  
• PK and PD biomarker blood sampling schedule 
• Optional procedures and assessments in the inpatient treatment period 
• Screening and follow-up activities in the EUT period 
• SoA in the EUT period 
The single-dose period refers to the combination of the inpatient treatment period (Study Day 1 
to Study Day 2), the PK/PD sampling period, and the 30 day follow-up period.  
 


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Table 1: 
Schedule of Activities for Screening and Follow up, Single-Dose Period, 
INS1009-201 
Procedure 
Screening 
Follow-up 
 
Up to 30 
Days 
48 h post 
TPIP dosea 
Study Day 30 
(± 2 days)b 
Informed Consent 
X 
-- 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
-- 
Demographics and Medical History 
X 
-- 
-- 
Smoking Status 
X 
-- 
-- 
Height, Weight, BMI Calculation 
X 
-- 
-- 
Prior/Concomitant Medications 
X 
X 
X 
Serology (HBsAg, HIV antibody, HCV 
antibody) 
X 
-- 
-- 
Serum Pregnancy Test (WOCBP only) 
X 
 
 
Urine Pregnancy Test (WOCBP only) 
-- 
 
X 
Hematology, Clinical Chemistry (Table 7) 
X 
X 
-- 
Coagulation Profile (Table 7) 
X 
-- 
-- 
NT-pro-BNP Sample (if needed, Section 5.1) 
X 
-- 
-- 
12-lead ECG 
X 
X 
-- 
Physical Examination 
X 
X 
-- 
Vital Signs 
X 
X 
-- 
6 Minute Walking Distance Test (if needed, 
Section 5.1) 
X 
-- 
-- 
Pulmonary Function Testing (if needed, 
(Section 5.1) 
X 
-- 
-- 
Adverse Eventsc 
X 
X 
X  
a 48 h safety follow-up assessments are to be conducted at the time of the visit for the 48h PK blood draw (Table 3). 
b Follow-up visit will be shortened and conducted just prior to administration of IMP in the extended treatment 
period if the visit overlaps with the start of the extended treatment period. 
c AE collection is from the time of signing the informed consent through the Day 30 safety follow-up. Events 
between ICF signing and TPIP dosing that are serious will be recorded as SAE; non-serious events during this 
period must be recorded as medical history. 
Note:  Additional safety follow-ups may be conducted at any time per the investigator’s discretion to ensure 
participant safety. The reason for any additional safety follow-up must be reported as an AE. 
BMI = body mass index; ECG = electrocardiogram WOCBP = woman of childbearing potential  


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Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 
Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administration 
TPIP 
Administration 
Post-TPIP Administration 
Procedure 
Day 1 Baseline  
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
24 h 
24 h to 
discharge 
Hematology, clinical 
chemistry, coagulation 
profile blood drawa 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
-- 
Urine pregnancy test 
(WOCBP only) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12-lead ECG 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Cardiac telemetry per 
institutional protocolb 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signsc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
collection 
X 
 
 
 
 
 
 
 
 
 
 
Place right heart 
catheter 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
PD assessments: PVR, 
MVO2, Hgb, RVP, 
PAP CO, PVR, RAP, 
oxygen consumption, 
PCWP (Baseline 
only)d, heart rate, 
SpO2, systemic blood 
pressuree  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
-- 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administration 
TPIP 
Administration 
Post-TPIP Administration 
Procedure 
Day 1 Baseline  
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
24 h 
24 h to 
discharge 
Administer TPIP 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Remove RHC 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Discharge/Safety 
Follow-up Instructions 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
a See Section 10.2, Table 7 for specific laboratory tests. 
b Routine cardiac telemetry readings will not be collected as study data unless they pertain to a relevant adverse event. 
c Heart rate, systemic blood pressure, and SpO2 are required PD measurements and will be collected as scheduled. They may be measured with pulse oximetry 
for heart rate and SpO2 and an automated inflatable arm cuff for blood pressure. Temperature and respiratory rate may be measured per institutional inpatient 
protocol. Respiratory rate will be measured as part of pulmonary gas exchange testing, if performed. 
d PCWP is measured at Baseline only to ensure study eligibility (Section 5.1). 
e Systemic blood pressure must include 3 values:  systolic, diastolic, and mean arterial pressure.  
CO = cardiac output; Hgb = hemoglobin; MVO2 = mixed venous oxygen saturation; PAP = pulmonary arterial pressure; PVR=pulmonary vascular resistance; 
RAP = right atrial pressure; RVP = right ventricular pressure; SpO2 = arterial blood oxygen saturation; WOCBP = woman of childbearing potential 
 
Table 3: 
PK and PD Biomarker Sampling Schedule, Single-Dose Period, INS1009-201 
-- 
Baseline 
Pre-TPIP 
Administration 
TPIP 
administration 
Post-TPIP Administration 
Time  
-- 
0 
30 (± 10) mins 
60 (± 10) mins 
2 h (± 20) mins 
4 (± 1) h 
8 (± 2) h 
24 (± 2) h 
48 (± 4) h 
PK samplinga 
X 
-- 
X 
X 
X 
X 
X 
X 
X 
Biomarker 
samplingb 
X 
-- 
-- 
-- 
-- 
X 
X 
-- 
-- 
a PK sampling for treprostinil palmitil and treprostinil; each PK sample will be approximately 10 mL. 
b Each biomarker sample will be approximately 5 to 7 mL. 


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Table 4: 
Schedule for Optional Procedures and Assessments, Inpatient Treatment Period, INS1009-201 
Inpatient Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
Post-TPIP 
Administration 
Procedure 
Study Day 
1 Baseline  
Time 0 
2-8 hr 
4-8 hr 
Transthoracic 
echocardiogram 
(LVEF,TVR maximum 
velocity, TAPSE, end 
diastolic right ventricular 
volume)  
X 
-- 
X 
-- 
Pulmonary CT scan (total 
blood volume, blood 
volume in vessels < 5 
mm2)  
X 
-- 
-- 
X 
-- 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
-- 
-- 
Study Day 
1 Baseline 
Time 0 
30 mins 
60 mins 
90 mins 
2 h 
3 h 
4 h 
8 h 
24 h 
Resting respiratory gas 
exchange assessmenta 
(respiratory rate, minute 
ventilation, VCO2, ETO2, 
ETCO2, SpO2  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
a Resting respiratory gas assessment parameters are collected at the same time points as RHC parameters. 
NOTE:  Parameters to be measured for each procedure are in parentheses. 
CT=computerized tomography; ETCO2 =end tidal carbon dioxide concentration; ETO2,=end tidal oxygen concentration; LVEF=left ventricular ejection fraction; 
SpO2=arterial blood oxygen saturation; TAPSE=tricuspid annular plane systolic excursion; TVR=tricuspid valve regurgitation; VCO2,=carbon dioxide 
production  


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Table 5: 
Schedule of Activities for Screening and Follow-up, Extended Use Treatment Period, INS1009-201 
Procedure 
Screeninga 
Follow-up 
 
EUT Study Day 1 
(± 3 days) 
EUT Study Day 142 
(± 3 days) 
Informed Consent 
X 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
Demographics 
X 
-- 
Smoking Status 
X 
-- 
Height, Weight, BMI Calculation 
X 
-- 
Prior/Concomitant Medications 
X 
X 
Urine Pregnancy Test (WOCBP only) 
X 
X 
Hematology, Clinical Chemistry (Table 7) 
X 
-- 
NT-pro-BNP Sample (if needed, Section 5.1) 
X 
-- 
Vital Signs 
X 
-- 
6 Minute Walking Distance Test (if needed, 
Section 5.1) 
X 
-- 
Adverse Eventsb 
X 
X  
a Participants will only be screened at EUT Day 1 if they enter the EUT period beyond 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period). 
b AEs for the period from the Study Day 30 follow-up until the enrollment in the EUT period will be collected during participants’ screening for the EUT. 
BMI = Body Mass Index; EUT = extended use treatment; WOCBP = woman of childbearing potential


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Table 6: 
Schedule of Activities for the Optional Extended Use Treatment Period, INS1009-201 
 
Period 
Extended Use Treatment Period 
Follow-Up 
E/Da 
Week 
EUT W1 
EUT W2  
EUT W3 
EUT W5 
EUT W10 
EUT W16 
EUT W20b 
 
Day 
EUT D1 
(Screeningc and 
Baseline)  
EUT D10 
(± 3 days) 
EUT D21 
(± 3 days) 
EUT D35d 
(± 3 days) 
EUT D70 
(± 3 days) 
EUT 
D112 
(± 3 days) 
EUT D142 
(± 3 days) 
 
Visit 
EUT V1 
EUT V2 
EUT V3 
EUT V4 
EUT V5 
EUT V6 
EUT V7 
 
Prior/concomitant 
medications 
 
Pregnancy test 
(WOCBP only)e 
X 
 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
 
X 
6MWD test 
X 
 
 
 
 
X 
 
 
Hematology, clinical 
chemistryc g 
Xc 
 
 
 
 
 
 
 
NT-pro-BNP Samplec 
Xc 
 
 
 
 
Xc 
 
 
Optional pulmonary CT 
scan (total blood 
volume, blood volume in 
vessels < 5 mm2) 
X 
 
 
 
 
X 
 
 
Study drug distributionh 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
self-administration 
re-assessmenti 
 
X 
X 
X 
X 
X 
 
 
Participant diary 
 
 
 
Adverse eventsj 
 
a Participants who enroll in the optional EUT period and discontinue before the end of study will be classified as early discontinuations.  
b Follow-up telephone call or visit will be 30 days after the EUT Week 16 visit.  
c Only required if first participant visit occurs after the 30 day follow-up period in the single-dose period. 
d At the Investigator’s discretion, an increase of 1 dose level may be allowed at EUT Week 5 if the participant has not achieved the 640 µg dose.  


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e Pregnancy test: Urine pregnancy tests will be performed in-clinic at EUT Baseline (EUT Day 1) in WOCBP. WOCBP will be provided home pregnancy test 
kits with instructions to conduct the pregnancy tests every 30 days or more if required during the treatment and follow-up periods. Study site personnel will 
contact the participant every 30 days by telephone and record the pregnancy test results. An additional on-site urine test must be performed prior to starting any 
procedure that requires the use of ionizing radiation. 
f Vital signs: Includes body temperature (°C), pulse rate (bpm), respiratory rate (breaths/min), blood pressure (systolic, diastolic and mean arterial [mmHg]), and 
SpO2. Vital signs will be measured at EUT Screening/Baseline (EUT Day 1), EUT Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16 and 
at the Early Discontinuation visit, if appropriate.  
g See Table 7 for additional information. 
h Participants will receive study drug supply on EUT Day 1 and at EUT Week 2, EUT Week 3, EUT Week 5, and EUT Week 10 visits. Participants who undergo 
a study drug taper will receive study drug supply at the EUT Week 16 visit. A telephone call from study personnel or the Investigator will be placed to 
participants assigned to a study drug taper to check on the participant’s well-being; timing of the telephone call will be based on the Investigator’s discretion, 
and any adverse events will be captured on the CRF. 
i  Assessment of study drug self-administration: Study drug self-administration will be overseen by study site personnel at all in-clinic visits.  
j AE collection from the 30 day follow-up period in the single-dose period to enrollment in the EUT period will be queried during EUT screening; All other AEs 
and SAEs will be collected from EUT Day 1 and followed up as described in Section 8.3.3. 
 6MWD = 6-minute walk distance; CT = computerized tomography; CRF = case report form; D = day; E/D = early discontinuation; EUT = extended use 
treatment; NT-pro-BNP = N-terminal pro B-type natriuretic peptide; W = week; WOCBP = woman of childbearing potential; V = Visit


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2. 
INTRODUCTION 
Pulmonary hypertension (PH), a hemodynamic state characterized by resting mean 
PAP > 20 mmHg per updated guidelines (Simonneau et al., 2019), is generally classified into 5 
groups based on the underlying pathology: Group 1 is PH due to pulmonary vascular disease, 
also known as pulmonary arterial hypertension (PAH); Group 2 is PH due to left heart disease; 
Group 3 is PH due to lung disease or hypoxia; Group 4 is PH due to chronic thromboembolic 
disease or other pulmonary vasculature obstruction; Group 5 is miscellaneous PH syndromes 
caused by a variety of disorders such as hemolytic anemias and sarcoidosis (Thenappan et al., 
2018). 
In Group 1 PH (PAH), the resting mean PAP > 20 mmHg occurs in the setting of normal 
pulmonary arterial wedge pressure of ≤15 mm Hg with PVR of ≥3 Wood Units (WU) 
(McLaughlin et al., 2009). In PAH the pulmonary vasculature is affected by vasoconstriction, 
vascular remodeling, increased rigidity of vessel walls and vascular fibrosis. These vascular 
anomalies increase PVR, which leads to increases in right ventricular afterload, and a cascade of 
maladaptive changes to the heart including right ventricular hypertrophy, ischemia and fibrosis, 
reducing right ventricular function and eventually leading to right ventricular failure and death 
(Thenappan et al., 2018). The pulmonary vascular lesions of PAH may be idiopathic, hereditary, 
or occur as a complication of drug use (e.g., anorexigens), connective tissue disease, portal 
hypertension, congenital cardiac malformations or HIV infection (Hoeper et al., 2017). 
Data from PAH registries around the world (Thenappan et al., 2018) estimate a global incidence 
ranging from 2.0 to 7.6 cases per million adults per year, with a prevalence of 11 to 26 cases per 
million adults; the incidence in females is approximately 4 times that in males. Most registries 
report a mean age of onset ranging from approximately 36 to 53 years. While overall median 
survival has improved from 2.8 years in the 1980’s to 6 years currently, mortality is high, with 
1 year survival ranging from 68% to 93% and 5 year survival ranging from 21% to 65%. Nearly 
half of the patients in these registries have PAH of idiopathic, heritable or anorexigen-induced 
origin.  
PAH is a debilitating progressive disease that causes a wide range of non-specific symptoms 
including, dyspnea, shortness of breath, chest pain, fatigue, generalized weakness and exertional 
syncope (Delcroix and Howard, 2015), severely affecting the patient’s physical mobility, 
emotional and social well-being, ability to perform activities of daily living and overall quality of 
life. Pharmacological treatments are available to mitigate disease symptoms and slow disease 
progression, but treatment-related AEs, inconvenience and side effects can be treatment-limiting 
and negatively influence the patient’s daily life (Delcroix and Howard, 2015). 
The currently available pharmacologic treatments for PAH include calcium channel blockers, 
guanylate cyclase stimulators, endothelin receptor antagonists, phosphoesterase type 5 inhibitors, 
and prostanoids and prostacyclin agonists. Prostanoids, such as TRE, are among the most 
effective medications for the treatment of PAH. However, they are limited by the need for 
inconvenient and frequent drug administration and dose-limiting side effects (Thenappan et al., 
2018). 


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2.1. 
Study Rationale 
Treprostinil palmitil (TP) is an inactive prodrug of treprostinil (TRE). TPIP is a dry powder for 
inhalation formulation of TP. TPIP is being developed for the treatment of PAH. TPIP is 
expected to provide extended release of TRE in the lung with the goals of less frequent and more 
convenient and consistent dosing while reducing the frequency and severity of dose-limiting side 
effects associated with the currently approved forms of TRE. TP has been previously studied in 
healthy volunteers as an inhalation suspension (treprostinil palmitil inhalation suspension, TPIS), 
in single doses up to 340 µg (Study INS1009-101), and TPIP has been previously studied in a 
single ascending dose/multiple ascending dose (SAD/MAD) study in healthy volunteers (Study 
INS1009-102). 
No studies of TP or TPIP have been conducted in participants with PAH. Study INS1009-201 is 
an open label, non-randomized, single- dose study designed to evaluate the safety, 
pharmacokinetics (PK), and pharmacodynamic (PD) effects of a single dose of TPIP in 
participants with PAH. An optional EUT period was added to maximize participant convenience 
and accessibility.   
2.2. 
Background 
Treprostinil is a tricyclic benzidene analogue of prostacyclin. As such, TRE has vasodilatory and 
anti-platelet activity within the pulmonary vascular system, thereby reducing blood flow 
resistance and improving the clinical state, functional class, exercise capacity, and quality of life 
of patients with PAH (Vachiery and Naeije, 2004). 
Treprostinil has a high potency but is short-lived in the body and must be administered by 
continuous IV or SC infusion, or given multiple times per day by inhaled or oral routes. At 
present, TRE is available in the United States in formulations of IV or SC infusion (Remodulin 
Package Insert, 2018), oral extended-release tablets (Orenitram Package Insert, 2019), and 
inhalation solution (Tyvaso Package Insert, 2017) to treat PAH. The clinical experience with 
TRE suggests that most of the AEs experienced are related to its effects on prostanoid 
metabolism (e.g., headache, nausea, diarrhea, flushing, and hypotension). Dose-limiting side 
effects correlate to systemic plasma concentrations of TRE.  
Treprostinil palmitil is a hexadecyl ester prodrug of TRE. In the lung, TP is hydrolyzed by 
esterase to TRE and hexadecanol. TPIP is a dry powder formulation of TP designed to provide 
sustained release of TRE in the lung over a prolonged period, thus providing prolonged 
vasodilation in the lung vasculature. This effect was demonstrated in a rat acute hypoxia model 
that showed a maximal reduction in PAP through the 3-hour monitoring limit with TP, while the 
effect of inhaled TRE started to diminish by 1 hour and was completely gone after approximately 
2.5 hours. The prolonged lung exposure and pharmacological action of TRE achieved with 
sustained release from the prodrug TP aims to reduce both dosing frequency and side effects 
driven by fluctuations of plasma levels of TRE. 
Treprostinil palmitil was well tolerated in rats and dogs following 16-week once-daily inhalation. 
At no observed adverse effect level (NOAEL) doses, the plasma Cmax and AUC of TRE at steady 


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state in rats (2000 μg/kg/day) were 11 ng/mL and 73 ng*h/mL, respectively, and in dogs (250 
μg/kg/day) were 1.2 ng/mL and 13 ng*h/mL, respectively. 
Thus far, TP has been studied in 2 Phase 1 studies of healthy participants: An SAD study of 
TPIS (Study INS1009-101) and an SAD/MAD study of TPIP (Study INS1009-102). Single 
doses of up to 675 μg and multiple doses of up to 225 μg for 7 days were administered to healthy 
participants. Overall, TP was well tolerated, with largely mild treatment-emergent adverse events 
(TEAEs) and an adverse effect profile consistent with that of inhaled prostacyclin analogs. 
Treprostinil exposures increased approximately dose-proportionately, were similar between TPIS 
and TPIP, and showed no accumulation with QD dosing. Doses of TP achieved were several-fold 
higher than label-indicated target dose of inhaled treprostinil (54 μg). When comparing TPIS to 
inhaled treprostinil, TP had a 10-fold lower maximum plasma concentration (89.0 pg/mL vs. 
958 pg/mL) and a markedly longer half-life (5.69 hours vs. 0.485 hours) than inhaled treprostinil 
at the molar equivalent dose. Half-life of TP was even longer with TPIP, ranging from 8.67 to 
11.6 hours. These differential PK of TP may offer therapeutic advantages over treprostinil with 
the need for less frequent administration (QD vs QID), fewer adverse effects, and potentially 
improved efficacy with higher tolerated dose.  
Additional information regarding the results of non-clinical and clinical studies of TP are 
provided in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
TEAEs for TPIP from clinical and non-clinical studies may be found in the Investigator’s 
Brochure.  
2.3.1. 
Risk Assessment 
There is no TPIP experience in participants with PAH; however, the active component, TRE, 
like other prostanoids and their agonists, has a well-characterized safety profile. This will help 
enable participants to be adequately monitored during the study. 
Insmed has conducted a SAD study of TPIS in healthy volunteer participants, with safety and 
tolerability findings similar to those of other prostanoids (Study INS1009-101). In this study, 
32 TEAEs were reported for 11 of 18 participant who received TPIS. No fatal TEAEs were 
reported and no TEAEs led to the withdrawal of participants. One participant who received a 
single dose of TPIS containing 340 µg of TP experienced several interrelated AEs that 
culminated in 2 TEAEs of severe and life-threatening intensity, as judged by the Investigator. 
The Investigator believed a severe TEAE of micturition syncope was precipitated by a TEAE of 
chest pain, which was assessed as probably related to the study IMP and increased vagal tone 
during micturition. Follow-up evaluation by an external cardiologist reveled that the participant 
had Tachy-Brady syndrome. A serious adverse event (SAE) of cardiac pause/nodal arrhythmia 
was reported for this participant and assessed as probably related to TPIS. Beyond this event, 
7 TEAEs were assessed as being of moderate intensity and 23 TEAEs to be of mild intensity. 
The most frequently reported TEAEs among participants receiving TPIS were cough (5 events 
for 5 participants), dyspnea (4 events for 4 participants), and throat irritation (4 events for 


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4 participants). Other TEAEs reported for more than 1 participant receiving TPIS included 
nausea (3 events for 3 participants) and headache (2 events for 2 participants). 
There was a dose-related trend in the incidence of TEAE reporting with increasing dose levels of 
TPIS: 5 TEAEs were reported for 2 participants after receiving a single TPIS dose containing 
85 µg of TP, 7 TEAEs were reported for 4 participants after receiving a single TPIS dose 
containing 170 µg of TP, and 20 TEAEs were reported for 5 participants after receiving a single 
TPIS dose containing 340 µg of TP. 
Safety results from a recently conducted SAD/MAD study of TPIP in healthy volunteer 
participants (Study INS1009-102) support the TPIP dosing and management of participant safety 
for this study. In this study, TPIP was generally safe and well tolerated. TEAEs reported with 
TPIP were consistent to those seen with other inhaled prostanoid therapies. The majority of 
TEAEs were judged by the Investigator to be of mild intensity; there were few moderate TEAEs 
and no severe TEAEs across the study. No participants reported AEs of severe intensity, and no 
SAEs were reported. There was 1 participant in the MAD panel who discontinued after 2 doses. 
TEAEs were more frequent with increasing TPIP doses. In the MAD panel, participants titrated 
from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 
225 µg QD at treatment initiation, and all TEAEs were of mild severity. 
Nonserious adverse events (AEs) observed in clinical studies to date are known for the 
pharmacological class of prostacyclin vasodilators and are considered expected for TPIP. No 
serious adverse reactions are considered expected for TPIP. Please refer to the Reference Safety 
Information in Section 6.1 of the Investigator’s Brochure. 
Risks inherent in study procedures and in the inpatient treatment period will be managed per 
Investigator and institutional processes. It is possible that the RHC-dependent Baseline 
parameters may indicate that the participant does not meet study inclusion criteria, may meet 
exclusion criteria, or is otherwise not suitable for study participation; in this case the Investigator 
may end the RHC procedure and not administer TPIP. 
In general, an RHC is left in place for 30 to 60 minutes to take necessary measurements. This 
study requires the RHC to be in place for approximately 24 hours. Excess risks with prolonged 
placement of the RHC may include but not be limited to dislodging of the RHC, infection, 
bleeding, clot formation, and participant discomfort. 
2.3.2. 
Benefit Assessment 
TPIP is being developed for the treatment of PAH. TPIP may or may not result in beneficial 
effects for participants with PAH by providing extended release of TRE in the lung with less 
frequent and more convenient dosing.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Although participants may or may not benefit individually from this study, risks to their well-
being will be carefully monitored and managed throughout their participation. Insmed considers 
the risks to be appropriate to the value of the knowledge gained in this study about the 
characteristics of this promising therapy. The well-characterized safety profile of TRE and the 


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continued safety monitoring by both the Investigator and SRC (in the inpatient treatment period, 
observation period, and optional EUT period, if applicable) will minimize risk to participants. 
Most TEAEs observed with exposure to this drug are events known to be associated with 
prostanoids and their agonists. Study inclusion and exclusion criteria will help to ensure that only 
appropriate participants are enrolled. Risks involved with study procedures and settings will be 
managed by the relevant Investigator and institutional processes. 
 






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• To assess the effect of TPIP on 
exercise capacity 
• Change from Baseline in 6MWD 
distance at EUT Baseline to EUT 
Week 16 
6MWD = 6-minute walk distance; EUT = extended use treatment period; PAH = pulmonary arterial hypertension; 
TEAE = treatment emergent adverse event; TPIP = treprostinil palmitil inhalation powder 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2a, open label, non-randomized study to assess the safety, tolerability, PD effects 
and PK of TPIP administered to participants with WHO Group 1 PH (PAH). This is the first 
patient study of TPIP. Each participant will receive a single dose of TPIP. The first participant 
will receive a dose containing 112.5 µg of TP. The TP dose level for each subsequent participant 
will be determined following review and adjudication of all available safety, PK, and PD data 
from the previous participant(s) by the SRC (Section 10.1.7). There is an optional extended-use 
period for 16 weeks in participants who have completed the core, single-dose period.  
This is a “proof of mechanism” study designed to investigate the following: 
1. The safety and tolerability of TPIP in participants with PAH, 
2. The relationship between the PK and PD effects of TPIP in participants with PAH, and 
3. The duration of the PD effects of a single dose of TPIP in participants with PAH. 
The cardiopulmonary and overall functional status of participants with PAH can be labile and 
medical instability can develop quickly. The study is designed to provide maximal safety and 
minimal risk to participants. As such, there considerable flexibility built into the protocol to 
allow Investigator discretion with the frequency, timing, and/or conduct of PD and PK 
assessments to ensure participant safety. Because the study requires an overnight inpatient 
treatment period, institutional requirements for elective inpatient admissions, which may vary 
from site to site, will be followed. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 48 (± 4) hours post 
TPIP dose will extend into Study Day 3. A remote safety follow-up visit is scheduled for Study 
Day 30 (± 2 days). The 48 hour PK visit will also include safety assessments including ECG, 
clinical laboratory evaluations, vital signs, physical examination, and AE collection (Table 1). 
The safety follow-up period will conclude with a remote (telephone or telemedicine) visit on 
Study Day 30 (± 2 days). The screening, treatment, and follow-up periods for the core, 
single-dose portion of the study are expected to be 62 days or less. An EUT period of 16 weeks 
will be optional for participants that complete the single-dose period, followed by a 30 day 
follow-up (± 3 days). This extends study participation to 142 days after enrollment in the EUT 
period.  
4.1.1. 
Screening Period 
The initial screening period will be up to 30 days. Required screening assessments are shown in 
Table 1. Participants who fail one or more screening assessments may be re-screened once at the 
Investigator’s discretion in order to meet study entry criteria. See Section 5.4 for additional 
information regarding participants who fail screening and/or are re-screened. 


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Participants who enter the optional EUT period more than 30 days after beginning the 
single-dose period (e.g., beyond the initial 30 day follow-up period) will be screened to ensure 
they continue to satisfy inclusion and exclusion criteria. Extended use treatment period screening 
assessments are shown in Table 5. 
4.1.2. 
Inpatient Treatment Period 
4.1.2.1. 
Baseline Procedures and Assessments 
The inpatient treatment period will be on Study Days 1 and 2. The participant may be required to 
undergo pre-admission assessments required by the Institution for elective admission, for 
example testing for common infectious pathogens. Signature of institutional elective admission 
documents and consents to procedures may be required. Data from required institutional 
assessments and consents will not be routinely collected as part of study data unless they pertain 
to a relevant AE or study endpoint. 
Participants will be admitted to an inpatient care setting such as an ICU, cardiac catheterization 
laboratory or other similar setting. They will have Baseline laboratory and safety assessments as 
shown in Table 2. An RHC will be placed for Baseline assessment of cardiopulmonary 
hemodynamics prior to TPIP administration and intermittent assessments of cardiopulmonary 
hemodynamics for 24 hours following TPIP administration. Institutional procedures and 
protocols for placement, care, monitoring, and removal of the RHC will be carried out but will 
not be collected as study data unless relevant. 
Some procedures and assessments for exploratory endpoints may not be offered at all sites. 
Participants will be asked to give informed consent only to those procedures that are being 
conducted by their Investigator at their site. These procedures include the following: 
• Transthoracic echocardiogram at Baseline and during a 2 to 8 hour window after TPIP 
administration (Table 4). 
• Pulmonary computerized tomography (CT) scan at Baseline and during a 4 to 8 hour 
window after TPIP administration (Table 4). 
• Resting respiratory gas exchange assessment at Baseline and intermittently after TPIP 
administration for up to 24 hours (Table 4). Resting respiratory gas exchange assessments 
will be standardized, with all participating investigators using similar equipment and 
procedures. 
For example, an Investigator who is doing only RHC and resting respiratory gas exchange 
assessments for this study will obtain informed consent for those procedures only and will not 
offer or ask the participant for informed consent for transthoracic echocardiogram or pulmonary 
CT scan as part of this study. 
Following completion of all Baseline assessments, including Baseline blood draws for PK and 
PD biomarkers (Table 3), the prescribed single dose of TPIP will be administered (Table 2).  


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4.1.2.2. 
Post-TPIP Administration 
Following TPIP administration, participants will have intermittent safety, clinical laboratory, PK, 
and PD assessments, as specified in the SoA (Table 2, Table 3, and Table 4). The study is 
designed to allow maximum flexibility for interventions and assessments at the discretion of the 
Investigator and institutional policies and procedures to ensure participant safety. At any time, 
the Investigator has the option to discontinue assessments for participant safety or tolerability 
reasons. Additional laboratory and/or hemodynamic assessments may be performed as deemed 
necessary for participant safety. Following completion of scheduled events, the Investigator has 
the option of continued laboratory and/or hemodynamic monitoring as deemed appropriate for 
participant safety.  
If, in the interest of participant safety, the Investigator omits scheduled assessments/procedures 
or performs additional assessments/procedures, the reason for doing so must be reported on the 
CRF as an AE in order to avoid a protocol violation.  
Following completion of protocol-required assessments and removal of the RHC, the participant 
will be discharged from the inpatient setting when deemed safe by the Investigator. Investigator 
and institutional usual care protocols for participant discharge and follow-up for an RHC 
procedure will apply. 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up 
The participant will be required to return as an outpatient for the 48 (± 4) hour post-TPIP 
administration PK sample. Additional safety assessments such as ECG, physical examination, 
vital signs, AE collection, and clinical laboratory evaluations will be completed at the 48 hour 
visit. Female participants who are women of child-bearing potential (WOCBP) will be given a 
self-administered pregnancy test kit with instructions to self-administer the test and report the 
results on the day of the Study Day 30 safety follow-up visit (Section 4.1.3). 
4.1.3. 
Safety Follow-up 
A remote (telephone call or telemedicine) safety follow-up visit is scheduled for Study Day 30, 
at which time participants who are WOCBP will also be asked to report the results of the self-
administered pregnancy test they were given at the 48 hour post-TPIP follow-up visit 
(Section 4.1.2.3, Table 1). 
4.1.4. 
Optional Extended Use Treatment Period 
All participants will be allowed to enter the optional 16 week EUT period after the completion of 
the inpatient treatment period and final PK sample collection. Entry into the optional EUT period 
will be at participant and Investigator discretion. A gap between the inpatient treatment period 
and EUT period is expected, but not required, and can be up to 6 months.  
After collection of the final PK sample, all participants will be allowed optional continued access 
to IMP for 16 weeks (includes a 3-week titration period) from first administration in the EUT 
period. At the Investigator’s discretion, participants may undergo a study drug taper for up to 
2 weeks after the Week 16 visit to help facilitate a safe withdrawal from study drug. 


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Participants will be screened to ensure they meet inclusion and exclusion criteria if they enter the 
EUT period more than 30 days after beginning the single-dose period (e.g., beyond the initial 30 
day follow-up period) (Table 5).  
Participant in-clinic study visits will be scheduled for EUT Baseline (EUT Day 1), EUT Week 2, 
EUT Week 3, EUT Week 5, EUT Week 10, and EUT Week 16. 
The CT scan will be performed according to instructions provided by the CT scan vendor. 
There will be a second safety follow-up visit 30 days (± 3 days) after EUT Week 16 for 
participants who elect to enter the EUT period. 
4.1.5. 
Open-label Extension Study  
When available, participants may be eligible to enroll in a separate OLE study that will have a 
duration of approximately 2 years. Details of the planned OLE study will be provided in a 
separate protocol. 
4.2. 
Scientific Rationale for Study Design 
The study is designed to understand the safety and acute PK and PD effects of TPIP in 
participants with PAH, the intended patient population. Intensive monitoring via RHC in an 
appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate relationships between dose, PK, and PD effects. Some 
assessments and study activities for exploratory endpoints are considered optional depending on 
Investigator preference and/or based on study site capabilities and procedures (Table 4). 
4.3. 
Justification for Dose 
4.3.1. 
Inpatient Treatment Period (Single-dose) 
Treprostinil palmitil has been previously studied in healthy volunteer participants as a liquid 
suspension for inhalation (TPIS) and has now been formulated as a dry powder for oral 
inhalation (TPIP). Data from pre-clinical pharmacology and safety studies supported the 
initiation of human studies with TPIS. Preclinical studies in rats and dogs showed that the plasma 
kinetics of TRE and TP after dosing with TPIP are similar to those of TPIS. Additional clinical 
PK and safety data from healthy participants after SAD and MAD dosing with TPIP supported 
the chosen study design and dose. For further information on the non-clinical pharmacology and 
safety studies of TPIS and TPIP, please refer to the Investigator’s Brochure.  
The current study utilizes the clinical experience of TPIS from Study INS1009-101 in healthy 
volunteer participants and the INS1009-102 SAD/MAD study of TPIP in healthy volunteer 
participants. In Study INS1009-101, doses of TPIS were administered in multiples of 85 µg TP 
to include 170 µg (2 × 85 µg) and 340 µg (4 × 85 µg) of TP. The systemic exposure for TRE at 
340 µg TP was low (AUC < 2.5 ng*h/mL) with an elimination t1/2 of approximately 7 hours.  
Data from the INS1009-102 SAD/MAD study of TPIP reinforced the study design and informed 
maximum dosage for the optional extended use portion of the study (Section 4.3.2). In the first 
SAD portion of INS1009-102 (SAD1), 18 participants were randomized to 1 of 3 TP dose levels 


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of TPIP: 112.5 μg, 225 μg, or 450 μg of TP (6 participants at each dose). Treprostinil peak 
concentrations in the SAD portion were attained at 1.5 to 3 hours post-dose; Cmax and AUC were 
dose-dependent and approximately proportional to the increase of dose; and elimination t1/2 was 
8.7 to 11.6 hours. Total treprostinil exposure (AUC) of treprostinil was found to be dose 
proportional following a single administration of TPIP across the dose range of 112.5 μg to 
675 μg.  
Administration of TPIP will be via inhalational dry powder packaged in single actuation 
capsules. Each capsule contains 7.5 mg of dry powder, containing 112.5 µg of the TP prodrug, 
the molar equivalent of 71 µg of TRE. Approximately 85 µg of TP (54 µg of TRE equivalent) 
will be emitted from the dry powder inhalation device. This is comparable to a single 
administration of Tyvaso for patients with PAH with the target dose being 54 µg QID. Single 
doses of up to 90 µg of Tyvaso have been administered in clinical studies of healthy volunteer 
participants (Tyvaso Package Insert, 2017). 
Each participant will receive a single dose administration of TPIP. A TPIP dose containing 
112.5 µg of TP will be given to the first participant in Study INS1009-201. All available data 
(PD, PK, safety) from the first participant will be assessed and evaluated by the SRC. Following 
this evaluation, the SRC will determine if it is safe to continue the study, the TPIP dose level and 
any changes to safety PD and PK assessments for the second participant (Figure 3). This process 
will be repeated using the total accrued data of all completed participants prior to determining 
the TPIP dose for each subsequent participant. There will be no simultaneous dosing of inpatient 
participants; each participant will be treated as an individual case for evaluation. The TP dose 
level for each subsequent participant may be increased, held stable or lowered, depending on the 
accumulating data from previous participants up to a maximum of 675 µg. TPIP dosing may also 
be stopped at any dose level as determined by the SRC. 
4.3.2. 
Optional Extended Use Treatment Period 
Selection of once-daily inhalation of TPIP at 80 – 640 µg was based on clinical PK and safety 
data from healthy participants, predicted efficacious dose levels using pre-clinical data, safety 
margin from rat and dog NOAEL doses, and Tyvaso® clinical experience.  
In Phase 1 studies, TRE PK was linear, and the systemic exposure was dose proportional. Single 
doses of up to 675 µg and multiple doses of up to 225 µg TPIP QD for 7 days were generally 
well tolerated. Most AEs observed were mild in severity and consistent with the safety profile of 
other prostanoid therapies.  
Based on exposures following a single dose of TPIP 675 µg in Study INS1009-102, TRE 
exposures in this study are not anticipated to exceed those following administration of the 
currently approved treprostinil product, Remodulin®. Treprostinil exposures following a 
continuous IV infusion of 10 ng/kg/min Remodulin (Cmax 1,470 pg/mL; AUC 25,690 pg*h/mL) 
are reported to be 2.1-fold and 4.7-fold higher, respectively, than those observed following 
administration of TPIP 675 μg (Cmax 717 pg/mL; AUC 5,480 pg*h/mL)(Laliberte et al., 2004). 
Minimal accumulation was observed following repeat doses of TPIP 225 μg QD for 7 days, and 
since a lower maximum dose (640 μg) will be used in the extended use portion of this study, 


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TRE exposures are expected to be lower than those observed following single doses of TPIP 
675 μg in Study INS1009-102. 
Based on the findings above, the TPIP dose will range from 80 µg to 640 µg QD in this 
treatment period.  
4.4. 
Study Completion 
A participant will be considered to have completed the study if he/she has completed the 
Study Day 30 safety follow-up (shown in Table 1) and has not elected to enter the optional EUT 
period. A participant who has entered the optional EUT period will be considered to have 
completed the study if he/she has completed the EUT period safety follow-up (EUT Day 142). 
The study will be considered completed on the date of the last safety follow-up of the last 
participant in the study.  
 


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5. 
STUDY POPULATION 
The study is expected to recruit approximately 6 to 10 participants at up to 7 centers with 
appropriate inpatient facilities in the United States. Eligible participants must have clinically 
stable disease of mild to moderate severity, with good to moderate functional status. Participants 
may not be taking more than 2 medications from the following classes: 
• Endothelin receptor antagonists (eg ambrisentan, bosentan, macitentan), 
• Phosphodiesterase type 5 inhibitors (eg sildenafil, tadalafil) 
• Guanylate cyclase stimulator (eg riociguat) 
It is expected that the site will recruit appropriate potential participants according to the criteria 
in Section 5.1 and Section 5.2. Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not permitted.  
 
The study inclusion and exclusion criteria include thresholds of selected RHC and ECG 
parameters that must be met at Baseline or the participant will not be considered eligible for the 
study. In this case, the participant is to be reported as a Screen Failure (Section 5.4). 
5.1. 
Inclusion Criteria 
 
Participants are eligible to be included in the study only if they meet all of the following criteriaa: 
Age:  
1. Participant must be ≥ 18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants must have a diagnosis of WHO Group 1 PH (PAH) with the following 
characteristics (Galie et al., 2016): 
a. Etiology of idiopathic, heritable, drug/toxin-induced or connective tissue 
disease (CTD)-related PAH; 
b. Right heart catheterization within the last 3 years with the following 
hemodynamic findings:  
- Mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest,  
- Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
- Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 
3. PAH diagnosis for at least 1 year  
4. New York Heart Association (NYHA)/WHO Functional capacity Class I-III 
5. No change in pulmonary hypertension medications (e.g., ambrisentan, bosentan, 
macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 90 days prior to 
Screening.  
6. No change in diuretic use or dosage for at least 30 days prior to Screening 


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7. Documented predicted percent forced vital capacity (FVC) > 70% within 1 year of 
Screening. If not available, pulmonary function testing will be performed at 
Screening (Table 1). 
8. At least 2 of the following European Respiratory Society/European Society for 
Cardiology (ERS/ESC) low risk criteria: 
a. NT-pro-BNP concentration < 300 ng/L within 6 months of Baseline (if not 
available will be obtained at Screening, Table 1). 
b. Historical documentation of 6- minute walk distance (6MWD) > 440 
meters within 6 months prior to Baseline. If not available will obtain 
6MWD test at Screening (Table 1). 
c. Right atrial pressure (RAP) < 8 mmHg within 1 year prior to Baseline 
d. Cardiac Index (CI) ≥ 2.5 L/min*m2 or mixed venous oxygen saturation 
(MVO2) > 65% within 1 year prior to Baseline 
9. Right heart catheterization at Baseline with the following hemodynamic findings: 
a. Mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest,  
b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
c. Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 
Weight 
10. Body mass index (BMI) within the range 19.0 - 32.0 kg/m2 (inclusive). 
Sex and Contraceptive/Barrier Requirements 
11. Male participants:  Male participants and their female partners of childbearing 
potential must agree to use highly effective contraception from Study Day 1 to at 
least 90 days after dosing. 
12. Female participants:  Women of child-bearing potential (WOCPB, defined as 
premenopausal, not surgically sterile for at least 3 months prior to Screening) must 
use a highly effective contraception method and agree to be tested for pregnancy 
from at Screening, Baseline, and 30 days after dosing. 
See Section 10.4 for contraceptive guidance. 
Informed Consent 
13. Capable of giving signed informed consent as described in Section 10.1.5 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
a Please note that participants who enroll in the optional EUT period beyond the initial 30 day follow-up period will 
be screened to confirm that they still meet inclusion/exclusion criteria. Please refer to Table 5.  
 


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5.2. 
Exclusion Criteria  
 
Participants are excluded from the study if they meet any of the following criteriaa: 
Medical Conditions 
1. Any PH other than idiopathic, hereditary, drug/toxin-induced, or connective tissue 
disease (CTD) associated PAH (e.g., congenital heart disease-associated PAH, 
portal hypertension-associated PAH, PH belonging to Groups 2 through 5) 
2. Allergy, or documented hypersensitivity or contraindication, to the ingredients of 
treprostinil palmitil inhalation powder (TPIP) or treprostinil (TRE). 
3. Previous intolerance to prostacyclin analogs or receptor agonists (e.g., selexipag) 
per Investigator discretion 
4. History of anaphylaxis or previously documented hypersensitivity reaction to any 
drug per Investigator discretion 
5. QTcF interval > 480 ms on resting ECG at Baseline 
6. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% 
or clinically significant valvular, constrictive, or atherosclerotic heart disease 
(myocardial infarction, etc) 
7. Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) 
at Screening. 
8. Active liver disease or hepatic dysfunction manifested as: 
a. Elevated liver function test results (ALT or AST > 2 × ULN) at Screening 
b. Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable 
if bilirubin is fractionated and direct bilirubin < 35%) at Screening. 
c. Known hepatic or biliary abnormalities, not including Gilbert's syndrome or 
asymptomatic gallstones at Screening.  
9. History of HIV infection/positive HIV serology test result at Screening. 
10. History of active/chronic Hepatitis B or C/ positive hepatitis B or C serology test 
result at Screening 
11. History of abnormal bleeding or bruising. 
12. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or 
otherwise recurrent infections of abnormal frequency, or prolonged infections 
suggesting an immune-compromised status, as judged by the Investigator. 


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13. Active and current symptomatic infection by SARS CoV 2. Additional COVID 19 
restrictions per institutional guidelines (See also Section 10.1.3.1.3) 
14. Participants with current or recent (past 4 weeks) lower respiratory tract infection 
(may be re-screened at appropriate time (Section 5.4) 
15. History of malignancy in the past 5 years, with exception of completely treated in 
situ carcinoma of the cervix and completely treated non-metastatic squamous or 
basal cell carcinoma of the skin. 
Concomitant Therapy 
16. Participants receiving triple combination therapy for PAH consisting of endothelin 
receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase 
stimulators (riociguat). 
17. Participants receiving prostanoids/prostacyclin agonists 
18. Participants receiving potent CYP2C8 inhibitors, such as gemfibrozil 
19. Other prior/concomitant therapies are allowed/disallowed at the Investigator’s 
discretion 
Prior/Concurrent Clinical Study Experience 
20. Have participated in any other interventional clinical studies within 30 days of 
Baseline 
Diagnostic assessments 
21. Any clinically significant abnormal laboratory, value, test result, or physical 
examination finding at Screening; diseases or diagnoses/disorders that, in the 
opinion of the Investigator, may put the participant or others at risk by participating 
in the study, interfere with the participant's treatment and assessment, or influence 
the results of the study; or have compliance issues with the study. 
Other Exclusions 
22. Current or history of substance and/or alcohol abuse per Investigator assessment 
23. Current user of cigarettes or e-cigarettes 
24. Pregnant or breastfeeding. 
a Please note that participants who enroll in the optional EUT period beyond the initial 30 day follow-up period will 
be screened to confirm that they still meet inclusion/exclusion criteria. Please refer to Table 5.  
 
 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are required. 


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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study because they did not meet all inclusion criteria or meet one 
or more exclusion criteria. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the Investigator’s discretion. If a participant can be rescreened, the PI is to 
consult with the Medical Monitor to determine whether some or all of the screening assessments 
must be repeated. Rescreened participants will sign a new ICF and will be assigned a new 
participant number. 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period 
Following successful screening and meeting of study eligibility criteria, the inpatient treatment 
period and RHC procedure must be scheduled without delay.  
 
The scheduled treatment period may be temporarily delayed no longer than 28 days by the 
Investigator in consultation with the Medical Monitor for valid reasons. Examples of valid 
reasons for delaying the treatment period may include such things as a life event for the 
participant (eg death in the family), local public health emergency (e.g., COVID 19 outbreak), 
site facility issues (e.g., catheterization lab or ICU bed availability), or pending TPIP dosing 
directives from the SRC. 
 
A temporary delay in the scheduled inpatient treatment period for a valid reason may result in 
previously met Inclusion Criteria that rely on a time window to be not met (e.g., 6MWD falls 
outside the 6 months prior to Baseline window). This is not considered to be a Screen Failure. In 
this case, the Investigator should consult with the Medical Monitor to identify which screening 
tests need to be conducted or repeated to ensure that the participant meets study inclusion criteria 
and can safely participate in the study.  
 
Deterioration of the participant’s medical condition is not a valid reason to delay start of the 
inpatient treatment period. In some cases, delaying the inpatient treatment period may cause the 
participant to meet one or more exclusion criteria (e.g., participant develops a lower respiratory 
infection). In this case the participant should be considered a Screen Failure and Section 5.4 
applies. 


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6. 
STUDY IMP AND CONCOMITANT THERAPY 
Study IMP is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study IMP Administered 
6.1.1. 
Inpatient Treatment Period (Single Dose) 
A single dose of TPIP will be used in the inpatient treatment period. Each TPIP capsule contains 
7.5 mg of dry powder, containing 112.5 µg of the TP prodrug. A dose may consist of a single 
capsule or of multiple capsules administered in succession. 
Name of 
Treatment 
Dose 
Supplied 
Formulation 
Route and 
Frequency of 
Administration 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or more single actuation 
capsules 
Single actuation 
capsules containing 
112.5 µg TP per 7.5 
mg powder 
Inhalation; single 
dose after Baseline 
assessments 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or two single actuation 
capsules 
(80 µg, 160 µg, 240 µg, 320 µg, 
400 µg, 480 µg, or 640 µg) 
Dry powder single 
actuation capsules 
containing 
80 µg, 160 µg, or 
320 μg 
Inhalation; single 
dose after Baseline 
assessments 
QD = once daily 
6.1.2. 
Optional Extended Use Treatment Period 
The IMP used in the EUT period will be capsules containing 1 of 3 dosage strengths of TPIP (80 
µg, 160 µg, or 320 µg). IMP should be taken around the same time every day. Administration of 
IMP will be via inhalational dry powder packaged in single actuation capsules. One or 2 capsules 
will be administered for each dose. Administration of 2 capsules should be done sequentially. 
Each TPIP capsule contains 8 mg, 16 mg, or 32 mg of dry powder containing 80 µg, 160 µg, or 
320 µg of the TP prodrug, respectively.  
 
Name of 
Treatment 
Dose 
Supplied Formulation 
Route of Administration 
Treprostinil 
palmitil 
inhalation 
powder (TPIP) 
One or two single 
actuation capsules 
(80 µg, 160 µg, 240 µg, 
320 µg, 400 µg, 480 µg 
or 640 µg QD) 
Dry powder single 
actuation capsules 
containing 
80 µg, 160 µg, or 320 μg 
Inhalation (QD) 
QD = once daily 


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6.1.3. 
Medical Devices 
In the planned clinical study, the TPIP will be administered by oral inhalation using a Plastiape 
capsule-based Dry Powder Inhaler (RS 01 Mod 7). A Type III Drug Master File is filed at the US 
FDA and the RS01 inhaler is classified as a Class I medical device. The Instructions for Use of 
the device document is provided separately as an Appendix to the Pharmacy Manual. 
 
All device deficiencies (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the Investigator throughout the clinical investigation (Section 8.3.7) 
and appropriately managed by Insmed. 
6.2. 
Preparation/Handling/Storage/Accountability 
Insmed Incorporated will provide the Investigator and clinical unit with adequate quantities of 
TPIP capsules. For 112.5 µg doses, TPIP-filled HPMC capsules will be delivered in HDPE 
bottles overwrapped with an aluminum pouch, containing a sachet of desiccant to prevent 
moisture ingress. For 80 µg, 160 µg, or 320 μg doses, HDPE bottles will be closed with the 
desiccant placed inside the bottle, and induction sealed. The powder will be administered by oral 
inhalation using a Plastiape capsule-based Dry Powder Inhaler. 
6.2.1. 
Inpatient Treatment Period (Single-dose) 
Directions for preparation and administration of the TPIP dose to the participant are provided in 
a separate document as an Appendix to the Pharmacy Manual for the single-dose Inpatient 
Period. 
All study IMP must be stored according to the labeled instructions in a secure cabinet or room 
with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. Current stability 
data supports the shelf life assigned to TPIP when stored at 2 to 8 °C. 
• The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study IMP received and any discrepancies are 
reported and resolved before use of the study IMP. 
• Only participants enrolled in the study may receive TPIP and only authorized site 
staff may supply or administer it. All TPIP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
• The Investigator, institution, and/or pharmacist or designee is responsible for study 
IMP and dosing devices accountability, reconciliation, and record maintenance (e.g., 
receipt, reconciliation, and final disposition records). 
• Study IMP and dosing device accountability records will be maintained for all clinical 
supplies. All transactions will be recorded on the drug and dosing device 
accountability records including shipment receipts and study participant doses. All 
transactions will be recorded on a real-time basis. 


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• The Investigator/site will maintain detailed documentation of the number and 
identification of bottles and dispensing units of TPIP with copies of these documents 
to be provided to Insmed at the end of the study. All used and unused study IMP and 
dosing devices will be maintained by the site until inventoried by the study monitor. 
Upon completion of the study IMP and dosing device inventory by the study monitor, 
used and any unused study IMP and dosing devices will be disposed of in accordance 
with instructions provided to sites and according to site destruction policies. 
Documentation of destruction must be provided to Insmed. 
• Further guidance and information for the final disposition of unused study IMP 
supplies can be obtained from Insmed. 
6.2.2. 
Optional Extended Use Treatment Period 
Directions for preparation and administration of IMP to the participant in-clinic are provided in 
the Pharmacy Manual for the optional EUT period. Directions for preparation and administration 
of IMP for home use will be provided to the participants. 
Only participants enrolled in the study may receive IMP, and only authorized study personnel 
may supply IMP. All IMP must be stored according to the labeled instructions with access 
restricted to necessary clinic personnel. The site will be required to keep a temperature log to 
establish a record of compliance with storage conditions. Refer to the Pharmacy Manual for the 
optional EUT period for shelf-life and storage conditions. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP and dosing devices accountability, reconciliation, and record maintenance 
(e.g., receipt, reconciliation, and final disposition records). Directions for storage, handling, 
accountability, and destruction are provided in the Pharmacy Manual for the optional EUT. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 
6.4. 
Study Intervention Compliance 
6.4.1. 
Inpatient Treatment Period (Single Dose) 
Study participants will receive the TPIP dose directly from the Investigator or designee, under 
medical supervision, in an appropriate inpatient setting. The date and time of the dose 
administered will be recorded in the source documents. The dose of TPIP and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the TPIP. 
6.4.2. 
Optional Extended Use Treatment Period 
At each in-clinic visit, participants will be dispensed adequate IMP to allow for daily dosing. 
When participants are dosed at the site, IMP administration will be overseen by study site 
personnel. The date and time of each dose self-administered in the clinic will be recorded in the 


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source documents. The dose of IMP and study participant identification will be confirmed at the 
time of dosing by a member of the study site personnel. 
When participants administer IMP at home, compliance with IMP will be assessed at each 
in-clinic visit. Participants will record their daily dose on paper dosing diaries. Compliance will 
be assessed by direct questioning, review of participant dosing diaries, and counting of returned 
capsules during the site visits. Participants will return unused capsules and used study capsules 
and devices to the study site at each in-clinic visit. Participants who undergo a study drug taper 
will return unused capsules and used capsules and devices to the study site at a follow-up visit. 
Unused capsules should be returned in the bottle they were dispensed in. Deviation(s) from the 
prescribed dosage regimen should be recorded.  
A record of the quantity of capsules dispensed to and administered by each participant must be 
maintained and reconciled with study drug logs and participant dosing diaries. Study drug start 
and stop dates, including dates for study drug interruptions and/or dose reductions will also be 
recorded. 
6.5. 
Dose Modification 
Dose modification is part of the study design and is described in detail in Section 4.3 and 
Section 1.3.2. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
An overdose is defined as the participant receiving any TPIP in excess of their assigned dose as 
predetermined by the SRC (Section 4.3). An overdose itself is not an AE. However, if the 
overdose results in clinical signs and symptoms, it requires expedited reporting as if it is an SAE. 
The Investigators must refer to the relevant documents for detailed information regarding 
warnings, precautions, contraindications, AEs, and other significant data pertaining to the study 
IMP. Such documents may include, but are not limited to, the Investigator’s brochure. 
In the event of an overdose, the Investigator must: 
• Contact the Medical Monitor within 24 hours. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, how to 
proceed with treatment period procedures and assessments. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until TP or 
TRE is likely to be sufficiently metabolized and/or excreted and/or can no longer be 
detected systemically. The frequency and duration of plasma sampling from the last dose 
of TPIP must be determined by the Investigator in conjunction with the study team and 
Medical Monitor. 
• The overdose must be fully documented (e.g., quantity of the excess dose, duration of the 
overdose, how it happened) in the CRF. 


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6.8. 
Concomitant Therapy 
Any medications, treatments, or therapies that the participant is receiving at Baseline 
(Study Day 1) or receives during the study (Study Day 1 through end of study [EOS]) are 
considered concomitant therapy and will be collected and documented in the study CRF.  
Documentation includes the name of the therapy, with the reason for use, the dates of 
administration including start and end dates, and dosage information including dose and 
frequency.  
Prior medications are those medications taken before the first dose of study IMP. A medication 
that starts prior to first dose but continues after the first dose of study IMP is classified both in 
prior and concomitant medications. Any procedures performed from Day 1 through EOS are 
considered concomitant procedures and will be collected and documented in the study CRF. 
The Medical Monitor must be contacted if there are any questions regarding concomitant or prior 
therapy. 
For participants who enroll in the EUT period, new concomitant therapy for the period from the 
single-dose Study Day 30 follow-up until the enrollment in the EUT will be collected during 
participant’s screening for the EUT. 


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7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study IMP 
7.1.1. 
Single-dose Period 
This is a single dose period; not applicable. 
7.1.2. 
Optional Extended Use Treatment Period 
If study drug is permanently discontinued, the participant will be encouraged to participate in 
their remaining study visits. See Table 6 for data to be collected at the time of discontinuation of 
IMP and follow-up. If a participant discontinues the study and needs to be started on another 
PAH medication, the Investigator should contact the Medical Monitor.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or compliance 
reasons.  
At the time of discontinuing from the study after study drug administration, if possible, an early 
discontinuation evaluation should be conducted to maximize participant safety. This final 
evaluation and the reason for participant withdrawal must be documented in the CRF.  
The participant will be permanently discontinued both from the study drug and from the study at 
that time. 
If the participant is discontinued from the study due to an SAE, the Investigator will follow the 
participant until the Investigator deems that the SAE has resolved or stabilized.  
The Investigator may withdraw the participant from the study due to absence of a PD response to 
TPIP. Lack of expected pharmacological action per se will not be reported as an AE or SAE. 
Such instances will be captured in the PK and PD assessments. 
If the participant withdraws consent for disclosure of future information, Insmed may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled follow-up visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of 


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maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
must be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered 
lost to follow-up and to have withdrawn from the study.  
• Site personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants, 
including those who did not get study IMP. Public sources may be searched 
for vital status information.  If vital status is determined as deceased, this will 
be documented and the participant will not be considered lost to follow-up. 
Insmed personnel will not be involved in any attempts to collect vital status 
information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.13.2). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Table 1, Table 2, Table 3, Table 4, Table 5, 
Table 6.  
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet eligibility criteria prior to scheduling the study RHC procedure and inpatient admission. 
The RHC procedure and inpatient admission must be scheduled for as soon as possible once the 
participant’s eligibility for the study is confirmed by screening. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., previous 
RHC, previous echocardiogram, previous 6MWD test) and obtained before signing of the ICF 
may be utilized for screening or Baseline purposes provided the procedures meet the protocol-
specified criteria and were performed within the time frames defined in the inclusion and 
exclusion criteria in Section 5.  
For participants who do not elect to enter the EUT period, the maximum amount of blood 
collected from each participant over the duration of the study, including any extra assessments 
that may be required is expected to be approximately 140 mL and will not exceed 200 mL. 
Approximately 80 mL will be required for PK sampling over 48 hours and approximately 20 mL 
for biomarker sampling. Safety and screening blood samples will require 
approximately 20 to 30 mL. Blood loss from the RHC procedure is anticipated to be negligible. 
For participants who do elect to enter the optional EUT period within the 30 day follow-up 
window in the single-dose period, there is no anticipated blood collection. For participants who 
elect to enter the optional EUT period after the 30 day follow-up in the single-dose period, 
Safety and screening blood samples will require approximately 20 to 30 mL. Blood loss from the 
RHC procedures is anticipated to be negligible.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples at the Investigator’s discretion. 
At any time, the Investigator has the option to discontinue assessments for participant safety or 
tolerability reasons. Additional laboratory, PK, and/or hemodynamic assessments may be 
performed as deemed necessary for participant safety. Following completion of scheduled 
events, the Investigator has the option of continued laboratory and/or hemodynamic monitoring 
as deemed appropriate for participant safety. If, in the interest of participant safety, the 
Investigator omits scheduled assessments/procedures or performs additional 
assessments/procedures, the reason for doing so must be reported on the CRF as an AE in order 
to avoid a protocol violation. 
8.1. 
Pharmacodynamic Assessments 
The results of each individual participant’s PD assessments will contribute to the dosing decision 
for the next participant (Section 4.3).  


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8.1.1. 
Required PD Assessments with RHC 
PVR, CO, PAP (mean), RAP (mean), RVP, hemoglobin, and MVO2 will be measured via the 
RHC at the time points indicated in the SoA (Table 2). Oxygen consumption is part of the MVO2 
calculation and may be measured or estimated at 125 mL O2 per square meter (m2) of body 
surface area (BSA). These or other parameters may be optionally measured at other time points 
or omitted to ensure participant safety at the Investigator’s discretion. If measurements are 
missed, or additional measurements are taken for safety purposes, the reason must be 
documented as an AE in the CRF. 
Institutional procedures for insertion, care, monitoring, and removal of the RHC will be 
followed. Specific technique and procedures for measurement of PVR, CO, PAP, RAP, RVP, 
hemoglobin, oxygen consumption, and MVO2 are provided in a separate Procedure Guide. 
8.1.2. 
Required Non-invasive PD Assessments 
Systemic blood pressure (mmHg) may be measured by inflatable cuff. Systemic blood pressure 
must include 3 values:  systolic, diastolic, and mean arterial pressure. Arterial oxygen saturation 
(SpO2, %) and heart rate (beats per minute) may be measured by pulse oximeter.  
8.1.3. 
Resting Respiratory Gas Exchange Assessments 
Specific measurements for resting respiratory gas exchange assessment include changes from 
Baseline in respiratory rate (breaths per minute), minute ventilation (mL per minute), carbon 
dioxide production (VCO2, mL per minute), end tidal oxygen concentration (ETO2, %), and end 
tidal carbon dioxide concentration (ETCO2, %). The gas exchange parameters will be monitored 
at the same time points as the PD assessments in Section 8.1.1 (Table 2, Table 4). Specific 
instructions for resting respiratory gas exchange assessment procedures and measurements are 
provided in a separate Procedure Guide. 
8.1.4. 
Transthoracic Echocardiogram Assessments 
Transthoracic echocardiogram is to be performed at Baseline and during a 2-8 hour window 
following TPIP administration (Table 4). Specific instructions for echocardiographic procedures 
and measurements are provided in a separate Procedure Guide. 
8.1.5. 
Pulmonary CT Scan 
8.1.5.1. 
Single-dose Period 
Pulmonary CT scanning to assess pulmonary vasculature and blood flow is scheduled for 
Baseline and during a 4-8 hour window following TPIP administration (Table 4). Specific 
requirements and instructions for pulmonary CT scanning and required parameters are provided 
in a separate Procedure Guide. 


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8.1.5.2. 
Optional Extended Use Treatment Period 
An optional pulmonary CT scan may be performed at first visit (±3 days) and at EUT Week 16 
(±3 days) in the optional EUT period, as indicated in Table 6. The CT scan will be performed 
according to instructions provided by the CT scan vendor. 
8.2. 
Safety Assessments 
 
Evaluation of the safety and tolerability of single doses of TPIP in participants with PAH is the 
primary objective of this study. Planned time points for all safety assessments are provided in 
Table 1 and Table 2. The results of the individual participant’s safety assessments during and 
after TPIP administration will contribute to the dosing decision for the next participant 
(Section 1.3.2). Participants who elect to enter the optional EUT period will also be monitored 
for safety, as listed in Table 6.  
8.2.1. 
Physical Examinations 
Screening: The physical examination must focus on those areas that determine the individual 
participant’s eligibility to participate in the study and do so safely at the Investigator’s discretion 
and will be documented accordingly.  
Baseline:  The physical examination must focus on the participant’s fitness for the study 
procedures and TPIP administration.  
Discharge:  The physical examination must focus on the participant’s fitness to be safely 
discharged to home from the inpatient setting.  Special attention must be paid to assessment of 
any new or ongoing AEs. 
Follow-up: The in-person physical examination must focus on participant safety and assessment 
of AEs that were ongoing at discharge or have occurred since discharge. 
8.2.2. 
Vital Signs 
8.2.2.1. 
Single-dose Period 
Temperature, heart rate, respiratory rate, and blood pressure at screening and 48 hour post-TPIP 
administration follow-up will be per the Investigator’s usual outpatient practice and documented 
accordingly. 
Baseline and post-TPIP administration:  Changes from Baseline in heart rate, respiratory rate, 
and systemic blood pressure are PD endpoints as well as safety variables and must be measured 
as specified (Section 8.1). Vital signs outside of PD endpoints will be monitored per the inpatient 
unit’s usual practices. 
8.2.2.2. 
Optional Extended Use Treatment Period 
Changes in heart rate, respiratory rate, body temperature, and systemic blood pressure will be 
monitored as described in Table 6. Vital signs will be measured at Extended Use 


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Screening/Baseline (EUT Day 1), EUT Week 2, EUT Week 3, EUT Week 5, EUT Week 10, and 
EUT Week 16 and at the Early Discontinuation visit, if appropriate. 
8.2.3. 
Electrocardiograms 
Screening:  a single 12-lead ECG will be conducted per the Investigator’s usual practice 
Baseline: A single 12-lead ECG will be performed to ensure the participant’s eligibility for the 
study (Section 5.2). Inpatient telemetry monitoring will be utilized per the unit’s usual practice 
until the participant is discharged from the inpatient setting, but routine telemetry readings will 
not be collected as study data unless they pertain to a relevant AE. 
48 hours post-TPIP administration follow-up:  a single 12-lead ECG will be conducted per the 
Investigator’s usual practice. 
8.2.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 (Table 7) for the list of clinical laboratory tests to be performed and the SoA 
(Table 1, Table 2, Table 5, Table 6) for the timing and frequency. All clinical laboratory tests 
will be performed locally by the study site. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 7 days after TPIP dosing must be repeated at the Investigator’s discretion, 
consistent with the participant’s level of disease until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator or Medical Monitor. 
• If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology must be identified, and Insmed 
notified.] 
• All protocol-required laboratory tests, as defined in Section 10, Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.4). 
• If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.5. 
Pregnancy Testing 
8.2.5.1. 
Single-dose Period 
Willingness of WOCBP to undergo serum or urine pregnancy testing is a study eligibility 
criterion. Pregnancy tests will be conducted at screening, baseline, and Study Day 30. WOCBP 


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participants will be provided a home pregnancy test kit with instructions to conduct and report 
test results at the Study Day 30 follow-up visit which is scheduled to be by telephone call or 
telemedicine. If the participant elects to enter the optional EUT period and the remote safety 
follow-up visit overlaps with the start of the EUT period, the results of a urine pregnancy test 
will be recorded at the first visit in the extended treatment period.  
8.2.5.2. 
Optional Extended Use Treatment Period 
Urine pregnancy tests will be performed in-clinic at EUT Baseline (EUT Day 1) in WOCBP. 
WOCBP participants will be provided home pregnancy test kits with instructions to conduct the 
pregnancy tests every 30 days or more if required during the treatment and follow-up periods. 
Study site personnel will contact the participant every 30 days by telephone and record the 
pregnancy test results. An additional on-site urine test must be performed prior to starting any 
procedure that requires the use of ionizing radiation. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). AEs may be solicited or unsolicited. Solicited and 
unsolicited AEs are defined in Section 10.3. 
The Investigator is responsible for detecting, documenting, and recording events that meet the 
definition of an AE or SAE as provided in the protocol and remain responsible for following up 
all AEs. 
The Investigator should proactively follow participants with AEs until the EOS for each 
participant. At the EOS visit, the Investigator will record the AE status (stable or not stable) in 
the electronic CRF. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs (serious and non-serious) for the core, single-dose period will be collected from the 
signing of the ICF until the Study Day 30 follow-up visit at the time points specified in the SoA 
(Table 1, Table 2). Medical occurrences that begin after obtaining informed consent but before 
TPIP administration will be recorded as Medical History/Current Medical Conditions, not as 
AEs. 
SAEs that occur after signing the ICF but before study IMP starts must be recorded and reported 
as SAEs. Non-serious medical occurrences that begin after obtaining informed consent but 
before TPIP administration will be recorded as Medical History/Current Medical Conditions, not 
as AEs. 


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For participants who enroll in the EUT period, AEs for the period from the single-dose Study 
Day 30 follow-up until the enrollment in the EUT will be collected during participant’s screening 
for the optional EUT period. All AEs and SAEs for participants who choose to enroll in the 
optional EUT period will be recorded at the time points specified in the SoA (Table 5, Table 6).  
All SAEs will be recorded and reported to Insmed or designee immediately and under no 
circumstance must this exceed 24 hours, as indicated in Appendix 3, (Section 10.3). The 
Investigator will submit any updated SAE data to Insmed within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IMP or study participation, the Investigator must promptly notify 
Insmed. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. The Investigator should proactively follow participants 
with AEs until the EOS for each participant. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool has been 
taken offline due to study completion, then the site can report this information to the Medical 
Monitor by email or telephone. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to Insmed of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
Insmed has a legal responsibility to notify relevant health authorities and regulatory agencies 
about the safety of a study drug under clinical investigation. This study is being conducted in the 
USA only; regulatory requirements relating to safety reporting to the US FDA, IRBs, and 
investigators will be followed. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from Insmed will review and then file it 
along with other study documents and will notify the IRB, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Insmed policy and forwarded to Investigators as necessary. No serious adverse 


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reactions are considered expected for TPIP. Please refer to the Reference Safety Information in 
Section 6.1 of the Investigator’s Brochure. 
8.3.5. 
Pregnancy 
Details of all pregnancies that occur in WOCBP participants within 30 days after TPIP 
administration will be collected. Male participants with WOCBP partners must continue to use 
contraception for 90 days after TPIP administration and report any pregnancies that occur within 
that time period.  
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to Insmed within 24 hours of learning of the pregnancy in a female participant 
or female partner of male participant and after obtaining the necessary signed informed consent 
from the female partner. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from the study. 
8.3.6. 
Adverse Events of Special Interest (AESI) 
There are no AESIs for TPIP that require special collection and rapid communication by the 
Investigator. 
8.3.7. 
Medical Device Deficiencies 
A medical device, the Plastiape capsule based Dry Powder Inhaler is being provided for use in 
this study to administer TPIP. To fulfill regulatory reporting obligations worldwide, the 
Investigator is responsible for the detection and documentation of events meeting the definitions 
of device deficiency that occur during the study with such devices. 
The definition of a Medical Device deficiency and reporting requirements and procedures for 
device deficiencies and AEs/SAEs resulting from device deficiencies can be found in 
Section 10.6.  
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, documented, 
and reported during all periods of the study in which the medical device is used. 
• If the Investigator learns of any device deficiency at any time after a participant has 
been discharged from the study, and such a deficiency is considered reasonably 
related to a medical device provided for the study, the Investigator will promptly 
notify Insmed. 
The method of documenting Medical Device Deficiency is provided in Section 10.6. 


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8.3.7.2. 
Follow-Up of Medical Device Deficiencies 
Follow-up applies to all participants who experienced a device deficiency. 
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the Investigator. 
8.3.7.3. 
Prompt Reporting of Device Deficiencies to Insmed 
Device deficiencies will be reported to Insmed within 24 hours after the Investigator determines 
that the event meets the protocol definition of a medical device deficiency. 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies 
The Investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for Insmed to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
The Investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB. 
8.4. 
Pharmacokinetic Assessments 
The schedule for PK assessments and sampling windows during the single-dose period is shown 
in Table 3. The 48 (± 4) hour post-TPIP administration blood draw is expected to be done on an 
outpatient basis. 
8.4.1. 
PK Sample Collection 
Plasma blood samples of approximately 10 mL each will be collected for measurement of plasma 
concentrations of TP and TRE as specified in the SoA (Section 1.4).  
A maximum of 2 samples may be collected at additional time points during the study if an SAE 
occurs or at early termination.  
Each PK plasma sample will be divided into 2 aliquots (1 each for PK analysis and the other for 
backup. All samples will be stored frozen (-70°C or -20°C) until shipment and then stored at -
70°C until analysis. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Full instructions for the collection and handling of PK samples will be provided by Insmed in a 
separate Laboratory Manual.  
8.4.2. 
PK Analysis 
Individual PK parameters of TRE and TP will be determined using non-compartmental analysis 
for the following parameters: Cmax, tmax, AUCt1–t2, AUC0–∞, CL/F, Vd/F, and t1/2. 


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8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Relationships between PK (TP dose and TRE exposure) and PD effects and safety will be 
explored and reported separately. 
8.5. 
Genetics / Pharmacogenomics 
Genetic and/or pharmacogenomic analyses are not included in this study. 
8.6. 
Biomarkers 
A blood sample for NT-pro-BNP will be taken at screening if needed as part of study inclusion 
criteria (Section 5.1).  
Blood samples (5-7 mL per time point) will be collected for biomarker measurement at Baseline 
and at 4 and 8 hours after TPIP administration. The plasma generated from the blood samples 
will be stored frozen (-70 C or lower is preferred) until shipment and analysis. 
Full instructions for the collection and handling of biomarker samples will be provided by 
Insmed in a separate Laboratory Manual. 
8.7. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity assessments do not apply to this study of a small molecule. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be evaluated in this study. 
9.2. 
Sample Size Determination 
The sample size for this study is not based on statistical power calculations. The planned number 
of evaluable participants to complete the study is approximately 6-10.  
9.3. 
Analysis Sets 
The analysis sets comprise participants who are considered evaluable for the parameters under 
consideration.  
All participants who receive a single dose of TPIP will be considered evaluable for safety and 
included in the safety population. 
All participants who receive a single dose of TPIP and have a least one measurable post-dose 
plasma TP/TRE concentration will be considered evaluable for PK and included in the PK 
population. 
All participants who receive a single dose of TPIP and have a Baseline datapoint and at least one 
measurable post-dose PD datapoint will be considered evaluable for PD and included in the PD 
population. 
All participants who receive a single dose of TPIP and have at least 1 measurable post-dose 
biomarker datapoint will be considered evaluable for biomarkers and included in the biomarker 
population. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to Database Lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1. 
General Considerations 
There is no hypothesis-testing in this study and no inferential statistical analyses will be 
conducted. There will be no proxy values for missing data. Participant PK, PD, and biomarker 
data will be presented individually in listings and graphs as appropriate for each variable.  
The frequency of TEAEs is the primary endpoint for this study. All safety analyses will be 
performed on the safety population. AE listings as required by ICH E3 guidelines will be 
produced. TEAEs, SAEs, AEs leading to treatment and/or study withdrawal, and AESIs will be 
listed for each participant along with outcome, severity, and relatedness to study IMP. Ad hoc 
summaries of TEAEs may be prepared if the volume of data allow.  
PK and PD values for secondary endpoints will be listed and graphed if appropriate for each 
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PK and PD values for exploratory endpoints will be listed and graphed as appropriate for each 
participant. 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values 
ECG data will be listed for each participant. Vital signs data that are not considered part of a PD 
assessment (Section 8.1) will be listed for each participant. Clinical laboratory values will be 
listed for each participant. 
9.5. 
Interim Analysis 
All available safety, PK, and PD data from each participant will be evaluated by the SRC prior to 
the next participant in order to determine the value of proceeding with the study and the TPIP 
dose for each subsequent participant (Section 4.3). 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
a. Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
b. Applicable ICH Good Clinical Practice (GCP) Guidelines 
c. Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, Instructions for Use of the 
Plastiape capsule based Dry Powder Inhaler, and other relevant documents must be 
submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
d. Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
e. Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
f. Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
10.1.2. 
Protocol Deviations 
The Investigator must conduct the study in compliance with the protocol as agreed to by Insmed 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRB. 
The Investigator must notify the IRB of deviations from the protocol in accordance with IRB 
reporting requirements.  
As of May 2020, due to concern regarding COVID-19, there may be restrictions to participant 
attendance at in-clinic visits or elective inpatient admissions. In the event participants are 
restricted to attend in-clinic visits, or if the participant has concern regarding travel and attending 
in-clinic visits (due to potential public health concerns), the site must contact Insmed on how to 


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conduct the scheduled assessments, and decisions must be documented in the source 
documentation. Where necessary, in-clinic visits may be conducted via telemedicine link and 
home health care visits. 
10.1.3. 
Public Health Emergency Situations 
During the COVID-19 public health emergency, Insmed, IRBs, and Investigators shall follow the 
most current version of local guidance to assure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. The continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms, 
which will remain in effect only for the duration of the local public health emergency. Examples 
of such mechanisms may include, but are not limited to, any of the following: telephone contact, 
virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use 
of local clinic or laboratory locations, and home visits by skilled staff. The site must contact 
Insmed on how and when to implement temporary and/or alternative mechanism of scheduled 
assessments, and all decisions taken must be documented in the source documentation. 
Additionally, all temporary mechanisms utilized, and the resulting deviations from planned study 
procedures are to be documented as being related to COVID-19. 
In a situation where local health authorities declare a public health emergency while the study is 
ongoing, the suggested guidance in the following subsections must be followed. 
10.1.3.1. Continuation or Suspension of the Study 
Ensuring the safety of trial participants is paramount. Insmed (Insmed Incorporated), in 
consultation with clinical Investigators and IRB, will determine if the protection of a 
participant’s safety, welfare, and rights are best served by continuing or stopping the trial at the 
specific site. Such decision will depend on specific circumstances, including the ability to 
conduct appropriate safety monitoring, the potential impact on the investigational product supply 
chain, and other considerations. 
If the decision is to continue the study, the following considerations will be taken into account: 
10.1.3.1.1. Study Recruitment 
Insmed will communicate to the sites the decision on whether to continue or suspend recruitment 
after considering the specific circumstances of each site, recommendation by the IRB, and its 
local health authority mandates. If, due to COVID-19, study discontinuation exceeds the 
assumed rate, Insmed may allow enrollment past the assumed sample size. 
10.1.3.1.2. Participants Already Enrolled in the Study 
If the decision is to continue the participation of participants already enrolled, the following steps 
must be taken:  
• If a participant is not able to complete a protocol specified study visit, it may be 
necessary to adjust the visit schedule, convert in-clinic visits to telemedicine visits, 
and/or postpone study procedures until the next available in-clinic study visit. If there 
is information available from previous visits (e.g., laboratory assessments) that 


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requires follow-up procedures or other safety assessments, the Investigator will 
decide if an on-site visit or home healthcare visit is required or whether the 
participant’s safety can be preserved by other means. 
10.1.3.1.3. Participants Infected by COVID-19 
If a participant has had a past documented mild to moderate COVID-19 infection prior to 
enrollment in the trial but the participant has recovered and the current diagnostic tests are 
negative (negative antigen by any diagnostic laboratory kit), the participant can be screened, at 
the Investigator’s discretion. Participants who experienced hospitalization, severe disease, and/or 
COVID-19 acute respiratory distress syndrome (ARDS) must be excluded. 
If a participant has a documented infection by COVID-19 while in the trial, the event will be 
reported as an AE or SAE, depending on the criteria. The Investigator will follow the guidance 
provided by health authorities in the treatment of those participants. 
10.1.4. 
Financial Disclosure 
The disclosed financial interest of the Investigator/sub-investigator must be collected before 
screening of the first participant, following study completion at the Investigator site and 1 year 
following overall study completion. The Investigator/sub-investigator must promptly update this 
information if any relevant changes occur during this period. 
10.1.5. 
Informed Consent Process 
Before a participant’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the participant or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any study IMPs are administered. 
A legally acceptable representative is an individual or other body authorized under applicable 
law to consent, on behalf of a prospective participant, to the participant’s participation in the 
clinical study. An informed consent document that includes both information about the study and 
the consent form will be prepared and given to the participant. This document will contain all the 
elements required by the ICH E6 (R2) Guideline for GCP and any additional elements required 
by local regulations. The written ICF must be prepared in the local language(s) of the potential 
participant population. 
 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirements, and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) must be 
approved by the IRB prior to being provided to potential participants. 
 
The participant’s written informed consent (written or electronic) must be obtained prior to 
his/her participation in the study, and must be documented in the participant’s medical records, 
as required by applicable regulations. The ICF must be signed and personally dated by the 
participant or a legally acceptable representative, and by the person who conducted the informed 
consent discussion (not necessarily the Investigator). The signed ICF must be retained in 
accordance with institutional policy, and a copy of the signed consent form must be provided to 


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the participant or legal representative. The date and time that informed consent was given must 
be recorded in the CRF.  
Participants who are rescreened are required to sign a new ICF. 
10.1.6. 
Protection of Participant Identification and Confidentiality 
The Investigators and Insmed will preserve the confidentiality of all participants taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the participant’s anonymity is maintained. On the CRF or other 
documents submitted to Insmed, participants must be identified by a unique participant identifier 
as designated by Insmed. Documents that are not for submission to Insmed (e.g., signed ICFs) 
must be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB direct 
access to review the participant’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the participant that his/her study-
related records will be reviewed by the above-named representatives without violating the 
confidentiality of the participant. 
Participant names will not be supplied to Insmed. A participant number will be recorded in the 
CRF, and if the participant name appears on any other document (e.g., laboratory report), it must 
be obliterated on the copy of the document to be supplied to Insmed. All records will be kept 
confidential to the extent provided by federal, state, and local laws. The participants will be 
informed that representatives of Insmed, IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
The Investigator will maintain a personal participant identification list (participant numbers with 
the corresponding participant names) to enable records to be identified. 
10.1.7. 
Committee Structure 
An SRC will be responsible for monitoring safety data. The SRC will comprise all Investigators 
and key members of the Insmed Study Team (including but not limited to Medical Monitor, 
Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, Clinical Pharmacologist) 
and external expert consultants. The SRC will continuously monitor all available safety, PD and 
PK data for each participant and will obtain consensus regarding the safety of continuing the 
study, the next TPIP dose, and clinical care of the next participant. Expert consultants may be 
invited to review and interpret participant data. With any safety findings, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to continue. 
Decisions regarding final database values for PD parameters may be adjudicated by the SRC. 
10.1.8. 
Dissemination of Clinical Study Data 
Insmed will provide study information for inclusion in national registries according to 
national/local regulatory requirements. 


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Results of this study will be disclosed according to the relevant national regulatory requirements. 
10.1.9. 
Data Quality Assurance 
The Investigator/investigational site will permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
10.1.9.1. Data Collection 
All data obtained for this study will be entered into a 21 CFR Part 11 compliant Data 
Management System provided by Insmed or its designee. These data will be recorded with an 
EDC system using CRFs. The Investigator will ensure the accuracy and completeness of the data 
reported to Insmed. All data entry, modification or deletion will be recorded automatically in an 
electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
Insmed to verify the proper transcription of data. Data reported in the CRFs must be consistent 
with and substantiated by the participant’s medical record and original source documents. The 
CRF data will be monitored by Insmed or designee. The final, completed CRF Casebook for 
each participant must be electronically signed and dated by the PI within the EDC system to 
signify that the Investigator has reviewed the CRF and certifies it to be complete and accurate. 
Insmed will retain the final CRF data and audit trail. A copy of all completed CRFs will be 
provided to the Investigator. 
10.1.9.2. Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, an Insmed 
representative will review the protocol, CRF, Investigator Brochure, and any study-related 
materials with the Investigators and their staff. During the study, Insmed study monitor or its 
designee will visit the site regularly to check the completeness of participant records, the 
accuracy of entries on the CRFs, adherence to the protocol, adherence to ICH GCP and 
applicable regulatory requirements, the progress of enrollment, and also to ensure that study IMP 
is being stored, dispensed, and accounted for according to specifications. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the CRF entries. Participant confidentiality will be maintained by the 
study center. Insmed monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording 
of primary activity and safety variables. Additional checks of the consistency of the source data 
with the CRFs are performed according to the study specific monitoring plan. 
10.1.9.3. Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB, and an auditor authorized by Insmed may 
request access to all source documents, CRFs, and other study documentation for onsite audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 


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provide support at all times for these activities. Medical records and other study documents may 
be copied during audit or inspection provided that participant names are obliterated on the copies 
to ensure confidentiality. 
If an inspection is requested by a regulatory authority, the Investigator will inform Insmed, 
immediately that this request has been made. 
10.1.9.4. Study Record Retention 
Study documents must be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents must be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of Insmed. It is the responsibility of Insmed to inform the Investigator when 
these documents no longer need to be retained. 
10.1.9.5. Source Documents 
Source documentation is the point of initial recording of a piece of data. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. Source documents 
provide evidence for the existence of the participant and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study Files and Materials 
Before the start of any study related procedures, all initial documents required by ICH GCP, 
Good Pharmacoepidemiology Practice, and applicable local regulations must be available in the 
relevant files maintained by Insmed (or delegate) and the Investigator. An Investigator Study File 
prepared by Insmed (or delegate), containing all applicable documents for use at the study site, 
will be made available to the Investigator before the start of the study. A list of personnel and 
organizations responsible for conduct of the study as well as the list of Investigator-delegates 
(e.g., sub-investigator) at each site will be included in the Investigator Study File. The respective 
files will be kept and updated by Insmed (or delegate) and the Investigator, as applicable. 


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All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by Insmed’s study monitor (or delegate) to determine that all 
required documentation is present and correct. 
The study may be audited by qualified delegates from Insmed or a competent regulatory 
authority. 
10.1.11. 
Use of Stored Samples and Data 
Stored samples will be labeled with study and participant information and secured with limited 
access and retained per protocol requirements and in accordance with the laboratory's operating 
procedures. Electronic data will be kept in password protected computers at the laboratory and 
then transferred to Insmed or CRO, as applicable, for data analysis. Samples and corresponding 
data will be tracked using the laboratory’s specimen tracking system. 
Prior Insmed and IRB approval are required before using or sharing study samples or data in 
ways not specifically specified in the study protocol during conduct of this study. 
Any loss or unanticipated destruction of samples (e.g., freezer malfunction) or data (e.g., loss of 
a data sheet with individually identifiable information) that violates or compromises the 
scientific integrity of study data must be reported to Insmed and the IRB. 
At any time, participants may inform the Investigator in writing that they do not wish to have 
their samples stored beyond the completion (termination) of the study. In this case, the 
Investigator will request that all known remaining samples be destroyed and report the 
disposition of samples to the requesting participants and the IRB. 
10.1.12. 
Disposition of Stored Samples and Data 
Participant samples will be secured with limited access and retained per protocol requirements 
and in accordance with the laboratory's operating procedures. Samples stored by the central 
laboratories will be labeled with the participant’s study identification information. Data will be 
kept in password protected computers at the laboratory and then transferred to the vendor for 
data analysis. Samples and corresponding data acquired will be tracked using the laboratory’s 
specimen tracking system. 
In the future, if other Investigators may wish to study these samples and/or data, they need to 
obtain Insmed approval and participant consent before any sharing of samples and/or data.  
Any loss or unanticipated destruction of samples (e.g., due to freezer malfunction) or data (e.g., 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to Insmed 
and the IRB. 
Additionally, participants may withdraw authorization in writing to decline their sample storage 
for a period of up to 2 years beyond the duration of the study. In this case, the PI will request the 
destruction of all known remaining samples and report what was done to both the participant and 
to the IRB. This decision will not affect the individual’s participation in the study. 


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10.1.13. 
Study and Site Start and Closure 
Before the start of the study at each study site, Insmed’s study monitor (or delegate) shall 
confirm adequacy of the facilities by study site visit or other acceptable methods. 
The Investigator may not enroll any participant into the study before Insmed has received written 
approval or a favorable opinion from the IRB for conducting the study and a formal meeting has 
been conducted by Insmed’s study monitor (or delegate) to initiate the study. This meeting will 
include a detailed review of the study plan, and completion of the CRF. 
10.1.13.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first participant screened for participation in the study is considered the first act 
of recruitment. 
10.1.13.2. Study/Site Termination 
Insmed or designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of Insmed. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Insmed or Investigator may include but are not 
limited to: 
For study termination: 
Discontinuation of further study IMP development 
For site termination: 
Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, Insmed's procedures, or GCP guidelines 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, Insmed shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and must assure appropriate participant 
therapy and/or follow-up. 
10.1.14. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by Insmed, before implementation. Amendments significantly affecting the 
safety of participants, the scope of the investigation, or the scientific quality of the study, require 
additional approval by the applicable regulatory authority(ies) and IRBs. Copies of the 
applicable written approvals must be filed in Insmed files and investigator site files. 


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The requirements for approval must in no way prevent any immediate action from being taken 
by the Investigator or by Insmed in the interests of preserving the safety of all participants 
included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, Insmed or its agent must be 
notified and the applicable regulatory authority(ies)/IRBs must be informed as soon as possible. 
Any other regional reporting requirements must be adhered to. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/IRB approval, but the regulatory authority(ies)/IRBs must 
be kept informed of such administrative changes in accordance with country specific 
requirements. 
10.1.15. 
Financing and Insurance 
10.1.15.1. Finances 
Prior to starting the study, the Investigator and/or institution will sign a clinical study agreement 
with Insmed. This agreement will include the financial information agreed upon by the parties. 
10.1.15.2. Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.15.3. Participant Reimbursement, Liability and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
Insmed will provide insurance to the Investigator if required by the applicable regulatory and 
legal requirement(s). 
If required by local law, participants taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
10.1.16. 
Publication Policy 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel of Insmed. Authorship will 
be determined by mutual agreement. For multi-center studies, it is mandatory that the first 
publication be based on data from all centers, analyzed as stipulated in the protocol by Insmed 
and statisticians, and not by the Investigators themselves. Investigators participating in multi 
center studies agree not to present data gathered from a single center or a small group of centers 
before the full, initial publication, unless formally agreed to by all other Investigators and 
Insmed. 
Insmed must receive copies of any intended communication in advance of publication (at least 
15 working days for an abstract or oral presentation and 45 working days for a journal 


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submission). Insmed will review the communications for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), verify that confidential information is 
not being inadvertently divulged, and to provide any relevant supplementary information. 
Authorship of communications arising from pooled data may include members from each of the 
contributing centers as well as Insmed personnel. 
At the conclusion of the study, after the data are analyzed, the results of study will be reported in 
a clinical study report. 
 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 7 will be performed by the local laboratory. If local laboratory results 
are used to make a study IMP decision or response evaluation, the results must be recorded. 
Protocol-specific clinical laboratory requirements for the inclusion or exclusion of participants 
are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 7: 
Protocol-Required Safety Laboratory Tests, INS1009-201 
Category 
Laboratory Parameters 
Clinical 
Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, 
phosphate, total bilirubin (with direct and indirect fractionation, if total 
bilirubin is elevated >2 ULN), alkaline phosphatase, LDH, AST, ALT, 
CPK, albumin, total protein, creatinine, urea-nitrogen, uric acid, estimated 
glomerular filtration rate  
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, leukocytes, 
differential blood count of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and platelets 
Coagulationa 
PT, PTT, INR 
Serologya 
HIV antibody, hepatitis B surface antigen [HBsAg], Hepatitis C virus 
antibody 
Pregnancy test 
Highly sensitive serum or urine hCG 
a Not included in EUT screening for participants enrolling in the extended use treatment period. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CO2 = carbon dioxide; CPK = creatine 
phosphokinase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin 
time; ULN = upper limit of normal 
Investigators must document their review of each laboratory safety report. 
 
 












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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Insmed clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than Drug-Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN and total 
bilirubin (TBL) ≥2×ULN at any point during the study irrespective of an increase in alkaline 
phosphatase (ALP). The elevations do not have to occur at the same time or within a specified 
time frame. 
Hy’s Law (HL) 
AST or ALT ≥3× ULN and TBL ≥2×ULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral 
hepatitis, another drug. The elevations do not have to occur at the same time or within a specified 
time frame. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any participant who meets any of the following identification criteria in isolation or in 
combination: 
1. ALT ≥ 3xULN 
2. AST ≥ 3xULN 
3. TBL ≥ 2xULN 
The Investigator will review without delay each new laboratory report and if the identification 
criteria are met will: 
1. Notify Insmed representative  
2. Determine whether the participant meets PHL criteria (see DEFINITIONS of this 
Appendix) by reviewing laboratory reports from all previous visits 


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3. Promptly enter the laboratory data into the laboratory CRF 
FOLLOW-UP 
POTENTIAL HY’S LAW CRITERIA NOT MET 
1. If the participant does not meet PHL criteria the Investigator will: 
2. Inform Insmed representative that the participant has not met PHL criteria. 
3. Perform follow-up on subsequent laboratory results according to the guidance provided 
in the clinical study protocol 
POTENTIAL HY’S LAW CRITERIA MET 
If the participant does meet PHL criteria the Investigator will: 
• Notify Insmed representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
• Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or Baseline levels, or as long as medically indicated 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
• Complete the 3 Liver CRF Modules as information becomes available 
• If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section must be followed for all cases where PHL criteria were met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than drug-induced liver injury caused 
by the IMP. The Insmed Medical Science Director and Global Safety Physician will also be 
involved in this review together with other participant matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
• If there is an agreed alternative explanation for the ALT or AST and TBL 
elevations, a determination of whether the alternative explanation is an AE will be 
made and subsequently whether the AE meets the criteria for a SAE 
• If the alternative explanation is not an AE, record the alternative explanation on 
the appropriate CRF 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow Insmed standard processes. 


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
•Report an SAE (report term ‘Hy’s Law’) according to Insmed standard processes. 
• The ‘Medically Important’ serious criterion must be used if no other serious 
criteria apply 
• As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ must be assigned. 
If there is an unavoidable delay, of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review 
 
 
 










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Any device deficiency that is associated with an SAE must be reported to Insmed within 
24 hours after the Investigator determines that the event meets the definition of a 
device deficiency. 
Insmed will review all device deficiencies and determine and document in writing whether 
they could have led to an SAE. These device deficiencies will be reported to the 
regulatory authorities and IRBs as required by national regulations. 
 
 
 


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11. 
REFERENCES 
Delcroix M, Howard L. Pulmonary arterial hypertension: the burden of disease and impact on 
quality of life. Eur Respir Rev. 2015;24(138):621-9. 
 
Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk 
Noordegraaf A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension 
of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): 
Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-
119. 
 
Hoeper MM, Ghofrani HA, Grunig E, Klose H, Olschewski H, Rosenkranz S. Pulmonary 
Hypertension. Dtsch Arztebl Int. 2017;114(5):73-84. 
Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state 
bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and 
subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004 Aug;44(2):209-14.  
McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, Kim NH, 
Oudiz RJ, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll 
Cardiol. 2009;54(1 Suppl):S97-107. 
 
Orenitram Package Insert.  2019. Accessed on: 23 October 2020.  
https://www.orenitram.com/pdf/Orenitram Full Prescribing Information.pdf 
 
Remodulin Package Insert.  2018. Accessed on: 23 October 2020.  
https://www.remodulinpro.com/files/remodulin-pi.pdf 
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical 
classification of pulmonary hypertension. Eur Respir J. 2019; 53(1):1801913. 
Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis 
and clinical management. BMJ. 2018;360:j5492. 
 
Tyvaso Package Insert.  2017. Accessed on: 23 October 2020.  
https://www.tyvaso.com/hcp/pdf/Tyvaso-PI.pdf?v=102017 
 
US Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers.  2005. Accessed on: 23 Oct 2020.  
https://www.fda.gov/media/72309/download 
 
Vachiery JL, Naeije R. Treprostinil for pulmonary hypertension. Expert Rev Cardiovasc Ther. 
2004;2(2):183-91. 


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Information contained in this document is proprietary to Insmed Incorporated. The information is provided to you in 
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give this document or any copy of it or reveal any proprietary information contained in it to any third party (other 
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CLINICAL STUDY PROTOCOL 
An Open-Label Single Dose Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation Powder in Participants with 
Pulmonary Arterial Hypertension 
Protocol Number: INS1009-201 
Version Number: 1 
Amendment Number: Not Applicable 
Compound: Treprostinil Palmitil Inhalation Powder (TPIP) 
Study Phase: 2a 
Insmed Name: Insmed Incorporated 
Legal Registered Address:  
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
USA 
Regulatory Agency Identifier Number(s) 
IND: 147264 
 
Date: 02 NOV 2020 
 
 




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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
ABBREVIATIONS .........................................................................................................................8 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Schema ........................................................................................................................13 
1.2.1. 
Participant Progression Through the Study ................................................................13 
1.2.1.1. 
Screening Period .........................................................................................................13 
1.2.1.2. 
Inpatient Treatment Period .........................................................................................13 
1.2.1.3. 
Follow-up period ........................................................................................................13 
1.2.2. 
Dose Selection ............................................................................................................14 
1.3. 
Schedule of Activities (SoA) ......................................................................................15 
2. 
INTRODUCTION ......................................................................................................20 
2.1. 
Study Rationale ...........................................................................................................21 
2.2. 
Background .................................................................................................................21 
2.3. 
Benefit/Risk Assessment ............................................................................................22 
2.3.1. 
Risk Assessment .........................................................................................................22 
2.3.2. 
Benefit Assessment .....................................................................................................23 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................23 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
4. 
STUDY DESIGN .......................................................................................................26 
4.1. 
Overall Design ............................................................................................................26 
4.1.1. 
Screening Period .........................................................................................................26 
4.1.2. 
Inpatient Treatment Period .........................................................................................27 
4.1.2.1. 
Baseline Procedures and Assessments ........................................................................27 
4.1.2.2. 
Post-TPIP administration ............................................................................................27 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up .................28 
4.1.3. 
Safety Follow-up ........................................................................................................28 
4.2. 
Scientific Rationale for Study Design ........................................................................28 


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4.3. 
Justification for Dose ..................................................................................................28 
4.4. 
Study Completion .......................................................................................................29 
5. 
STUDY POPULATION .............................................................................................31 
5.1. 
Inclusion Criteria ........................................................................................................31 
5.2. 
Exclusion Criteria .......................................................................................................32 
5.3. 
Lifestyle Considerations .............................................................................................34 
5.4. 
Screen Failures ............................................................................................................34 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period ..................................35 
6. 
STUDY IMP AND CONCOMITANT THERAPY ...................................................36 
6.1. 
Study IMP Administered ............................................................................................36 
6.1.1. 
Medical Devices .........................................................................................................36 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................36 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................37 
6.4. 
Study Intervention Compliance ..................................................................................37 
6.5. 
Dose Modification ......................................................................................................37 
6.6. 
Continued Access to Study Intervention after the End of the Study ..........................37 
6.7. 
Treatment of Overdose ...............................................................................................37 
6.8. 
Concomitant Therapy .................................................................................................38 
7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................39 
7.1. 
Discontinuation of Study IMP ....................................................................................39 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................39 
7.3. 
Lost to Follow Up .......................................................................................................39 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
8.1. 
Pharmacodynamic Assessments .................................................................................41 
8.1.1. 
Required PD Assessments with RHC .........................................................................41 
8.1.2. 
Required Non-invasive PD Assessments ....................................................................42 
8.1.3. 
Resting Respiratory Gas Exchange Assessments .......................................................42 
8.1.4. 
Transthoracic Echocardiogram Assessments .............................................................42 
8.1.5. 
Pulmonary CT Scan ....................................................................................................42 
8.2. 
Safety Assessments .....................................................................................................42 
8.2.1. 
Physical Examinations ................................................................................................42 
8.2.2. 
Vital Signs ..................................................................................................................43 


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8.2.3. 
Electrocardiograms .....................................................................................................43 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................43 
8.2.5. 
Pregnancy Testing ......................................................................................................44 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................44 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................44 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................45 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................45 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................45 
8.3.5. 
Pregnancy ...................................................................................................................45 
8.3.6. 
Cardiovascular and Death Events ...............................................................................46 
8.3.7. 
Adverse Events of Special Interest (AESI) ................................................................46 
8.3.8. 
Medical Device Deficiencies ......................................................................................46 
8.3.8.1. 
Time Period for Detecting Medical Device Deficiencies ...........................................46 
8.3.8.2. 
Follow-up of Medical Device Deficiencies ................................................................46 
8.3.8.3. 
Prompt Reporting of Device Deficiencies to Insmed .................................................47 
8.3.8.4. 
Regulatory Reporting Requirements for Device Deficiencies ...................................47 
8.4. 
Pharmacokinetic Assessments ....................................................................................47 
8.4.1. 
PK Sample Collection .................................................................................................47 
8.4.2. 
PK Analysis ................................................................................................................47 
8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations ................................................47 
8.5. 
Genetics / Pharmacogenomics ....................................................................................48 
8.6. 
Biomarkers ..................................................................................................................48 
8.7. 
Medical Resource Utilization and Health Economics ................................................48 
8.8. 
Immunogenicity Assessments ....................................................................................48 
9. 
STATISTICAL CONSIDERATIONS .......................................................................49 
9.1. 
Statistical Hypotheses .................................................................................................49 
9.2. 
Sample Size Determination ........................................................................................49 
9.3. 
Analysis Sets ...............................................................................................................49 
9.4. 
Statistical Analyses .....................................................................................................49 
9.4.1. 
General Considerations ...............................................................................................49 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values ...........................................................50 
9.5. 
Interim Analysis ..........................................................................................................50 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................51 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................51 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................51 
10.1.2. 
Protocol Deviations ....................................................................................................51 
10.1.3. 
Public Health Emergency Situations ..........................................................................52 
10.1.3.1. 
Continuation or Suspension of the Study ...................................................................52 
10.1.4. 
Financial Disclosure ...................................................................................................53 
10.1.5. 
Informed Consent Process ..........................................................................................53 
10.1.6. 
Protection of Participant Identification and Confidentiality .......................................54 
10.1.7. 
Committee Structure ...................................................................................................54 
10.1.8. 
Dissemination of Clinical Study Data ........................................................................54 
10.1.9. 
Data Quality Assurance ..............................................................................................55 
10.1.9.1. 
Data Collection ...........................................................................................................55 
10.1.9.2. 
Study Monitoring ........................................................................................................55 
10.1.9.3. 
Audits and Inspections ................................................................................................55 
10.1.9.4. 
Study Record Retention ..............................................................................................56 
10.1.9.5. 
Source Documents ......................................................................................................56 
10.1.10. 
Study Files and Materials ...........................................................................................56 
10.1.11. 
Use of Stored Samples and Data ................................................................................57 
10.1.12. 
Disposition of Stored Samples and Data ....................................................................57 
10.1.13. 
Study and Site Start and Closure ................................................................................57 
10.1.13.1. First Act of Recruitment .............................................................................................58 
10.1.13.2. Study/Site Termination ...............................................................................................58 
10.1.14. 
Protocol Amendments ................................................................................................58 
10.1.15. 
Financing and Insurance .............................................................................................59 
10.1.15.1. Finances ......................................................................................................................59 
10.1.15.2. Reimbursement, Indemnity, and Insurance ................................................................59 
10.1.15.3. Participant Reimbursement, Liability and Insurance ..................................................59 
10.1.16. 
Publication Policy .......................................................................................................59 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................60 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................61 


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10.3.1. 
Definition of AE .........................................................................................................61 
10.3.2. 
Definition of SAE .......................................................................................................62 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................63 
10.3.4. 
Reporting of SAEs ......................................................................................................65 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................66 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ..............67 
10.6. 
Appendix 6 Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies ............................70 
10.6.1. 
Definition of Medical Device AE and ADE ...............................................................70 
10.6.2. 
Definition of Medical Device SAE, SADE and USADE ...........................................70 
10.6.3. 
Definition of Device Deficiency .................................................................................71 
10.6.4. 
Recording and Follow-Up of AE and/or SAE and Device Deficiencies ....................71 
10.6.5. 
Reporting of SAEs ......................................................................................................73 
10.6.6. 
Reporting of SADEs ...................................................................................................73 
11. 
REFERENCES ...........................................................................................................74 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Screening and Follow-up, INS1009-201 ......................15 
Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 .......................17 
Table 3: 
PK and PD Biomarker Sampling Schedule, INS1009-201 ........................................18 
Table 4: 
Schedule for Echocardiogram, Pulmonary CT Scan, and Resting Respiratory 
Gas Exchange Assessments, Inpatient Treatment Period, INS1009-201 ...................19 
Table 5: 
Protocol-Required Safety Laboratory Tests, INS1009-201 ........................................60 
 
LIST OF FIGURES 
Figure 1: 
Participant Progression Through INS1009-201 Study ...............................................14 
Figure 2: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 ..........14 
 
 
 


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ABBREVIATIONS  
AE  
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine amino transferase 
AST 
aspartate amino transferase 
AUC  
area under the concentration-time curve 
AUC0–∞ 
area under the concentration-time curve from time zero to infinity 
AUCt1–t2 
area under the plasma concentration-time curve from time zero to time of 
last measurable concentration 
CL/F 
apparent total clearance of drug from plasma after extravascular 
administration 
Cmax 
maximum (peak) plasma concentration of the drug 
CO 
cardiac output 
CRF 
case report form 
CRO 
contract research organization 
CT 
computerized tomography 
DILI 
drug induced liver injury 
DPI 
dry powder inhalation 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HL 
Hy’s Law 
ICF 
informed consent form 


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ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IMP 
investigational medicinal product 
IRB 
investigational review board 
IV 
intravenous 
MAD 
multiple ascending dose 
MVO2 
mixed venous oxygen saturation 
NT-pro-BNP 
N-terminal (NT)-pro hormone brain natriuretic peptide 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary arterial pressure 
PD 
pharmacodynamic(s) 
PH 
pulmonary hypertension 
PHL 
potential Hy’s Law 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PVR 
pulmonary vascular resistance 
QID 
four times daily 
RAP 
right atrial pressure 
RHC 
right heart catheter 
RVP 
right ventricular pressure  
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS CoV 2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 


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SoA 
schedule of activities/assessments 
SUSAR 
suspected unexpected serious adverse reaction 
SRC 
Safety Review Committee 
t1/2 
elimination half-life 
TBL 
total bilirubin 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment emergent adverse event 
tmax 
time to maximum (peak) plasma concentration following drug administration 
TPIP 
treprostinil palmitil inhalation powder 
TPIS 
treprostinil palmitil inhalation suspension 
TRE 
treprostinil 
TP 
treprostinil palmitil 
TVR 
tricuspid valve regurgitation 
ULN 
upper limit of  normal 
US 
United States 
VCO2 
carbon dioxide production 
Vd/F 
apparent volume of distribution at terminal phase 
WHO 
World Health Organization 
WOCBP 
woman of child-bearing potential 
 
 
 




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• To evaluate the PK of TPIP as 
TRE in participants with PAH 
• Cmax, tmax, AUCt1–t2, AUC0–∞, t1/2 
of TRE in plasma 
TPIP=treprostinil palmitil inhalation powder; PAH=pulmonary arterial hypertension; TEAE=treatment emergent 
adverse event; PD=pharmacodynamic; PVR=pulmonary vascular resistance; PK=pharmacokinetics; TP=treprostinil 
palmitil; TRE=treprostinil; Cmax=maximum observed concentration; tmax=time to maximum concentration after drug 
administration; AUCt1–t2= area under the concentration time curve from time zero to last sampling timepoint with 
measurable concentration; AUC0–∞=area under the concentration time curve from time zero to infinity; 
t1/2=elimination half-life 
Overall Design: 
This is a Phase 2a, open-label, nonrandomized single-dose study to assess the safety, tolerability, 
PD effects, and PK of TPIP administered to participants with PAH. This is the first study of 
TPIP in patients with PAH. Each participant will receive a single dose of TPIP, which may vary 
from participant to participant, as determined by the Safety Review Committee (SRC) for the 
study. The study includes a 24-hour inpatient observation period following TPIP dosing, during 
which PK, PD, and safety parameters will be assessed. The study is designed to ensure the safety 
of and maintain minimal risk to participants. The cardiopulmonary and overall functional status 
of patients with PAH can be labile and medical instability can develop quickly. As such, there is 
considerable flexibility built into the protocol to allow Investigator discretion with the frequency, 
timing, and/or conduct of PD and PK assessments to again ensure participants' safety. 
Brief Summary: 
The study is designed to investigate the safety and acute pharmacokinetic (PK) and 
pharmacodynamic (PD) effects of a single dose of trepostinil palmitil inhalation powder (TPIP) 
in participants with pulmonary arterial hypertension (PAH). Intensive monitoring of pulmonary 
vascular resistance, cardiac output, right ventricular pressure, pulmonary arterial pressure, 
hemoglobin, right atrial pressure, and mixed venous oxygen saturation via right heart catheter in 
an appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate dose- and PK-effect relationships. Some assessments and study 
activities (resting respiratory gas exchange assessment, transthoracic echocardiogram, pulmonary 
computerized tomography scan) for exploratory endpoints are optionally left to the discretion of 
the individual Investigator, based on participant safety and study site capabilities. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 36 and 48 hours 
post TPIP dose will extend into Study Day 3. A remote safety follow-up visit (telephone visit) is 
scheduled for Study Day 30 (± 2 days). 
Number of Participants: 
Approximately 6 to 10 evaluable participants are planned. Evaluable participants for safety are 
those who receive a single dose of TPIP; evaluable participants for PD and PK endpoints are 
those who receive a single dose of TPIP and have at least 1 post-TPIP administration PK or PD 
datapoint. 


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Treatment Groups and Duration: 
This is a single-dose, open-label, non-randomized study. There are no predefined treatment 
groups. The dose determination for each participant will be made based on all available PK, PD, 
and safety data at the time of the participant’s entry into the study 
Safety Review Committee:  
A Safety Review Committee (SRC) will be chartered. The SRC will comprise all Investigators 
and key members of the Insmed Study Team (including but not limited to Medical Monitor, 
Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, Clinical Pharmacologist) 
and possible external expert consultants. The SRC will continuously monitor all available safety, 
PD and PK data for each participant and will obtain consensus regarding the safety of continuing 
the study, the next TPIP dose, and clinical care of the next participant. Expert consultants may be 
invited to review and interpret participant data. With any safety findings, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to continue. 
Decisions regarding final database values for PD parameters may be adjudicated by the SRC. 
1.2. 
Schema 
1.2.1. 
Participant Progression Through the Study 
The study comprises an outpatient screening period, an inpatient treatment period, and an 
outpatient follow-up period. Participant progression through the study is shown in Figure 1. 
1.2.1.1. 
Screening Period 
The outpatient screening period will last up to 30 days. After participants complete screening and 
have met the study eligibility criteria, the RHC procedure and inpatient treatment period should 
be scheduled without delay. 
1.2.1.2. 
Inpatient Treatment Period 
The inpatient treatment period will start on Study Day 1 and extend overnight into Study Day 2. 
Because the study requires an inpatient treatment period, institutional requirements for elective 
inpatient admissions, which may vary from site to site, will be followed. The participant may be 
required to undergo pre-admission assessments required by the institution for elective admission, 
for example testing for common infectious pathogens. Signature of elective admission 
documents and other consents may be required by the institution. A right heart catheter (RHC) 
will be placed. Following completion of Baseline assessments, a single dose of TPIP will be 
administered via a dry powder inhaler. Safety, PD, and PK assessments will continue at 
scheduled intervals through 24 hours following TPIP administration. Following the final 
assessments at 24 hours, the RHC will be removed and the participant will be discharged from 
the inpatient setting when deemed safe for the participant.  
1.2.1.3. 
Follow-Up Period 
PK blood draws for 36 (± 3) hours and 48 (± 4) hours after TPIP dosing will be done on an 
outpatient basis as arranged by the site. The 48-hour post-TPIP visit will also include safety 
assessments including physical examination, clinical laboratory evaluations, ECG, AE collection 


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and vital signs. An additional safety follow-up will be conducted by telephone call or 
telemedicine on Study Day 30 (± 2 days). 
Figure 1: 
Participant Progression Through INS1009-201 Study 
 
PD-pharmacodynamic assessments; PK=pharmacokinetic assessments; h=hours; d=days 
1.2.2. 
Dose Selection 
Each participant will enter the study in a serial fashion, following review of available safety, PK, 
and PD data from all previous participants by the Safety Review Committee (SRC). Each 
participant will receive a single-dose administration of TPIP via a dry powder inhaler. TPIP will 
be administered to only one participant at a time, with full evaluation of all available data prior to 
dosing the next patient. 
The first participant will receive a dose of TPIP containing 112.5 µg of TP. The SRC will then 
review all available safety, PD, and PK data including data from the first participant and select 
the TPIP dose and any changes to the assessments for the second participant. Then, following 
review of all available data including that from the first and second participants, the SRC will 
select the dose for the third participant. Similarly, all available data from previous studies and 
participants will be assessed prior to determining the dose for the next participant, until such a 
time as the SRC believes the study must conclude. Figure 2 describes the planned dose-selection 
and study continuation process. 
Figure 2: 
Schematic of Study Continuation Planning after Participant 1, INS1009-201 
 
SRC=Safety Review Committee 
 
 


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1.3. 
Schedule of Activities (SoA) 
The SoA is divided into 4 tables:  
• Screening and follow-up activities 
• Inpatient treatment period 
• PK and PD biomarker blood sampling schedule 
• Optional procedures and assessments  
Table 1: 
Schedule of Activities for Screening and Follow-up, INS1009-201 
Procedure 
Screening 
Follow-up 
 
Up to 30 
Days 
48 h post 
TPIP dosea 
Study Day 30 
(± 2  days) 
Informed Consent 
X 
-- 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
-- 
Demographics and Medical History 
X 
-- 
-- 
Smoking Status 
X 
-- 
-- 
Height, Weight, BMI Calculation 
X 
-- 
-- 
Prior/Concomitant Medications 
X 
X 
X 
Serology (HBsAg, HIV antibody, HCV 
antibody) 
X 
-- 
-- 
Serum Pregnancy Test (WOCBP only) 
X 
 
 
Urine Pregnancy Test (WOCBP only) 
-- 
 
X 
Hematology, Clinical Chemistry (Table 5) 
X 
X 
-- 
Coagulation Profile (Table 5 ) 
X 
-- 
-- 
NT-pro-BNP Sample (if needed, Section 5.1) 
X 
-- 
-- 
12-lead ECG 
X 
X 
-- 
Physical Examination 
X 
X 
-- 
Vital Signs 
X 
X 
-- 
6 Minute Walking Distance Test (if needed, 
Section 5.1) 
X 
-- 
-- 
Pulmonary Function Testing (if needed, 
(Section 5.1) 
X 
-- 
-- 
Adverse Eventsb 
X 
X 
X  
a 48 h safety follow-up assessments are to be conducted at the time of the visit for the 48h PK blood draw Table 3) 


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b AE collection is from the time of signing the informed consent through the Day 30 safety follow-up. Events 
between ICF signing and TPIP dosing that are serious will be recorded as SAE; non-serious events during this 
period must be recorded as medical history. 
Note:  Additional safety follow-ups may be conducted at any time per the investigator’s discretion to ensure 
participant safety. The reason for any additional safety follow-up must be reported as an AE 
BMI = body mass index; ECG = electrocardiogram WOCBP = woman of childbearing potential;  
 


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Table 2: 
Schedule of Activities for Inpatient Treatment Period, INS1009-201 
Treatment Period (StudyDay 1 to Study Day 2) 
 
Pre-TPIP 
Administration 
TPIP 
Administration 
Post-TPIP Administration 
Procedure 
Day 1 Baseline  
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
24 h 
24 h to 
discharge 
Hematology, clinical 
chemistry, coagulation 
profile blood drawa 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
-- 
Urine pregnancy test 
(WOCBP only) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12-lead ECG 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Cardiac telemetry per 
institutional protocolb 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signsc 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
collection 
X 
 
 
 
 
 
 
 
 
 
 
Place right heart 
catheter 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
PD assessments: PVR, 
MVO2, Hgb, RVP, 
PAP CO, PVR, RAP, 
oxygen consumption, 
PCWP (Baseline 
only)d, heart rate, 
SpO2, systemic blood 
pressuree  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
-- 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Period (StudyDay 1 to Study Day 2) 
 
Pre-TPIP 
Administration 
TPIP 
Administration 
Post-TPIP Administration 
Procedure 
Day 1 Baseline  
Time 0 
30 
min 
60 
min 
90 
min 
2 h 
3 h 
4 h 
8 h 
24 h 
24 h to 
discharge 
Administer TPIP 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Remove RHC 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Discharge/Safety 
Follow-up Instructions 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
a See Section 10.2 , Table 5 for specific laboratory tests 
b Routine cardiac telemetry readings will not be collected as study data unless they pertain to a relevant adverse event 
c Heart rate, systemic blood pressure, and SpO2 are required PD measurements and will be collected as scheduled. They may be measured with pulse oximetry 
for heart rate and SpO2 and an automated inflatable arm cuff for blood pressure. Temperature and respiratory rate may be measured per institutional inpatient 
protocol. Respiratory rate will be measured as part of pulmonary gas exchange testing, if performed (Table 4) 
d PCWP is measured at Baseline only to ensure study eligibility (Section 5.1). 
e Systemic blood pressure must include 3 values:  systolic, diastolic, and mean arterial pressure.  
CO = cardiac output; Hgb = hemoglobin; MVO2 = mixed venous oxygen saturation; PAP = pulmonary arterial pressure; PVR=pulmonary vascular resistance; 
RAP = right atrial pressure; RVP = right ventricular pressure;SpO2 = arterial blood oxygen saturation; WOCBP = woman of childbearing potential 
Table 3: 
PK and PD Biomarker Sampling Schedule, INS1009-201 
-- 
Baseline 
Pre-TPIP 
Administration 
TPIP 
administration 
Post-TPIP Administration 
Time  
-- 
0 
30 (± 10) 
mins 
60 (± 10) 
mins 
2 h (± 20 
mins) 
4 (± 1) h 
8 (± 2) h 
24 (± 2) h 
36 (± 3) h  
48 (± 4) h 
PK samplinga b 
X 
-- 
X 
X 
X 
X 
X 
X 
X 
X 
Sample to be 
frozen for 
biomarker 
analysisc 
X 
-- 
-- 
-- 
-- 
X 
X 
-- 
-- 
-- 
a PK sampling for treprostinil palmitil and treprostinil 
b Each PK sample will be approximately 10 mL 
c Each biomarker sample will be approximately 5 to 7 mL 


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Table 4: 
Schedule for Echocardiogram, Pulmonary CT Scan, and Resting Respiratory Gas Exchange Assessments, 
Inpatient Treatment Period, INS1009-201 
Inpatient Treatment Period (Study Day 1 to Study Day 2) 
 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
Post-TPIP 
Administration 
Procedure 
StudyDay 
1 Baseline  
Time 0 
2-8 hr 
4-8 hr 
Transthoracic 
echocardiogram 
(LVEF,TVR maximum 
velocity, TAPSE, end 
diastolic right ventricular 
volume)  
X 
-- 
X 
-- 
Pulmonary CT scan (total 
blood volume, blood 
volume in vessels < 5 
mm2)  
X 
-- 
-- 
X 
-- 
Pre-TPIP 
Administ
ration 
TPIP 
Administrat
ion 
-- 
-- 
Study Day 
1 Baseline 
Time 0 
30 mins 
60 mins 
90 mins 
2 h 
3 h 
4 h 
8 h 
24 h 
Resting respiratory gas 
exchange assessmenta 
(respiratory rate, minute 
ventilation, VCO2, ETO2, 
ETCO2, SpO2  
X 
-- 
X 
X 
X 
X 
X 
-- 
X 
X 
a Resting respiratory gas assessment parameters are collected at the same time points as RHC parameters 
NOTE:  Parameters to be measured for each procedure are in parentheses 
CT=computerized tomography; ETCO2 =end tidal carbon dioxide concentration; ETO2,=end tidal oxygen concentration; LVEF=left ventricular ejection fraction; 
SpO2=arterial blood oxygen saturation; TAPSE=tricuspid annular plane systolic excursion; TVR=tricuspid valve regurgitation; VCO2,=carbon dioxide production  
 
 


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2. 
INTRODUCTION 
Pulmonary hypertension (PH), a hemodynamic state characterized by resting mean 
PAP ≥ 25 mmHg, is generally classified into 5 groups based on the underlying pathology: Group 
1 is PH due to pulmonary vascular disease, also known as PAH; Group 2 is PH due to left heart 
disease; Group 3 is PH due to lung disease or hypoxia; Group 4 is PH due to chronic 
thromboembolic disease or other pulmonary vasculature obstruction; Group 5 is miscellaneous 
PH syndromes caused by a variety of disorders such as hemolytic anemias and sarcoidosis 
(Thenappan et al., 2018). 
In Group 1 PH (PAH), the resting mean PAP ≥ 25 mmHg occurs in the setting of normal 
pulmonary arterial wedge pressure of ≤15 mm Hg with PVR of ≥3 Wood Units (WU) 
(McLaughlin et al., 2009). In PAH the pulmonary vasculature is affected by vasoconstriction, 
vascular remodeling, increased rigidity of vessel walls and vascular fibrosis. These vascular 
anomalies increase PVR, which leads to increases in right ventricular afterload, and a cascade of 
maladaptive changes to the heart including right ventricular hypertrophy, ischemia and fibrosis, 
reducing right ventricular function and eventually leading to right ventricular failure and death 
(Thenappan et al., 2018). The pulmonary vascular lesions of PAH may be idiopathic, hereditary, 
or occur as a complication of drug use (eg, anorexigens), connective tissue disease, portal 
hypertension, congenital cardiac malformations or HIV infection (Hoeper et al., 2017). 
Data from PAH registries around the world (Thenappan et al., 2018) estimate a global incidence 
ranging from 2.0 to 7.6 cases per million adults per year, with a prevalence of 11 to 26 cases per 
million adults; the incidence in females is approximately 4 times that in males. Most registries 
report a mean age of onset ranging from approximately 36 to 53 years. While overall median 
survival has improved from 2.8 years in the 1980’s to 6 years currently, mortality is high, with 
1 year survival ranging from 68% to 93% and 5 year survival ranging from 21% to 65%. Nearly 
half of the patients in these registries have PAH of idiopathic, heritable or anorexigen-induced 
origin.  
PAH is a debilitating progressive disease that causes a wide range of non-specific symptoms 
including, dyspnea, shortness of breath, chest pain, fatigue, generalized weakness and exertional 
syncope (Delcroix and Howard, 2015), severely affecting the patient’s physical mobility, 
emotional and social well-being, ability to perform activities of daily living and overall quality of 
life. Pharmacological treatments are available to mitigate disease symptoms and slow disease 
progression, but treatment-related AEs, inconvenience and side effects can be treatment-limiting 
and negatively influence the patient’s daily life (Delcroix and Howard, 2015). 
The currently available pharmacologic treatments for PAH include calcium channel blockers, 
guanylate cyclase stimulators, endothelin receptor antagonists, phosphoesterase type 5 inhibitors, 
and prostanoids and prostacyclin agonists. Prostanoids, such as TRE, are among the most 
effective medications for the treatment of PAH. However, they are limited by the need for 
inconvenient and frequent drug administration and dose-limiting side effects (Thenappan et al., 
2018) 


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2.1. 
Study Rationale 
Treprostinil palmitil (TP) is an inactive prodrug of TRE. TPIP is a dry powder for inhalation 
formulation of TP. TPIP is being developed for the treatment of PAH. TPIP is expected to 
provide extended release of TRE in the lung with the goals of less frequent and more convenient 
and consistent dosing while reducing the frequency and severity of dose-limiting side effects 
associated with the currently approved forms of TRE. TP has been previously studied in healthy 
volunteers as an inhalation suspension (treprostinil palmitil inhalation suspension, TPIS), in 
single doses up to 340 µg (Study INS1009-101). TPIP is being studied in a SAD/MAD study in 
healthy volunteers (Study INS1009-102). 
No studies of TP or TPIP have been conducted in patients with PAH. Study INS1009-201 is an 
open label, non-randomized, single- dose study designed to evaluate the safety, pharmacokinetics 
(PK), and pharmacodynamic (PD) effects of a single dose of TPIP in patients with PAH. 
2.2. 
Background 
Treprostinil is a tricyclic benzidene analogue of prostacyclin. As such, TRE has vasodilatory and 
anti-platelet activity within the pulmonary vascular system, thereby reducing blood flow 
resistance and improving the clinical state, functional class, exercise capacity, and quality of life 
of patients with PAH (Vachiery and Naeije, 2004). 
Treprostinil has a high potency but is short-lived in the body and must be administered by 
continuous IV or SC infusion, or given multiple times per day by inhaled or oral routes. At 
present, TRE is available in the United States in formulations of IV or SC infusion (Remodulin 
Package Insert, 2018), oral extended-release tablets (Orenitram Package Insert, 2019), and 
inhalation solution (Tyvaso Package Insert, 2017) to treat PAH. The clinical experience with 
TRE suggests that most of the AEs experienced are related to its effects on prostanoid 
metabolism (eg, headache, nausea, diarrhea, flushing, and hypotension). Dose-limiting side 
effects correlate to systemic plasma concentrations of TRE.  
Treprostinil palmitil is a hexadecyl ester prodrug of TRE. In the lung, TP is hydrolyzed by 
esterase to TRE and hexadecanol. TPIP is a dry powder formulation of TP designed to provide 
sustained release of TRE in the lung over a prolonged period, thus providing prolonged 
vasodilation in the lung vasculature. This effect was demonstrated in a rat acute hypoxia model 
that showed a maximal reduction in PAP through the 3-hour monitoring limit with TP, while the 
effect of inhaled TRE started to diminish by 1 hour and was completely gone after approximately 
2.5 hours. The prolonged lung exposure and pharmacological action of TRE achieved with 
sustained release from the prodrug TP aims to reduce both dosing frequency and side effects 
driven by fluctuations of plasma levels of TRE. 
Treprostinil palmitil was well tolerated in rats and dogs following 16-week once-daily inhalation. 
At NOAEL doses, the plasma Cmax and AUC of TRE at steady state in rats (2000 μg/kg/day) 
were 11 ng/mL and 73 ng*h/mL, respectively, and in dogs (250 μg/kg/day) were 1.2 ng/mL and 
13 ng*h/mL, respectively. 
Treprostinil palmitil has been administered to adult healthy volunteers as a nebulized inhalation 
suspension (TPIS) in a SAD clinical study (Study INS1009-101) that compared TP inhalation at 
ascending doses (85 to 340 µg) with a Tyvaso® inhalation dose of 54 µg. PK data from this study 


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demonstrated that TPIS provided a longer duration of TRE exposure than Tyvaso inhalation. 
With TP inhalation, TRE exposures increased approximately dose proportionally with increasing 
dose. The mean (%CV) of plasma Cmax for TRE ranged from 89 to 318 pg/mL (24.9% to 49.2%) 
across doses and the TRE AUC ranged from 674 to 2490 pg*h/mL (7.8% to 24.3%) across 
doses. The tmax was 0.8 to 2 hours and the t1/2 was approximately 7 hours. The TP plasma 
concentrations were low with AUC approximately 7-fold lower than that for TRE. Following 
Tyvaso inhalation at 54 μg, TRE Cmax was 958 pg/mL (26.5%), AUC0-24 was 872 pg*h/mL and 
t1/2 was 0.485 hour. 
Additional information regarding the results of non-clinical and clinical studies of TP are 
provided in the Investigators’ Brochure. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
TEAEs for TPIP from clinical and non-clinical studies may be found in the Investigator’s 
Brochure.  
2.3.1. 
Risk Assessment 
There is no TPIP experience in patients with PAH, however, the active component, TRE, like 
other prostanoids and their agonists, has a well-characterized safety profile. This will help enable 
participants to be adequately monitored during the study. 
The Insmed has conducted a SAD study of TPIS in healthy volunteer participants, with safety 
and tolerability findings similar to those of other prostanoids (Study INS1009-101). In this study, 
32 TEAEs were reported for 11 of 18 participant who received TPIS. No fatal TEAEs were 
reported and no TEAEs led to the withdrawal of participants. One participant who received a 
single dose of TPIS containing 340 µg of TP experienced several interrelated AEs that 
culminated in 2 TEAEs of severe and life-threatening intensity. The Investigator believed a 
severe TEAE of micturition syncope was precipitated by a TEAE of chest pain, which was 
assessed as probably related to the study IMP and increased vagal tone during micturition. 
Follow-up evaluation by an external cardiologist reveled that the participant had Tachy-Brady 
syndrome. An SAE of cardiac pause/nodal arrhythmia was reported for this participant and 
assessed as probably related to TPIS. Beyond this event, 7 TEAEs were assessed as being of 
moderate intensity and 23 TEAEs to be of mild intensity. 
The most frequently reported TEAEs among participants receiving TPIS were cough (5 events 
for 5 participants), dyspnea (4 events for 4 participants) and throat irritation (4 events for 
4 participants. Other TEAEs reported for more than 1 participant receiving TPIS included nausea 
(3 events for 3 participants) and headache (2 events for 2 participants). 
There was a dose-related trend in the incidence of TEAE reporting with increasing dose levels of 
TPIS: 5 TEAEs were reported for 2 participants after receiving a single TPIS dose containing 
85 µg of TP, 7 TEAEs were reported for 4 participants after receiving a single TPIS dose 
containing 170 µg of TP, and 20 TEAEs were reported for 5 participants after receiving a single 
TPIS dose containing 340 µg of TP. 
Available safety, PK, and PD data from a recently conducted SAD/MAD study of TPIP in 
healthy volunteer participants (INS1009-102) will inform the TPIP dosing and management of 


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participant safety for this study. In Study INS1009-102 TPIP single doses of 112.5, 225, 450, and 
675 µg are being evaluated. Data were still blinded at the time of protocol finalization. 
No serious adverse reactions are considered expected for TPIP. Please refer to the Reference 
Safety Information in Section 6.1 of the Investigator’s Brochure. 
Risks inherent in study procedures and in the inpatient treatment period will be managed per 
Investigator and institutional processes. It is possible that the RHC-dependent Baseline 
parameters may indicate that the participant does not meet study inclusion criteria, may meet 
exclusion criteria, or is otherwise not suitable for study participation; in this case the Investigator 
may end the RHC procedure and not administer TPIP. 
In general, an RHC is left in place for 30 to 60 minutes to take necessary measurements. This 
study requires the RHC to be in place for approximately 24 hours. Excess risks with prolonged 
placement of the RHC may include but not be limited to dislodging of the RHC, infection, 
bleeding, and participant discomfort. 
2.3.2. 
Benefit Assessment 
Participants in this study are not expected to receive any clinical benefit. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Although participants are not expected to benefit individually from this study, risks to their well-
being will be carefully monitored and managed throughout their participation. The Insmed 
considers the risks to be appropriate to the value of the knowledge gained in this study about the 
characteristics of this promising therapy. The well-characterized safety profile of TRE and the 
inpatient treatment and observation period will enable participants to be adequately monitored 
during the study. Most TEAEs observed with exposure to this drug are events known to be 
associated with prostanoids and their agonists. Study inclusion and exclusion criteria will help to 
ensure that only appropriate participants are enrolled. Risks involved with study procedures and 
settings will be managed by the relevant Investigator and institutional processes. 
 




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• To evaluate the effects of TPIP on 
resting respiratory gas exchange in 
participants with PAHa 
• Change from Baseline in respiratory 
rate, minute ventilation, VCO2, ETO2, 
ETCO2, SpO2 over 24 hours after 
TPIP administration 
• To evaluate the effects of TPIP on 
parameters of right ventricular 
function in participants with PAH as 
measured by transthoracic 
echocardiogramb 
• Change from Baseline in LVEF, TVR 
maximum velocity, TAPSE, and end 
diastolic right ventricular volume at 2 
to 8 hours after TPIP administration 
• To evaluate the effects of TPIP on 
pulmonary vasculature and blood flow 
parameters in participants with PAH 
as measured by pulmonary CT scanc 
• Change from Baseline in total blood 
volume, blood volume in 
vessels < 5mm2 at 4 to 8 hours after 
TPIP administration 
a Respiratory gas exchange testing optional at investigator discretion 
b Echocardiogram optional at investigator discretion 
c Pulmonary CT scan optional at investigator discretion 
AUC0–∞ = area under the concentration time curve from time zero to infinity; AUCt1-t2 = area under the concentration 
time  curve from time zero to last sampling timepoint with measurable concentration; Cmax = maximum observed 
concentration after drug administration; CL/F = apparent total clearance; CO = cardiac output; CT = computerized 
tomography; ETCO2 = end tidal carbon dioxide concentration; ETO2 = end tidal oxygen concentration; LVEF = left 
ventricular ejection fraction; MVO2 = mixed venous oxygen saturation; PAH = pulmonary arterial hypertension; 
PAP = pulmonary arterial pressure; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PVR = pulmonary 
vascular resistance; SpO2 = arterial blood oxygen saturation; TAPSE = tricuspid annular plane systolic excursion; 
TEAE = treatment emergent adverse event; TP = treprostinil palmitil; TPIP = treprostinil palmitil inhalation powder; 
TRE = treprostinil; TVR = tricuspid valve regurgitation; tmax = time of maximum observed concentration following 
drug administration;  t1/2 = elimination half-life; Vd/F = apparent volume of distribution at terminal phase; 
VCO2 = carbon dioxide production  


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2a, open label, non-randomized single-dose study to assess the safety, 
tolerability, PD effects and PK of TPIP administered to participants with WHO Group 1 PH 
(PAH). This is the first patient study of TPIP. Each participant will receive a single dose of TPIP. 
The first participant will receive a dose containing 112.5 µg of TP. The TP dose level for each 
subsequent participant will be determined following review and adjudication of all available 
safety, PK, and PD data from the previous participant(s)by the SRC (Section 10.1.7). 
This is a “proof of mechanism” study designed to investigate the following: 
1. The safety and tolerability of TPIP in participants with PAH, 
2. The relationship between the PK and PD effects of TPIP in participants with PAH, and 
3. The duration of the PD effects of a single dose of TPIP in participants with PAH. 
The cardiopulmonary and overall functional status of patients with PAH can be labile and 
medical instability can develop quickly. The study is designed to provide maximal safety and 
minimal risk to participants. As such, there considerable flexibility built into the protocol to 
allow Investigator discretion with the frequency, timing, and/or conduct of PD and PK 
assessments to ensure participant safety. Because the study requires an overnight inpatient 
treatment period, Institutional requirements for elective inpatient admissions, which may vary 
from site to site, will be followed. 
For individual participants, the study will consist of an outpatient screening period lasting up to 
30 days. The inpatient treatment period will start on Study Day 1 and is expected to last 
overnight into Study Day 2. Outpatient PK sampling and safety follow-up at 
36 (± 3) and 48 (± 4) hours post TPIP dose will extend into Study Day 3. A remote safety 
follow-up visit is scheduled for Study Day 30 (± 2 days).The 48 hour PK visit will also include 
safety assessments including ECG, clinical laboratory evaluations, vital signs, physical 
examination, and AE collection (Table 1). The safety follow-up period will conclude with a 
remote (telephone or telemedicine) visit on Study Day 30 (± 2 days). Including the Screening, 
Treatment, and Follow-Up Periods, the study participation period is expected to be 62 days or 
less. Any study-related safety issues that extend past Study Day 30 will continue to be followed 
until they resolve.  
4.1.1. 
Screening Period 
The screening period will be up to 30 days. Required Screening assessments are shown in 
Table 1. Participants who fail one or more screening assessments may be re-screened once at the 
Investigator’s discretion in order to meet study entry criteria. See Section 5.4 for additional 
information regarding participants who fail screening and/or are re-screened. 


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4.1.2. 
Inpatient Treatment Period 
4.1.2.1. 
Baseline Procedures and Assessments 
The inpatient treatment period will be on Study Days 1 and 2. The participant may be required to 
undergo pre-admission assessments required by the Institution for elective admission, for 
example testing for common infectious pathogens. Signature of Institutional elective admission 
documents and consents to procedures may be required. Data from required institutional 
assessments and consents will not be routinely collected as part of study data unless they pertain 
to a relevant AE or study endpoint. 
Participants will be admitted to an inpatient care setting such as an ICU, cardiac catheterization 
laboratory or other similar setting. They will have Baseline laboratory and safety assessments as 
shown in Table 2. A RHC will be placed for Baseline assessment of cardiopulmonary 
hemodynamics prior to TPIP administration and intermittent assessments of cardiopulmonary 
hemodynamics for 24 hours following TPIP administration. Institutional procedures and 
protocols for placement, care, monitoring, and removal of the RHC will be carried out but will 
not be collected as study data unless relevant. 
Some procedures and assessments for exploratory endpoints may not be offered at all sites. 
Participants will be asked to give informed consent only to those procedures that are being 
conducted by their Investigator at their site. These procedures include the following: 
• Transthoracic echocardiogram at Baseline and during a 2 to 8 hour window after TPIP 
administration (Table 4). 
• Pulmonary CT scan at Baseline and during a 4 to 8 hour window after TPIP 
administration (Table 4). 
• Resting respiratory gas exchange assessment at Baseline and intermittently after TPIP 
administration for up to 24 hours (Table 4). Resting respiratory gas exchange assessments 
will be standardized, with all participating investigators using similar equipment and 
procedures. 
For example, an Investigator who is doing only RHC and resting respiratory gas exchange 
assessments for this study will obtain informed consent for those procedures only and will not 
offer or ask the participant for informed consent for transthoracic echocardiogram or pulmonary 
CT scan as part of this study. 
Following completion of all Baseline assessments, including Baseline blood draws for PK and 
PD biomarkers (Table 3), the prescribed single dose of TPIP will be administered (Table 2).  
4.1.2.2. 
Post-TPIP Administration 
Following TPIP administration, participants will have intermittent safety, clinical laboratory, PK, 
and PD assessments, as specified in the SoA (Table 2 Table 3 Table 4). The study is designed to 
allow maximum flexibility for interventions and assessments at the discretion of the Investigator 
and institutional policies and procedures to ensure participant safety. At any time, the 
investigator has the option to discontinue assessments for participant safety or tolerability 
reasons. Additional laboratory and/or hemodynamic assessments may be performed as deemed 
necessary for participant safety. Following completion of scheduled events, the investigator has 


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the option of continued laboratory and/or hemodynamic monitoring as deemed appropriate for 
participant safety.  
If, in the interest of participant safety, the Investigator omits scheduled assessments/procedures 
or performs additional assessments/procedures, the reason for doing so must be reported on the 
CRF as an AE in order to avoid a protocol violation.  
Following completion of protocol-required assessments and removal of the RHC, the participant 
will be discharged from the inpatient setting when deemed safe by the Investigator. Investigator 
and institutional usual care protocols for patient discharge and follow-up for an RHC procedure 
will apply. 
4.1.2.3. 
Post-discharge Outpatient Visits for PK Sampling and Safety Follow-up 
The participant will be required to return as an outpatient for the 36 (± 3) and 48 (± 4) hour post 
TPIP administration PK samples. Additional safety assessments such as ECG, physical 
examination, vital signs, AE collection, and clinical laboratory evaluations will be completed at 
the 48 hour visit. Female participants who are WOCBP will be given a self-administered 
pregnancy test kit with instructions to self-administer the test and report the results on the day of 
the Study Day 30 safety follow-up visit (Section 4.1.3). 
4.1.3. 
Safety Follow-up 
A remote (telephone call or telemedicine) safety follow-up visit is scheduled for Study Day 30, 
at which time participants who are WOCBP will also be asked to report the results of the self-
administered pregnancy test they were given at the 48 hour post-TPIP follow-up visit 
(Section 4.1.2.3, Table 1). 
4.2. 
Scientific Rationale for Study Design 
The study is designed to understand the safety and acute PK and PD effects of TPIP in 
participants with PAH, the intended patient population. Intensive monitoring via RHC in an 
appropriate inpatient setting is essential to understand how TPIP affects cardiopulmonary 
hemodynamics and to elucidate relationships between dose, PK, and PD effects. Some 
assessments and study activities for exploratory endpoints are considered optional depending on 
Investigator preference and/or based on study site capabilities and procedures (Table 4). 
4.3. 
Justification for Dose 
Treprostinil palmitil has been previously studied in healthy volunteer participants as a liquid 
suspension for inhalation (TPIS) and has now been formulated as a dry powder for oral 
inhalation (TPIP). Data from pre-clinical pharmacology and safety studies supported the 
initiation of human studies with TPIS. Preclinical studies in rats and dogs showed that the plasma 
kinetics of TRE and TP after dosing with TPIP are similar to those of TPIS. For further 
information on the non-clinical pharmacology and safety studies of TPIS and TPIP, please refer 
to the Investigator’s Brochure. 
The selection of TP dose levels for this study was primarily based on the safety and tolerability 
of TPIS in healthy participants following single dose inhalation at 85 to 340 µg (Study 
INS1009 101).The starting dose of 85 μg TP administered as TPIS in Study INS1009-101 was 


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selected as molar equivalent to the single dose of TRE in Tyvaso. Based on the formula used to 
predict the human equivalent dose from animal dose and animal weight (US Food and Drug 
Administration, 2005), this dose is 4-fold lower than the calculated maximum safe starting dose 
of 324 µg and 3-fold lower than the calculated human lung-equivalent dose of 255 µg. A safety 
factor of less than 10 was considered appropriate in selection of this dose as TRE is a member of 
a well-characterized class of compounds (prostanoids) and has been previously studied in 
4 different formulations (inhaled, SC, IV, and oral) (Remodulin Package Insert, 2018), oral 
extended-release tablets (Orenitram Package Insert, 2019), and inhalation solution (Tyvaso 
Package Insert, 2017). 
The current study utilizes the clinical experience of TPIS from Study INS1009-101 in healthy 
volunteer participants and the ongoing INS1009-102 SAD/MAD study of TPIP in healthy 
volunteer participants. In Study INS1009-101, doses of TPIS were administered in multiples of 
85 µg TP to include 170 µg (2 × 85 µg) and 340 µg (4 × 85 µg) of TP. The systemic exposure 
for TRE at 340 µg TP was low (AUC < 2.5 ng*h/mL) with an elimination t1/2 of approximately 
7 hours. In the first SAD portion of INS1009-102 (SAD1) 18 participants were randomized to 1 
of 3 TP dose levels of TPIP: 112.5 μg, 225 μg, or 450 μg of TP (6 participants at each dose). 
Preliminary concentration data for this cohort, when normalized by dose, appear to be similar to those 
from Study INS1009-101, suggesting a similar bioavailability in humans between TPIP and TPIS. The 
safety and PK results of single doses of the 3 dose levels of TPIP in the 18 healthy participants 
will inform dosing in the current study. 
Administration of TPIP will be via inhalational dry powder packaged in single actuation 
capsules. Each capsule contains 7.5 mg of dry powder, containing 112.5 µg of the TP prodrug, 
the molar equivalent of 71 µg of TRE. It is expected that about 85 µg of TP (54 µg of TRE 
equivalent) will be emitted from the dry powder inhalation device. This is comparable to a single 
administration of Tyvaso for patients with PAH with the target dose being 54 µg QID. Single 
doses of up to 90 µg of Tyvaso have been administered in clinical studies of healthy volunteer 
participants (Tyvaso Package Insert, 2017). 
Each participant will receive a single dose administration of TPIP. A TPIP dose containing 
112.5 µg of TP will be given to the first participant in Study INS1009-201. All available data 
(PD, PK, safety) from the first participant will be assessed and evaluated by the SRC, as well as 
available data from the ongoing INS1009-102 study. Following this evaluation, the SRC will 
determine if it is safe to continue the study, the TPIP dose level and any changes to safety PD 
and PK assessments for the second participant (Figure 2). This process will be repeated using the 
total accrued data of all completed participants prior to determining the TPIP dose for each 
subsequent participant. There will be no simultaneous dosing of participants; each participant 
will be treated as an individual case for evaluation. The TP dose level for each subsequent 
participant may be increased, held stable or lowered, depending on the accumulating data from 
previous participants.  TPIP doses containing < 112.5 µg TP will not be used. TPIP dosing may 
be stopped at any dose level as determined by the SRC. 
4.4. 
Study Completion 
A participant will be considered to have completed the study if he/she has completed all phases 
of the study including the Study Day 30 safety follow-up (the last scheduled procedure shown in 
Table 1). 


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The study will be considered completed on the date of the last safety follow-up of the last 
participant in the study.  
 


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5. 
STUDY POPULATION 
The study is expected to recruit approximately 6 to 10 participants at up to 4 centers with 
appropriate inpatient facilities in the United States. Eligible participants must have clinically 
stable disease of mild to moderate severity, with good to moderate functional status. Participants 
may not be taking more than 2 medications from the following classes: 
• Endothelin receptor antagonists (eg ambrisentan, bosentan, macitentan), 
• Phosphodiesterase type 5 inhibitors (eg sildenafil, tadalafil) 
• Guanylate cyclase stimulator (eg riociguat) 
It is expected that the site will recruit appropriate potential participants according to the criteria 
in Section 5.1 and Section 5.2. Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not permitted.  
 
The study inclusion and exclusion criteria include thresholds of selected RHC and ECG 
parameters that must be met at Baseline or the participant will not be considered eligible for the 
study. In this case, the participant is to be reported as a Screen Failure (Section 5.4). 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if they meet all of the following criteria: 
Age: 
1. Participant must be ≥ 18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants must have a diagnosis of WHO Group 1 PH (PAH) with the following 
characteristics (Galie et al., 2016): 
a. Etiology of idiopathic, heritable, drug/toxin-induced or connective tissue 
disease (CTD)-related PAH; 
b. Right heart catheterization within the last 3 years with the following 
hemodynamic findings:  
- Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest,  
- Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
- Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 
3. PAH diagnosis for at least 1 year and less than 10 years 
4. New York Heart Association (NYHA)/WHO Functional capacity Class II-III 
5. No change in pulmonary hypertension medications (eg, ambrisentan, bosentan, 
macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 90 days prior to 
Screening.  
6. No change in diuretic use or dosage for at least 30 days prior to Screening 


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7.  Documented predicted percent forced vital capacity (FVC) > 70% within 1 year 
of Screening. If not available, pulmonary function testing will be performed at 
Screening (Table 1) 
8. At least 2 of the following European Respiratory Society/European Society for 
Cardiology (ERS/ESC) low risk criteria: 
a. NT-pro-BNP concentration < 300 ng/L within 6 months of Baseline (if not 
available will be obtained at Screening, Table 1) 
b. Historical documentation of 6- minute walk distance (6MWD) > 440 
meters within 6 months prior to Baseline. If not available will obtain 
6MWD test at Screening (Table 1) 
c. Right atrial pressure (RAP) < 8 mmHg within 1 year prior to Baseline 
d. Cardiac Index (CI) ≥ 2.5 L/min*m2or mixed venous oxygen saturation 
(MVO2) > 65% within 1 year prior to Baseline 
9. Right heart catheterization at Baseline with the following hemodynamic findings: 
10. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest,  
11. - Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and  
12. - Pulmonary vascular resistance (PVR) of ≥ 3 Wood Units (WU) 
Weight 
13. Body mass index (BMI) within the range 19.0 - 32.0 kg/m2 (inclusive). 
Sex and Contraceptive/Barrier Requirements 
14. Male participants:  Male participants and their female partners of childbearing 
potential must agree to use highly effective contraception from Study Day 1 to at 
least 90 days after dosing. 
15. Female participants:  Women of child-bearing potential (WOCPB, defined as 
premenopausal, not surgically sterile for at least 3 months prior to Screening) must 
use a highly effective contraception method and agree to be tested for pregnancy 
from at Screening, Baseline, and 30 days after dosing. 
See Section 10.4 for contraceptive guidance. 
Informed Consent 
16. Capable of giving signed informed consent as described in Section 10.1.5 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if they meet any of the following criteria: 


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Medical Conditions 
1. Any PH other than idiopathic, hereditary, drug/toxin-induced, or connective tissue 
disease (CTD) associated PAH (eg, congenital heart disease-associated PAH, portal 
hypertension-associated PAH, PH belonging to Groups 2 through 5) 
2. Allergy, or documented hypersensitivity or contraindication, to the ingredients of 
treprostinil palmitil inhalation powder (TPIP) or treprostinil (TRE). 
3. Previous intolerance to prostacyclin analogs or receptor agonists (eg, selexipag) per 
investigator discretion 
4. History of anaphylaxis or previously documented hypersensitivity reaction to any 
drug per Investigator discretion 
5. QTcF interval > 480 ms on resting ECG at Baseline 
6. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% 
or clinically significant valvular, constrictive, or atherosclerotic heart disease 
(myocardial infarction, etc) 
7. Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) 
at Screening. 
8. Active liver disease or hepatic dysfunction manifested as: 
a. Elevated liver function test results (ALT or AST > 2 × ULN) at Screening 
b. Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable 
if bilirubin is fractionated and direct bilirubin < 35%) at Screening. 
c. Known hepatic or biliary abnormalities, not including Gilbert's syndrome or 
asymptomatic gallstones at Screening.  
9. History of HIV infection/positive HIV serology test result at Screening. 
10. History of active/chronic Hepatitis B or C/ positive hepatitis B or C serology test 
result at Screening 
11. History of abnormal bleeding or bruising. 
12. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or 
otherwise recurrent infections of abnormal frequency, or prolonged infections 
suggesting an immune-compromised status, as judged by the investigator. 
13. Active and current symptomatic infection by SARS CoV 2. Additional COVID 19 
restrictions per institutional guidelines (See also Section 10.1.3.1.3) 
14. Patients with current or recent (past 4 weeks) lower respiratory tract infection (may 
be re-screened at appropriate time (Section 5.4) 


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15. History of malignancy in the past 5 years, with exception of completely treated in 
situ carcinoma of the cervix and completely treated non-metastatic squamous or 
basal cell carcinoma of the skin. 
Concomitant Therapy 
16. Patients receiving triple combination therapy for PAH consisting of endothelin 
receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase 
stimulators (riociguat). 
17. Patients receiving prostanoids/prostacyclin agonists 
18. Other prior/concomitant therapies are allowed/disallowed at the Investigator’s 
discretion 
Prior/Concurrent Clinical Study Experience 
19. Have participated in any other interventional clinical studies within 30 days of 
Baseline 
Diagnostic assessments 
20. Any clinically significant abnormal laboratory, value, test result, or physical 
examination finding at Screening; diseases or diagnoses/disorders that, in the 
opinion of the Investigator, may put the participant or others at risk by participating 
in the study, interfere with the participant's treatment and assessment, or influence 
the results of the study; or have compliance issues with the study. 
Other Exclusions 
21. Current or history of substance and/or alcohol abuse per Investigator assessment 
22. Current user of cigarettes or e-cigarettes 
23. Pregnant or breastfeeding. 
 
 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study because they did not meet all inclusion criteria or meet one 
or more exclusion criteria. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the Investigator’s discretion. If a participant can be rescreened, the PI is to 


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consult with the Medical Monitor to determine whether some or all of the Screening assessments 
must be repeated. Rescreened participants will sign a new ICF and will be assigned a new 
participant number. 
5.5. 
Criteria for Temporarily Delaying Inpatient Treatment Period 
Following successful screening and meeting of study eligibility criteria, the inpatient treatment 
period and RHC procedure must be scheduled without delay.  
 
The scheduled treatment period may be temporarily delayed no longer than 28 days by the 
Investigator in consultation with the Medical Monitor for valid reasons. Examples of valid 
reasons for delaying the treatment period may include such things as a life event for the 
participant (eg death in the family), local public health emergency (eg, COVID 19 outbreak), site 
facility issues (eg, catheterization lab or ICU bed availability), or pending TPIP dosing directives 
from the SRC. 
 
A temporary delay in the scheduled inpatient treatment period for a valid reason may result in 
previously met Inclusion Criteria that rely on a time window to be not met (eg, 6MWD falls 
outside the 6 months prior to Baseline window). This is not considered to be a Screen Failure. In 
this case, the Investigator should consult with the Medical Monitor to identify which Screening 
tests need to be conducted or repeated to ensure that the participant meets study inclusion criteria 
and can safely participate in the study.  
 
Deterioration of the participant’s medical condition is not a valid reason to delay start of the 
inpatient treatment period. In some cases delaying the inpatient treatment period may cause the 
participant to meet one or more exclusion criteria (eg, participant develops a lower respiratory 
infection). In this case the participant should be considered a Screen Failure and Section 5.4 
applies. 


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6. 
STUDY IMP AND CONCOMITANT THERAPY 
Study IMP is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study IMP Administered 
A single dose of TPIP is the only study IMP. Each TPIP capsule contains 7.5 mg of dry powder, 
containing 112.5 µg of the TP prodrug. A dose may consist of a single capsule or of multiple 
capsules administered in succession. 
Name of Treatment 
Dose 
Supplied Formulation 
Route and Frequency 
of Administration 
Treprostinil palmitil 
inhalation powder 
(TPIP) 
One or more single 
actuation capsules 
Single actuation 
capsules containing 
112.5 µg TP per 7.5 mg 
powder 
Single dose after 
Baseline assessments 
6.1.1. 
Medical Devices 
In the planned clinical study, the TPIP will be administered by oral inhalation using a Plastiape 
capsule-based Dry Powder Inhaler (RS 01 Mod 7). A Type III Drug Master File is filed at the US 
FDA and the RS01 inhaler is classified as a Class I medical device. The Instructions for Use of 
the device document is provided separately as an Appendix to the Pharmacy Manual. 
 
All device deficiencies (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the investigator throughout the clinical investigation (Section 8.3.8) 
and appropriately managed by Insmed. 
6.2. 
Preparation/Handling/Storage/Accountability 
Insmed Incorporated will provide the investigator and clinical unit with adequate quantities of 
TPIP capsules. TPIP-filled HPMC capsules will be delivered in HDPE bottles overwrapped with 
an aluminum pouch, containing a sachet of desiccant to prevent moisture ingress. The powder 
will be administered by oral inhalation using a Plastiape capsule-based Dry Powder Inhaler 
(Section 6.1.1). Directions for preparation and administration of the TPIP dose to the participant 
are provided in a separate document as an Appendix to the Pharmacy Manual. 
All study IMP must be stored according to the labeled instructions in a secure cabinet or room 
with access restricted to necessary clinic personnel. The site will be required to keep a 
temperature log to establish a record of compliance with storage conditions. Current stability 
data supports a shelf life of 6 months for TPIP when stored at 2 to 8 °C. 
• The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study IMP received and any discrepancies are 
reported and resolved before use of the study IMP. 
• Only participants enrolled in the study may receive TPIP and only authorized site 
staff may supply or administer it. All TPIP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 


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with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
• The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study IMP and dosing devices accountability, reconciliation, and 
record maintenance (eg, receipt, reconciliation, and final disposition records). 
• Study IMP and dosing device accountability records will be maintained for all clinical 
supplies. All transactions will be recorded on the drug and dosing device 
accountability records including shipment receipts and study participant doses. All 
transactions will be recorded on a real-time basis. 
• The Investigator/site will maintain detailed documentation of the number and 
identification of bottles and dispensing units of TPIP with copies of these documents 
to be provided to Insmed at the end of the study. All used and unused study IMP and 
dosing devices will be maintained by the site until inventoried by the study monitor. 
Upon completion of the study IMP and dosing device inventory by the study monitor, 
used and any unused study IMP and dosing devices will be disposed of in accordance 
with instructions provided to sites and according to site destruction policies. 
Documentation of destruction must be provided to Insmed. 
• Further guidance and information for the final disposition of unused study IMP 
supplies can be obtained from Insmed. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. 
6.4. 
Study Intervention Compliance 
Study participants will receive the TPIP dose directly from the investigator or designee, under 
medical supervision, in an appropriate inpatient setting. The date and time of the dose 
administered will be recorded in the source documents. The dose of TPIP and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the TPIP. 
6.5. 
Dose Modification 
Dose modification is part of the study design and is described in detail in Section 4.3. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
An overdose is defined as the participant receiving any TPIP in excess of their assigned dose as 
predetermined by the SRC (Section 4.3). An overdose itself is not an AE. However, if the 
overdose results in clinical signs and symptoms, it requires expedited reporting as if it is an SAE. 
The Investigators must refer to the relevant documents for detailed information regarding 


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warnings, precautions, contraindications, AEs, and other significant data pertaining to the study 
IMP. Such documents may include, but are not limited to, the Investigator’s brochure. 
In the event of an overdose, the investigator must: 
• Contact the Medical Monitor within 24 hours. 
• Evaluate the participant to determine, in consultation with the Medical Monitor, how to 
proceed with treatment period procedures and assessments. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until TP or 
TRE is likely to be sufficiently metabolized and/or excreted and/or can no longer be 
detected systemically. The frequency and duration of plasma sampling from the last dose 
of TPIP must be determined by the Investigator in conjunction with the study team and 
Medical Monitor. 
• The overdose must be fully documented (eg, quantity of the excess dose, duration of the 
overdose, how it happened) in the CRF. 
6.8. 
Concomitant Therapy 
Any medications, treatments, or therapies that the participant is receiving at Baseline (Study Day 
1) or receives during the study (Study Day 1 through Study Day 30) are considered concomitant 
therapy and will be collected and documented in the study CRF. Documentation includes the 
name of the therapy, with the reason for use, the dates of administration including start and end 
dates, and dosage information including dose and frequency.  
 
Prior medications are those medications taken before the first dose of study IMP. A medication 
that starts prior to first dose but continues after the first dose of study IMP is classified both in 
prior and concomitant medications. Any procedures performed from Day 1 through Day 30 are 
considered concomitant procedures and will be collected and documented in the study CRF. 
 
The Medical Monitor must be contacted if there are any questions regarding concomitant or prior 
therapy. 


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7. 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study IMP 
This is a single dose study; not applicable 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. 
• At the time of discontinuing from the study after TPIP administration, if possible, an 
early discontinuation evaluation must be conducted at the Investigator’s discretion to 
maximize participant safety. This final evaluation and the reason for participant 
withdrawal must be documented in the CRF.  
• If the participant is discontinued from the study due to an AE, the Investigator will follow 
the participant until the Investigator deems that the AE has resolved or stabilized. In case 
of unresolved AEs including significant abnormal laboratory values at the end of study 
assessment, these events will be followed up until resolution or until they become stable. 
• The Investigator may withdraw the participant from the study due to absence of a PD 
response to TPIP. Lack of expected pharmacological action per se will not be reported as 
an AE or SAE. Such instances will be captured in the PK and PD assessments. 
• The participant will be permanently discontinued both from the study IMP and from the 
study at that time. 
• If the participant withdraws consent for disclosure of future information, Insmed may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled follow-up visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
must be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered 
lost to follow-up and to have withdrawn from the study.  


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• Site personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants, 
including those who did not get study IMP. Public sources may be searched 
for vital status information.  If vital status is determined as deceased, this will 
be documented and the participant will not be considered lost to follow-up. 
Insmed personnel will not be involved in any attempts to collect vital status 
information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.13.2). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Table 1, Table 2, Table 3, and Table 4.  
All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet eligibility criteria prior to scheduling the study RHC procedure and 
inpatient admission. The RHC procedure and inpatient admission must be scheduled for 
as soon as possible once the participant’s eligibility for the study is confirmed by 
screening. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., previous 
RHC, previous echocardiogram, previous 6MWD test) and obtained before signing of the 
ICF may be utilized for Screening or Baseline purposes provided the procedures meet the 
protocol-specified criteria and were performed within the time frames defined in the 
inclusion and exclusion criteria in Section 5  
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required is expected to be 
approximately 150 mL and will not exceed 200 mL. Approximately 90 mL will be 
required for PK sampling over 48 hours and approximately 20 mL for biomarker 
sampling. Safety and Screening blood samples will require approximately 20 to 30 mL. 
Blood loss from the RHC procedure is anticipated to be negligible. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples at the Investigator’s discretion. 
At any time, the Investigator has the option to discontinue assessments for participant safety 
or tolerability reasons. Additional laboratory, PK, and/or hemodynamic assessments may 
be performed as deemed necessary for participant safety. Following completion of 
scheduled events, the investigator has the option of continued laboratory and/or 
hemodynamic monitoring as deemed appropriate for participant safety. If, in the interest 
of participant safety, the Investigator omits scheduled assessments/procedures or 
performs additional assessments/procedures, the reason for doing so must be reported on 
the CRF as an AE in order to avoid a protocol violation. 
8.1. 
Pharmacodynamic Assessments 
The results of each individual participant’s PD assessments will contribute to the dosing decision 
for the next participant (Section 4.3).  
8.1.1. 
Required PD Assessments With RHC 
PVR, CO, PAP (mean), RAP (mean), RVP, hemoglobin, and MVO2 will be measured via the 
RHC at the timepoints indicated in the SoA (Table 2). Oxygen consumption is part of the MVO2 
calculation and may be measured or estimated at 125 mL O2 per square meter (m2) of body 
surface area (BSA). These or other parameters may be optionally measured at other timepoints or 
omitted to ensure participant safety at the Investigator’s discretion. If measurements are missed, 
or additional measurements are taken for safety purposes, the reason must be documented as an 
AE in the CRF. 


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Institutional procedures for insertion, care, monitoring, and removal of the RHC will be 
followed. Specific technique and procedures for measurement of PVR, CO, PAP, RAP, RVP, 
hemoglobin, oxygen consumption, and MVO2 are provided in a separate Procedure Guide. 
8.1.2. 
Required Non-invasive PD Assessments 
Systemic blood pressure (mmHg) may be measured by inflatable cuff. Systemic blood pressure 
must include 3 values:  systolic, diastolic, and mean arterial pressure. Arterial oxygen saturation 
(SpO2, %) and heart rate (beats per minute) may be measured by pulse oximeter.  
8.1.3. 
Resting Respiratory Gas Exchange Assessments 
Specific measurements for resting respiratory gas exchange assessment include changes from 
Baseline in respiratory rate (breaths per minute), minute ventilation (mL per minute), carbon 
dioxide production (VCO2, mL per minute), end tidal oxygen concentration (ETO2, %), and end 
tidal carbon dioxide concentration (ETCO2, %). The gas exchange parameters will be monitored 
at the same timepoints as the PD assessments in Section 8.1.1 (Table 2 Table 4). Specific 
instructions for resting respiratory gas exchange assessment procedures and measurements are 
provided in a separate Procedure Guide. 
8.1.4. 
Transthoracic Echocardiogram Assessments 
Transthoracic echocardiogram is to be performed at Baseline and during a 2-8 hour window 
following TPIP administration (Table 4). Specific instructions for echocardiographic procedures 
and measurements are provided in a separate Procedure Guide. 
8.1.5. 
Pulmonary CT Scan 
Pulmonary CT scanning to assess pulmonary vasculature and blood flow is scheduled for 
Baseline and during a 4-8 hour window following TPIP administration (Table 4). Specific 
requirements and instructions for pulmonary CT scanning and required parameters are provided 
in a separate Procedure Guide. 
8.2. 
Safety Assessments 
Evaluation of the safety and tolerability of single doses of TPIP in participants with PAH is the 
primary objective of this study. Planned time points for all safety assessments are provided in 
Table 1 and Table 2. The results of the individual participant’s safety assessments during and 
after TPIP administration will contribute to the dosing decision for the next participant 
(Section 1.2.2). 
8.2.1. 
Physical Examinations 
Screening: The physical examination must focus on those areas that determine the individual 
participant’s eligibility to participate in the study and do so safely at the Investigator’s discretion 
and will be documented accordingly. 
Baseline:  The physical examination must focus on the participant’s fitness for the study 
procedures and TPIP administration. 


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Discharge:  The physical examination must focus on the participant’s fitness to be safely 
discharged to home from the inpatient setting.  Special attention must be paid to assessment of 
any new or ongoing AEs. 
Follow-up: The in-person physical examination must focus on patient safety and assessment of 
AEs that were ongoing at discharge or have occurred since discharge. 
8.2.2. 
Vital Signs 
Temperature, heart rate, respiratory rate, and blood pressure at Screening and 48 hour post-TPIP 
administration follow-up will be per the Investigator’s usual outpatient practice and documented 
accordingly. 
Baseline and post-TPIP administration:  Changes from Baseline in heart rate, respiratory rate, 
and systemic blood pressure are PD endpoints as well as safety variables and must be measured 
as specified (Section 8.1). Vital signs outside of PD endpoints will be monitored per the inpatient 
unit’s usual practices. 
8.2.3. 
Electrocardiograms 
Screening:  a single 12-lead ECG will be conducted per the Investigator’s usual practice 
Baseline: A single 12-lead ECG will be performed to ensure the participant’s eligibility for the 
study (Section 5.2). Inpatient telemetry monitoring will be utilized per the unit’s usual practice 
until the patient is discharged from the inpatient setting, but routine telemetry readings will not 
be collected as study data unless they pertain to a relevant AE. 
48 hours post-TPIP administration follow-up:  a single 12-lead ECG will be conducted per the 
Investigator’s usual practice. 
8.2.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 (Table 5) for the list of clinical laboratory tests to be performed and to the 
SoA (Table 1, Table 2) for the timing and frequency. All clinical laboratory tests will be 
performed locally by the study site. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after TPIP dosing must be repeated at the 
Investigator’s discretion, consistent with the participant’s level of disease until the values 
return to normal or baseline or are no longer considered clinically significant by the 
investigator or Medical Monitor. 
o If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology must be identified, and 
Insmed notified.] 
o All protocol-required laboratory tests, as defined in Section 10, Appendix 2, must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 


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o If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.5. 
Pregnancy Testing 
Willingness of WOCBP to undergo serum or urine pregnancy testing is a study eligibility 
criterion. Pregnancy tests will be conducted at Screening, Baseline, and Study Day 30. WOCBP 
participants will be provided a home pregnancy test kit with instructions to conduct and report 
test results at the Study Day 30 follow-up visit which is scheduled to be by telephone call or 
telemedicine. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). AEs may be solicited or unsolicited. Solicited and 
unsolicited AEs are defined in Section 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until the Study Day 30 follow-up visit at 
the time points specified in the SoA (Table 1, Table 2). Medical occurrences that begin after 
obtaining informed consent but before TPIP administration will be recorded as Medical 
History/Current Medical Conditions, not as AEs. 
All SAEs will be collected from the signing of the ICF until the Study Day 30 follow-up visit at 
the time points specified in the SoA (Table 1, Table 2). SAEs that occur after signing the ICF but 
before study IMP starts must be recorded and reported as SAEs. 
All SAEs will be recorded and reported to Insmed or designee immediately and under no 
circumstance must this exceed 24 hours, as indicated in Appendix 3, (Section 10.3). The 
investigator will submit any updated SAE data to Insmed within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IMP or study participation, the investigator must promptly notify 
Insmed. 


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8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AESIs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is provided in Appendix 3 
(Section 10.3). 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to Insmed of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The Insmed has a legal responsibility to notify relevant health authorities and regulatory agencies 
about the safety of a study IMP under clinical investigation. This study is being conducted in the 
USA only; regulatory requirements relating to safety reporting to the US FDA, IRBs, and 
investigators will be followed. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from Insmed will review and then file it 
along with other study documents and will notify the IRB, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Insmed policy and forwarded to investigators as necessary. No serious adverse 
reactions are considered expected for TPIP. Please refer to the Reference Safety Information in 
Section 6.1 of the Investigators Brochure. 
8.3.5. 
Pregnancy 
Details of all pregnancies that occur in WOCBP participants within 30 days after TPIP 
administration will be collected. Male participants with WOCBP partners must continue to use 
contraception for 90 days after TPIP administration and report any pregnancies that occur within 
that time period.  
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to Insmed within 24 hours of learning of the pregnancy in a female participant 
or female partner of male participant and after obtaining the necessary signed informed consent 
from the female partner. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 


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The pregnant participant/pregnant female partner of a male participant will be followed to 
determine the outcome of the pregnancy. The investigator will collect follow-up information on 
the pregnant participant/pregnant female partner of a male participant and the neonate and the 
information will be forwarded to Insmed. 
Any post-study pregnancy-related SAE considered reasonably related to the study IMP by the 
investigator will be reported to Insmed as described in Section 8.3.4. While the investigator is 
not obligated to actively seek this information in pregnant former study participants or their 
pregnant female partner, he or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study, prior to TPIP 
dosing will be discontinued from the study. 
8.3.6. 
Cardiovascular and Death Events 
Cardiovascular and death events must be reported as AEs/SAEs per the reporting instructions in 
Section 10.3. 
8.3.7. 
Adverse Events of Special Interest (AESI) 
AESIs are AEs related to prostacyclins, and prostacyclin analogs or receptor agonists. These 
include: headache, flushing, nausea, vomiting, diarrhea, cough, chest pain, abdominal 
pain/discomfort, jaw pain, back pain, extremity pain (musculoskeletal), and hypotension. 
8.3.8. 
Medical Device Deficiencies 
A medical device, the Plastiape capsule based Dry Powder Inhaler is being provided for use in 
this study to administer TPIP. To fulfill regulatory reporting obligations worldwide, the 
investigator is responsible for the detection and documentation of events meeting the definitions 
of device deficiency that occur during the study with such devices. 
The definition of a Medical Device deficiency and reporting requirements and procedures for 
device deficiencies and AEs/SAEs resulting from device deficiencies can be found in 
Section 10.6.  
8.3.8.1. 
Time Period for Detecting Medical Device Deficiencies 
Medical device deficiencies that result in an incident will be detected, documented, and reported 
during all periods of the study in which the medical device is used. 
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such a deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify Insmed. 
The method of documenting Medical Device Deficiency is provided in Section 10.6. 
8.3.8.2. 
Follow-Up of Medical Device Deficiencies 
Follow-up applies to all participants who experienced a device deficiency. 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 


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New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator. 
8.3.8.3. 
Prompt Reporting of Device Deficiencies to Insmed 
Device deficiencies will be reported to Insmed within 24 hours after the investigator determines 
that the event meets the protocol definition of a medical device deficiency. 
8.3.8.4. 
Regulatory Reporting Requirements for Device Deficiencies 
The investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for Insmed to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. 
The investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB. 
8.4. 
Pharmacokinetic Assessments 
The schedule for PK assessments and sampling windows is shown in Table 3. The 36 (± 3) and 
48 (± 4) hour post-TPIP administration blood draws are expected to be done on an outpatient 
basis. 
8.4.1. 
PK Sample Collection 
Plasma blood samples of approximately 10 mL each will be collected for measurement of plasma 
concentrations of TP and TRE as specified in the SoA (Section 1.3).  
A maximum of 2 samples may be collected at additional time points during the study if an SAE 
occurs or at early termination.  
Each PK plasma sample will be divided into 2 aliquots (1 each for PK analysis and the other for 
backup. All samples will be stored frozen (-70°C or -20°C) until shipment and then stored at -
70°C until analysis. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Full instructions for the collection and handling of PK samples will be provided by Insmed in a 
separate Laboratory Manual.  
8.4.2. 
PK Analysis 
Individual PK parameters of TRE and TP will be determined using non-compartmental analysis 
for the following parameters: Cmax, tmax, AUCt1–t2, AUC0–∞, CL/F, Vd/F, and t1/2. 
8.4.3. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Relationships between PK (TP dose and TRE exposure) and PD effects and safety will be 
explored and reported separately. 


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8.5. 
Genetics / Pharmacogenomics 
Genetic and/or pharmacogenomic analyses are not included in this study. 
8.6. 
Biomarkers 
A blood sample for NT-pro-BNP will be taken at Screening if needed as part of study inclusion 
criteria (Section 5.1).  
Blood samples (5-7 mL per time point) will be collected for biomarker measurement at Baseline 
and at 4 and 8 hours after TPIP administration. The plasma generated from the blood samples 
will be stored frozen (-70 C or lower is preferred) until shipment and analysis. 
Full instructions for the collection and handling of biomarker samples will be provided by 
Insmed in a separate Laboratory Manual. 
8.7. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity assessments do not apply to this study of a small molecule. 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be evaluated in this study. 
9.2. 
Sample Size Determination 
The sample size for this study is not based on statistical power calculations. The planned number 
of evaluable participants to complete the study is approximately 6-10.  
9.3. 
Analysis Sets 
The analysis sets comprise participants who are considered evaluable for the parameters under 
consideration.  
All participants who receive a single dose of TPIP will be considered evaluable for safety and 
included in the safety population. 
All participants who receive a single dose of TPIP and have a least one measurable post-dose 
plasma TP/TRE concentration will be considered evaluable for PK and included in the PK 
population. 
All participants who receive a single dose of TPIP and have a Baseline datapoint and at least one 
measurable post-dose PD datapoint will be considered evaluable for PD and included in the PD 
population. 
All participants who receive a single dose of TPIP and have at least 1 measurable post-dose 
biomarker datapoint will be considered evaluable for biomarkers and included in the biomarker 
population. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to Database Lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1. 
General Considerations 
There is no hypothesis-testing in this study and no inferential statistical analyses will be 
conducted. There will be no proxy values for missing data. Participant PK, PD, and biomarker 
data will be presented individually in listings and graphs as appropriate for each variable.  
The frequency of TEAEs is the primary endpoint for this study. All safety analyses will be 
performed on the safety population. AE listings as required by ICH E3 guidelines will be 
produced. TEAEs, SAEs, AEs leading to treatment and/or study withdrawal, and AESIs will be 
listed for each participant along with outcome, severity, and relatedness to study IMP. Ad hoc 
summaries of TEAEs may be prepared if the volume of data allow.  
PK and PD values for secondary endpoints will be listed and graphed if appropriate for each 
evaluable participant. 


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PK and PD values for exploratory endpoints will be listed and graphed as appropriate for each 
participant. 
9.4.2. 
ECG, Vital Signs, Clinical Laboratory Values 
ECG data will be listed for each participant. Vital signs data that are not considered part of a PD 
assessment (Section 8.1) will be listed for each participant. Clinical laboratory values will be 
listed for each participant. 
9.5. 
Interim Analysis 
All available safety, PK, and PD data from each participant will be evaluated by the SRC prior to 
the next participant in order to determine the value of proceeding with the study and the TPIP 
dose for each subsequent participant (Section 4.3). 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
a. Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
b. Applicable ICH Good Clinical Practice (GCP) Guidelines 
c. Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, Instructions for Use of the 
Plastiape capsule based Dry Powder Inhaler, and other relevant documents must be 
submitted to an IRB by the investigator and reviewed and approved by the IRB before the 
study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
d. Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
e. Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
f. Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
10.1.2. 
Protocol Deviations 
The Investigator must conduct the study in compliance with the protocol as agreed to by Insmed 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRB. 
The Investigator must notify the IRB of deviations from the protocol in accordance with IRB 
reporting requirements.  
As of May 2020, due to concern regarding COVID-19, there may be restrictions to participant 
attendance at in-clinic visits or elective inpatient admissions. In the event participants are 
restricted to attend in-clinic visits, or if the participant has concern regarding travel and attending 
in-clinic visits (due to potential public health concerns), the site must contact Insmed on how to 
conduct the scheduled assessments, and decisions must be documented in the source 


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documentation. Where necessary, in-clinic visits may be conducted via telemedicine link and 
home health care visits. 
10.1.3. 
Public Health Emergency Situations 
During the COVID-19 public health emergency, Insmed, IRBs, and Investigators shall follow the 
most current version of local guidance to assure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. The continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms, 
which will remain in effect only for the duration of the local public health emergency. Examples 
of such mechanisms may include, but are not limited to, any of the following: telephone contact, 
virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use 
of local clinic or laboratory locations, and home visits by skilled staff. The site must contact 
Insmed on how and when to implement temporary and/or alternative mechanism of scheduled 
assessments, and all decisions taken must be documented in the source documentation. 
Additionally, all temporary mechanisms utilized, and the resulting deviations from planned study 
procedures are to be documented as being related to COVID-19. 
In a situation where local health authorities declare a public health emergency while the study is 
ongoing, the suggested guidance in the following subsections must be followed. 
10.1.3.1. Continuation or Suspension of the Study 
Ensuring the safety of trial participants is paramount. The Insmed (Insmed Incorporated), in 
consultation with clinical investigators and IRB, will determine if the protection of a 
participant’s safety, welfare, and rights are best served by continuing or stopping the trial at the 
specific site. Such decision will depend on specific circumstances, including the ability to 
conduct appropriate safety monitoring, the potential impact on the investigational product supply 
chain, and other considerations. 
If the decision is to continue the study, the following considerations will be taken into account: 
10.1.3.1.1. Study Recruitment 
The Insmed will communicate to the sites the decision on whether to continue or suspend 
recruitment after considering the specific circumstances of each site, recommendation by the 
IRB, and its local health authority mandates. If, due to COVID-19, study discontinuation exceeds 
the assumed rate, Insmed may allow enrollment past the assumed sample size. 
10.1.3.1.2. Participants Already Enrolled in the Study 
If the decision is to continue the participation of participants already enrolled, the following steps 
must be taken:  
• If a participant is not able to complete a protocol specified study visit, it may be 
necessary to adjust the visit schedule, convert in-clinic visits to telemedicine visits, 
and/or postpone study procedures until the next available in-clinic study visit. If there 
is information available from previous visits (ie, laboratory assessments) that requires 
follow-up procedures or other safety assessments, the Investigator will decide if an 


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on-site visit or home healthcare visit is required or whether the participant’s safety 
can be preserved by other means. 
10.1.3.1.3. Participants Infected by COVID-19 
If a participant has had a past documented mild to moderate COVID-19 infection  prior to 
enrollment in the trial but the participant has recovered and the current diagnostic tests are 
negative (negative antigen by any diagnostic laboratory kit), the participant can be screened, at 
the Investigator’s discretion. Participants who experienced hospitalization, severe disease, and/or 
COVID-19 acute respiratory distress syndrome (ARDS) must be excluded. 
If a participant has a documented infection by COVID-19 while in the trial, the event will be 
reported as an AE or SAE, depending on the criteria. The Investigator will follow the guidance 
provided by health authorities in the treatment of those participants. 
10.1.4. 
Financial Disclosure 
The disclosed financial interest of the Investigator must be collected before Screening of the first 
participant, following study completion at the Investigator site and 1 year following overall study 
completion. The Investigator must promptly update this information if any relevant changes 
occur during this period. 
10.1.5. 
Informed Consent Process 
Before a participant’s participation in the study, it is the Investigator’s responsibility to obtain 
freely given consent, in writing, from the participant or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any study IMPs are administered. 
A legally acceptable representative is an individual or other body authorized under applicable 
law to consent, on behalf of a prospective participant, to the participant’s participation in the 
clinical study. An informed consent document that includes both information about the study and 
the consent form will be prepared and given to the participant. This document will contain all the 
elements required by the ICH E6 (R2) Guideline for GCP and any additional elements required 
by local regulations. The written ICF must be prepared in the local language(s) of the potential 
participant population. 
 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirements, and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) must be 
approved by the IRB prior to being provided to potential participants. 
 
The participant’s written informed consent (written or electronic) must be obtained prior to 
his/her participation in the study, and must be documented in the participant’s medical records, 
as required by applicable regulations. The ICF must be signed and personally dated by the 
participant or a legally acceptable representative, and by the person who conducted the informed 
consent discussion (not necessarily the Investigator). The signed ICF must be retained in 
accordance with institutional policy, and a copy of the signed consent form must be provided to 
the participant or legal representative. The date and time that informed consent was given must 
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Participants who are rescreened are required to sign a new ICF. 
10.1.6. 
Protection of Participant Identification and Confidentiality 
The Investigators and Insmed will preserve the confidentiality of all participants taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the participant’s anonymity is maintained. On the CRF or other 
documents submitted to Insmed, participants must be identified by a unique participant identifier 
as designated by Insmed. Documents that are not for submission to Insmed (eg, signed ICFs) 
must be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB direct 
access to review the participant’s original medical records for verification of study-related 
procedures and data. The Investigator is obligated to inform the participant that his/her study-
related records will be reviewed by the above-named representatives without violating the 
confidentiality of the participant. 
Participant names will not be supplied to Insmed. A participant number will be recorded in the 
CRF, and if the participant name appears on any other document (eg, laboratory report), it must 
be obliterated on the copy of the document to be supplied to Insmed. All records will be kept 
confidential to the extent provided by federal, state, and local laws. The participants will be 
informed that representatives of Insmed, IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
The Investigator will maintain a personal participant identification list (participant numbers with 
the corresponding participant names) to enable records to be identified. 
10.1.7. 
Committee Structure 
A Safety Review Committee (SRC) will be chartered. The SRC will comprise all Investigators 
and key members of the Insmed Study Team (including but not limited to Medical Monitor, 
Medical Director(s), Safety/Pharmacovigilance Physician, Statistician, Clinical Pharmacologist) 
and possible external expert consultants. The SRC will continuously monitor all available safety, 
PD and PK data for each participant and will obtain consensus regarding the safety of continuing 
the study, the next TPIP dose, and clinical care of the next participant. Expert consultants may be 
invited to review and interpret participant data. With any safety findings, a decision will be 
made, based on the review, as to whether enrollment in the study will be allowed to continue.  
Decisions regarding final database values for PD parameters may adjudicated by the SRC. 
10.1.8. 
Dissemination of Clinical Study Data 
The Insmed will provide study information for inclusion in national registries according to 
national/local regulatory requirements. 
Results of this study will be disclosed according to the relevant national regulatory requirements. 


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10.1.9. 
Data Quality Assurance 
The Investigator/investigational site will permit study-related monitoring, audits, IRB review and 
regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
10.1.9.1. Data Collection 
All data obtained for this study will be entered into a 21 CFR Part 11 compliant Data 
Management System provided by Insmed or its designee. These data will be recorded with an 
EDC system using CRFs. The Investigator will ensure the accuracy and completeness of the data 
reported to Insmed. All data entry, modification or deletion will be recorded automatically in an 
electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
Insmed to verify the proper transcription of data. Data reported in the CRFs must be consistent 
with and substantiated by the participant’s medical record and original source documents. The 
CRF data will be monitored by Insmed or designee. The final, completed CRF Casebook for 
each participant must be electronically signed and dated by the PI within the EDC system to 
signify that the Investigator has reviewed the CRF and certifies it to be complete and accurate. 
The Insmed will retain the final CRF data and audit trail. A copy of all completed CRFs will be 
provided to the Investigator. 
10.1.9.2. Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Insmed 
representative will review the protocol, CRF, Investigator Brochure, and any study related 
materials with the Investigators and their staff. During the study, the study Insmed monitor or its 
designee will visit the site regularly to check the completeness of participant records, the 
accuracy of entries on the CRFs, adherence to the protocol, adherence to ICH GCP and 
applicable regulatory requirements, the progress of enrollment, and also to ensure that study IMP 
is being stored, dispensed, and accounted for according to specifications. 
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the CRF entries. Participant confidentiality will be maintained by the 
study center. The study Insmed monitoring standards require full verification for the presence of 
informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the 
recording of primary activity and safety variables. Additional checks of the consistency of the 
source data with the CRFs are performed according to the study specific monitoring plan. 
10.1.9.3. Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB, and an auditor authorized by Insmed may 
request access to all source documents, CRFs, and other study documentation for onsite audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. Medical records and other study documents may 
be copied during audit or inspection provided that participant names are obliterated on the copies 
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If an inspection is requested by a regulatory authority, the Investigator will inform the study 
Insmed, immediately that this request has been made. 
10.1.9.4. Study Record Retention 
Study documents must be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents must be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the 
written consent of Insmed. It is the responsibility of Insmed to inform the Investigator when 
these documents no longer need to be retained. 
10.1.9.5. Source Documents 
Source documentation is the point of initial recording of a piece of data. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. Source documents 
provide evidence for the existence of the participant and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study Files and Materials 
Before the start of any study related procedures, all initial documents required by ICH GCP, 
Good Pharmacoepidemiology Practice, and applicable local regulations must be available in the 
relevant files maintained by Insmed (or delegate) and the Investigator. An Investigator Study File 
prepared by Insmed (or delegate), containing all applicable documents for use at the study site, 
will be made available to the Investigator before the start of the study. A list of personnel and 
organizations responsible for conduct of the study as well as the list of Investigator-delegates 
(eg, sub-investigator) at each site will be included in the Investigator Study File. The respective 
files will be kept and updated by Insmed (or delegate) and the Investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by Insmed’s study monitor (or delegate) to determine that all 
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The study may be audited by qualified delegates from Insmed or a competent regulatory 
authority. 
10.1.11. 
Use of Stored Samples and Data 
Stored samples will be labeled with study and participant information and secured with limited 
access and retained per protocol requirements and in accordance with the laboratory's operating 
procedures. Electronic data will be kept in password protected computers at the laboratory and 
then transferred to Insmed or CRO, as applicable, for data analysis. Samples and corresponding 
data will be tracked using the laboratory’s specimen tracking system. 
Prior Insmed and IRB approval are required before using or sharing study samples or data in 
ways not specifically specified in the study protocol during conduct of this study. 
Any loss or unanticipated destruction of samples (eg, freezer malfunction) or data (eg, loss of a 
data sheet with individually identifiable information) that violates or compromises the scientific 
integrity of study data must be reported to Insmed and the IRB. 
At any time, participants may inform the Investigator in writing that they do not wish to have 
their samples stored beyond the completion (termination) of the study. In this case, the 
Investigator will request that all known remaining samples be destroyed and report the 
disposition of samples to the requesting participants and the IRB. 
10.1.12. 
Disposition of Stored Samples and Data 
Participant samples will be secured with limited access and retained per protocol requirements 
and in accordance with the laboratory's operating procedures. Samples stored by the central 
laboratories will be labeled with the participant’s study identification information.  Data will be 
kept in password protected computers at the laboratory and then transferred to the vendor for 
data analysis.  Samples and corresponding data acquired will be tracked using the laboratory’s 
specimen tracking system. 
In the future, if other Investigators may wish to study these samples and/or data, they need to 
obtain Insmed approval and participant consent before any sharing of samples and/or data.  
Any loss or unanticipated destruction of samples (eg, due to freezer malfunction) or data (eg, 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to Insmed 
and the IRB 
Additionally, participants may withdraw authorization in writing to decline their sample storage 
for a period of up to 2 years beyond the duration of the study. In this case, the PI will request the 
destruction of all known remaining samples and report what was done to both the participant and 
to the IRB. This decision will not affect the individual’s participation in the study. 
10.1.13. 
Study and Site Start and Closure 
Before the start of the study at each study site, Insmed’s study monitor (or delegate) shall 
confirm adequacy of the facilities by study site visit or other acceptable methods. 
The Investigator may not enroll any participant into the study before Insmed has received written 
approval or a favorable opinion from the IRB for conducting the study and a formal meeting has 


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been conducted by Insmed’s study monitor (or delegate) to initiate the study. This meeting will 
include a detailed review of the study plan, and completion of the CRF. 
10.1.13.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first patient screened for participation in the study is considered the first act of 
recruitment. 
10.1.13.2. Study/Site Termination 
The Insmed or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of Insmed. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Insmed or investigator may include but are not 
limited to: 
For study termination: 
Discontinuation of further study IMP development 
For site termination: 
Failure of the investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, Insmed's procedures, or GCP guidelines 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, Insmed shall promptly inform the 
investigators, the IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and must assure appropriate participant therapy 
and/or follow-up. 
10.1.14. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by Insmed, before implementation. Amendments significantly affecting the 
safety of participants, the scope of the investigation, or the scientific quality of the study, require 
additional approval by the applicable regulatory authority(ies) and IRBs. Copies of the 
applicable written approvals must be filed in Insmed files and investigator site files. 
The requirements for approval must in no way prevent any immediate action from being taken 
by the Investigator or by Insmed in the interests of preserving the safety of all participants 
included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, the study Insmed or its agent must 
be notified and the applicable regulatory authority(ies)/IRBs must be informed as soon as 
possible. Any other regional reporting requirements must be adhered to. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/IRB approval, but the regulatory authority(ies)/IRBs must 


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be kept informed of such administrative changes in accordance with country specific 
requirements. 
10.1.15. 
Financing and Insurance 
10.1.15.1. Finances 
Prior to starting the study, the Investigator and/or institution will sign a clinical study agreement 
with Insmed. This agreement will include the financial information agreed upon by the parties. 
10.1.15.2. Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.15.3. Participant Reimbursement, Liability and Insurance 
The civil liability of the involved parties with respect to financial loss due to personal injury and 
other damage that may arise as a result of this study being conducted are governed by the 
applicable legal requirement(s). 
The Insmed will provide insurance to the Investigator if required by the applicable regulatory 
and legal requirement(s). 
If required by local law, participants taking part in this study will be insured against any injury 
caused by the study in accordance with the applicable regulatory and legal requirement(s). 
10.1.16. 
Publication Policy 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel of the study Insmed. 
Authorship will be determined by mutual agreement. For multi-center studies, it is mandatory 
that the first publication be based on data from all centers, analyzed as stipulated in the protocol 
by the study Insmed and statisticians, and not by the Investigators themselves. Investigators 
participating in multi center studies agree not to present data gathered from a single center or a 
small group of centers before the full, initial publication, unless formally agreed to by all other 
Investigators and study Insmed. 
The study Insmed must receive copies of any intended communication in advance of publication 
(at least 15 working days for an abstract or oral presentation and 45 working days for a journal 
submission). The study Insmed will review the communications for accuracy (thus avoiding 
potential discrepancies with submissions to regulatory authorities), verify that confidential 
information is not being inadvertently divulged, and to provide any relevant supplementary 
information. Authorship of communications arising from pooled data may include members from 
each of the contributing centers as well as the study Insmed personnel. 
At the conclusion of the study, after the data are analyzed, the results of study will be reported in 
a clinical study report. 
 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed by the local laboratory. If local laboratory results 
are used to make a study IMP decision or response evaluation, the results must be recorded. 
Protocol-specific clinical laboratory requirements for the inclusion or exclusion of participants 
are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 5: 
Protocol-Required Safety Laboratory Tests, INS1009-201 
Category 
Laboratory Parameters 
Clinical 
Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, 
phosphate, total bilirubin (with direct and indirect fractionation, if total 
bilirubin is elevated >2 ULN), alkaline phosphatase, LDH, AST, ALT, 
CPK, albumin, total protein, creatinine, urea-nitrogen, uric acid, estimated 
glomerular filtration rate  
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, leukocytes, 
differential blood count of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and platelets 
Coagulation 
PT, PTT, INR 
Serology 
HIV antibody, hepatitis B surface antigen [HBsAg], Hepatitis C virus 
antibody 
Pregnancy test 
Highly sensitive serum or urine hCG 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CO2 = carbon dioxide; CPK = creatine 
phosphokinase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin 
time; ULN = upper limit of normal 
Investigators must document their review of each laboratory safety report. 
 
 












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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
Contraceptive use by men and women of childbearing potential (WOCBP) must be consistent 
with local regulations regarding the methods of contraception for those participating in clinical 
studies. 
Highly effective contraception methods include true abstinence (refraining from heterosexual 
intercourse during the study); combined (estrogen and progestogen containing) or progestogen 
only hormonal contraception associated with inhibition of ovulation and supplemented with a 
double barrier (preferably male condom); intrauterine devices; intrauterine hormone-releasing 
systems; or vasectomized partner. 
 
 
 


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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Insmed clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than Drug-Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN and total 
bilirubin (TBL) ≥2×ULN at any point during the study irrespective of an increase in alkaline 
phosphatase (ALP). The elevations do not have to occur at the same time or within a specified 
time frame. 
Hy’s Law (HL) 
AST or ALT ≥3× ULN and TBL ≥2×ULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug. The elevations do not have to occur at the same time or within a specified 
time frame. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any participant who meets any of the following identification criteria in isolation or in 
combination: 
1. ALT ≥ 3xULN 
2. AST ≥ 3xULN 
3. TBL ≥ 2xULN 
The Investigator will review without delay each new laboratory report and if the identification 
criteria are met will: 
1. Notify Insmed representative  
2. Determine whether the participant meets PHL criteria (see DEFINITIONS of this 
Appendix) by reviewing laboratory reports from all previous visits 
3. Promptly enter the laboratory data into the laboratory CRF 


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FOLLOW-UP 
POTENTIAL HY’S LAW CRITERIA NOT MET 
1. If the participant does not meet PHL criteria the Investigator will: 
2. Inform Insmed representative that the participant has not met PHL criteria. 
3. Perform follow-up on subsequent laboratory results according to the guidance provided 
in the clinical study protocol 
POTENTIAL HY’S LAW CRITERIA MET 
If the patient does meet PHL criteria the Investigator will: 
• Notify Insmed representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
• Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or Baseline levels, or as long as medically indicated 
• Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
• Complete the 3 Liver CRF Modules as information becomes available 
• If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section must be followed for all cases where PHL criteria were met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than drug-induced liver injury caused 
by the IMP. The Insmed Medical Science Director and Global Safety Physician will also be 
involved in this review together with other participant matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
• If there is an agreed alternative explanation for the ALT or AST and TBL 
elevations, a determination of whether the alternative explanation is an AE will be 
made and subsequently whether the AE meets the criteria for a SAE 
• If the alternative explanation is not an AE, record the alternative explanation on 
the appropriate CRF 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow Insmed standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
•Report an SAE (report term ‘Hy’s Law’) according to Insmed standard processes. 


Treprostinil Palmitil Inhalation Powder (TPIP) 
Insmed Incorporated 
Clinical Trial Protocol INS1009-201 
Version 1, 02 NOV 2020 
 
Confidential 
Page 69 of 74 
 
• The ‘Medically Important’ serious criterion must be used if no other serious 
criteria apply 
• As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ must be assigned. 
If there is an unavoidable delay, of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review 
 
 
 










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Clinical Trial Protocol INS1009-201 
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Confidential 
Page 74 of 74 
 
11. 
REFERENCES 
 
Delcroix M, Howard L. Pulmonary arterial hypertension: the burden of disease and impact on 
quality of life. Eur Respir Rev. 2015;24(138):621-9. 
 
Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk 
Noordegraaf A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension 
of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): 
Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-
119. 
 
Hoeper MM, Ghofrani HA, Grunig E, Klose H, Olschewski H, Rosenkranz S. Pulmonary 
Hypertension. Dtsch Arztebl Int. 2017;114(5):73-84. 
 
McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galie N, Gibbs JS, Kim NH, 
Oudiz RJ, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll 
Cardiol. 2009;54(1 Suppl):S97-107. 
 
Orenitram Package Insert.  2019. Accessed on: 23 October 2020.  
https://www.orenitram.com/pdf/Orenitram Full Prescribing Information.pdf 
 
Remodulin Package Insert.  2018. Accessed on: 23 October 2020.  
https://www.remodulinpro.com/files/remodulin-pi.pdf 
 
Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis 
and clinical management. BMJ. 2018;360:j5492. 
 
Tyvaso Package Insert.  2017. Accessed on: 23 October 2020.  
https://www.tyvaso.com/hcp/pdf/Tyvaso-PI.pdf?v=102017 
 
US Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers.  2005. Accessed on: 23 Oct 2020.  
https://www.fda.gov/media/72309/download 
 
Vachiery JL, Naeije R. Treprostinil for pulmonary hypertension. Expert Rev Cardiovasc Ther. 
2004;2(2):183-91. 
 
 

SAP_001.pdf: 
Official Title: 
NCT Number: 
Document Date: 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation 
Powder in 
Participants with Pulmonary Arterial Hypertension 
NCT04791514 
SAP Version 1: 27 September 2022 


 
 
Insmed Incorporated 
Statistical Analysis Plan: INS1009-201 
 
23 September 2022 
 
 
 
 
1 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
An Open-Label Study to Assess the Safety, Pharmacokinetics, and 
Pharmacodynamics of Treprostinil Palmitil Inhalation Powder in 
Participants with Pulmonary Arterial Hypertension 
Study Number: INS1009-201 
IND Number: 147264 
EudraCT Number: 2022-000839-23 
 
 
Insmed Incorporated 
700 US Highway 202/206 
Bridgewater, NJ 08807-1704 
 
 
 
Version Number 
Amendment  
Date 
Statistical Analysis 
Plan 
Final 1.0 
 
23 September 2022 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Insmed Incorporated. The information 
is provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement. Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Insmed Incorporated. 
 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS......................................................................... 6 
2. 
INTRODUCTION .......................................................................................... 9 
3. 
STUDY OBJECTIVES AND ENDPOINTS .................................................. 9 
3.1. 
Primary Objective and Endpoints ................................................................... 9 
3.2. 
Secondary Objectives and Endpoints ............................................................. 9 
3.3. 
Exploratory Objectives and Endpoints ......................................................... 10 
3.4. 
Exploratory Objectives and Endpoints for the Optional Extended Use 
Treatment Period........................................................................................... 11 
4. 
STUDY DESIGN ......................................................................................... 11 
4.1. 
Summary of Study Design ............................................................................ 11 
4.2. 
Study Intervention/Treatment ....................................................................... 13 
4.2.1. 
Inpatient Treatment Period (Single Dose) .................................................... 13 
4.2.2. 
Optional Extended Use Treatment Period .................................................... 14 
4.3. 
Sample Size Determination .......................................................................... 14 
4.4. 
Randomization .............................................................................................. 14 
5. 
PLANNED ANALYSES .............................................................................. 15 
5.1. 
Interim Analyses ........................................................................................... 15 
5.2. 
Final Analyses .............................................................................................. 15 
5.3. 
Safety Review Committee Review ............................................................... 15 
6. 
ANALYSIS SETS ........................................................................................ 15 
6.1. 
Safety Analysis Set ....................................................................................... 15 
6.2. 
Pharmacokinetic Analysis Set ...................................................................... 15 
6.3. 
Pharmacodynamic Analysis Set ................................................................... 15 
6.4. 
Biomarker Analysis Set ................................................................................ 15 
7. 
GENERAL STATISTICAL CONSIDERATIONS ...................................... 16 
7.1. 
Baseline Definition ....................................................................................... 16 
7.2. 
Handling of Missing Data ............................................................................. 16 
7.2.1. 
Missing Start and Stop Dates for Prior and Concomitant Medication ......... 16 
7.2.2. 
Missing Start and Stop Dates for Adverse Events ........................................ 17 
7.3. 
Derived and Transformed Data .................................................................... 17 
7.3.1. 
Durations ....................................................................................................... 17 
7.3.2. 
Study Day ..................................................................................................... 17 
8. 
STUDY POPULATION SUMMARIES ...................................................... 17 
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8.1. 
Participants Disposition ................................................................................ 17 
8.2. 
Protocol Deviations ...................................................................................... 18 
8.3. 
Demographics, Baseline Characteristics, Medical History .......................... 18 
8.3.1. 
Demographics ............................................................................................... 18 
8.3.2. 
Medical History ............................................................................................ 18 
8.4. 
Medications and Treatments ......................................................................... 19 
8.4.1. 
Prior, Concomitant and Post Medications .................................................... 19 
8.4.2. 
Medical and Surgical Treatment Procedures ................................................ 19 
8.5. 
COVID-19 Impact ........................................................................................ 20 
9. 
SAFETY AND EFFICACY ......................................................................... 20 
9.1. 
Primary Endpoint .......................................................................................... 20 
9.2. 
Secondary Endpoints .................................................................................... 20 
9.2.1. 
Evaluation of Change in Pulmonary Vascular Resistance ........................... 20 
9.2.2. 
Evaluation of Pharmacokinetics of Treprostinil ........................................... 20 
9.3. 
Exploratory Objectives ................................................................................. 20 
9.3.1. 
Evaluation of Pharmacodynamics ................................................................ 20 
9.3.2. 
Evaluation of Selected Biomarker ................................................................ 21 
9.3.3. 
Evaluation of Changes in Selected Laboratory Parameter ........................... 21 
9.3.4. 
Evaluation of Pharmacokinetics of Treprostinil Palmitil ............................. 21 
9.3.5. 
Evaluation of Respiratory Gas Exchange ..................................................... 21 
9.3.6. 
Evaluation of TPIP on Parameters of Right Ventricular Function ............... 21 
9.3.7. 
Evaluation of TPIP on Pulmonary Vasculature and Blood Flow Parameters
21 
9.3.8. 
Evaluation of TPIP on Exercise Capacity (6MWD), Extended Use 
Treatment Only ............................................................................................. 21 
10. 
SAFETY ....................................................................................................... 22 
10.1. 
Exposure to Study Drug and Compliance .................................................... 22 
10.2. 
Adverse Events ............................................................................................. 22 
10.3. 
Deaths ........................................................................................................... 24 
10.4. 
Clinical Laboratory Evaluation ..................................................................... 24 
10.5. 
Vital Signs .................................................................................................... 24 
10.6. 
Physical Examination ................................................................................... 25 
10.7. 
Electrocardiograms ....................................................................................... 25 
10.8. 
Pregnancy ..................................................................................................... 25 
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11. 
PHARMACOKINETIC ANALYSIS ........................................................... 25 
11.1. 
Pharmacokinetic Sample Analysis ............................................................... 25 
11.2. 
Pharmacokinetic Sampling ........................................................................... 25 
11.3. 
Below the Limit of Quantification Values / Missing Values ....................... 25 
11.4. 
Pharmacokinetic Parameters ......................................................................... 25 
11.5. 
Pharmacokinetic Statistical Analysis ............................................................ 26 
12. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ............................ 27 
13. 
REFERENCES ............................................................................................. 27 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ...................................................................................... 6 
Table 2: 
TEAE Assignment in Case of Missing AE Start Date Elements .................. 23 
Table 3: 
Protocol-Required Safety Laboratory Tests ................................................. 24 
Table 4: 
PK Parameters to be determined ................................................................... 26 
 
LIST OF FIGURES 
Figure 1: 
Study Design, Participant Progression Through INS1009-201 Studya ........ 12 
Figure 2: 
Participant Progression Through the Optional Extended Use Treatment 
Period ............................................................................................................ 13 
 
 
 
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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
6MWD 
6-minute walk distance 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-inf 
area under the plasma concentration versus time curve from time zero to 
infinity 
AUC0-t 
area under the plasma concentration versus time curve from time zero to 
time of last quantifiable concentration 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BSA 
body surface area 
Cmax 
maximum (peak) plasma concentration of study drug 
CI 
cardiac index 
CL/F 
apparent total clearance of study drug from plasma after extravascular 
administration  
CO 
cardiac output 
CO2 
carbon dioxide 
CPK 
creatine phosphokinase 
CSR 
clinical study report 
CT 
computerized tomography 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EOT 
end of treatment 
ETCO2 
end tidal carbon dioxide concentration 
ETO2 
end tidal oxygen concentration 
EUT 
extended use treatment 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
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Abbreviation 
Term 
ICH 
International Council for Harmonisation 
IMP 
investigational medical product 
INR 
international normalized ratio 
LVEF 
left ventricular ejection fraction 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MVO2 
mixed venous oxygen saturation 
n 
number of participants 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary arterial pressure 
PCWP 
pulmonary capillary wedge pressure 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PTT 
partial thromboplastin time 
PVR 
pulmonary vascular resistance 
QD 
once daily 
RAP 
right atrial pressure 
RHC 
right heart catheter 
RVP 
right ventricular pressure 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SPO2 
arterial blood oxygen saturation 
SRC 
safety review committee 
t1/2 
elimination half life 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum (peak) plasma concentration following study drug 
administration 
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Abbreviation 
Term 
TP 
treprostinil palmitil 
TPIP 
dry powder for inhalation formulation of treprostinil palmitil 
TRE 
Treprostinil 
TVR 
tricuspid valve regurgitation 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution at terminal phase 
VCO2 
carbon dioxide production 
VE/VCO2 
minute ventilation-CO2 production ratio 
WHO 
World Health Organization 
 
 
 
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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to define the planned statistical 
analysis of the study data to be included in clinical study report (CSR). This SAP is 
written based  on study protocol INS1009-201 amendment 2, Version 3.0, dated 
03 Mar 2022. 
The reader is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for a participant to 
complete the participation in this study. 
The SAP is intended to be in agreement with the study protocol. However, the SAP may 
contain more details or other types of analyses (e.g., other endpoints). When differences 
exist in descriptions or explanations provided in the study protocol and this SAP, the 
SAP prevails; the differences will be explained in the CSR. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Primary Objective and Endpoints 
 
Objective 
Endpoint 
1. To evaluate the safety and tolerability 
of single doses of dry powder for 
inhalation formulation of treprostinil 
palmitil (TPIP) in participants with 
pulmonary arterial hypertension 
(PAH) 
x Frequency of treatment-emergent 
adverse events (TEAEs) 
 
3.2. 
Secondary Objectives and Endpoints 
 
Objective 
Endpoint 
1. To evaluate the effects of single doses 
of TPIP on pulmonary vascular 
resistance (PVR) in participants with 
PAH over the first 24 hours following 
administration 
x Change from Baseline in PVR at 8 
and 24 hours after TPIP 
administration 
2. To evaluate the pharmacokinetic (PK) 
of treprostinil (TRE) in participants 
with PAH 
x Cmax, tmax, AUCt1–t2, AUC0–inf, t1/2 of 
TRE in plasma 
 
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3.3. 
Exploratory Objectives and Endpoints 
 
Objective 
Endpoint 
1. To evaluate the pharmacodynamic 
(PD) effects of single doses of TPIP 
in participants with PAH over 24 
hours following administration 
x Change from Baseline in PVR, PAP, 
RVP, RAP, CO, oxygen 
consumption, MVO2, SpO2, heart 
rate, systemic blood pressure, 
hemoglobin, at selected timepoints 
after TPIP administration 
2. To evaluate the effect of single doses 
of TPIP on selected biomarkers in 
participants with PAH over 24 hours 
following administration 
x 
Change from Baseline in selected 
biomarker concentrations at 
selected time points after TPIP 
administration 
3. To evaluate changes in clinical 
laboratory parameters in participants 
with PAH after TPIP administration 
x Clinically relevant change from 
Baseline in hematology, coagulation, 
and clinical chemistry parameters 
(Section 10.2, Table 5 of study 
protocol) 
4. To evaluate the PK of treprostinil 
palmitil (TP) in participants with 
PAH 
 
To evaluate the PK of TRE in 
participants with PAH 
x Plasma PK parameters of TP, such as 
Cmax, tmax, AUCt1–t2, AUC0–inf, t1/2, 
CL/F and Vd/F 
x Plasma PK parameters of TRE, such 
as Cmax, tmax, AUCt1–t2, AUC0–inf, t1/2, 
CL/F and Vd/F 
5. To evaluate the effects of TPIP on 
resting respiratory gas exchange in 
participants with PAHa 
x Change from Baseline in respiratory 
rate, minute ventilation, VCO2, ETO2, 
ETCO2, SpO2 over 24 hours after 
TPIP administration 
6. To evaluate the effects of TPIP on 
parameters of right ventricular 
function in participants with PAH as 
measured by transthoracic 
echocardiogramb 
x Change from Baseline in LVEF, TVR 
maximum velocity, TAPSE, and end 
diastolic right ventricular volume at 2 
to 8 hours after TPIP administration 
7. To evaluate the effects of TPIP on 
pulmonary vasculature and blood 
flow parameters in participants with 
PAH as measured by pulmonary CT 
scanc 
x Change from Baseline in total blood 
volume, blood volume in vessels < 
5mm2 at 4 to 8 hours after TPIP 
administration 
a Respiratory gas exchange testing optional at Investigator discretion 
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b Echocardiogram optional at investigator discretion 
c Pulmonary CT scan optional at investigator discretion 
AUC0–inf = area under the concentration time curve from time zero to infinity; AUCt1-t2 = area under the 
concentration time curve from time zero to last sampling timepoint with measurable concentration; Cmax 
= maximum observed concentration after drug administration; CL/F = apparent total clearance; CO = 
cardiac output; CT = computerized tomography; ETCO2 = end tidal carbon dioxide concentration; 
ETO2 = end tidal oxygen concentration; LVEF = left ventricular ejection fraction; MVO2 = mixed 
venous oxygen saturation; PAP = pulmonary arterial pressure; RAP = right atrial pressure; RVP = right 
ventricular pressure; SpO2 = arterial blood oxygen saturation; TAPSE = tricuspid annular plane systolic 
excursion; TVR = tricuspid valve regurgitation; tmax = time of maximum observed concentration 
following drug administration; t1/2 = elimination half-life; Vd/F = apparent volume of distribution at 
terminal phase; VCO2 = carbon dioxide production 
 
3.4. 
Exploratory Objectives and Endpoints for the Optional 
Extended Use Treatment Period 
 
Objective 
Endpoint 
1. To evaluate the safety and tolerability 
of TPIP in participants with PAH 
x Frequency of TEAEs during extended 
use treatment (EUT) 
2. To assess the effect of TPIP on 
exercise capacity 
x Change from Baseline in 6MWD 
distance at EUT Baseline to EUT 
Week 16 
6MWD = 6-minute walk distance 
 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 2a, open label study to assess the safety, tolerability, PD effects and PK 
of TPIP administered to participants with PAH (approximately 6 to 10 evaluable 
participants are planned for the study). This is the first study of TPIP in participants with 
PAH. Each participant will receive a single dose of TPIP. The first participant will 
receive a dose containing 112.5 μg of TP. The TP dose level for each subsequent 
participant will be determined following review and adjudication of all available safety, 
PK, and PD data from the previous participant(s) by the safety review committee (SRC) 
(Section 1.3.2.1 of study protocol). 
This is a “proof of mechanism” study designed to investigate the following: 
1. The safety and tolerability of TPIP in participants with PAH; 
2. The relationship between the PK and PD effects of TPIP in participants with 
PAH, and 
 
 
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3. The duration of the PD effects of a single dose of TPIP in participants with 
PAH. 
The cardiopulmonary and overall functional status of patients with PAH can be labile 
and medical instability can develop quickly. The study is designed to provide maximal 
safety and minimal risk to participants. As such, there is considerable flexibility built 
into the protocol to allow Investigator discretion with the frequency, timing, and/or 
conduct of PD and PK assessments to ensure participant safety. Because the study 
requires an overnight inpatient treatment period, Institutional requirements for elective 
inpatient admissions, which may vary from site to site, will be followed. 
For individual participants, the study will consist of an outpatient screening period 
lasting up to 30 days. The inpatient treatment period will start on Study Day 1 and is 
expected to last overnight into Study Day 2. Outpatient PK sampling and safety follow-
up at 48 (± 4) hours post TPIP dose will extend into Study Day 3. A remote safety 
follow-up visit is scheduled for Study Day 30 (± 2 days). The 48 hour PK visit will also 
include safety assessments including electrocardiogram (ECG), clinical laboratory 
evaluations, vital signs, physical examination, and adverse event (AE) collection. 
An optional extended treatment period of 16 weeks will be available to participants who 
have completed the single-dose inpatient treatment period. There will be a second safety 
follow-up visit 30 days (± 3 days) after EUT Week 16 for participants who elect to enter 
the EUT period. If the initial remote safety follow-up visit overlaps with the start of the 
extended treatment period, the initial remote safety visit will be shortened and conducted 
just prior to administration of investigational medical product (IMP) in the extended 
treatment period. 
The procedures and assessments conducted at each study visit in the study are provided 
in Table 1 to 6 of the study protocol. Please refer to Figure 1 and Figure 2 for a 
schematic diagram of the study design. 
Figure 1: 
Study Design, Participant Progression Through INS1009-201 Studya 
 
h=hours; d=days 
a Does not include optional EUT period; the 30 day follow-up visit will be shortened and conducted just 
prior to administration of IMP in the extended treatment period if the visit overlaps with the start of the 
extended treatment period. 
 
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Figure 2: 
Participant Progression Through the Optional Extended Use 
Treatment Period 
 
a The 30 day follow-up visit from the single dose period will occur on EUT Day 1 if the visit 
overlaps with the start of the extended treatment period. 
b At the Investigator’s discretion, participants may undergo a study drug taper for up to 2 weeks 
after the Week 16 visit. 
c The follow-up telephone call or visit will be 30 days after the Week 16 visit. QD = once daily; EOT = 
end of treatment 
 
4.2. 
Study Intervention/Treatment 
4.2.1. 
Inpatient Treatment Period (Single Dose) 
A single dose of TPIP will be used in the inpatient treatment period, as listed below. A 
dose may consist of a single capsule or of multiple capsules administered in succession. 
 
 
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The study drug will be administered by oral inhalation using a Plastiape capsule-based 
Dry Powder Inhaler (RS 01 Mod 7). 
Name of 
Treatment 
Dose 
Supplied 
Formulation 
Route and 
Frequency of 
Administration 
TPIP 
One or more single 
actuation capsules 
Single actuation 
capsules containing 
112.5 μg TP per 7.5 
mg powder 
Inhalation; single 
dose after Baseline 
assessments 
TPIP 
One or two single 
actuation capsules 
(80 μg, 160 μg, 240 μg, 
320 μg, 
400 μg, 480 μg, or 640 μg) 
Dry powder single 
actuation capsules 
containing 
80 μg, 160 μg, or 
320 μg 
Inhalation; single 
dose after Baseline 
assessments 
 
4.2.2. 
Optional Extended Use Treatment Period 
The IMP used in the EUT period will be capsules containing 1 of 3 dosage strengths of 
TPIP (80 μg, 160 μg, or 320 μg). IMP should be taken around the same time every day. 
Administration of IMP will be via inhalational dry powder packaged in single actuation 
capsules. One or 2 capsules will be administered for each dose. Administration of 2 
capsules should be done sequentially. 
Each TPIP capsule contains 8 mg, 16 mg, or 32 mg of dry powder containing 80 μg, 160 
μg, or 320 μg of the TP prodrug, respectively. 
The study drug will be administered by oral inhalation using a Plastiape capsule-based 
Dry Powder Inhaler (RS 01 Mod 7). 
Name of 
Treatment 
Dose 
Supplied 
Formulation 
Route of 
Administration 
TPIP 
One or two 
single actuation 
capsules 
(80 μg, 160 μg, 240 μg, 
320 μg, 400 μg, 480 μg 
or 640 μg QD) 
Dry powder single 
actuation capsules 
containing 
80 μg, 160 μg, or  
320 μg 
Inhalation (QD) 
 
4.3. 
Sample Size Determination 
The sample size for this study is not based on statistical power calculations. The planned 
number of evaluable participants to complete the study is approximately 6-10. 
4.4. 
Randomization 
There is no randomization in this study. 
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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
No interim analysis is planned for this study. 
5.2. 
Final Analyses 
Final analysis is planned to be conducted after database lock of the study. 
The study was terminated by Insmed. At time of study termination only 1 subject was 
enrolled into the study and treated. Therefore the collected study data will only be listed, 
there will be no summaries. 
The sections below describing the planned statistical analysis, which was planned for the 
full study population according to study protocol. 
5.3. 
Safety Review Committee Review 
All available safety, PK, and PD data from each participant will be evaluated by the SRC 
prior to the next participant in order to determine the value of proceeding with the study 
and the TPIP dose for each subsequent participant. 
6. 
ANALYSIS SETS 
6.1. 
Safety Analysis Set 
All participants who receive a single dose of TPIP will be considered evaluable for 
safety and included in the safety population. 
A separate safety population for participants of EUT will be determined. 
6.2. 
Pharmacokinetic Analysis Set 
All participants who receive a single dose of TPIP and have at least one measurable 
post-dose plasma TP/TRE concentration will be considered evaluable for PK and 
included in the PK population. 
6.3. 
Pharmacodynamic Analysis Set 
All participants who receive a single dose of TPIP and have a baseline datapoint and at 
least one measurable post-dose PD datapoint will be considered evaluable for PD and 
included in the PD population. 
6.4. 
Biomarker Analysis Set 
All participants who receive a single dose of TPIP and have at least one measurable 
post-dose biomarker datapoint will be considered evaluable for biomarkers and included 
in the biomarker population. 
A separate biomarker population for participants of EUT will be determined. 
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7. 
GENERAL STATISTICAL CONSIDERATIONS 
Due to the limited number of participants in the study and planned dose escalation after 
each participant, the observed study data will be presented in by-participant listings. By-
participant listings will comprise of all observed data, e.g., single-dose inpatient 
treatment period and EUT. For selected data points, summaries will be provided only for 
an overall group. If three or more participants have received the same dose of study 
drug, summary tables will be provided for those dose group(s). 
All statistical analyses will be conducted using statistical analysis system SAS® 
Version  9.4 or higher (SAS Institute, Cary, NC). 
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), 
median, minimum, maximum, 1st quartile and 3rd quartile (if required). Summaries of 
continuous variables that have some values recorded using approximate values (e.g., < 
or >) will use the numeric part of the value in calculations. Listings will present the data 
in its original format. 
Categorical variables will be tabulated by counts and by percentage of participants in 
corresponding categories. Footnotes will specify the basis for the percentages. 
Data from unscheduled visits will not be used in summaries, except for the derivation of 
baseline. 
Listings corresponding to all summaries in this section will be provided. Listings will 
show data from scheduled and unscheduled visits. 
7.1. 
Baseline Definition 
Baseline for single-dose inpatient treatment period will be defined as the last non-
missing assessment (including repeated and unscheduled assessments) before the first 
study drug administration, unless otherwise specified. 
Baseline for EUT will be defined as the assessment at EUT Day 1 visit. 
The start of EUT period is defined as the date of EUT Day 1 visit. 
Change from baseline will be calculated as: 
x Change from baseline = post baseline value – baseline value. 
7.2. 
Handling of Missing Data 
The imputations described in the following sections will be performed after all efforts 
fail to obtain the data. 
All other data will be reported on available values and no imputations will be performed. 
7.2.1. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
The rules to categorize medications to 'Prior' or 'Concomitant' are described in Section 
8.4.1. Missing or partially missing start or stop dates will be not imputed. 
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7.2.2. 
Missing Start and Stop Dates for Adverse Events 
The rules to categorize AEs to 'TEAE' or 'non-TEAE' are described in Section 10.2. 
Missing or partially missing start or stop dates will be not imputed. 
7.3. 
Derived and Transformed Data 
7.3.1. 
Durations 
A duration between one date (date1) and another later date (date2) is calculated using 
the following formula: 
x Duration (days) = date2 – date1 + 1 
x Duration (weeks) = duration (days) / 7. 
7.3.2. 
Study Day 
Study Day is calculated as date of event minus the date of first exposure to study drug 
plus one (1) if the date of event is on or after the date of first exposure to study drug. 
If the date of event is before the date of first exposure to study drug, the Study Day will 
have negative values and is calculated as (date of event minus the date of first exposure 
to study drug). 
Consequently, there is no Study Day zero (0). 
8. 
STUDY POPULATION SUMMARIES 
The safety analysis set will be used for all study population summaries unless otherwise 
stated. 
8.1. 
Participants Disposition 
For participants screened (participants who have signed the informed consent) the 
following will be summarized for overall (if applicable also by dose group): 
x the number of participants who are screened; 
x the number of participants who continue into the study (number of participants 
who are not screen failure); 
x the number of participants who failed screening and the reasons for screen 
failure; 
x the number of participants who are treated in single-dose inpatient treatment 
period; 
x the number of participants who completed the study (single-dose inpatient 
treatment period); 
x the number of participants who discontinued treatment and the reason for 
discontinuation (single-dose inpatient treatment period); 
x the number of participants who discontinued from study and the reason for 
discontinuation (single-dose inpatient treatment period); 
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x the number of participants in EUT; 
x the number of participants who completed the EUT; 
x the number of participants who discontinued treatment in EUT and the reason for 
discontinuation; 
x the number of participants who discontinued from EUT and the reason for 
discontinuation; 
x the number of participants in each analysis population. 
A separate summary (if applicable) will be provided for subjects screened for EUT. 
Participant disposition data will also be presented in a by-participant listing for screened 
participants. 
8.2. 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (referred to as a major 
deviation) is a subset of protocol deviations that leads to a participant being discontinued 
from the study, or significantly affects the participant’s rights, safety, or well-being or 
the completeness, accuracy, and reliability of the study data. An important deviation can 
include nonadherence to inclusion or exclusion criteria or nonadherence to Food and 
Drug Administration regulations or International Council for Harmonisation (ICH) 
E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The investigator will be notified in writing by the monitor of 
deviations. The Institutional Review Board should be notified of all protocol deviations, 
if appropriate, in a timely manner. 
All protocol deviations will be presented in a by-participant listing, including the 
categorization of the deviation as major or not. 
8.3. 
Demographics, Baseline Characteristics, Medical History 
8.3.1. 
Demographics 
The demographic characteristics consist of age (years), sex, race, and ethnicity. Baseline 
characteristics were observed in terms of screening weight (kg), height (cm), body mass 
index (BMI) (kg/m2), body surface area (BSA) (m2), and tobacco use. 
Participant demographic and baseline characteristics will be summarized for overall 
treatment group (if applicable also by dose group) and presented in a by-participant 
listing. 
A separate summary (if applicable) and listing will be provided for safety analysis set of 
EUT. 
8.3.2. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 25.0). 
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Medical history will be summarized by system organ class (SOC) and preferred term 
(PT) for overall treatment group (if applicable also by dose group) and presented in a 
by-participant listing. 
8.4. 
Medications and Treatments 
8.4.1. 
Prior, Concomitant and Post Medications 
Information regarding prior medications taken by the participant within the 30 days 
before signing the informed consent form (ICF) will be recorded in the participants 
electronic case report form (eCRF). 
Any concomitant medication deemed necessary for the welfare of the participant during 
the study may be given at the discretion of the investigator. If a concomitant medication 
is taken, except for those specified in the protocol, a joint decision will be made by the 
investigator and the sponsor to continue or discontinue the participant based on the time 
the medication was administered, its pharmacology and PK, and whether the use of the 
medication will compromise the safety of the participant or the interpretation of the data. 
The investigator is responsible for ensuring that details regarding the medication are 
adequately recorded in the eCRF. 
Prior, concomitant and post medications will be coded using the latest version of the 
World Health Organization (WHO) Drug Dictionary (202203). 
Concomitant medications are those medications taken on or after the first dose of study 
drug, i.e., the end date is on or after the date of first study drug dosing (but before 30 
days after last dose of study drug) or ongoing. If the end date of a medication is partially 
missing, and the possible interval for the end date includes the date of first study drug 
dosing or the date of 30 days after last dose of study drug dosing, the medication is 
considered 'Concomitant'. 
Post medications are those medications taken on or after the date of 30 days after last 
dose of study drug, i.e., the start date is on or after 30 days of last study drug dosing. 
Prior medications are those medications taken before the first dose of study drug. A 
medication that starts prior to first dose of study drug but continues after the first dose of 
study drug is classified both in prior and concomitant medications. If the medication 
continues after the date of 30 days after last study drug dosing, the medication will be 
also classified as ‘Post’. A medication is classified as 'Prior' if the eCRF question 
'Started prior to study drug' is answered ‘Yes’. 
All prior, concomitant and post medications will be summarized for overall treatment 
group (if applicable also by dose group) and presented in a by-participant listing. 
8.4.2. 
Medical and Surgical Treatment Procedures 
All medical and surgical treatment procedures will be coded using MedDRA, Version 
25.0. All medical and surgical treatment procedures will be presented in a by-participant 
listing. 
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8.5. 
COVID-19 Impact 
Potential COVID-19 impact is captured in the eCRF and will be summarized and listed 
as part of respective summaries or by-participant listings. 
Disposition summary and listing will include: 
x Screen failure related to COVID-19; 
x Early termination of study related to COVID-19. 
AE overview table and listings will include: 
x AEs that fall into the category of COVID-19 related. 
Listing of protocol deviations will include: 
x Protocol deviations due to COVID-19. 
9. 
SAFETY AND EFFICACY 
9.1. 
Primary Endpoint 
The analysis of primary endpoint in terms of frequency of TEAEs will be described in 
Sections 10.2 to 10.3 of this SAP. 
9.2. 
Secondary Endpoints 
9.2.1. 
Evaluation of Change in Pulmonary Vascular Resistance 
PVR and the change from baseline in PVR at 8 and 24 hours after TPIP administration 
in single-dose inpatient treatment period will be summarized by dose group (if 
applicable) for the PD population. All measurements of PVR will be included in a by-
participant listing. 
9.2.2. 
Evaluation of Pharmacokinetics of Treprostinil 
The analysis of TRE plasma PK parameter of Cmax, tmax, AUCt1–t2, AUC0–inf, t1/2 will be 
described in Section 11. 
9.3. 
Exploratory Objectives 
9.3.1. 
Evaluation of Pharmacodynamics 
PD assessments of PAP, RVP, RAP, CO, oxygen consumption, MVO2, SpO2, (from 
right heart catheter (RHC)), heart rate, systemic blood pressure, hemoglobin, pulmonary 
capillary wedge pressure (PCWP), cardiac index (CI) and changes from baseline at 8 
and 24 hours after TPIP administration in single-dose inpatient treatment period will be 
summarized by dose group (if applicable) for the PD population. In a by-participant 
listing all observed time points together with their changes at 8 and 24 hours after TPIP 
administration will be listed. 
Individual profiles using planned sampling times will be provided for PD assessments 
(all participant profiles of one parameter will be shown in one plot, [spaghetti plot]). 
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9.3.2. 
Evaluation of Selected Biomarker 
Biomarker N-terminal (NT)-pro hormone brain natriuretic peptide (NT-pro-BNP) and 
changes from baseline at 4 and 8 hours after TPIP administration in single-dose inpatient 
treatment period will be summarized by dose group (if applicable) for the biomarker 
population. In a by-participant listing all observed time points together with their 
changes at 4 and 8 hours after TPIP administration will be listed. 
A separate summary (if applicable) and listing will be provided for biomarker analysis 
set of EUT. 
9.3.3. 
Evaluation of Changes in Selected Laboratory Parameter 
The analysis of relevant changes in selected laboratory parameter will be described in 
Section 10.4. 
9.3.4. 
Evaluation of Pharmacokinetics of Treprostinil Palmitil 
The analysis of TP plasma PK parameter of Cmax, tmax, AUCt1–t2, AUC0–inf, t1/2, CL/F and 
Vd/F will be described in Section 11. 
9.3.5. 
Evaluation of Respiratory Gas Exchange 
Respiratory gas exchange parameter of minute ventilation, VCO2, ETCO2, SpO2 (from 
respiratory gas exchange), oxygen pulse, oxygen consumption, heart rate, minute 
ventilation-CO2 production ratio (VE/VCO2) and its changes over 24 hours after TPIP 
administration in single-dose inpatient treatment period will be summarized by dose 
group (if applicable) and presented in a by-participant listing for the safety population. 
9.3.6. 
Evaluation of TPIP on Parameters of Right Ventricular Function 
Observed values of LVEF, TVR maximum velocity, TAPSE, and end diastolic right 
ventricular volume (indexed to BSA) and their changes from baseline at 2 to 8 hours 
after TPIP administration in single-dose inpatient treatment period will be summarized 
by dose group (if applicable) and presented in a by-participant listing for the safety 
population. 
9.3.7. 
Evaluation of TPIP on Pulmonary Vasculature and Blood Flow 
Parameters 
Pulmonary vasculature and blood flow parameters observed by a pulmonary CT scan for 
total blood volume, blood volume in vessels < 5mm2 and their changes from baseline at 
4 to 8 hours after TPIP administration in single-dose inpatient treatment period will be 
summarized by dose group (if applicable) and presented in a by-participant listing for 
the safety population. 
9.3.8. 
Evaluation of TPIP on Exercise Capacity (6MWD), Extended Use 
Treatment Only 
Observed values for 6MWD and the change in 6MWD from Baseline EUT to EUT 
Week 16 will be summarized by dose group (if applicable) for the safety population. A 
by-participant listing, using the same analysis population, will present the observed 
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values of single-dose inpatient treatment period and all observed values and its changes 
of EUT. 
10. 
SAFETY 
Unless otherwise stated, the safety population will be used for summaries and listings of 
safety variables. 
10.1. 
Exposure to Study Drug and Compliance 
As there is only one study drug administration in single-dose inpatient treatment period 
under direct observation of site personnel, an administration of study drug as planned 
will be assumed for this period. 
The total exposure to study drug in EUT period will be calculated. The duration of EUT 
period will be calculated as described in Section 7.3.1. The start date duration of 
exposure in EUT will be the date of first dispensed study drug in EUT, the end date of 
EUT for duration of exposure will be the date of last study drug returned in EUT or the 
date of discontinuation of EUT (whatever occurs first).Compliance to intake of study 
drug will not be calculated and listed. 
The exposure will be presented in a by-participant listing (study drug dosing date/time, 
date/time of discharge from hospital in single-dose inpatient treatment period, length of 
EUT period, total dose in EUT period) for the safety population. 
10.2. 
Adverse Events  
An AE is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. All AEs will be captured on the 
eCRF. The AE verbatim descriptions (investigator terms from the eCRF) will be 
classified into standardized medical terminology using MedDRA. AEs will be coded to 
primary SOC and PT using MedDRA, Version 25.0 or higher. 
TEAEs are those AEs that occurred on or after the date/time of first study drug dosing 
and up to (and including) Study Day 30 follow-up visit or Study Day 30 follow-up of 
EUT for participants attending the EUT. 
Where AE start dates are missing or partially missing, AEs will be assumed to be 
treatment-emergent, except if the partial start dates or the AE end date indicate that the 
AE started before the study drug dosing (see  
 
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Table 2). 
 
 
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Table 2: 
TEAE Assignment in Case of Missing AE Start Date Elements 
Missing elements 
of AE start 
Rule 
 
Regardless of any missing information for AE start: 
AE end date < first study drug dosing date 
non-TEAE 
Otherwise (i.e., if AE end date ≥ first study drug dosing date) 
 
- 
all 
 
TEAE 
- 
day and 
month 
AE start year ≥ first study drug dosing year 
TEAE 
AE start year < first study drug dosing year 
non-TEAE 
- 
day 
AE start month / year ≥ first study drug dosing 
month / year 
TEAE 
AE start month / year < first study drug dosing 
month / year 
non-TEAE 
 
Duration of AEs will be calculated in days (see Section 7.3.1). If date of onset or end 
date of event is not complete, duration will be set to missing. 
An AE overview table for overall treatment group (if applicable also by dose group) will 
include number and percentage of participants and number of events with: 
x AE; 
x TEAE; 
x Maximum severity of TEAE by participant; 
x Treatment-related TEAE; 
x Serious TEAE; 
x Treatment-related Serious TEAE; 
x TEAE leading to withdrawal of study drug, based on end of treatment eCRF; 
x TEAE leading to withdrawal from study, based on end of study eCRF; 
x TEAE resulting in death; 
x AE related to COVID-19; 
x TEAE related to COVID-19. 
The overview table will be given for the whole study period, single-dose inpatient 
treatment period and EUT. The start of EUT will be the date of EUT Day 1. 
A frequency table for overall treatment group (if applicable also by dose group) 
displaying TEAEs by SOC and PT will be provided. The summary will be ordered by 
descending number of participants with that SOC, the same is PT within each SOC. If 
more than one SOC is affected by the same number of participants, those SOC will be 
ordered alphabetically, the same is for PTs with the same SOC. The summary table will 
be given for the whole study period, single-dose inpatient treatment period and EUT. 
All AEs . The listing will include all data collected for AEs, including a flag indicating 
treatment-emergency, onset day in relation to study drug dosing, duration of AE, and 
assignment of AE to single-dose inpatient treatment period or EUT. 
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10.3. 
Deaths 
A by-participant listing of all AEs resulting in death will be provided. 
10.4. 
Clinical Laboratory Evaluation 
Laboratory test results and their changes from baseline (for numerical outcomes, if 
applicable) for hematology, clinical chemistry, coagulation, and serology tests will be 
summarized by time point. 
All laboratory results and changes from baseline will be presented in a by-participant 
listing. 
Table 3: 
Protocol-Required Safety Laboratory Tests 
Category 
Laboratory Parameters 
Hematology 
Hemoglobin, erythrocytes, hematocrit, MCH, MCV, MCHC, 
leukocytes, differential blood count of neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, and platelets 
Clinical Chemistry 
Sodium, chloride, potassium, CO2, magnesium, calcium, glucose, 
phosphate, total bilirubin (with direct and indirect fractionation, if 
total bilirubin is elevated >2 ULN), alkaline phosphatase, LDH, 
AST, ALT, CPK, albumin, total protein, creatinine, urea-nitrogen, 
uric acid, and estimated glomerular filtration rate 
Coagulation 
Prothrombin time, PTT, INR 
Serology 
HIV antibody, HBsAg, hepatitis C virus antibody 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CO2 = carbon dioxide; CPK = 
creatine phosphokinase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; 
HBsAg  = hepatitis B surface antigen; INR = international normalized ratio; LDH = lactate 
dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = mean corpuscular volume; PTT = partial thromboplastin time; ULN = upper limit 
of normal 
10.5. 
Vital Signs 
Heart rate, respiratory rate, systolic and diastolic blood pressure, body temperature, 
mean arterial pressure, and oxygen saturation will be collected at protocol specified 
visits and time points in single-dose inpatient treatment period and EUT. Measured 
values together with changes from baseline will be summarized by descriptive statistics 
by time point and by dose group (if applicable) and presented in a by-participant listing. 
A separate summary (if applicable) and listing will be provided for safety analysis set of 
EUT. 
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10.6. 
Physical Examination 
Any abnormalities noticed by investigator during the physical examination at screening 
will be recorded in the medical history, or as an AE if occurred or worsens after ICF was 
signed. 
Dates of physical examination will not be listed. 
10.7. 
Electrocardiograms 
The results of overall investigator 12-lead ECG interpretation will be summarized by 
time point and by dose group (if applicable) and presented in a by-participant listing. 
10.8. 
Pregnancy 
Pregnancy results will be listed for all participants with outcome. 
11. 
PHARMACOKINETIC ANALYSIS 
11.1. 
Pharmacokinetic Sample Analysis 
PK samples will be analyzed using a validated liquid chromatography coupled with 
tandem mass spectrometry assay for TRE and TP in human plasma. Assay results and 
validation details will be provided in a separate bioanalytical report. 
11.2. 
Pharmacokinetic Sampling 
Blood samples for PK analysis of TRE and TP will be collected at pre-dose, 30min, 
60min, 2, 4, 8, 24, and 48h after dosing with TPIP in single-dose inpatient treatment 
period. 
For the PK sampling, a window of ± 10min will be allowed for sample collection at 
30min, 60min, at 2h a window of ± 20min, at 4h a window of ± 1h, at 8 and 24h a 
window of ± 2h, and a window of ± 4h will be allowed at 48h planned sampling time. 
Samples that are collected outside these windows will be logged as protocol deviations, 
but it is anticipated that PK data will still be used for PK parameter derivation. 
11.3. 
Below the Limit of Quantification Values / Missing Values 
For PK parameter calculations, pre-dose below the limit of quantification (BLQ) data 
will be treated as zero. All post-dose values BLQ will be considered as “missing”. For 
descriptive statistical summaries and graphing, BLQ data will be considered as zero. 
11.4. 
Pharmacokinetic Parameters 
PK parameters will be derived from plasma concentrations of TRE and TP using 
noncompartmental methods with Phoenix WinNonlin (Certara USA Inc., Princeton, 
New Jersey) Version 8.4 or higher. This derivation will be done at Parexel. The 
following plasma PK parameters will be calculated as endpoints for TRE and TP using 
actual sampling times, as shown in Table 4. 
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Table 4: 
PK Parameters to be determined 
Parameter 
Description 
Cmax 
Maximum observed plasma concentration of study drug, obtained 
directly from the concentration-time data 
tmax 
Time to maximum observed plasma concentration, obtained directly from 
the concentration-time data 
AUC0-t 
Area under the plasma concentration versus time curve (AUC) from time 
0 to the last quantifiable concentration, calculated using linear- up/log-
down method 
AUC0-inf 
AUC from time 0 extrapolated to infinity 
t1/2 
Elimination half-life which will be estimated by linear regression of 
concentration versus time data presented in a log-linear scale. A 
minimum of 3 data points in the elimination phase, not including Cmax, 
will be used for the calculation. The λz will not be estimated if r-squared 
is less than 0.8. 
CL/F 
Apparent total clearance of study drug from plasma after extravascular 
administration, calculated from;  
               CL/F = 
Dose
AUC0-inf 
 
Vd/F 
Apparent volume of distribution at terminal phase, calculated from; 
                                        CL/F/ Oz 
The PK parameters for each participant will be determined as data permit and as 
appropriate. 
11.5. 
Pharmacokinetic Statistical Analysis 
Plasma concentrations of TRE and TP will be presented in a by-participant listing for the 
PK analysis set. 
Plasma concentration versus time profiles based on actual sampling times for each 
participant will be presented graphically at linear and log scale. 
PK parameters for TRE and TP will be presented in a by-participant listing for the PK 
analysis set. 
 
 
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12. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
 
Data for ETO2, as a parameter of respiratory gas exchange, are not covered by eCRF nor 
available in any other data source. Therefore those data will be not part of any summary 
nor at any by-participant listing. 
13. 
REFERENCES 
1) International Council for Harmonisation (ICH) E6 (R2) GCP: Integrated Addendum 
to ICH E6 (R1) Guidance for Industry, published in the Federal Register (83 Federal 
Register 8882 [2018]) (https://www.fda.gov/media/93884/download.) 
2) Protocol INS1009-201: A Phase 2a, An Open-Label Single Dose Study to Assess the 
Safety, Pharmacokinetics, and Pharmacodynamics of Treprostinil Palmitil Inhalation 
Powder in Participants with Pulmonary Arterial Hypertension, Version 1.0, 02 Nov 
2020 
3) Protocol INS1009-201: A Phase 2a, An Open-Label Single Dose Study to Assess the 
Safety, Pharmacokinetics, and Pharmacodynamics of Treprostinil Palmitil Inhalation 
Powder in Participants with Pulmonary Arterial Hypertension, Version 2.0, 
Amendment 1, 30 Sep 2021 
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