Clinical trial NCT04456998
Conditions: Pulmonary Artery Hypertension
Keywords: seralutinib
Sponsor: GB002, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.
Start date: 2020-11-12; Completion date: 2022-11-01
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective for this trial is to determine the effect of GB002 (seralutinib) on improving pulmonary hemodynamics in subjects with World Health Organization (WHO) Group 1 PAH who are Functional Class (FC) II and III. The secondary objective for this trial is to determine the effect of GB002 (seralutinib) on improving exercise capacity in this population.

Detailed description:

Arms: arm 1: GB002 (seralutinib) inhaled orally twice per day (BID) for 24 weeks arm 2: Placebo inhaled orally BID for 24 weeks
Interventions: intervention 1: GB002 (seralutinib) intervention 2: Placebo intervention 3: Generic Dry Powder Inhaler
Intervention descriptions: intervention 1: Capsule containing GB002 (seralutinib) intervention 2: Matching capsule containing placebo intervention 3: Generic dry powder inhaler for GB002 (seralutinib) or placebo delivery

Protocol documents:
Prot_000.pdf: 
GB002 
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Confidential 
 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of GB002, Inc. Acceptance of this document 
constitutes agreement by the recipient that no previously unpublished information contained herein will be 
published or disclosed without the prior written approval of GB002, Inc. The following exceptions may occur 
under the condition that the party has agreed to keep this information confidential: 1) disclosure of information 
to the extent necessary to obtain informed consent, 2) disclosure of the document to study personnel under your 
supervision who need to know the contents for conducting the study, and 3) disclosure of the document to 
appropriate Institutional Review Boards (IRBs)/Independent Ethics Committees (IEC). The foregoing shall not 
apply to disclosure required by governmental regulations or laws; however, GB002, Inc. shall be promptly 
notified of any such disclosure. 
Protocol Title:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Multi-Center Clinical Study to Evaluate the Efficacy and 
Safety of Oral Inhalation of GB002 for the Treatment of 
WHO Group 1 Pulmonary Arterial Hypertension (PAH) 
Short Title: 
GB002 in Adult Subjects with PAH 
Protocol Number:  
GB002-2101  
Investigational 
Product:  
GB002 (oral inhalation) 
Study Phase:  
Phase 2 
Sponsor Name: 
GB002, Inc. 
Legal Registered 
Address: 
3013 Science Park Road, Suite 200 
San Diego, CA 92121, USA 
Regulatory Agency 
Identifier Number(s): 
 
 
Version: 
4.0.0   
Approval Date: 
18 November 2021 
 
 
 
 
 




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INVESTIGATOR AGREEMENT 
Protocol Title:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Multi-Center Clinical Study to Evaluate the Efficacy and 
Safety of Oral Inhalation of GB002 for the Treatment of 
WHO Group 1 Pulmonary Arterial Hypertension (PAH) 
Protocol Number:  
GB002-2101, v4.0.0 
 
 
I have read this protocol and agree to conduct this study in accordance with ethical principles as 
outlined in the International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice, any applicable laws and requirements and any additional conditions mandated by a 
regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I acknowledge that I am responsible for the overall study conduct and I agree to personally 
conduct or supervise the described clinical study. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of GB002, Inc. 
 
 
 
 
 
Signature 
 
 
 
Name of Investigator 
 
Date 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Global 
Version 
number and 
Date 
Region #1 
(UK) 
Version 
Number and 
Date 
Region #2 
(Spain) 
Version 
Number and 
Date 
Region #3 
(France) 
Version 
Number and 
Date 
Region #4 
(Germany) 
Version 
Number and 
Date 
Region #5 
(Canada) 
Version 
Number and 
Date 
Region #6 
(Czech 
Republic) 
Version 
Number and 
Date 
Original 
Protocol, 
Global 
v1.0.0, 10 
April 2020 
Region-
specific, 
v1.1.0, 
15 June 
2020 
NA 
NA 
NA 
NA 
NA 
Global 
v2.0.0, 
18 June 
2020 
Region-
specific, 
v2.3.0, 
08 October 
2020 
Region-
specific, 
v2.1.0, 
06 August 
2020 
Region-
specific, 
v2.2.0, 08 
October 
2020 
Region-
specific, 
v2.4.0, 13 
October 
2020 
Region-
specific, 
v2.5.0, 19 
October 
2020 
Region-
specific, 
v2.6.0, 04 
December 
2020 
Global 
v2.0.0, 
18 June 
2020 
NA 
NA 
NA 
Region-
specific, 
v2.4.1, 24 
November 
2020 
 Region-
specific 
v.2.5.1, 18
December 
2020 
NA 
Global 
v3.0.0, 18 
December 
2020 
NA 
NA 
NA 
NA 
NA 
NA 
Global 
v3.0.1, 15 
January 
2021 
NA 
NA 
NA 
NA 
NA 
NA 
Global 
v4.0.0, 18 
November 
2021 
NA 
NA 
NA 
NA 
NA 
NA 
Amendment 4 (v4.0.0; 18 November 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment from v3.0.1 to v4.0.0 is to update the requirements 
relating to concomitant medications based on recent results from the drug-drug interaction study 
 and the human ADME study
.  
Additional minor changes have been made to the protocol which are summarized below. 








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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Study Scheme .............................................................................................................16 
1.3. 
Schedule of Activities (SoA) ......................................................................................17 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Study Rationale ...........................................................................................................29 
2.2. 
Background .................................................................................................................29 
2.3. 
Benefit/Risk Assessment ............................................................................................30 
2.3.1. 
Risk Assessments........................................................................................................30 
2.3.2. 
Benefit Assessment .....................................................................................................34 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................34 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
4. 
STUDY DESIGN .......................................................................................................38 
4.1. 
Overall Study Design ..................................................................................................38 
4.2. 
Scientific Rationale for Study Design ........................................................................38 
4.2.1. 
Rationale for Study Population ...................................................................................39 
4.3. 
Dose Rationale ............................................................................................................40 
4.4. 
Study Duration ............................................................................................................40 
4.5. 
End of Study Definition ..............................................................................................40 
5. 
STUDY POPULATION .............................................................................................41 
5.1. 
Inclusion Criteria ........................................................................................................41 
5.2. 
Exclusion Criteria .......................................................................................................43 
5.3. 
Screen Failure .............................................................................................................45 
6. 
INVESTIGATIONAL PRODUCT AND CONCOMITANT THERAPY .................47 
6.1. 
Investigational Product ...............................................................................................47 
6.2. 
Shipping/Handling/Storage/Accountability ................................................................48 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................48 
6.3.1. 
Randomization and Stratification ...............................................................................48 


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6.3.2. 
Assignment of Subject Number ..................................................................................48 
6.3.3. 
Assignment of Investigational Product Kit Number ..................................................48 
6.3.4. 
Unblinding of an Individual Subject ...........................................................................48 
6.4. 
Study Intervention Compliance ..................................................................................49 
6.5. 
Dose Modifications .....................................................................................................49 
6.5.1. 
Investigational Product ...............................................................................................49 
6.5.2. 
Background PAH Disease-Specific Therapy ..............................................................50 
6.6. 
Treatment of Overdose ...............................................................................................50 
6.7. 
Concomitant Medications and Therapies ...................................................................50 
6.7.1. 
PAH Disease-Specific Background Medications .......................................................51 
6.7.2. 
CYP3A Substrate Drugs .............................................................................................52 
6.7.3. 
Digoxin .......................................................................................................................52 
6.7.4. 
Prohibited Medications and Medications to be Used with Medical Monitor 
Advisement .................................................................................................................52 
6.8. 
Intervention After the End of the Study .....................................................................52 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT WITHDRAWAL FROM STUDY ............................................................53 
7.1. 
Interruption of Investigational Product, Stopping Rules, and Discontinuation 
of Investigational Product ...........................................................................................53 
7.1.1. 
Liver Function: Actions ..............................................................................................54 
7.1.2. 
Respiratory Function: Action .....................................................................................54 
7.1.3. 
Cardiac Function: Action ............................................................................................55 
7.1.4. 
Bleeding: Action .........................................................................................................55 
7.1.5. 
Immunosuppression: Action .......................................................................................55 
7.1.6. 
Pregnancy ...................................................................................................................56 
7.1.7. 
Fluid Retention: Action ..............................................................................................56 
7.1.8. 
Neutropenia: Action ....................................................................................................56 
7.1.9. 
Thrombocytopenia: Action .........................................................................................57 
7.1.10. 
ECG Changes Including Prolonged QTc: Action .......................................................57 
7.2. 
Subject Withdrawal from the Study ...........................................................................57 
7.3. 
Lost to Follow-up .......................................................................................................58 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
8.1. 
Efficacy Assessments .................................................................................................59 


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8.1.1. 
Right Heart Catheterization ........................................................................................59 
8.1.2. 
Six Minute Walk Test (6MWT) .................................................................................59 
8.1.3. 
Echocardiogram (ECHO) ...........................................................................................60 
8.1.4. 
Functional Class ..........................................................................................................60 
8.1.5. 
Assessments for Protocol-Defined Clinical Worsening Events and Risk 
Categorization .............................................................................................................61 
8.1.6. 
Oxygen Saturation ......................................................................................................62 
8.1.7. 
Pulmonary Function Testing.......................................................................................62 
8.1.8. 
Substudies ...................................................................................................................62 
8.1.8.1. 
Functional Respiratory Imaging (Sub-study) .............................................................62 
8.1.8.2. 
Heart Rate Monitoring Sub-Study ..............................................................................62 
8.1.9. 
Patient Reported Outcomes ........................................................................................62 
8.1.9.1. 
EuroQol – 5 Dimensions – 5 Levels (EQ-5D-5L) ......................................................62 
8.2. 
Safety Assessments .....................................................................................................63 
8.2.1. 
Physical Examinations ................................................................................................63 
8.2.2. 
Vital Signs, Body Weight, and Height .......................................................................63 
8.2.3. 
Electrocardiograms .....................................................................................................63 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................64 
8.2.4.1. 
Male Fertility Assessment (Optional) .........................................................................64 
8.3. 
Adverse Events, Serious Adverse Events, and Adverse Events of Special 
Interest ........................................................................................................................64 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................65 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................65 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................65 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................65 
8.3.5. 
Pregnancy ...................................................................................................................66 
8.3.6. 
Death Events ...............................................................................................................66 
8.3.7. 
Adverse Events of Special Interest .............................................................................66 
8.4. 
Pharmacokinetics ........................................................................................................67 
8.5. 
Pharmacodynamics and Biomarkers...........................................................................67 
8.6. 
Pharmacogenetics .......................................................................................................68 
8.6.1. 
Use and Analysis of DNA ..........................................................................................68 
8.6.2. 
N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) .......................................69 


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8.7. 
Other Assessments ......................................................................................................69 
8.7.1. 
User Device Survey ....................................................................................................69 
9. 
STATISTICAL CONSIDERATIONS .......................................................................70 
9.1. 
Statistical Hypotheses .................................................................................................70 
9.2. 
Sample Size Determination ........................................................................................70 
9.3. 
Population for Analyses ..............................................................................................70 
9.4. 
Statistical Analyses .....................................................................................................71 
9.4.1. 
Efficacy Analyses .......................................................................................................71 
9.4.1.1. 
Primary Endpoint ........................................................................................................71 
9.4.1.2. 
Secondary and Exploratory Endpoints .......................................................................71 
9.4.2. 
Safety Analyses ..........................................................................................................72 
9.4.3. 
Pharmacokinetic Analyses ..........................................................................................72 
9.5. 
Interim Analyses .........................................................................................................72 
9.5.1. 
Independent Data Monitoring Committee ..................................................................73 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................74 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations (Site 
Responsibilities) .........................................................................................................74 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................74 
10.1.2. 
Informed Consent Process ..........................................................................................74 
10.1.3. 
Data Protection ...........................................................................................................75 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................75 
10.1.5. 
Data Quality Assurance ..............................................................................................75 
10.1.6. 
Source Documents ......................................................................................................76 
10.1.7. 
Study and Site Closure................................................................................................76 
10.1.8. 
Publication Policy .......................................................................................................77 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................78 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow up, and Reporting ........................................................................81 
10.3.1. 
Definition of AE .........................................................................................................81 
10.3.2. 
Definition of SAE .......................................................................................................82 
10.3.3. 
Definition of Suspected and Unsuspected Adverse Reaction .....................................83 
10.3.4. 
Recording and Follow Up of Adverse Events and Serious Adverse Events ..............83 


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10.3.5. 
Reporting of SAEs ......................................................................................................85 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................86 
10.4.1. 
Definitions ..................................................................................................................86 
10.4.2. 
Contraception Guidance .............................................................................................87 
10.4.3. 
Collection of Pregnancy Information .........................................................................89 
10.5. 
Appendix 5: Genetics .................................................................................................90 
10.6. 
Appendix 6: Prohibited Medications and Medications to be Used with 
Agreement of Medical Monitor ..................................................................................91 
10.7. 
Appendix 7: Abbreviations .........................................................................................93 
10.8. 
Appendix 8:  Guidance to Address a Pandemic or Other Global Health 
Emergencies and Potential Impact on the Clinical Study ...........................................99 
10.9. 
Appendix 9: Protocol Amendment History ..............................................................101 
11. 
REFERENCES .........................................................................................................122 
 
LIST OF TABLES 
Table 1: 
Treatment Groups .......................................................................................................15 
Table 2: 
Schedule of Activities .................................................................................................17 
 
 
Table 4: 
Investigational Product Description ...........................................................................47 
Table 5: 
Summary of Allowed PAH Background Medications ...............................................51 
Table 6: 
World Health Organization Function Class for Pulmonary Hypertension .................60 
Table 7: 
Risk Score Categories .................................................................................................62 
Table 8: 
Pharmacokinetic Collection Schedule ........................................................................67 
Table 9: 
Biomarkers Collection Schedule ................................................................................68 
Table 10: Protocol-Required Safety Laboratory Assessments ...................................................78 
Table 11: Liver Safety Laboratory Assessments ........................................................................80 
 
LIST OF FIGURES 
Figure 1: 
Study Scheme .............................................................................................................16 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Clinical Study to Evaluate the Efficacy and Safety of Oral Inhalation of GB002 for the 
Treatment of WHO Group 1 Pulmonary Arterial Hypertension (PAH) 
Short Title: GB002 in Adult Subjects with PAH 
Rationale 
Despite the use of multiple approved agents and the use of these agents in combination, the 
morbidity and mortality of pulmonary arterial hypertension (PAH) remains unacceptably high 
(Farber, 2015; Galie, 2015). 
Increased platelet-derived growth factor receptor (PDGFR) signaling has been strongly implicated 
in playing an important role in the pathogenesis of PAH for a number of reasons. These include 
the expression of PDGFR and its ligands in human PAH lung tissue, the efficacy of 
platelet-derived growth factor (PDGF) pathway inhibitors in animal models of PAH, and the 
observation that imatinib, an orally administered PDGFR and Abelson murine leukemia viral 
oncogene homolog (Abl) kinase inhibitor, improved cardiopulmonary hemodynamics in patients 
with PAH in a Phase 2 and Phase 3 study (Ghofrani, 2010; Hoeper, 2013a; Medarametla, 2014; 
Wu, 2008). The animal model data particularly highlight that inhibiting the PDGFR pathway may 
prevent/reverse the cellular proliferation of the intimal lining of the pulmonary arteries, a key 
characteristic of PAH. Thus, drugs that target this pathway may have a clinical benefit distinct 
from the benefit observed with the currently approved vasodilators for the treatment of PAH. 
Although the studies of imatinib in PAH demonstrated proof of concept, imatinib was associated 
with poor tolerability and serious side effects (Frost, 2015; Hoeper, 2013a) suggesting that while 
targeting the PDGF pathway was relevant as a potential therapeutic for PAH, a drug with an 
improved therapeutic window would be more optimal. 
Based on this rationale, GB002 was developed as a highly potent, small molecule PDGFR kinase 
inhibitor that is formulated to be delivered via inhalation to limit systemic exposure and thereby 
improve the tolerability and side effect profile of this class of drugs. 


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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• Determine the effect of GB002 on 
improving pulmonary hemodynamics in 
subjects with World Health 
Organization (WHO) Group 1 PAH 
who are WHO Functional Class (FC) II 
or III 
• Change in pulmonary vascular 
resistance (PVR) using right heart 
catheterization (RHC) from Baseline to 
Week 24 
Secondary 
 
• Determine the effect of GB002 on 
improving exercise capacity in this 
population 
• Change in distance achieved on the six-
minute walk test (6MWT), (Δ6MWD) 
from Baseline to Week 24 
Safety 
• Evaluate the safety of GB002 in this 
population 
• Incidence of treatment-emergent 
adverse events (TEAEs), serious 
TEAEs (SAEs), and treatment-emergent 
adverse event of special interest 
(AESIs) 
 
Overall Design 
This is a double-blind, placebo-controlled, randomized Phase 2 study. This study will evaluate 
the oral inhalation of GB002 in adult subjects with WHO Group 1 PAH who are WHO FC II and 
III and have a PVR of ≥ 400 dyne•s/cm5. 
After signing an informed consent form (ICF), subjects will be screened for study eligibility for 
up to a 5-week screening period. Subjects must continue on stable doses of background PAH 
medications from 4 weeks before consent and throughout the treatment period. Dose 
modification of background PAH medications will not be allowed during the screening period. 
On Day 1 (Baseline visit), eligible subjects will be randomized 1:1 to 1 of 2 treatment groups to 
receive GB002 twice per day (BID) or placebo (Table 1). Subjects will initiate dosing with 
60 mg BID and, after 2 weeks, will up titrate to 90 mg BID (6 inhalations BID). Investigational 
product (IP) dose may be reduced due to tolerability or AEs as described in Section 6.5. 
Randomization will be stratified by PVR. Subjects will receive IP, BID, over 24 weeks inhaled 
orally with a dry powder inhaler (DPI). Following initiation of IP in the clinic on Day 1 (Visit 2), 
subjects will have study visits every 4 weeks through Week 12 and subsequent visits at Weeks 
18 and 24; subjects will be evaluated as specified in the Schedule of Activities (SoA), see 
Table 2. Subjects will also be contacted by phone at Weeks 2 (Visit 3) and 6 (Visit 4) and, for 
those subjects not willing or not eligible to participate in the open-label extension study, an in 
person Week 28 (Visit 9) Follow-up visit at the clinic is required. For the Week 4 (Visit 3.5), 


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Week 8 (Visit 5), and Week 18 (Visit 7) visits, subjects or study personnel may choose to have a 
home-health visit rather than an in-clinic visit. For home-health care visits, IP shipment to the 
subject’s home may be arranged. 
An Independent Data Monitoring Committee (IDMC), comprised of external expert physician(s) 
and an external biostatistician, will regularly monitor overall safety and emerging efficacy 
results, as well as general aspects of study conduct, to ensure that the benefits and risks to 
subjects of study participation remain acceptable. 
 Subjects may be eligible to participate in an open-label extension (OLE) study under a different 
protocol provided they have completed study treatment and all assessments and procedures 
required at the Week 24 visit.    
Treatment Groups, Number of Subjects and Duration: 
Subjects will be randomized 1:1 to 1 of 2 treatment groups described in Table 1. 
Table 1: 
Treatment Groups 
Treatment 
Group 
Dose Level, Schedule and Route of 
Administration 
Number of Subjects 
GB002 
90 mg BID orally inhaled (see Section 6.5.1) 
Subjects with tolerability issues at 90 mg BID 
will be permitted to down titrate to 60 mg or 
45 mg BID, as appropriate. 
40 
Placebo 
BID, orally inhaled placebo 
40 
 
Duration 
For each subject, study participation is expected to last up to 33 weeks as follows:  
Screening:  
up to 5 weeks 
Treatment period:  
24 weeks (-3, to +14 days) 
Follow-up: 
For subjects not enrolling in the OLE, 4 weeks (±7 days) after the last 
dose of IP. This will be defined as the last study visit (Week 36 for male 
subjects participating in the semen analysis).  
 
 
Independent Data Monitoring Committee: Yes 




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1.3. 
Schedule of Activities (SoA) 
Table 2: 
Schedule of Activities 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
May be obtained prior to Visit 1. 
Eligibility criteria 
X 
X* 
 
 
 
 
 
 
 
 
 
* Confirm eligibility prior to randomization. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X* 
 
 
 
 
 
 
 
 
 
* Update prior to dosing, as applicable. 
PAH diagnosis and PAH 
background medication history 
X 
 
 
 
 
 
 
 
 
 
 
 


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Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
WHO FC assessment 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs and body weight 
X* 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
* Measure height at screening 
Physical examination  
X 
 
 
 
 
 
X 
 
X 
 
X 
 
12-lead electrocardiogram 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Conduct prior to 6MWT for weeks where 12-lead 
electrocardiogram and 6MWT are both done.   
V/Q lung scan, CT-angiogram, 
or pulmonary angiogram 
X* 
 
 
 
 
 
 
 
 
 
 
*If clinically indicated at screening or if not performed at 
any point prior to screening. 
Computed tomography (CT); ventilation-perfusion (V/Q) 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
19 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Six-minute walk test (6MWT) 
X* 
X 
 
 
 
 
X 
 
X 
 
X 
*Two 6MWTs at least 2 hours apart will be done at 
Screening according to the 6MWT manual. 
Continuous heart rate monitoring during the 6MWT will 
be conducted as a substudy at select participating sites. 
Pulmonary function tests 
(PFTs) and diffusion capacity 
of the lungs for carbon 
monoxide (DLCO) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Echocardiogram (ECHO) 
X 
 
 
 
 
 
X 
 
X 
 
X* 
* For subjects who withdraw from the study Week 12 or 
later 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
20 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Right heart catheterization 
X 
 
 
 
 
 
 
 
X** 
 
X* 
* For subjects who withdraw from the study Week 12 or 
later 
** Refer to Section 10.8.  
Dispense handheld device if all 
screening criteria are met 
 
X 
 
 
 
 
 
 
 
 
 
Handheld device will be used by patient at home to 
complete daily dosing diary. 
Collect handheld device 
 
 
 
 
 
 
 
 
X 
 
X 
 
EQ-5D-5L survey 
 
X 
 
 
 
 
X 
 
X 
 
X 
Perform predose at the clinic using ePRO tablet. 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
21 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Serology and urine drug screen 
X* 
 
 
 
 
 
 
 
 
 
 
Serology includes: Hepatitis B virus surface antigen 
(HbsAg), hepatitis C virus (HCV) antibody, human 
immunodeficiency virus (HIV) antibody, tuberculosis 
(TB). 
Urine drug screen includes amphetamines, 
methamphetamines, cocaine, and phencyclidine. 
*If a subject has a positive test, confirmatory serology will 
be performed. 
TSH, free T4  
X 
 
 
 
 
 
X 
 
X 
 
X 
Thyroid stimulating hormone (TSH) 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
22 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Clinical laboratory tests  
X 
X* 
 
X 
 
X 
X 
X 
X 
X 
X 
Fasting required 
*After randomization, collect predose. 
Testosterone, LH, FSH, 
estradiol, and inhibin B  
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
For male subjects only. To be collected in the morning 
under fasting conditions. 
Male fertility assessment* 
 
X 
 
 
 
 
X 
 
X 
X‡ 
 
*Optional: Samples will be collected from male subjects 
who are willing and able to provide semen samples (see 
Section 8.2.4.1). 
‡ Male subjects who provided semen samples during the 
study will be asked to provide a final semen sample at 12 
weeks (+2 weeks) after the Week 24 visit. 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
23 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Coagulation laboratory tests  
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Urinalysis 
X* 
 
 
 
 
 
X 
 
X* 
 
X 
*Full urinalysis (dipstick plus microscopic evaluation) to 
be performed only at the screening and EOT visits. 
Pregnancy test (WOCBP) 
S 
U* 
 
U 
 
U 
U** 
U** 
U 
U 
U 
Women of childbearing potential (WOCBP) 
If urine (U) is positive, collect serum (S) to confirm. 
**At-home urine pregnancy tests will be provided for 
required monthly pregnancy testing. Any positive at-home 
urine pregnancy test should be confirmed with an on-site 
serum pregnancy test. 
*A negative result must be observed before dosing. 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
24 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Serum digoxin concentration* 
X 
 
 
 
 
 
 
 
 
 
 
*Only for subjects taking digoxin 
To be checked locally as clinically indicated to adjust 
dosing for therapeutic monitoring of digoxin levels used in 
PAH 
Exploratory biomarkers sample 
 
X 
 
 
 
 
X 
 
X 
 
X 
Blood samples will be collected as specified in Table 9. 
GB002 pharmacokinetic (PK) 
sample 
 
X 
 
 
 
 
X 
 
X 
 
X 
Blood samples will be collected as specified in Table 8.  
PAH background medication 
PK sample 
 
X 
 
 
 
 
X 
 
X 
 
X 
Blood samples will be collected as specified in Table 5.  


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
25 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Pharmacogenetic sample 
 
X* 
 
 
 
 
 
 
 
 
 
* If consent provided, sample can be collected at any visit 
post-randomization. 
NT-proBNP sample 
 
X* 
 
X 
 
X 
X 
 
X 
X 
X 
N-terminal pro b-type natriuretic peptide (NT-proBNP) 
*After randomization, collect predose. 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense IP 
 
X 
 
X 
 
X 
X 
X 
 
 
 
Investigational product (IP) 
Inhalation and DPI device 
training* 
 
X 
 
 
 
 
 
 
 
 
 
 
* As needed during the treatment period 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
26 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Administer IP  
 
X* 
←======= Daily (BID) =======→ 
 
 
At the clinic; for all clinic visits, morning dose will be 
administered at the clinic 
* Observe subject for 2 hours post-dose.  
Dose escalation* 
 
 
 
←==============→ 
 
 
*May occur at any point up until Week 20, including 
phone call check-in. Refer to Section 6.5.1.  
Administer oral PAH 
background medications in the 
clinic 
 
X 
 
 
 
 
X 
 
X 
 
X 
The morning doses of oral PAH disease-specific 
background medications should be taken immediately 
prior to GB002 dosing in clinic on PK sampling days. 
Complete dosing diary 
 
←======= Daily (BID) =======→ 
 
 
To be completed on handheld device daily from Baseline 
to Week 24. 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
27 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Collect used investigational 
product/conduct accountability 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of Risk Score 
 
X 
 
 
 
 
X 
 
X 
 
 
Refer to Table 7. 
Assessment of Clinical 
Worsening 
 
X 
 
 
 
 
X 
 
X 
 
 
Refer to Section 8.1.5. 
User Device Survey 
 
 
 
 
 
 
 
 
X 
 
X 
 
Functional Respiratory Imaging 
Substudy 
 
X 
 
 
 
 
 
 
X 
 
X* 
At selected sites (Section 8.1.8) 
*ET only to be collected if ET occurs after 16 weeks of 
study drug. 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
28 
Confidential 
 
Screening  
Baseline  
Treatment Period a 
Notes: 
End of Treatment (EOT) 
Early termination (ET) 
Investigational product (IP) 
Double-Blind, Placebo-Controlled 
EOT Visit 
Follow-Up  
ET 
Visit Number 
1 
2 
3 
3.5 
4 
5 
6 
7 
8 
9 
 
Week 
-5 to 
-1 b.e 
Day 1 e 
2 c 
4 d 
6 c 
8 d 
12 e 
18 d 
24 e 
28 f 
ET g 
b Screening period is from -5 weeks to -1 day; assessments 
may be performed at any time during the screening period, 
as needed. 
c Telephonic Contact: 
 Collection of AEs and concomitant medications. At 
the discretion of the investigator, an unscheduled 
visit may also be scheduled for additional 
assessments. 
 Confirm dosing compliance and proper use of dry 
powder inhaler (DPI). Book unscheduled visit for 
dosing re-training, if necessary 
d In-clinic visit with home-health visit option (defined in 
Section 8)  
e Mandatory in-clinic visit.  
f At least 4 weeks after last dose of IP. A 28-day safety 
follow-up will not be required for subjects transitioning to 
OLE.  
g If needed. Last dose at the Early Termination visit will 
be at the discretion of the study physician based on subject 
safety and dependent on subject’s continued consent. 
Visit window (days) 
 
 
±3 
±7 
±3 
±7 
±7 
±7 
-3 to 
+14 
+7 
 
 
Heart Rate Monitoring 
Substudy 
 
X 
 
 
 
 
X 
 
X 
 
X* 
At selected sites (Section 8.1.8) 
* ET only to be collected if ET occurs after 16 weeks of 
study drug. 
a Guidance to address a pandemic or other global health emergencies and potential impact on this clinical study are provided in Section 10.8, Appendix 8. 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
29 
Confidential 
2. 
INTRODUCTION 
GB002, formulated for oral inhalation delivery as a dry powder for treatment of pulmonary arterial 
hypertension (PAH), is a highly potent, small molecule platelet-derived growth factor receptor 
(PDGFR) kinase inhibitor. PDGFR is a tyrosine kinase receptor that induces cell proliferation when 
activated by its agonist ligands. 
2.1. 
Study Rationale 
Despite the use of multiple approved agents and the use of these agents in combination, the 
morbidity and mortality of PAH remains unacceptably high (Farber, 2015; Galie, 2015). 
Increased PDGFR signaling has been strongly implicated in playing an important role in the 
pathogenesis of PAH for a number of reasons. These include the expression of PDGFR and its 
ligands in human PAH lung tissue, the efficacy of platelet-derived growth factor (PDGF) 
pathway inhibitors in animal models of PAH, and the observation that imatinib, an orally 
administered PDGFR and Abelson murine leukemia viral oncogene homolog (Abl) kinase 
inhibitor, improved cardiopulmonary hemodynamics in patients with PAH in a Phase 2 and 
Phase 3 study (Ghofrani, 2010; Hoeper, 2013a; Medarametla, 2014; Wu, 2008). The animal model 
data particularly highlight that inhibiting the PDGFR pathway may prevent/reverse the cellular 
proliferation of the intimal lining of the pulmonary arteries, a key characteristic of PAH. Thus, 
drugs that target this pathway may have a clinical benefit distinct from the benefit observed with 
the currently approved vasodilators for the treatment of PAH. Although the studies of imatinib in 
PAH demonstrated proof of concept, imatinib was associated with poor tolerability and serious 
side effects (Frost, 2015; Hoeper, 2013a) suggesting that while targeting the PDGF pathway was 
relevant as a potential therapeutic for PAH, a drug with an improved therapeutic window would 
be more optimal. 
Based on this rationale, GB002 was developed as a highly potent, small molecule PDGFR kinase 
inhibitor that is formulated to be delivered via inhalation to limit systemic exposure and thereby 
improve the tolerability and side effect profile of this class of drugs. 
2.2. 
Background 
PAH is an orphan disease associated with high morbidity and mortality (Fisher, 2006; Launay, 
2013; Simonneau, 2013). Despite recent advances in vasodilator therapy for PAH, more effective 
treatments are needed. PAH has been defined by parameters obtained at right heart catherization 
(RHC): a mean pulmonary arterial pressure (mPAP) of ≥ 25 mm Hg and a pulmonary capillary 
wedge pressure (PCWP) of ≤ 15 mm Hg (Hoeper, 2013b). The 6th World Symposium on 
Pulmonary Hypertension Task Force has proposed revising this definition as follows: an 
mPAP > 20 mm Hg, PCWP ≤ 15 mm Hg, and a pulmonary vascular resistance (PVR) ≥ 3 Wood 
Units (Simonneau, 2019). 
The clinical manifestations of PAH result from an increase in resistance to blood flow through 
the pulmonary circulation due to a decrease in the cross-sectional area of the pulmonary 
arterioles and pulmonary vasoconstriction (Humbert, 2014). This decrease is due to in large part 
to proliferative remodeling of the pulmonary artery vasculature (Galie, 2010). Pulmonary 
vascular remodeling consists of two major components: (1) concentric and plexiform lesions in 


GB002 
GB002, Inc. 
Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
30 
Confidential 
small precapillary pulmonary arterioles that decrease overall cross-sectional area of the 
pulmonary arterioles, and (2) abnormal muscularization, hypertrophy, and hyperresponsiveness 
of pulmonary arterioles (Cool, 1997; Tuder, 1994). The proliferative component of pulmonary 
vascular remodeling may be due to a clonal expansion of apoptosis-resistant endothelial cells, as 
well as abnormal proliferation of myofibroblasts (Rai, 2008; Yi, 2000). Both primary and 
secondary proliferation of smooth muscle cells in pulmonary arterioles also play an important 
role in the pathogenesis and progression of PAH (Eickelberg, 2007; Yi, 2000). The pulmonary 
vasoconstriction component is due to abnormal muscularization and hypertrophy of pulmonary 
arterioles as well as changes in calcium handling and regulation of actin-myosin interactions 
within the vascular smooth muscle cells of the vessel media (Wu, 2008). 
A large body of basic and translational research, including genetic dissection studies, functional 
assays, animal models, and histopathologic analysis of human PAH lung samples has shown that 
PDGF signaling through the two major isoforms of the PDGFR receptor plays a critical role in 
the two major components of pulmonary vascular remodeling: (1) the abnormal muscularization, 
hypertrophy, and hyperresponsiveness of the pulmonary arterioles, and (2) the neointimal 
proliferative lesions that compromise the lumen of the pulmonary arterioles. Thus, by inhibiting 
PDGF signaling it should be possible to address these two key components of pulmonary 
vascular remodeling, restore a more normal phenotype of the pulmonary arterioles and thereby 
reverse the pathological remodeling in the PAH pulmonary vasculature. Clinically, this 
pulmonary vascular remodeling that results in an increase in resistance to blood flow through the 
pulmonary vasculature can be measured by the pulmonary vascular resistance at the time of right 
heart catheterization. 
Consistent with this hypothesis, imatinib, a PDGF receptor kinase inhibitor, has been shown to 
inhibit PDGF homodimer (PDGF-BB)-induced proliferation and migration of primary 
pulmonary artery smooth muscle cells (PASMCs), and to ameliorate pulmonary vascular 
remodeling in animal models of PAH (Heldin, 1999; Perros, 2008). Because of these 
demonstrated favorable effects of imatinib, it would be expected that pulmonary vascular 
resistance would improve, accordingly. Although PVR may decrease in response to vasodilator 
therapies in responsive subjects, there is a subset of subjects with WHO FC II and III who, 
despite vasodilator therapy, suffer worsening disease as reflected in a high PVR. The inadequate 
response to vasodilator therapy in this resistant population is likely due to limited effects on the 
two key components of pulmonary vascular remodeling of currently available treatments. In this 
target population, it would be expected that an improvement in PVR would be a result of 
favorable effects on pulmonary vascular remodeling by PDGFR inhibition. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and potential risks of GB002 
may be found in the Investigator’s Brochure. 
2.3.1. 
Risk Assessments 
Orally inhaled GB002 has been well-tolerated in healthy subjects without drug-associated 
respiratory or cardiac effects in Phase 1 studies that evaluated up to 1 week of repeat dosing at 
both 48 mg three times per day (TID) and 90 mg BID. Review of available safety data confirms 
no findings with respect to electrocardiogram (ECG), chest X-rays, and pulmonary function 










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Objectives 
Endpoints 
Safety 
• 
Evaluate the safety of GB002 in this 
population 
• 
Incidence of treatment-emergent adverse 
events (TEAEs), serious TEAEs (SAEs), 
and treatment-emergent adverse event of 
special interests (AESIs) 
Exploratory 
• 
Evaluate the effect of GB002 on right heart 
function measures in this population 
• 
Change from Baseline in tricuspid annular 
peak systolic velocity (TAS’), right 
ventricular (RV) Tei index and right 
ventricular free wall strain (RVFWS) by 
echocardiogram (ECHO)  
• 
Evaluate the effect of GB002 on other 
measures of efficacy  
• 
Changes in: 
− 
WHO FC 
− 
European QOL - 5 Dimensions - 5 
Levels (EQ-5D-5L) 
− 
Right ventricle (RV) function by 
imaging (echocardiography) 
− 
Sub-study: Functional respiratory 
imaging (FRI) by computed 
tomography (CT) scan (in subjects 
with prior CT imaging) 
• 
Time from first dose of GB002 to first 
event of protocol-defined clinical 
worsening event, assessed by measuring the 
first occurrence of any one of the following 
events: 
− 
Death (all causes) 
− 
Hospital admission for worsening 
PAH, as a result of any of the 
following: 
o 
Non-elective hospitalization 
caused by clinical conditions 
directly related to PAH and/or 
right heart failure 
o 
Need for intravenous (IV) 
diuretics (more than a single dose 
in 24 hours) 
o 
Lung or heart/lung transplantation 
o 
Atrial septostomy 


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Objectives 
Endpoints 
o 
Initiation of parenteral (IV 
infusion or subcutaneous 
injection) therapy with a 
prostacyclin (if not previously 
utilizing parenteral prostacyclin 
therapy) 
− 
Disease progression, defined as: 
o 
Worsening symptoms of right 
heart failure requiring initiation of 
a new PAH disease-specific 
medication or an increase in dose, 
or change in disease-specific 
background PAH medications or 
initiation of chronic oxygen 
therapy (ie, requires oxygen for 
>24 hours with the intent of long-
term use); or 
o 
A decrease in distance on 6MWT 
(6MWD) of at least 15% from 
Baseline, directly related to PAH 
progression, confirmed by 2 
assessments of 6MWD performed 
at 2 consecutive visits and 
worsening in WHO FC for 
subjects with WHO FC I/II/III; or 
o 
Worsening Risk Score Category 
(as in Table 7) (Leuchte, 2018). 
Defined as a change in two 
components of the Risk 
Assessment to a worse risk 
category 
• 
Evaluate the safety of GB002 on other 
measures of tolerability 
• 
Change from Baseline in clinical laboratory 
parameters, ECG parameters, pulmonary 
function and vital signs 
• 
Evaluate the pharmacokinetics (PK) of 
GB002 
• 
Plasma concentrations of GB002 and its 
metabolites, if appropriate 
• 
Evaluate the pharmacodynamics (PD) of 
GB002 in this population 
• 
Change from Baseline in N-terminal pro b-
type natriuretic peptide (NT-proBNP) 
• 
Changes from Baseline in biomarkers 
measured in blood samples  
• 
Evaluate the effects of GB002 on Heart 
Rate Expenditure and Heart Rate Recovery 
• 
Change from Baseline in heart rate 
expenditure and heart rate recovery as 


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Objectives 
Endpoints 
during 6MWT – Substudy at select 
participating sites 
measured by continuous heart rate 
monitoring during the 6MWT 
• 
Evaluate changes in the pulmonary 
vasculature by High-resolution CT – 
Substudy at select participating sites. 
• 
Change from Baseline in pulmonary 
vasculature blood volume, pulmonary 
blood volume as a percent of total lung 
volume, fibrosis score, and image-based 
ventilation to perfusion score. 
• 
Determine the effect of GB002 on Risk 
Score Category 
• 
Change from Baseline in Risk Score 
Category based on REVEAL v2.0 and 
European Society of Cardiology 
(ESC)/European Respiratory Society 
(ERS) 


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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a double-blind, placebo-controlled, randomized study of oral inhalation of GB002 in 
adult subjects with WHO Group 1 PAH who are WHO FC II and III and have a PVR of 
≥ 400 dyne•s/cm5. 
After signing an informed consent form (ICF), subjects will be screened for study eligibility for 
up to a 5-week period. Standard of care tests/procedures that were performed prior to signing the 
consent may be used as part of the screening assessments as long as the procedures meet the 
protocol-required timelines (ie, within 5 weeks of randomization for these procedures). Subjects 
must continue on stable doses of background PAH medications from 4 weeks before consent and 
throughout the treatment period. Dose modification of background PAH therapy will not be 
allowed during the screening period; for dose adjustment during the study, refer to Section 6.5.2. 
On Day 1 (Baseline visit), eligible subjects will be randomized 1:1 to 1 of 2 treatment groups 
described in Table 1. Subjects will initiate dosing with 60 mg BID and, after 2 weeks, will up 
titrate to 90 mg BID (6 inhalations BID). IP dose may be reduced due to tolerability or AEs as 
described in Section 6.5. Randomization will be stratified by PVR as described in Section 6.3.1. 
Subjects will receive IP, BID, over 24 weeks inhaled orally with a dry powder inhaler (DPI). 
Following initiation of IP in the clinic on Day 1 (Visit 2), subjects will have study visits every 4 
weeks through Week 12 and subsequent visits at Weeks 18 and 24; subjects will be evaluated as 
specified in the Schedule of Activities (SoA), see Table 2. Subjects will also be contacted by 
phone at Weeks 2 (Visit 3) and 6 (Visit 4) and, for those subjects not willing or not eligible to 
participate in the open-label extension study, an in person Week 28 (Visit 9) Follow-up visit at 
the clinic is required. An interim analysis may be conducted as described in Section 9.5. For the 
Week 4 (Visit 3.5), Week 8 (Visit 5), and Week 18 (Visit 7) visits, subjects or study personnel 
may choose to have a home-health visit rather than an in-clinic visit. For home-health care visits, 
IP shipment to the subject’s home may be arranged. 
In addition to the Sponsor’s regular monitoring of overall safety, an IDMC will meet to review 
overall safety and emerging efficacy results, as well as general aspects of study conduct, to 
ensure that the benefits and risks to subjects of study participation remain acceptable at intervals 
as defined under a separate charter (Section 9.5.1). 
Subjects may be eligible to participate in an open-label extension (OLE) study under a different 
protocol provided they have completed study treatment and all assessments and procedures 
required at the Week 24 visit.  
4.2. 
Scientific Rationale for Study Design 
The study is designed as a double-blind, randomized, placebo-controlled study. All subjects will 
be on background PAH therapy. This approach is consistent with the development of new 
medications as add-on therapy in PAH studies (Abraham, 2010; Sitbon, 2010; Sitbon, 2019; 
Studer, 2014). The study is placebo-controlled to minimize bias and provide a control group to 
which the efficacy of GB002 can be compared. Comparisons between the GB002 and placebo 
treatment groups will facilitate differentiation of the GB002 safety profile from that of the 
background PAH therapy. A placebo group, in contrast to an active control, will help to 


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understand whether the occurrence of an AE in the GB002 group is different from that which 
would occur in this population in the absence of GB002. Lastly, there is an unmet need in this 
patient population, as most patients who are on 2-3 background therapies have exhausted active 
therapeutic classes. 
This study will explore an expected clinically active dose of GB002 in comparison to placebo. 
To assess efficacy, parameters related to exercise tolerance (eg, 6MWT), vascular 
hemodynamics (eg, PVR), and measures of right heart function will be evaluated. 
The primary endpoint is change in PVR by RHC from Baseline to Week 24. PVR is a clinically 
meaningful outcome correlated with morbidity and mortality (Wensel, 2013). Improvements in 
PVR have been demonstrated for all major classes of currently approved PAH therapies 
including phosphodiesterase type 5 (PDE-5) inhibitors, guanylate cyclase (GC) stimulators, 
endothelin receptor antagonists, and prostanoids (Blalock, 2010; Galie, 2015; Galie, 2017; 
Ghofrani, 2013; Klinger, 2011; Shapiro, 2017; Voswinckel, 2006). PVR is a relevant endpoint 
for drugs that target the PDGFR pathway and pulmonary remodeling, based on the IMPRES 
study (Hoeper, 2013a). Thus, based on these analyses, PVR is an acceptable indicator for clinical 
benefit in PAH and is acceptable as the primary endpoint. 
The change in 6MWD is also a clinically important and relevant endpoint. Objective measures of 
improvement in exercise tolerance have been observed with every new major class of therapy 
approved for use in PAH. Additionally, the European Medicines Agency (EMA) guidance on the 
development of new therapeutic agents for PAH lists 6MWD as one of the important measures 
for evaluation (in combination with time to clinical worsening). (European Medicines Agency, 
2010). 
One of the exploratory endpoints is change from Baseline to Week 24 in right ventricular 
function as measured by ECHO. The key echocardiographic parameters will include evaluation 
of TAS’, RV Tei index and RVFWS. The literature supports evaluating these parameters using 
ECHO (da Costa Junior, 2017; Fine, 2013; Hulshof, 2019; Li, 2013; Shukla, 2018). 
4.2.1. 
Rationale for Study Population 
The target patient population for GB002 represents a population with significant risk for 
worsening of their PAH and for whom there are few therapeutic options available; therefore, this 
target population has a significant unmet medical need. All subjects will be WHO FC II or III for 
whom current guidelines recommend treatment with 1, 2 or 3 medications as part of their 
background therapy. The IMPRES study utilized a cutoff of 800 dyne•s/cm5 (Hoeper, 2013a). 
However, a lower threshold has been chosen for this study based upon literature that suggests 
that PVR is an independent risk factor for morbidity and mortality that increases in a continuous 
manner (Benza, 2019; Wensel, 2013). A PVR of ≥ 400 dyne•s/cm5 is selected as a key eligibility 
criterion because this threshold has been shown to be associated with increased risk of mortality 
based on the REVEAL 2.0 risk score (Benza, 2019). 


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4.3. 
Dose Rationale 
The study will explore the safety, tolerability and efficacy of 90 mg GB002 or placebo BID but 
allows for down titration to 60 mg or 45 mg BID based on safety and tolerability (refer to 
Section 6.5.1 for dose modifications). This dose range is anticipated to be clinically active and 
has been selected based upon the following:  
• Comparison of the human PK to the rat PK of GB002 suggests human doses of 45 to 
90 mg BID are projected to cover rat PAH model efficacious exposure range. 
• Population PK/PD modeling/simulation comparing imatinib doses that were effective 
in the IMPRES study (Hoeper, 2013a) to GB002 predicts that GB002 between 45 and 
90 mg BID doses would achieve similar inhibition of PDGFRα signaling and better 
inhibition of PDGFRβ signaling in the pulmonary region. 
• GB002 was well tolerated and safe in Phase 1a studies in healthy volunteer subjects 
following 1 week of repeat dosing up to 90 mg BID doses. 
• Data from an ongoing Phase 1B study in subjects with PAH has demonstrated 
adequate safety and tolerability at doses up to 90 mg BID. 
4.4. 
Study Duration 
For each subject, study participation is expected to last up to 33 weeks as follows: 
Screening:  
up to 5 weeks 
Treatment period:  
24 weeks (-3, to +14 days) 
Follow-up: 
For subjects not enrolling in the OLE, 4 weeks (+7 days) after the last 
dose of IP. This will be defined as the last study visit (or Week 36 for 
male subjects participating in the semen analysis). 
 
4.5. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all study visits, 
including the Week 28 Follow-Up visit (+4 weeks after last dose of IP. A 4-week safety follow 
up will not be required for subjects transitioning to OLE). Note: Week 36 is the last visit for 
male subjects participating in the semen analysis who do not continue to participate in the OLE.  
The end of the study is defined as the date of the last visit of the last subject in the study. 


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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
To be eligible for participation in this study, subjects must meet all the following: 
Age and Sex 
1. Adult female subjects aged 18 to 75 years, inclusive, or adult male subjects aged 50 to 75 
years, inclusive, at the time of signing the ICF prior to initiation of any study-specific 
activities/procedures.  
Type of Subject and Disease Characteristics 
2. A current diagnosis of symptomatic PAH classified by one of the following: 
a. Idiopathic PAH (IPAH) or heritable pulmonary arterial hypertension (HPAH). 
b. PAH associated with connective tissue disease (CTD-APAH): 
− Systemic sclerosis, 
− Mixed CTD or overlap syndrome, 
− Systemic lupus erythematosus 
− Other CTD established by ACR/EULAR guidelines 
c. PAH associated with anorexigen or methamphetamine use. 
d. Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after 
surgical repair. 
3. 6MWD ≥ 150 meters and ≤ 550 meters at screening. The lower of 2 distances should be 
within 15% of the higher distance. 
4. WHO FC II or III symptomatology. 
5. Treatment with standard of care PAH background therapies. Medications should remain 
stable for the past 4 weeks prior to consent and throughout the screening period. 
Exception: As needed (PRN) diuretics for intermittent weight gain and/or edema are allowed 
and will be considered a stable dose for this study. 
6. Documentation of cardiac catheterization within the screening period that is consistent 
with the diagnosis of PAH and meeting the following criteria, to be confirmed by the 
central hemodynamic core laboratory (note, mmHg and PVR [dyne∙sec/cm5] values 
below are rounded to the nearest whole number): 
a. mPAP ≥ 25 mmHg (at rest), AND 
b. PVR ≥400 dyne∙sec/cm5, AND 
c. PCWP or LVEDP ≤12 mm Hg if PVR ≥400 to <500 dyne∙sec/cm5 
OR 
d. PCWP or LVEDP ≤15 mmHg if PVR ≥500 dyne∙sec/cm5  
7. Pulmonary function tests (PFTs) at screening with the following criteria met: 


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a. Forced expiratory volume in 1 second (FEV1) divided by the forced vital capacity 
(FVC) ≥ 70%, 
b. Total lung capacity (TLC) or FVC ≥ 70% predicted  
If the subject uses continuous oxygen therapy, they must be able to complete PFTs 
without oxygen. Subjects who are unable to complete PFTs without oxygen therapy are 
not eligible for the study. 
Contraception 
Contraception use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
8. Women of childbearing potential must have a negative serum pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at 
screening and a negative urine pregnancy test on Day 1 before first administration of IP. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is 
required, and results must be negative. 
9. Women of nonchildbearing potential: Evidence of post-menopausal status. Women will 
be considered post-menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause. The following age-specific requirements apply: 
− Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy, tubal ligation, or 
hysterectomy). 
− Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses > 1 year 
ago, had chemotherapy-induced menopause with last menses > 1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, 
tubal ligation,  or hysterectomy). 
10. Women of childbearing potential who are not abstinent and intend to be sexually active 
with a non-sterilized male partner must be willing to use a highly effective method of 
contraception (defined in Appendix 4 in Section 10.4 of the protocol) from consent 
through 30 days following the last administration of IP; acceptable methods include 
hormonal contraception (oral contraceptives – as long as on stable dose, patch, implant, 
or injection), intrauterine devices or other form of highly effective contraception. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable. 
Note: A vasectomized partner is acceptable. 
11. Male subjects: Non-sterilized male subjects who are not abstinent and intend to be 
sexually active with a female partner of childbearing potential must use a male condom 


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from consent through 90 days after the last dose of IP. Male subjects should refrain from 
sperm donation throughout this period, except for the purpose of fertility analysis as part 
of this protocol. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable. 
Informed Consent 
12.  Evidence of a personally signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study prior to initiation of any 
subject-mandated procedures. Willingness and ability to comply with scheduled visits, 
treatment plan, laboratory tests, and other study procedures. 
5.2. 
Exclusion Criteria 
The subject must be excluded from participating in the study if he/she meets any of the 
following: 
Medical Conditions 
1. Evidence of chronic thromboembolic disease or acute pulmonary embolism as assessed by 
ventilation-perfusion (V/Q) scan, computed tomography (CT)-angiogram, or pulmonary 
angiogram prior to screening. If not available previously, then test should be performed 
during the screening period. 
2. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 
160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during screening visit after a 
period of rest. 
3. Systolic blood pressure < 90 mm Hg during screening and baseline visits. 
4. WHO Pulmonary Hypertension Group 2–5. 
5. HIV-associated PAH. 
6. History of left-sided heart disease and/or clinically significant cardiac disease, including but 
not limited to any of the following: 
a. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild 
aortic insufficiency, mild aortic stenosis (AS), mild mitral stenosis (MS), moderate 
mitral regurgitation (MR); 
b. Mechanical cardiac valve requiring anticoagulation; 
c. Pericardial constriction or pericardial effusion with tamponade physiology; 
d. Restrictive cardiomyopathy; 
e. Left ventricular ejection fraction (LVEF) ≤ 50% by echocardiography (ECHO) within 
6 weeks prior to screening; if ECHO from the prior 6 weeks is not available, the 
screening ECHO results may be used to establish this criterion. 
Note: If ECHO images are not adequate to provide an accurate estimate of LVEF 
then a multigated acquisition (MUGA) or cardiac magnetic resonance imaging 


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(cMRI) scan or single photon emission computed tomography (SPECT) imaging can 
be used to obtain an accurate LVEF. 
f. Left Atrial Area greater than 29cm2 by ECHO within 6 weeks prior to screening; if 
ECHO from the prior 6 weeks is not available, screening ECHO results may be used 
to establish this criterion. 
g. Documented uncontrolled symptomatic coronary disease (ie, unstable angina or 
percutaneous coronary intervention or coronary artery bypass graft within 12 months 
prior to screening, or planned coronary intervention or coronary artery bypass 
surgery). 
7. Untreated severe obstructive sleep apnea. 
8. History of atrial septostomy within 180 days prior to screening. 
9. Pulmonary venous occlusive disease (PVOD). 
10. Subjects with a history of portopulmonary hypertension or portal hypertension due to 
cirrhosis classified as Child-Pugh Class A or higher; or baseline ALT or AST > 2 x ULN or 
Total Bilirubin ≥ 2 X ULN. 
11. History of malignancy within 5 years prior to screening, with the exception of localized non-
metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix. 
12. History of a potentially life-threatening cardiac arrhythmia with an ongoing risk. 
13. Uncontrolled bacterial, viral, or fungal infections which require systemic therapy. 
14. Severe acute or chronic medical or laboratory abnormality that may increase the risk 
associated with study participation or IP administration (eg, history of intracranial 
hemorrhage), or absolute neutrophil count (ANC) < 1x109/L or platelet count < 50x109/L.  
15. Any musculoskeletal disease or any other disease that limits evaluation of 6MWT. 
16. Pregnant or nursing or intends to become pregnant during the duration of the study. 
Diagnostic Assessments 
17. Body weight < 40 kg at screening. 
18. Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) 
< 45 mL/min/1.73m2 via CKD-epi (Levey, 2009) at screening or requires dialytic therapy or 
hemofiltration. 
19. Hemoglobin (Hgb) concentration < 8.5 g/dL at screening. 
20. Evidence of active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or 
tuberculosis (TB) infections. 
Prior Therapy 
21. Inhaled prostanoids; these drugs may be withdrawn ≥ 4 weeks prior to screening, if 
clinically indicated. 
22. Use of oral anticoagulants (ie, warfarin or novel oral anticoagulants [NOAC]) at 
randomization; if on warfarin or a NOAC, these drugs can be withdrawn, if clinically 


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appropriate, during the screening period, and subjects should have normal coagulation 
parameters prior to the randomization (see Section 10.6 for examples of prohibited 
anticoagulants). 
23. Requirement of intravenous (IV) inotropes (ie, levosimendan, dopamine, dobutamine, 
milrinone, norepinephrine) other than an IV prostanoid within 4 weeks of screening. 
Prior/Concurrent Clinical Study Experience 
24. Prior participation in GB002 studies and/or prior treatment with GB002. 
25. Currently participating in or has participated in a study of an investigational agent or has 
used an investigational device for the treatment of PAH within 4 weeks prior to screening. 
Note: Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks or at least 5 half-lives (whichever is greater) after 
the last dose of the previous investigational agent. 
Other Exclusion Criteria 
26. Current use of inhaled tobacco and/or inhaled marijuana. 
27. Current alcohol use disorder as defined by DSM-5, and/or a positive test for drugs of abuse 
(amphetamines, methamphetamines, cocaine, phencyclidine [PCP]). Retest may be 
performed for potential false positive results. Subjects with a history of methamphetamine 
abuse must be abstinent for a minimum of 1 year prior to screening, in the opinion of the 
investigator. Certain drugs may be allowed IF prescribed by medical personnel and is under 
medical supervision for documented medical conditions (ie, opioids for pain, 
benzodiazepines for anxiety).  Ingestible or topical marijuana is allowed, per local 
restrictions and regulations.  
28. Subjects with a history of severe milk protein allergy. In addition, subjects with known 
intolerance or hypersensitivity to lactose who, in the opinion of the investigator, may 
experience severe symptoms following the ingestion of lactose.  
29. QTcF of > 480 msec recorded on a screening or baseline ECG or receiving concurrent 
treatment with medications that prolong QT interval. Please refer to Table 5. 
30. Have any other condition or reason that, in the opinion of the Investigator or Medical 
Monitor, would prohibit the subject from participating in the study.  
5.3. 
Screen Failure 
Subjects will be assigned a subject number at the time of signing the ICF. Subjects who do not 
randomize will be labeled as screen failures. 
A minimal set of screen failure information is required to ensure transparent reporting of Screen 
failure subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes informed consent date, demography, screen failure details (including eligibility criteria), 
and any SAE. 


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Subjects who are not randomized may be eligible to rescreen upon approval by the Medical 
Monitor (or designee). A new subject number will be assigned if approved to rescreen. One 
rescreen is permitted per subject. 


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6. 
INVESTIGATIONAL PRODUCT AND CONCOMITANT 
THERAPY 
6.1. 
Investigational Product  
The investigational product, GB002 Powder for Inhalation, is comprised of GB002 capsules 
(drug product) and the dry powder inhaler (device). GB002 capsules are comprised of GB002 
spray-dried powder for inhalation in size 3 hydroxypropyl methylcellulose (HPMC) capsules. 
The device is a 
 dry powder inhaler (DPI). The placebo capsule is 
identical in size, shape, and color, with the same excipients and with the active drug replaced 
with lactose monohydrate. 
Table 4: 
Investigational Product Description 
Investigational Product 
Name 
Active: GB002 
Control: Placebo 
Dose Formulation 
Capsule containing GB002 spray-
dried powder 
Matching capsule containing placebo 
spray-dried powder 
Inhaler Device 
 dry powder inhaler (DPI) 
Unit Dose Strength(s) 
15 mg per capsule 
placebo capsule 
Dose regimen 
45 mg: 3 x 15 mg capsule, BID 
3 capsules BID 
60 mg: 4 x 15 mg capsule, BID 
4 capsules BID 
90 mg: 6 x 15 mg capsule, BID 
6 capsules BID  
Route of Administration 
and Instructions 
Oral inhalation 
IP to be taken 12 hours apart (BID dosing) at approximately the same time 
each day, within ±2 hours. 
Subjects and/or caretaker will receive instructions and training regarding 
the correct use of the DPI devices.  
Subjects to be observed for 2 hours post first dose.  
Sourcing 
IP will be provided to the site centrally by the Sponsor or designated 
representative. 
Packaging 
GB002 and placebo capsules are contained within foil induction-sealed, 
child-resistant, high-density polyethylene (HDPE) bottles, which are 
enclosed in foil pouches. Each bottle contains 80 capsules. Foil pouches 
(and bottles) are uniquely numbered and will be dispensed in an appropriate 
quantity for each dosing period. All IP kits appear identical between GB002 
and placebo. 
The DPI devices are packaged in a suitable secondary packaging kit 
appropriate for dispensing to subjects for each dosing period. Each device 
kit is uniquely numbered and closed with tamper-evident seals. 
Labelling 
Label text will at a minimum include the protocol number, lot number, 
storage conditions, and Sponsor name and address. Labels will comply with 
local regulatory requirements for Ips. 


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6.2. 
Shipping/Handling/Storage/Accountability 
1. The kits containing GB002 capsules and placebo will be shipped using temperature 
monitoring devices and stored at controlled room temperature between 20°C and 25°C (68°F 
and 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). The 
Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and resolved 
before dispensation of the IP. 
2. The kits containing DPI devices will be shipped at ambient conditions and stored indoors 
away from direct sunlight. 
3. Only subjects enrolled in the study may receive IP, and only authorized site staff may supply 
or administer IP. All IP 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. 
4. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization and Stratification 
All subjects will be centrally randomized 1:1 to 1 of 2 groups as specified in Table 1 using 
interactive response technologies (IRT). 
Randomization will be stratified by PVR (<800 dyne•s/cm5, ≥ 800 dyne•s/cm5). 
Before the study is initiated, appropriate IRT training and the log-in information and directions 
will be provided to each site. 
6.3.2. 
Assignment of Subject Number 
At the screening visit, each subject will have a unique subject number assigned for subject 
identification in the study. 
6.3.3. 
Assignment of Investigational Product Kit Number 
IP(s) will be dispensed at the study visits as summarized in the SoA. The IP(s) kit number(s) will 
be assigned by the IRT system upon obtaining the subject’s randomized treatment group. 
For subsequent visits when IP is dispensed, the IRT system will assign IP kits based on the 
subject’s randomized treatment group. 
6.3.4. 
Unblinding of an Individual Subject 
The IRT system will be programmed with blind-breaking instructions. In case of a medical 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
subject’s randomized treatment is warranted. Subject safety must always be the first 
consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator, when possible, should make efforts to contact the Sponsor’s Medical 


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Monitor (or designee) to discuss unblinding a subject’s treatment assignment before doing so, 
unless this could delay emergency medical treatment of the subject. If a subject’s treatment 
assignment is unblinded, the Sponsor must be notified within 24 hours after breaking the blind. 
The date and reason that the blind was broken must be recorded in the source documentation and 
electronic case report form (eCRF). 
Appropriate personnel at the Sponsor will unblind suspected unexpected serious adverse 
reactions (SUSARs) for the purpose of regulatory reporting. The Sponsor will submit SUSARs 
to Regulatory Agencies in blinded or unblinded fashion according to local law. The Sponsor will 
submit SUSARs to Investigators in a blinded fashion. 
Appropriate personnel at the Sponsor (or designee) will have access to unblinded individual 
subject treatment assignments for the purposes of study-required activities including 
management of IP inventory, production of summary tables and figures for IDMC review, and 
performance of bioanalytical analysis of PK concentrations. These personnel will not be 
involved in data collection or final analysis of safety and efficacy results. Subjects, investigators, 
other site personnel, and Sponsor (and/or designee) personnel who are directly involved in the 
conduct of the study, collection of the data, and analysis of the final safety and efficacy results 
will remain blinded to treatment assignments until after the completion of the study and the 
database has been locked. 
6.4. 
Study Intervention Compliance 
IP accountability will be assessed at each visit, as appropriate, by counting returned unused 
capsules. Deviation(s) from the prescribed dosage regimen will be evaluated. Subjects who 
demonstrate poor IP compliance should be reeducated on the importance of taking their 
medications as prescribed. 
For visits where PK samples are collected, the subject will be instructed to take their dose in the 
evening before the visit at their regular dosing time and to record the time of dosing. For all 
clinic visits, the morning dose will be administered at the clinic. 
Guidance for Missed Dose(s)   
If a dose is missed, subjects should be instructed to skip the missed dose if there are less than 
6 hours before the time of the next dose, resume dosing at their next scheduled dosing time 
±2 hour and document the missed dose. 
6.5. 
Dose Modifications 
Please also refer to Section 7.1 for dose interruption and stopping rules for more details. 
6.5.1. 
Investigational Product 
All subjects will be randomized to 90 mg BID of GB002 or placebo administered via inhalation. 
Subjects will begin dosing with GB002 60 mg or Placebo BID.  After 2 weeks, all subjects 
should be dose escalated, as tolerated, to 90 mg BID (Refer to Table 4 for acceptable dose 
levels).  For those subjects who have not achieved a dose of 90 mg BID, dose escalation should 
be attempted approximately every 2 weeks until Week 20.  
 


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In the event of tolerability issues and/or an AE thought to be due to IP administration, dose 
reduction will be allowed to 60 mg BID (4 inhalations BID) with further reduction to 45 mg BID 
(3 inhalations BID), if required. Any dose reduction needs to be discussed with the Sponsor’s 
Medical Monitor (or designee). If tolerated, the dose may be increased back to 90 mg BID at the 
discretion of the Investigator and discussion with the Sponsor’s Medical Monitor. 
Should a dose reduction be required, after discussion with the Sponsor’s Medical Monitor (or 
designee), dose reduction to 60 mg BID, and if not tolerated, further dose reduction to 45mg BID 
will be allowed. If tolerated, the dose may be increased back to 90 mg BID at the discretion of 
the Investigator and discussion with the Sponsor’s Medical Monitor. 
Further up titrations should not be attempted after Week 20. 
6.5.2. 
Background PAH Disease-Specific Therapy 
Subjects should remain on their stable PAH disease-specific background therapy from 4 weeks 
prior to consent and for the duration of their time on study (if clinically appropriate). If a 
subject’s condition worsens during the treatment period and this change meets the definition of 
the protocol’s clinical worsening criteria (Section 8.1.5), they may need to increase dose of 
current disease-specific background PAH therapy above their baseline stable dose at the 
Investigator’s discretion if it is in the best interest of the subject’s health. Any increases in PAH 
disease-specific background therapies should be discussed with the Sponsor’s Medical Monitor 
(or designee) if possible. 
6.6. 
Treatment of Overdose 
For this study, any dose of IP greater than the prescribed daily dose will be considered an 
overdose. There is no specific treatment recommended to treat an overdose of IP, and the subject 
should receive treatment directed towards any symptoms manifested. 
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor (or designee) as soon as possible. 
• Closely monitor the subject for any AE/SAE and laboratory abnormalities. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor (or designee) based on clinical evaluation of the subject. 
6.7. 
Concomitant Medications and Therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Name of medication/therapy (generic name) 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 


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Concomitant medications necessary for the health and well-being of the subject and that do not 
interfere with study assessments are permitted during the study at the Investigator’s discretion. 
This includes the use of appropriate medications for the treatment of AEs and/or concurrent 
illnesses under the direction of the Principal Investigator. All medications must be recorded in 
the source and on the appropriate electronic case report forms (eCRFs). 
The Sponsor’s Medical Monitor (or designee) should be contacted if there are any questions 
regarding concomitant or prior therapy. 
6.7.1. 
PAH Disease-Specific Background Medications 
Review of the prescribing labels of these PAH disease-specific background medications listed in 
Table 5 revealed that no clinically relevant drug-drug interactions (DDIs) are expected and no 
dose adjustment is needed when they are co-administered with GB002 based on the completed 
DDI assessments summarized in the IB, except for sildenafil. When sildenafil is co-administered 
to patients receiving GB002, adjustment of sildenafil dose should be administered only after a 
careful benefit-risk assessment; a downward dose adjustment to 20 mg twice daily for tablet or 
oral suspension, or 10 mg twice daily for injection should be considered. Overall, these 
background medications are permitted for co-administration with GB002. The review also 
revealed that no clinically relevant DDIs are expected and no dose adjustment is needed for 
GB002 when it is co-administered with the PAH disease-specific background medications. 
Table 5: 
Summary of Allowed PAH Background Medications 
PAH Background 
Medication 
Coadministration 
Permitted? 
Background 
Medication Dose 
Adjustment? 
GB002 Dose 
Adjustment? 
Ambrisentan 
Yes 
No 
No 
Macitentan 
Yes 
No 
No 
Bosentan 
Yes 
No 
No 
Sildenafil 
Yes 
Should be considereda 
No 
Tadalafil 
Yes 
No 
No 
Riociguat 
Yes 
No 
No 
Treprostinilb 
Yes 
No 
No 
Epoprostenol 
Yes 
No 
No 
Selexipag 
Yes 
No 
No 
Iloprostc 
Yes 
No 
No 
a Any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose 
adjustment to 20 mg twice daily for tablet or oral suspension, or 10 mg twice daily for injection should be 
considered when sildenafil is co-administered to patients receiving GB002. 
b Inhaled Treprostinil (not approved for marketing in the European Union) is prohibited; Treprostinil injection for 
SC or IV infusion or Treprostinil extended-release tablet for oral use (not approved for marketing in the European 
Union) are allowed.  
c Iloprost solution for infusion is allowed; iloprost nebulizer solutions are prohibited. 


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6.7.2. 
CYP3A Substrate Drugs 
GB002 is a moderate CYP3A inhibitor.  For PAH background medications which are CYP3A 
substrates (sildenafil, tadalafil, riociguat, bosentan, and macitentan), refer to Section 6.7.1 for 
instructions. 
For other CYP3A substrate drugs, consult their labels on how they should be co-administered 
with a moderate CYP3A inhibitor. 
6.7.3. 
Digoxin 
For subjects taking digoxin, measure serum digoxin concentrations before initiating GB002. 
When co-administering with GB002, modify dose and/or dosing frequency as required to keep 
digoxin within the therapeutic range typically used in PAH patients. 
6.7.4. 
Prohibited Medications and Medications to be Used with Medical Monitor 
Advisement 
Medications specifically prohibited in the exclusion criteria, such as anti-coagulants, are not 
allowed during the ongoing study.  
However, if there is a clinical indication for any medication specifically prohibited during the 
study (Appendix 6), the Investigator should discuss these medications with the Sponsor’s 
Medical Monitor (or designee), prior, if possible, to administration of prohibited medications and 
treatments.  
The final decision on any supportive therapy rests with the Investigator and/or the subject’s 
primary physician. However, the decision to dose a subject with IP or concomitant medications 
requires the mutual agreement of the Investigator, the Sponsor and the subject, this decision 
should be documented and retained in the local site records. 
Please refer to Appendix 6 (Section 10.6) for prohibited medications. Any investigational agent, 
other than GB002, is also prohibited. 
6.8. 
Intervention After the End of the Study 
The final intervention in this protocol is the Week 24 visit followed by a Week 28 safety Follow-
up Visit (Week 36 for male subjects participating in the semen analysis), or the Early 
Termination Visit, if applicable.   


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7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT WITHDRAWAL FROM STUDY 
7.1. 
Interruption of Investigational Product, Stopping Rules, and 
Discontinuation of Investigational Product 
Dosing of IP must be interrupted for any serious adverse events assessed by the investigator as 
related to IP. Restart of dosing may be considered upon discussion with and approval by the 
Sponsor’s Medical Monitor (or designee) after resolution of IP treatment-related events to 
baseline. In cases where subject has been off IP for more than 14 consecutive days, restart of IP 
may only be allowed with Sponsor’s Medical Monitor approval.   
Permanent discontinuation of IP does not mean withdrawal from the study, and the subject will 
be encouraged to remain in the study and continue to complete all study visits as per the SoA 
(Table 2).  
If a subject discontinues IP for lack of efficacy (disease progression), background disease-
specific PAH therapy may be adjusted, as needed. 
A subject may discontinue IP(s) for reasons including but not limited to: 
• Adverse event 
• Death 
• Lost to follow-up 
• Non-compliance with study drug 
• Physician decision Section 7.1.2 Section 7.1.2  
• Pregnancy 
• Progressive disease 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by subject 
The reason for subject discontinuation from IP will be recorded in the eCRF. 
For liver function abnormalities, dose modification is based on guidelines in Section 7.1.1. For 
additional abnormalities, refer to Section 7.1.2 , Section 7.1.3, Section 7.1.4, Section 7.1.5, 
Section 7.1.7, Section 7.1.8 Section 7.1.9, and Section 7.1.10. A blood sample for PK analysis 
may be collected for subjects experiencing any of the below stopping rules, or as requested by 
the Sponsor.  
Pregnancy is a mandatory criterion for permanent discontinuation of IP (see Section 7.1.6). 


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7.1.1. 
Liver Function: Actions 
Liver function tests (LFTs) will be evaluated as specified in the SoA (Table 2). Scheduled and 
unscheduled liver function tests alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and bilirubin, will be evaluated and actions specified per the following criteria. 
Weekly (or more frequently as clinically indicated) LFT values will be performed for confirmed 
results of ALT or AST ≥ 3 × upper limit of normal (ULN). The confirmation laboratory sample 
is collected ideally within 24 hours. After 4 weeks, the frequency and discontinuation of 
additional monitoring will be decided by the investigator and the Sponsor. 
All ALT or AST ≥ 3 × ULN will be evaluated for an etiology (for example viral hepatitis, drug 
and herbal supplements, environmental exposure, and other) in consultation with the Sponsor.  
Liver Function: IP Interruption 
IP dosing will be paused for the following confirmed liver laboratory values: 
• ALT or AST ≥ 5 × ULN 
IP may be restarted if the ALT and/or AST return to baseline values or stabilize to < 3 x ULN. 
The decision to restart IP must be approved by the Sponsor. 
Liver Function: IP Discontinuation 
IP will be permanently discontinued for the following confirmed liver laboratory values: 
• ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN, or 
• ALT or AST ≥ 8 × ULN 
7.1.2. 
Respiratory Function: Action 
Respiratory Function: IP Interruption 
If subject experiences signs and symptoms of moderate change from baseline in respiratory 
function (regardless of the investigator’s reported relationship to IP), dosing with IP will be 
interrupted. Because changes in respiratory function may be due to factors other than IP (eg, 
worsening underlying disease, fluid overload, respiratory infection), further evaluation should be 
undertaken. After appropriate medical evaluation and management, IP dosing may be resumed if 
clinical status improves. Following agreement between the Sponsor’s Medical Monitor (or 
designee) and the investigator, the same dose, a lower dose, or permanent discontinuation, in 
accordance with discontinuation criteria, of IP will occur depending on the clinical status of the 
subject.  
Respiratory Function: IP Discontinuation 
Adverse events related to respiratory function will be monitored.  IP will be permanently 
discontinued for the following: 
• Respiratory related adverse events considered by the Investigator as related to IP and 
resulting in hospitalization with need for intervention or  
• If IP was interrupted per respiratory function interruption criterion and restart 
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7.1.3. 
Cardiac Function: Action 
Cardiac Function: IP Interruption 
If subject experiences signs and symptoms of moderate or severe change from baseline in cardiac 
function (regardless of the investigator’s reported relationship to IP), dosing with IP will be 
interrupted. Because changes in cardiac function may be due to factors other than IP (eg, 
worsening underlying disease, fluid overload), further evaluation should be undertaken. After 
appropriate medical evaluation and management, IP dosing may be resumed if clinical status 
improves. Following agreement between the Sponsor’s Medical Monitor (or designee) and the 
investigator, the same dose, a lower dose, or permanent discontinuation, in accordance with the 
discontinuation criteria, of IP will occur depending on the clinical status of the subject. 
Cardiac Function: IP Discontinuation 
Adverse events related to cardiac function will be monitored. IP will be permanently 
discontinued for the following: 
• New onset heart failure that requires hospitalization and intervention and that is 
considered related to IP or  
• If IP was interrupted per cardiac function interruption criterion and restart conditions 
were not achieved 
7.1.4. 
Bleeding: Action 
Bleeding: IP Interruption 
If subject experiences signs and symptoms of minor bleeding (eg, limited epistaxis, 
mucocutaneous signs) which is an adverse event considered by the investigator as related to IP 
and which is not major hemorrhage meeting criteria for permanent IP discontinuation, dosing 
with IP should be interrupted, and further evaluation should be undertaken. After appropriate 
medical evaluation and management, IP dosing may be resumed following discussion with the 
Sponsor’s Medical Monitor (or designee). A lower dose of IP should be considered depending on 
the outcome of clinical evaluation.  
Bleeding: IP Discontinuation 
Adverse events related to bleeding will be monitored. IP will be permanently discontinued for 
the following adverse event: 
• Hemorrhage (other than traumatic injury) where invasive intervention or transfusion 
is required. 
7.1.5. 
Immunosuppression: Action 
Immunosuppression: IP Interruption  
If subject experiences signs and symptoms of localized or systemic infection, dosing with IP may 
be interrupted and further evaluation should be undertaken. Because localized or systemic 
infections may be due to factors other than IP, further evaluation should be undertaken. After 
appropriate medical evaluation and management, IP dosing may be resumed depending upon the 
clinical status of the subject. Following agreement between the Sponsor’s Medical Monitor (or 


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designee) and the investigator, the same dose, a lower dose, or permanent discontinuation of IP, 
in accordance with the discontinuation criteria, will occur depending on clinical status of the 
subject. If infection is accompanied by neutropenia, additionally refer to neutropenia actions 
(Section 7.1.8) for dose interruption and discontinuation criteria. 
Immunosuppression: IP Discontinuation 
Adverse events related to infections will be monitored. IP will be permanently discontinued for 
the following: 
• Severe opportunistic infections requiring anti-fungal or anti-viral therapies or 
prolonged intravenous antibiotics regardless of whether it results in hospitalization or 
not or 
• If IP was interrupted per immunosuppression interruption criterion and restart 
conditions were not achieved  
7.1.6. 
Pregnancy 
A subject with a positive urine pregnancy test must temporarily discontinue GB002. If the serum 
pregnancy test is negative, the subject may restart GB002. A subject must permanently 
discontinue IP if she becomes pregnant (as confirmed by serum pregnancy test). See Appendix 4 
(Section 10.4.3) and Section 8.3.5 for additional details, including for female partners of male 
subjects). 
See the SoA (Table 2) for data to be collected at the time of IP discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.1.7. 
Fluid Retention: Action 
Fluid Retention: IP Interruption 
If subject experiences signs and symptoms of severe fluid retention and/or experiences a 20% 
increase in weight from baseline, dosing with IP should be interrupted if considered by 
Investigator as related to IP, and further evaluation should be undertaken. After appropriate 
medical evaluation and management, IP dosing may be resumed following discussion with the 
Sponsor’s Medical Monitor (or designee). A lower dose of IP should be considered depending on 
the outcome of clinical evaluation.  
Fluid Retention: IP Discontinuation 
Adverse events related to fluid retention will be monitored.  IP will be permanently discontinued 
for adverse events considered by the investigator as related to IP for the following: 
• Severe fluid retention related events that do not respond to appropriate medical 
management or IP dose reduction 
7.1.8. 
Neutropenia: Action 
Neutropenia: IP Interruption 
If subject has a confirmed absolute neutrophil count (ANC) < 1109/L, dosing with IP should be 
interrupted. ANC should be monitored weekly and GB002 dosing can resume when ANC 
> 1.5 109/L. IP dosing should resume at a lower dose level and ANC monitored weekly for the 


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first 2 weeks and, if stable, every 2 weeks for the next month, then as per the protocol laboratory 
evaluation schedule. 
Neutropenia: IP Discontinuation 
Laboratory parameters will be monitored for the development of neutropenia. IP will be 
permanently discontinued for the following: 
• Confirmed ANC < 1109/L and persistence despite IP dose reduction 
7.1.9. 
Thrombocytopenia: Action 
Thrombocytopenia: IP Interruption 
If subject has confirmed platelet count < 50 109/L, dosing with IP should be interrupted.  
Platelet count should be monitored weekly and GB002 dosing can resume when platelet count 
> 100109/L. IP dosing should resume at a lower dose level and platelet count monitored 
weekly for the first 2 weeks and, if stable, every 2 weeks for the next month, then as per the 
protocol laboratory evaluation schedule. 
Thrombocytopenia: IP Discontinuation  
Laboratory parameters will be monitored for the development of thrombocytopenia. IP will be 
permanently discontinued for the following: 
• Confirmed platelet count < 50 109/L and persistence despite IP dose reduction  
7.1.10. 
ECG Changes Including Prolonged QTc: Action 
ECG changes including prolonged QTc: IP Interruption 
Not applicable. 
ECG changes including prolonged QTc: IP Discontinuation 
ECGs will be monitored for clinically significant abnormalities.  IP should be permanently 
discontinued for the following: 
• The development of a new life-threatening cardiac arrythmia 
• QTcF > 500 msec or change from baseline > 60 msec 
7.2. 
Subject Withdrawal from the Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. A subject may 
withdraw from the study for reasons including but not limited to: 
• Death 
• Withdrawal by subject 
• Lost to follow-up 
• Study terminated by Sponsor. 
The reason for subject withdrawal from the study will be recorded in the eCRF. 


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If a subject is withdrawing from the study and has previously discontinued IP, as soon as 
possible, an ET Visit should be conducted, as shown in the SoA (Table 2). If the subject is 
simultaneously discontinuing IP and withdrawing early from the study, the ET visit should be 
conducted at the time of IP administration. A last dose at the ET visit will be at the discretion of 
the Investigator based on subject safety and dependent on subject’s continued consent. Subjects 
should be encouraged to return 4 weeks later for a Follow-up Visit. See the SoA for data to be 
collected at the time of study withdrawal and at follow-up and for any further evaluations that 
need to be completed. 
If a subject withdraws from the study, he/she may request destruction of any biological samples 
collected and not yet assayed, and the Investigator must document this request in the site study 
records. The Sponsor should be notified of this request. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls to the 
subject’s last known phone number, and, if necessary, a certified letter sent to the 
subject’s last known mailing address, or local equivalent methods). These contact 
attempts should be documented in the subject’s medical record. 
• The Sponsor may also attempt to ascertain vital status on subjects deemed lost to 
follow-up. 
• Should the subject continue to be unreachable, he/she will be considered lost to follow-
up. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness of occurrence to determine if the subject should continue or 
discontinue IP(s). 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3) is essential and required for study conduct. 


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• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a log to record 
details of all subjects screened (including demographic data) and to confirm 
eligibility or record reasons for screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management and 
obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• For the Weeks 4, 8, and 18 visits, subjects or study personnel may choose to have a 
home-health visit rather than an in-clinic visit. For home-health care visits, IP 
shipment to the subject’s home may be arranged.  
8.1. 
Efficacy Assessments 
8.1.1. 
Right Heart Catheterization 
RHC will be done to assess the severity of hemodynamic impairment and to subsequently help to 
identify risk status of subjects with a diagnosis of PAH. These data will also be used to evaluate 
the efficacy of GB002. 
The key RHC parameters are as follows: 
1. Right atrial pressure 
2. RV systolic pressure 
3. Pulmonary artery systolic and diastolic pressures 
4. Mean pulmonary arterial pressure 
5. End expiratory pulmonary capillary wedge pressure (PCWP), or if PCWP not accurate 
then left ventricular end diastolic pressure or mean left atrial pressure (mLAP) (in which 
case left heart catheterization to measure LVEDP may be needed) 
6. Cardiac output and cardiac index 
7. PVR, calculated as: 
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚−𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
𝐶𝐶𝐶𝐶
 𝑥𝑥 80 dyne • s/cm5  
where mPAP = mean pulmonary arterial pressure in mm Hg, PCWP = pulmonary capillary 
wedge pressure in mm Hg, and CO = cardiac output in liters/minute. 
RHC should be performed by an experienced operator in an appropriate cardiac catheterization 
laboratory. If access is obtained via the internal jugular vein, then ultrasound guidance should be 
used. Femoral or brachial vein access is permitted. Subclavian vein access should be avoided. 
Details are provided in the RHC Manual. 
8.1.2. 
Six Minute Walk Test (6MWT)  
A standardized 6MWT will be performed in the clinic at specified visits, in accordance with the 
guidelines of the American Thoracic Society (American Thoracic Society Committee, 2002). 


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The 6MWT will be carried out by trained study staff. If an ECG is required at the same visit as a 
6MWT, the 6MWT must be performed after the ECG. For further details, refer to the 6MWT 
manual. 
8.1.3. 
Echocardiogram (ECHO) 
A full echocardiogram (including two-dimensional, Doppler, and speckle tracking), assessed 
centrally, will be used to evaluate RV and LV function. The digital image and results will be 
available to the Sponsor; every effort should be made to include the appropriate images and 
results of RV and LV function. Further details are described in the imaging manual. 
• The two-dimensional echocardiography parameters to be measured or calculated 
include: right and left heart chamber volumes, such as RV fractional area change 
(RVFAC), LV eccentricity index, and tricuspid annular plane systolic excursion 
(TAPSE) and tricuspid annular peak systolic velocity (TAS’). In addition, presence 
and size of a pericardial effusion will be determined. 
• Doppler echocardiographic parameters will be measured or calculated to evaluate RV 
function, including Tei index (Tei, 1996). 
• Speckle tracking echocardiography will be used to measure RV and LV strain. 
For further details refer to ECHO manual. 
8.1.4. 
Functional Class 
Description of each WHO functional class for pulmonary hypertension is provided in Table 6. 
Table 6: 
World Health Organization Function Class for Pulmonary Hypertension  
WHO 
Functional 
Class 
Description 
I 
Patients with pulmonary hypertension but without any resulting limitation of physical 
activity. Ordinary physical activity does not cause dyspnea, fatigue, chest pain or near 
syncope. 
II 
Patients with pulmonary hypertension resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity causes undue dyspnea, fatigue, 
chest pain or near syncope. 
III 
Patients with pulmonary hypertension resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes undue dyspnea, fatigue, 
chest pain or near syncope. 
IV 
Patients with pulmonary hypertension with inability to carry out any physical activity 
without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or 
fatigue may even be present at rest. Discomfort is increased by any physical activity. 
Syncope or near syncope can occur. 


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8.1.5. 
Assessments for Protocol-Defined Clinical Worsening Events and Risk 
Categorization 
For assessment of clinical worsening, data will be captured related to the following: 
• Death (all causes) 
• Hospital admission for worsening PAH, as a result of any of the following: 
− Non-elective hospitalization caused by clinical conditions directly related to PAH 
and/or right heart failure 
− Need for IV diuretics (more than a single dose in 24 hours)  
− Lung or heart/lung transplantation 
− Atrial septostomy 
− Initiation of parenteral (IV infusion or subcutaneous injection) therapy with a 
prostacyclin (if not previously utilizing parenteral prostacyclin therapy) 
• Disease progression, defined as 
− Worsening symptoms of right heart failure requiring initiation of a new PAH 
disease-specific medication or an increase in dose, or change in disease-specific 
background PAH medications or initiation of chronic oxygen therapy (ie, requires 
oxygen for >24 hours with the intent of long-term use); or 
− A decrease in 6MWD of at least 15% from Baseline, directly related to PAH 
progression, confirmed by 2 assessments of 6MWD performed at 2 consecutive 
visits and worsening in WHO FC for subjects with WHO FC I/II/III; or 
− Worsening Risk Score Category (as in Table 7) (Leuchte, 2018). Defined as a 
change in two components of the Risk Assessment to a worse risk category 
Risk will be evaluated using the ESC/ERS guidelines (Galie, 2016) as well as the Registry for 
the Characterization of Primary Pulmonary Hypertension (REVEAL) 2.0 risk calculator as 
described by Benza et al (Benza, 2019; McGoon, 2012). 
Risk assessment will be performed according to one or more of the approaches described by 
Leuchte et al (Leuchte, 2018) and may include variables recommended by the ESC/ERS 
guidelines (eg, WHO FC, 6MWD, right atrial pressure [RAP], cardiac index [CI], stroke volume 
[SV], right atrial [RA] area, presence of a pericardial effusion, and NT-pro-BNP).  
For assessment of Risk Score, the date of determination that a change in two Risk Assessment 
components has occurred (in the case of NT-proBNP, the date of the laboratory result) will be 
reported in the case report form as the date of the Clinical Worsening Event.  


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Table 7: 
Risk Score Categories 
Risk Assessment 
Score 
Low risk 
Intermediate risk 
High risk 
WHO functional 
class 
I, II 
III 
IV 
6MWD 
> 440 m 
165–440 m 
< 165 m 
NT-proBNP plasma 
levels 
NT-proBNP 
<300 ng·L−1 
NT-proBNP 300–
1400 ng·L−1 
NT-proBNP 
>1400 ng·L−1 
Source: Leuchte, 2018 
8.1.6. 
Oxygen Saturation 
Oxygen saturation will be measured using pulse oximetry. 
8.1.7. 
Pulmonary Function Testing 
Pulmonary function tests (PFTs) will be measured using electronic spirometry, with the highest 
of three technically acceptable measurements recorded in the eCRF. Measurements will include 
forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and DLCO. 
If the subject uses continuous oxygen therapy, they must be able to complete PFTs without 
oxygen. 
8.1.8. 
Substudies 
8.1.8.1. 
Functional Respiratory Imaging (Sub-study)  
A functional respiratory imaging (FRI) by high-resolution chest CT sub-study using specialized 
software to determine change from baseline in pulmonary vasculature blood volume, pulmonary 
blood volume as a percent of total lung volume, fibrosis score, and image-based ventilation to 
perfusion score will be performed at Baseline and Week 24 at select participating sites. For 
further information, please refer to the corresponding sub-study manual.  
8.1.8.2. 
Heart Rate Monitoring Sub-Study  
A heart rate monitoring sub-study utilizing a wearable ECG device (VivaLNK) during the 
6MWT will be conducted to evaluate the change in heart rate expenditure and heart rate recovery 
from Baseline to Week 24 at select participating sites. For further information, please refer to the 
6MWT sub-study manual. 
8.1.9. 
Patient Reported Outcomes 
8.1.9.1. 
EuroQol – 5 Dimensions – 5 Levels (EQ-5D-5L) 
EQ-5D-5L (five severity levels EQ-5D), developed by the EuroQoL Group, is a standardized 
instrument to be completed by the subject for use as a measure of health outcome applicable to a 
wide range of health conditions (Herdman, 2011). It comprises five dimensions of health: 


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mobility, ability to self-care, ability to undertake usual activities, pain and discomfort, and 
anxiety and depression. Based on qualitative and quantitative studies conducted by the EuroQol 
Group, there are five options (levels) under each domain: ‘no problems’, ‘slight problems’, 
‘moderate problems’, ‘severe problems’ and ‘unable to/extreme problems’. The responses to all 
five dimensions, can be converted to a single summary index, utility (range: 0 to 1), by using 
value sets. Higher index values represent better health states. The EQ-5D-5L also includes a 20 
cm vertical, visual analog scale for recording the subject’s self-rated health from ‘the best health 
you can imagine’ and ‘the worst health you can imagine’.  
The EQ-5D-5L will be captured at the clinic via an ePRO device (tablet). 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 2). Study 
procedures should be completed within the windows provided in the SoA and as specified in this 
section. 
8.2.1. 
Physical Examinations 
• A complete physical examination will be performed and will include, at a minimum, 
assessments of the cardiovascular, respiratory, gastrointestinal and neurological 
systems. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs, Body Weight, and Height 
• Vital signs (pulse rate, respiratory rate, temperature and blood pressure) will be 
measured after 5 minutes rest and prior to ECG measurements. 
• Blood pressure and pulse measurements will be assessed with the subject in a sitting 
position with a completely automated device. Manual techniques will be used only if 
an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the subject in a quiet setting without distractions (eg, television, cell phones). 
• Body weight will be measured and recorded. Subjects will be encouraged to weigh 
themselves at home as part of standard of care; if a subject experiences abnormal 
lower extremity swelling and/or weight gain, they will be instructed to contact the 
clinical study site or primary care physician for further evaluation. 
• Height will be measured and recorded only at screening. 
8.2.3. 
Electrocardiograms 
• Assessment of a single 12-lead ECG will be obtained as outlined in the SoA (see  
Table 2) to determine heart rate and measure PR, QRS, QT, and QTc intervals. 
• ECGs must be performed prior to the 6MWT. 


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8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
at the visits designated in the SoA (Table 2). Details for collection, processing and 
shipping of samples to the central laboratory are provided in a separate Laboratory 
Manual. 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The signed laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not associated 
with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
• All laboratory tests with values considered abnormal and clinically significant during 
participation in the study should be repeated per standard practices until the values 
return to normal or baseline or are no longer considered clinically relevant by the 
Investigator or Sponsor’s Medical Monitor (or designee). 
 
Note: If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
• All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the Laboratory Manual and the 
SoA (Table 2). 
• If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the Investigator, then the events must be recorded 
in the eCRF and retained in source documents. 
8.2.4.1. 
Male Fertility Assessment (Optional) 
The male fertility assessment will be done in male subjects who are willing and able to provide a 
semen sample to evaluate semen volume, total sperm per ejaculate, sperm concentration, sperm 
progressive motility, and sperm morphology. Collected specimens will be evaluated by a local 
laboratory. Participating male subjects with abnormal values at baseline will not be included in 
further fertility assessments. 
Semen samples will be collected at Baseline, Week 12 and Week 24. A follow-up semen sample 
will be collected at approximately Week 36 (12 weeks after the last dose of IP at Week 24). 
For all semen samples, subjects should abstain from ejaculation for 48 hours before and a 
maximum 1 week before each semen collection. 
8.3. 
Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest 
The definitions of an AE, SAE, and AESI can be found in Appendix 3 (Section 10.3). 


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AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of AE, SAE, or AESI. A review of all system organ 
classes, including the reproductive system, should be performed at the time of Adverse Event 
assessment. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs will be collected from the first dose of IP until the end of study follow-up. SAEs will be 
collected beginning at the time of consent until the end of study follow-up. All medical 
occurrences, with the exception of SAEs, that begin after obtaining ICF and before the first dose 
of IP will be recorded on the Medical History/Current Medical Conditions section of the eCRF 
and not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately upon the site 
learning of an event, and under no circumstance should the initial notification exceed 24 hours, 
as indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to 
the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs that start after conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the IP or study participation, the Investigator must promptly notify the Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
Care is to be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire whether 
AEs occurred. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification of an SAE by the Investigator to the Sponsor is essential so that 
the Sponsor’s legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of IP under clinical investigation can be met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of an IP under clinical investigation. 


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The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to regulatory authorities, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) (defined in Section 10.3.3) according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate, according to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies will be collected as outlined in Appendix 4 (Section 10.4). 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
• Participating male subjects who are willing and able to provide semen samples will 
undergo fertility assessments. Sperm samples will be collected at the timepoints 
specified in the SoA (Table 2) and will be evaluated for semen volume, total sperm 
per ejaculate, sperm concentration, sperm progressive motility and sperm 
morphology. 
8.3.6. 
Death Events 
Timelines for reporting of death events are identical to the requirements for SAE reporting. 
(Appendix 3, Section 10.3). 
8.3.7. 
Adverse Events of Special Interest 
Bleeding and cardiac effects (as described below) are considered potential risks and are deemed 
AESIs. Additional information will be required for AESIs and recorded on the CRFs. All AESIs 
will be followed to resolution or stabilization. The Sponsor will review all AESIs and may report 
these events as expedited to regulatory authorities. 
Bleeding 
Risk of bleeding is a class safety concern for PDGFR kinase inhibitors. Bleeding is an AE of 
interest and will include preferred terms in the Standard Medical Dictionary for Regulatory 
Activities (MedDRA) Query (SMQ) of Haemorrhage terms (excluding laboratory terms) that are 
assessed as severe, defined as indicating a transfusion or invasive intervention or necessitating a 
hospitalization. 


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Cardiac effects 
Risk of cardiac effects, specifically congestive heart failure, have been observed within the class 
of kinase inhibitors. These effects are AESIs and will include the preferred term of heart failure 
that is assessed as severe, defined as the new onset of symptoms at rest or with minimal activity 
or necessitating a hospitalization. 
8.4. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of GB002 and its 
metabolites, if applicable, as specified in Table 8. The actual time and date of each sample 
collection will be recorded in eCRF. The actual time and date of the morning dosing of GB002 
(start and stop times) and oral PAH on the PK days and the last dosing of them before the PK 
days will be recorded in eCRF. A more detailed description of plasma sample preparation will be 
provided in the Laboratory Manual. 
PK samples will be analyzed with a validated method; for metabolites, the samples may be 
analyzed with a fit-for-purpose method(s). The samples may be used for metabolite profiling or 
bioanalytical method development and validation. The samples may also be used for measuring 
concentrations of PAH background medications. 
Table 8: 
Pharmacokinetic Collection Schedule 
Visit 
Timepoint  
Dose 
Time 
PK 
Collection 
PK Collection Time 
Window 
2 
Day 
1/Baseline 
morning Predose* 
X 
-1 hour 
2 hours postdose 
X 
± 10 minutes 
6 
Week 12  
morning Predose* 
X 
-1 hour 
2 hours postdose 
X 
± 10 minutes 
8 
Week 24  
morning Predose* 
X 
-1 hour 
5 minutes postdose 
X* 
± 2 minutes 
3 hours postdose 
X 
± 10 minutes 
Early 
Termination 
Visit  
any time 
after 
Baseline 
none 
Anytime 
X 
 
*Five minutes at Week 24. If the dose administration takes more than 5 minutes, the 5-minute blood sample will 
be collected within 1 minute of the completion of the dose administration. 
* The predose sample may be collected anytime within 1 hour prior to dosing. PAH-disease specific background 
medication should be dosed ahead of GB002. 
8.5. 
Pharmacodynamics and Biomarkers 
Samples for exploratory biomarker analysis will be collected as specified in Table 9 and may be 
used as the basis for multiple exploratory assays to evaluate the effect of GB002 on a range of 
potential target engagement and PD biomarkers. 


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Samples may be stored at a facility selected by the Sponsor, to enable further analysis of 
biomarker responses to GB002, for a maximum of 8 years (or according to local regulations) 
following the last subject’s last visit for the study. 
Residual blood may be stored for potential future identification of factors or profiles that 
correlate with measures of response to GB002. 
Table 9: 
Biomarkers Collection Schedule 
Assay 
Collection Schedule  
mRNA assay (disease modification [DM])  
At Day 1/Baseline, Weeks 12, 24, and ET1 visit: 
• 
Predose (-1 hour)1 
• 
2 hours postdose (± 10 minutes)1 
Proteomics and methylation patterns assays 
(DM) 
At Day 1/Baseline, Weeks 12 and 24, and ET visit: 
• 
Predose (-1 hour) 
1 Biomarkers for the early termination visit will be collected at any time during the visit. 
8.6. 
Pharmacogenetics 
8.6.1. 
Use and Analysis of DNA 
Germ line variation may impact a subject’s response to IP, susceptibility to, and severity and 
progression of disease. Variable response to IP may be due to genetic determinants that impact 
drug absorption, distribution, metabolism, and excretion (ADME), the mechanism of action of 
the drug, disease etiology, and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, and subjects consent, a pharmacogenetic sample 
may be collected for DNA analysis. 
Pharmacogenetic samples may be analyzed for genetic variations in genes which have the 
potential to affect the PK of GB002, the safety, and/or efficacy profile. Often, a large variability 
in the plasma concentration–time profiles of any medicine can be linked to loss of function 
mutations in the drug metabolizing enzymes and/or transporters. For example, substantial efforts 
have been made in reducing the risk of drug-drug interactions related to cytochrome P450 (CYP) 
enzymes and variability caused by polymorphic expression of metabolizing enzymes (eg, 
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 & 
CYP3A5) and transporter proteins (eg, P-glycoprotein [P-gp], breast cancer resistance protein 
[BCRP], organic anion transporting polypeptide [OATP]1B1, OATP1B3, ornithine 
aminotransferase [OAT]3, organic cation transporter [OCT]2, multidrug and toxin extrusion 
[MATE]1 & MATE2K). The effects of single nucleotide polymorphisms (SNPs) on the PK of 
GB002 uncovered in the course of this study may help guide future clinical studies and 
regulatory review of GB002. Additional pharmacogenetic analyses may be conducted if it is 
hypothesized that doing so may help resolve issues with the clinical data (eg, safety and/or PD 
observations) during the study. 
The results of these analyses may be reported in a separate study summary. 


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The Sponsor will store the samples in a secure storage space with adequate measures to protect 
confidentiality. 
The samples will be retained while research on GB002 continues but no longer than 8 years or 
other period as per local requirements. 
The Sponsor may elect to measure the naturally occurring variation across a range of relevant 
pharmacogenetic markers using a laboratory test such as the ThermoFisher DMETTM Plus 
Solution. This assay would cover 1,936 genetic variants across 231 relevant genes using a single 
array. This particular assay, for example, would include many genetic variants that cannot easily 
be detected, eg, SNPs and insertion and deletions (INDELs) with secondary polymorphisms in 
close proximity, triallelic markers, and variants from multi-gene families. Particular emphasis 
would, in this case, be placed on covering the PharmaADME “Core ADME Genes” (32 genes) 
and PharmaADME “Core Markers” (185 variants). If the Sponsor finds it necessary, it may 
move beyond the PharmaADME core content to cover common and functional variants 
associated with hepatic detoxification for processing xenobiotics and environmental toxins (eg, 
markers associated with newly described adverse drug events–CYP3A4 [392A>G]; structural 
variants in transporter genes which are important pharmaceutical targets–ABCG2 [421C>A]; 
enrichment for mutations in ADME regulatory genes–PPARD; inclusion of many population 
specific markers–VKORC1). 
8.6.2. 
N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) 
N-terminal pro b-type natriuretic peptide (NT-proBNP) may be elevated in subjects with PAH 
and is an independent risk predictor in these subjects (Galie, 2016; Leuchte, 2007). Blood 
samples will be collected to assess change in NT-proBNP from baseline will be assessed to 
provide potential prognostic information at the time of screening and during follow-up 
assessments (Warwick, 2008). 
8.7. 
Other Assessments 
8.7.1. 
User Device Survey 
All subjects will be requested to complete a User Device Survey as specified in the SoA to 
evaluate ease of use of the DPI. 


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9. 
STATISTICAL CONSIDERATIONS 
Unless specified otherwise, all statistical analyses will be performed using a 2-sided hypothesis 
test at the 5% level of significance. Continuous data will be presented using descriptive statistics: 
number of subjects (n), mean, standard deviation (SD), median, minimum and maximum. 
Descriptive statistics on continuous efficacy measures will also include the standard error (SE). 
Categorical data will be summarized by the number and percent of subjects. Time-to-event data 
will be summarized using the median (if estimable) and the 25th and 75th percentiles. Confidence 
intervals (CI) will be 95% and two-sided, unless otherwise stated. All efficacy and safety data 
will be summarized by treatment group. 
9.1. 
Statistical Hypotheses 
The superiority of GB002 over placebo will be evaluated by testing the following null 
hypotheses (H0) vs. the alternative hypotheses (Ha). 
• H0: There is no difference in ∆PVR after 24 weeks in PAH subjects treated with 
GB002 compared to placebo 
• Ha: This is a difference in ∆PVR after 24 weeks in PAH subjects treated with GB002 
compared to placebo 
9.2. 
Sample Size Determination 
Based upon the results from a Phase 2 study with the PDGFR inhibitor imatinib (Ghofrani, 
2010), the mean (SD) decrease from baseline in PVR over 24 weeks is assumed to be 
300 (340) dyne•s/cm5 for the GB002 group and 79 (270) dyne•s/cm5 for the placebo group, 
resulting in a GB002 treatment effect (SD) of 221 (305) dyne•s/cm5. Assuming this treatment 
effect, 40 subjects per treatment group has approximately 90% power to detect a statistically 
significant difference between GB002 and placebo using Satterthwaite’s t-test with α = 0.05, 
two-sided. 
9.3. 
Population for Analyses 
The following populations are defined: 
• Intent-to-Treat (ITT) Population: All subjects who are randomized will be included in 
the ITT Population. This population will be used as the primary analysis population 
for all efficacy endpoints. Subjects will be grouped in this population according to 
their randomized treatment assignment. 
• Safety Population: All subjects who receive any dose amount of IP will be included in 
the Safety Population. This population will be used for all summaries of safety data. 
Subjects will be grouped as follows: any subject that receives only placebo doses will 
be in the placebo group. Any subject that receives at least one dose of GB002 will be 
in the GB002 group. 


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9.4. 
Statistical Analyses 
The number and percentage of subjects in each analysis population will be summarized. Subject 
disposition, including the number of subjects screened, randomized, dosed, taking at least 80% 
of their expected number of doses for their time on study, completing study treatment, not 
completing study treatment by reason for discontinuation, completing study, and not completing 
study by reason for withdrawal will be summarized. Subject demographics will be summarized 
for the ITT Population and will include age, age category, sex, race, ethnicity, height, weight, 
and body mass index (BMI). Age, age category, sex, race, and ethnicity will also be summarized 
for consented subjects who fail screening. Baseline disease characteristics will be summarized 
for the ITT population and will include WHO FC, age at PAH diagnosis, duration of PAH, 
previous PAH-specific therapy, type of PAH-specific background therapy, pulmonary 
hemodynamic parameters, and 6MWD. 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Endpoint 
The primary estimand to address the efficacy objective with respect to PVR is the change in PVR 
from Baseline to Week 24 for each subject in the ITT Population with missing Week 24 PVR 
values imputed using multiple imputation (MI) techniques under the assumption that missing 
data are missing at random (MAR), comparing the estimated least-squares mean differences 
(LSMDs) between the GB002 group and the placebo group using an analysis of covariance 
(ANCOVA) model adjusted for Baseline PVR. Possible intercurrent events that could affect 
whether a post-Baseline PVR value is missing not at random (MNAR) or that could affect an 
observed post-Baseline value itself are initiation of a new PAH medication or increase in dose of 
a background PAH medication, death, or discontinuation due to disease progression. 
The primary analysis of mean change in PVR from Baseline to Week 24 will be carried out using 
an ANCOVA model adjusted for Baseline PVR. Results will be expressed as mean changes in 
PVR and associated SDs, LSMDs and SEs with associated 95% CIs, and p-values. Missing PVR 
values at Week 24 will be imputed using MI. The resulting complete datasets obtained through 
MI will be analyzed and the estimates combined to produce a single inference that incorporates 
the uncertainty due to missing data (Rubin, 1987). A sensitivity analysis will be conducted using 
the tipping point approach (Ouyang, 2017) to both assess the appropriateness of the MAR 
assumption and whether patients with any of the intercurrent events noted above who have 
observed post-baseline PVR data might have had their results affected by the intercurrent event. 
In this analysis, the same analytic model will be used as in the primary analysis, however the MI 
approach will be expanded to allow for varying impact of missing data and intercurrent events by 
incorporating a shift parameter in the imputation model exploring the varying missing data 
assumptions from MAR to MNAR. Supplementary analyses will include repeating the primary 
and sensitivity analyses on percent change in PVR and analyzing the subgroup of subjects with 
observed PVR values at Week 24. 
9.4.1.2. 
Secondary and Exploratory Endpoints 
Secondary and exploratory endpoints involving continuous measurements will be analyzed using 
ANCOVA or mixed-effects models for repeated measures (MMRM) adjusted for PVR strata and 


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baseline value of the measurement of interest, or a Wilcoxon rank sum test as appropriate. 
Categorical endpoints will be analyzed using a Cochran-Mantel-Haenszel (CMH) test adjusted 
for PVR strata. Time-to-event endpoints will be analyzed using Kaplan-Meier methods and Cox 
proportional hazards models. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed using the Safety Population. All safety data will be 
summarized by treatment group. 
AEs that start during or after the first dose of IP administration, or AEs with an onset prior to the 
first dose of IP administration that worsen during or after the first dose of IP administration will 
be considered TEAEs. All TEAEs will be coded and tabulated by system organ class (SOC) and 
preferred term (PT). Incidence of TEAEs, SAEs, and AESIs will be summarized and presented 
in descending order of frequency according to the GB002 treatment group. Aes leading to IP 
discontinuation and/or study withdrawal will be summarized and listed separately. 
Associated laboratory parameters such as hepatic profile, lipid profile, renal function, and 
hematology values will be grouped and presented together in summary tables. For each 
laboratory test, individual subject values will be listed and values outside of the standard 
reference range will be flagged. Shift tables will be produced showing the frequency of shifts 
from Baseline to the lowest and to the highest on-study value in and out of normal range as well 
as by visit. The change from Baseline in laboratory parameters will also be summarized by visit. 
The change from Baseline to each visit for each of the vital sign variables will be summarized. 
Abnormal vital sign values will be flagged and listed. Changes from Baseline in ECG results will 
be summarized. 
9.4.3. 
Pharmacokinetic Analyses 
GB002 concentrations may be summarized descriptively by PK sampling times and visits. The 
GB002 concentration data obtained in this study may be used for population PK and exposure-
response analyses (including PK-PD, as appropriate) and may be reported separately. Analyses 
may be performed to assess if co-administration of GB002 affects the concentrations of PAH 
background medications and if there is a correlation between the concentrations and efficacy 
endpoints; these analyses may be reported separately. 
9.5. 
Interim Analyses 
An unblinded interim analysis may be conducted after at least 40 subjects undergo the Week 24 
RHC. If the interim analysis is conducted, the conditional power (CP) for the primary and 
secondary endpoint will be estimated assuming the interim analysis treatment effect.  If 50% ≤ 
CP < 80%, the sample size may be adjusted upward to recover the planned statistical power of 
approximately 90%. If the CP falls outside of this “promising zone”, the sample size may not be 
adjusted.  Following the Haybittle-Peto α-spending function, α = 0.001 will be spent at the 
interim analysis, resulting in a final α-level of 0.050. Results of this unblinded interim analysis 
will be reviewed by a small group of Sponsor employees who are not part of the study team as 
well as by the IDMC. 


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9.5.1. 
Independent Data Monitoring Committee 
An IDMC, comprised of 2 independent external expert physicians (including the Chair) and an 
independent biostatistician will regularly monitor overall safety and emerging efficacy results, as 
well as general aspects of study conduct, to ensure that the benefits and risks to subjects of study 
participation remain acceptable. Based on these regular reviews of emerging results, the IDMC 
will recommend to the Sponsor continuation, modification, or termination of the study. Makeup 
of the IDMC, meeting structure, schedule, and procedures, including communication between 
the Sponsor and the IDMC, the content and format of IDMC reports, and other relevant details, 
are detailed in the IDMC charter. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations (Site Responsibilities) 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure, Dosing Diary and other relevant 
subject-facing documents (eg, surveys, instructions for use, advertisements) must be submitted to 
an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of title 21 Code of Federal Regulations (CFR) (or equivalent for non-
IND sites), ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
10.1.2. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50 (or equivalent for non-IND sites), local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 


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The medical record must include a statement that written informed consent was obtained before 
the subject entered the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
A pharmacogenetics consent form must be offered to all subjects, and the process must be 
documented, unless prohibited by local regulations. 
10.1.3. 
Data Protection 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law(s). The level of disclosure must also be 
explained to the subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.4. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be an integrated clinical and statistical report prepared according to the ICH E3 
guidelines. 
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
10.1.5. 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The Investigator must maintain attributable, legible, contemporaneous, original, and accurate 
documentation (source data) that supports the information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Details describing monitoring strategy (eg, risk-based initiatives in operations and quality such 
as risk management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 


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The Sponsor or designee is responsible for the data management of this study including quality 
review of the data. 
The Sponsor maintains ultimate responsibility for the quality and integrity of study data, even if 
study-related duties and functions are transferred to other individuals or organizations (eg, 
contractors or contract research organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are attributable, legible, contemporaneous, original, and 
accurate from source documents; that the safety and rights of subjects 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 applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator per ICH-GCP and local regulations or institutional policies. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor. 
10.1.6. 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents should be generated utilizing good documentation 
practices and are filed at the Investigator’s site. 
Source documents are original documents, data, and records from which the subject’s CRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
Data entered in the eCRF 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. 
10.1.7. 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion. 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. 


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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further IP development. 
10.1.8. 
Publication Policy 
The publication policy is located within the Clinical Study Agreement with the Investigator 
and/or Institution. 


















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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterilized (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of IP, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 


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10.4.2. 
Contraception Guidance 
Male Subjects: 
Male subjects 50 years and older are eligible to participate if they agree to the following from 
informed consent through 90 days after the last dose of IP: 
• Refrain from donating sperm, except for the purpose of fertility analysis as part of 
this protocol 
PLUS, either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier (a male condom) 
Female Subjects: 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
− Is not a woman of childbearing potential (WOCBP) 
OR 
− Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), preferably with low user dependency (see table 
below), from consent through 30 days after the last dose of IP, and agrees not to 
donate eggs (ova, oocytes) for the purpose of reproduction during this period. The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of IP. 
− A WOCBP must have negative serum pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours 
prior to receiving the first administration of IP and a negative urine pregnancy test 
before first administration of IP. If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test is required and results must be negative. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical studies. 


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Highly Effective Methodsa That Have Low User Dependency  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)b 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsa That Are User-Dependent  
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
• Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the IP. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the subject.) 
a Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
b If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction). 
 


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10.4.3. 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant: 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. 
• After obtaining the necessary signed ICF from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
Sponsor will attempt to follow the female partner to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. The Sponsor will follow the female partner until birth or termination of 
pregnancy when possible. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Subjects who become pregnant 
Any female subject who becomes pregnant while participating in the study will discontinue 
IP(s). Additionally: 
• The investigator will collect pregnancy information, which will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
subject’s pregnancy. 
• The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. The subject will be followed until birth 
or termination of pregnancy. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
IP by the investigator will be reported to the Sponsor as described in Section 10.3.5. 
While the investigator is not obligated to actively seek this information in former 
study subjects, he or she may learn of an SAE through spontaneous reporting. 


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10.5. 
Appendix 5: Genetics 
Pharmacogenetic samples will be collected from subjects who have consented to participate in 
the genetic analysis component of the study, where permitted by law and local authorities and 
allowed by IRB/IEC. Participation is a subject-level decision, and those subjects who do not 
wish to participate in the genetic research may still participate in the overall study. While a 
particular biosample may be collected from consenting subjects to facilitate the ease of the 
genetic analysis, consent would apply to all biosamples provided by the subject. 
The Sponsor will store the samples in a secure storage space with adequate measures to protect 
confidentiality. 
If the samples are assayed, the resulting data will be coded with a specific number, and neither 
subject name nor other personally-identifying information (initials, date of birth, Social 
Insurance number) will be used. This process allows the Sponsor to connect the assay results 
with other study results for research purposes, and to more securely store the data. Data obtained 
from this study is for research purposes only. The results may be shared with the site, upon 
request of the Investigator, if available, with the understanding that the results cannot be used for 
diagnostic and/or therapeutic purposes. The subject will not be identified in any reports or 
publications resulting from this study. The results and other information from this study may be 
submitted to the U.S. Food and Drug Administration (FDA) and governmental agencies in other 
countries where GB002 may be considered for approval. Unless required by law or regulatory 
authorities for the purpose of verifying the legitimacy of data obtained from this study, only the 
Sponsor and its authorized personnel and agents will have access to the data. 
The results of these analyses may be reported in in independent, post hoc study report, without 
identifying the subject donor. 
The samples will be retained while research on GB002 continues, but no longer than 8 years 
from end of study (as defined in Section 4.5) or other period so as to comply with local 
requirements.  


















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10.8. 
Appendix 8:  Guidance to Address a Pandemic or Other Global 
Health Emergencies and Potential Impact on the Clinical Study 
In the occurrence of a global health pandemic affecting the conduct of the ongoing study, such as 
COVID-19, the study may be adjusted due to trial subjects being in self-isolation/quarantine, 
limited access to public places (including hospitals) due to the risk of spreading infections, and 
health care professionals being committed to critical tasks. [Source: EMA Guidance on the 
Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, Version 3 
(28 April 2020).] 
Vaccines for the SARS-CoV-2 virus should be recorded as described in protocol section 6.7. 
Please discuss timing of first vaccine dose administration with the medical monitor. 
The GB002-2101 protocol assessments may be conducted as described below, in line with 
Regulatory Authorities Guidance in order to assure the safety of study participants, maintain 
compliance with good clinical practice (GCP), and minimize the risks to trial integrity during the 
COVID-19 pandemic. Source: EMA, April 2020; FDA, March 2020; Health Canada, 03 April 
2020; MHRA, 22 April 2020); the FDA guidance was amended 04 December 2020 
Informed Consent 
• If written consent by the study subject is not possible (for example because of 
physical isolation due to COVID-19 or other global health emergencies), consent 
could be given orally by the study subject. 
• Study subjects and the person obtaining consent could sign and date separate ICFs. 
• In case a written informed consent cannot be obtained at the clinical site, electronic 
informed consent can be obtained remotely. Alternatively, the consent form may be 
sent to the subject or the subject’s legally authorized representative by facsimile or 
e-mail, and the consent interview may then be conducted by telephone/teleconference 
when the subject or subject’s legally authorized representative can read the consent 
form during the discussion; the subject or subject’s legally authorized representative 
will be requested to sign and date a blank piece of paper with a written statement 
affirming that they agree to participate in the study. 
• If re-consent is necessary for the implementation of new urgent changes in study 
conduct (mainly expected for reasons related to global health emergencies or 
important safety issues for other studies), alternative ways of obtaining consent may 
include contacting the study subject via phone or video-calls and obtaining oral 
consents, to be documented in the study subjects’ medical records, supplemented with 
e-mail confirmation. 
• The informed consent procedure is to remain compliant with the study protocol as 
well as local regulatory requirements. All relevant records should be archived in the 
Investigator's site master file. A correctly signed and dated informed consent form 
should be obtained from the study subjects later, as soon as possible. 


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Study Visits and Procedures 
• In the case of missed visits due to COVID-19 (or other health pandemic)-related 
reasons: 
− The site should make every effort to contact the subject to confirm and document 
the reason for the missed visit, and at minimum evaluate AEs/SAEs, concomitant 
medications, Functional Class and a complete review of symptoms (modified 
physical exam) in order to assess subject safety.  
− Week 24 RHC may be scheduled up to 8 weeks beyond the Week 24 visit with 
the subject remaining in this study and on IP. An optional IP dispensing visit may 
be necessary to support the additional 8 weeks. Further delays require discussion 
with the Sponsor’s Medical Monitor.  
− Delays with any other Week 24 assessments require discussion with the Sponsor’s 
Medical Monitor.   
• In order to maintain the integrity of the study, alternative methods of collecting data 
from study procedures, such as questionnaires, may be considered where possible. 
− EQ-5D-5L survey will be administered via telephone by qualified site personnel 
following a documented process. 
− The dosing diary will continue to be self-recorded by the subject at home. 
• Alternative methods of supplying IP to enrolled study subjects (eg, direct-to-subject 
shipment from site) may be considered where possible. 
− Additional IP will not be released to the subject without an evaluation of subject 
safety by the Principal Investigator and clearance verbally communicated to the 
subject with minimum clinical safety laboratory assessments including 
hematology, coagulation, chemistry (Protocol Section 10.2 , Table 7), NT-
proBNP and, for women of child-bearing potential, a urine or serum pregnancy 
test with confirmed negative result. 
− A local laboratory or mobile nurse (e.g., home-health or site nurse) may be 
utilized for collection of laboratory assessments, if available. 
• In the event a subject has a confirmed positive test for SARS-COV-2 (test approved 
by local Health Authority), the infection should be recorded as an AE/SAE, and the 
PI should consult with the medical monitor regarding continuation of IP. 
 
 
 
 
 
 
 












































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11. 
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Rubin DB. Multiple imputation for nonreponse ins surveys. New York: John Wiley and Sons; 
1987. 
 
Shapiro S, Torres F, Feldman J, et al. Clinical and hemodynamic improvements after adding 
ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension 
exhibiting a suboptimal therapeutic response (ATHENA-1). Respir Med. 2017;126:84-92. 
 


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Protocol GB002-2101 
Version 4.0.0, 18 November 2021 
125 
Confidential 
Shukla M, Park JH, Thomas JD, et al. Prognostic value of right ventricular strain using speckle-
tracking echocardiography in pulmonary hypertension: a systematic review and meta-analysis. 
Can J Cardiol. 2018;34(8):1069-1078. 
 
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary 
hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41. 
 
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical 
classification of pulmonary hypertension. Eur Respir J. 2019;53(1). 
 
Sitbon O, Galie N. Treat-to-target strategies in pulmonary arterial hypertension: the importance 
of using multiple goals. Eur Respir Rev. 2010;19(118):272-278. 
 
Sitbon O, Gomberg-Maitland M, Granton J, et al. Clinical trial design and new therapies for 
pulmonary arterial hypertension. The European respiratory journal. 2019;53(1):1801908. 
 
Studer SM, Gilkin RJ, Jr. Clinical trial designs in PAH: shifting from functional measurements 
to long-term clinical outcomes. Am J Manag Care. 2014;20(6 Suppl):S115-122. 
 
Tei C, Dujardin KS, Hodge DO, et al. Doppler echocardiographic index for assessment of global 
right ventricular function. J Am Soc Echocardiogr. 1996;9(6):838-847. 
 
Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements 
of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 
1994;144(2):275-285. 
 
Voswinckel R, Enke B, Reichenberger F, et al. Favorable effects of inhaled treprostinil in severe 
pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol. 
2006;48(8):1672-1681. 
 
Warwick G, Thomas PS, Yates DH. Biomarkers in pulmonary hypertension. Eur Respir J. 
2008;32(2):503-512. 
 
Wensel R, Francis DP, Meyer FJ, et al. Incremental prognostic value of cardiopulmonary 
exercise testing and resting haemodynamics in pulmonary arterial hypertension. Int J Cardiol. 
2013;167(4):1193-1198. 
 
Wu E, Palmer N, Tian Z, et al. Comprehensive dissection of PDGF-PDGFR signaling pathways 
in PDGFR genetically defined cells. PLoS One. 2008;3(11):e3794. 
 
Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular 
phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical 
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SAP_001.pdf: 
CONFIDENTIAL 
 
Page 1 of 47 
STATISTICAL ANALYSIS PLAN  
 
Protocol Number GB002-2101 
 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Clinical Study to Evaluate the Efficacy and Safety of Oral Inhalation of GB002 
for the Treatment of WHO Group 1 Pulmonary Arterial Hypertension (PAH) 
 
 
 
FINAL 
Version 1.0 
27 October 2022 
 
 
 
SPONSORED BY 
 
GB002, Inc. 
3013 Science Park Road, Suite 200 
San Diego, CA 92121 
USA 
 
 
 
PREPARED BY 
 
Gossamer Bio Services, Inc. 
3013 Science Park Road, Suite 200 
San Diego, CA 92121 
USA 
 
 
 
 
 
 
 
This document is confidential and proprietary to GB002, Inc. Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein will be reproduced, published, or otherwise disclosed 
without the prior written approval of GB002, Inc., except that this document may be disclosed to appropriate 
Institutional Review Boards under the condition that they keep the information confidential. 




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Protocol No. GB002-2101 
 
 
 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
APPROVALS ..................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ......................................................................................................10 
2. 
PROTOCOL SUMMARY ..........................................................................................11 
2.1. 
Study Objectives and Endpoints .................................................................................11 
2.2. 
Overall Study Design and Plan ...................................................................................13 
2.3. 
Study Population .........................................................................................................14 
2.4. 
Randomization and Blinding ......................................................................................14 
2.5. 
Sample Size Determination ........................................................................................14 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................15 
3.1. 
General Considerations ...............................................................................................15 
3.2. 
Definition of Baseline .................................................................................................16 
3.3. 
Calculation of Change and Percent Change from Baseline ........................................16 
3.4. 
Study Day Calculation for Reporting Purposes ..........................................................16 
3.5. 
Visit Windowing .........................................................................................................16 
4. 
ANALYSIS POPULATIONS ....................................................................................19 
4.1. 
Enrolled Population ....................................................................................................19 
4.2. 
Intent-to-Treat Population ..........................................................................................19 
4.3. 
Safety Population ........................................................................................................19 
5. 
STUDY SUBJECTS ...................................................................................................20 
5.1. 
Disposition of Subjects ...............................................................................................20 
5.2. 
Protocol Deviations ....................................................................................................20 
6. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS, AND MEDICAL 
HISTORY ...................................................................................................................21 
6.1. 
Demographic and Baseline Characteristics ................................................................21 
6.2. 
Baseline Disease Characteristics ................................................................................21 
6.3. 
Medical History ..........................................................................................................22 
7. 
TREATMENTS AND MEDICATIONS ....................................................................23 
7.1. 
Prior and Concomitant Medications ...........................................................................23 
7.2. 
Extent of Time on Study, Study Drug Exposure, and Compliance ............................23 


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8. 
EFFICACY EVALUATION ......................................................................................25 
8.1. 
Primary Endpoint ........................................................................................................25 
8.1.1. 
Statistical Hypothesis and Estimand ...........................................................................25 
8.1.2. 
Primary Efficacy Analysis ..........................................................................................25 
8.1.3. 
Sensitivity and Supplemental Analyses ......................................................................26 
8.1.4. 
Other Analyses of RHC Results .................................................................................26 
8.2. 
Secondary Endpoint ....................................................................................................27 
8.3. 
Exploratory Endpoints ................................................................................................28 
8.3.1. 
Echocardiography Endpoint .......................................................................................28 
8.3.2. 
Time to Clinical Worsening ........................................................................................29 
8.3.3. 
WHO Functional Class ...............................................................................................30 
8.3.4. 
EQ-5D-5L ...................................................................................................................30 
8.3.5. 
NT-proBNP .................................................................................................................31 
8.3.6. 
Risk Score ...................................................................................................................31 
9. 
SAFETY EVALUATION ..........................................................................................33 
9.1. 
Adverse Events ...........................................................................................................33 
9.1.1. 
Treatment-Emergent Adverse Events .........................................................................33 
9.2. 
Clinical Laboratory Evaluation ...................................................................................34 
9.2.1. 
Serum Chemistry ........................................................................................................35 
9.2.2. 
Hematology .................................................................................................................35 
9.2.3. 
Coagulation .................................................................................................................35 
9.2.4. 
Urinalysis ....................................................................................................................35 
9.2.5. 
Other Laboratory Assessments ...................................................................................36 
9.3. 
Vital Signs ..................................................................................................................36 
9.4. 
12-Lead ECGs ............................................................................................................37 
9.5. 
Pulmonary Function Tests ..........................................................................................37 
10. 
INTERIM ANALYSES AND DATA MONITORING .............................................38 
11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................39 
12. 
REFERENCES ...........................................................................................................40 
13. 
APPENDICES ............................................................................................................41 
13.1. 
Study Schema .............................................................................................................41 
13.2. 
Categories of PAH Disease-Specific Background Medications .................................42 


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13.3. 
REVEAL 2.0 Risk Score Calculator ..........................................................................43 
13.4. 
REVEAL Lite 2 Risk Score Calculator ......................................................................44 
13.5. 
Imputation of Partial and Missing Data ......................................................................45 
13.6. 
MedDRA Terminology SOC List: Internationally Agreed Order ..............................46 
13.7. 
Document Revision History .......................................................................................47 
 
 
  










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Protocol No. GB002-2101 
 
 
 
 
 
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1. 
INTRODUCTION 
This clinical study is being conducted under the sponsorship of GB002, Inc. The data 
management and the statistical analyses are being performed under contract by
 
 with oversight from GB002, Inc. 
 is a contract research organization 
(CRO). 
This statistical analysis plan (SAP) has been developed based on protocol GB002-2101 version 
4.0.0, dated 18 November 2021. This SAP presents a detailed plan of the statistical methods to 
be used during the analysis and reporting of efficacy and safety data collected under this 
protocol. This SAP does not include the planned analysis and reporting of pharmacokinetic (PK) 
assessments, selected biomarker assessments, the substudy of heart rate monitoring, and the 
substudy of changes in the pulmonary vasculature by high-resolution computed tomography 
(HRCT). Planned analyses of those results will be presented in separate analysis plans, as 
needed. 
This SAP was prepared prior to database lock (DBL) to provide full details of the analyses to be 
presented in the clinical study report (CSR), including a technical and detailed elaboration of the 
efficacy and safety analysis methods presented in the protocol. Revisions can be made to this 
SAP while the study is ongoing; however, this SAP must be finalized prior to unblinding the 
study to perform the final analysis. Any deviations from the plan provided in this SAP will be 
considered post-hoc and will be documented as such in the final CSR.   
This SAP is being written in accordance with the recommendations outlined in the International 
Conference for Harmonisation (ICH) E9 Guidance for Industry on Statistical Principles for 
Clinical Trials (FDA, 1998) and the ICH E3 Guidance for Industry on Structure and Content of 
Clinical Study Reports (FDA, 1996). 
This SAP should be read in conjunction with the study protocol and the electronic case report 
forms (eCRFs). 




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• Time from first dose of GB002 to first event of protocol-
defined clinical worsening, assessed by measuring the first 
occurrence of any of the following: 
• 
Death (all causes) 
• 
Hospital admission for worsening PAH, as a result of 
any of the following: 
o Non-elective hospitalization caused by clinical 
conditions directly related to PAH and/or right heart 
failure 
o Need for intravenous (IV) diuretics (more than a 
single dose in 24 hours) 
o Lung or heart-lung transplantation 
o Atrial septostomy 
o Initiation of parenteral (IV infusion or subcutaneous 
injection) therapy with a prostacyclin (if not 
previously utilizing parenteral prostacyclin therapy) 
• 
Disease progression, defined as: 
o Worsening symptoms of right heart failure requiring 
initiation of a new PAH disease-specific medication 
or an increase in dose, or change in disease-specific 
background PAH medications or initiation of 
chronic oxygen therapy (ie, requires oxygen for 
> 24 hours with the intent of long-term use); or 
o A decrease in distance on 6MWT (6MWD) of at 
least 15% from Baseline, directly related to PAH 
progression, confirmed by 2 assessments of 6MWD 
performed at 2 consecutive visits and worsening in 
WHO FC for subjects with WHO FC I/II/III; or 
o Worsening Risk Score Category, defined as a 
change in two components of the Risk Assessment 
to a worse risk category 
• Evaluate the safety of GB002 
on other measures of tolerability 
• Change from Baseline in clinical laboratory parameters, 
electrocardiogram (ECG) parameters, pulmonary function 
and vital signs 
• Evaluate the PK of GB002 
• Plasma concentrations of GB002 and its metabolites, if 
appropriate 
• Evaluate the pharmacodynamics 
(PD) of GB002 in this 
population 
• Change from Baseline in N-terminal pro b-type natriuretic 
peptide (NT-proBNP) 
• Changes from Baseline in biomarkers measured in blood 
samples 


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• Evaluate the effects of GB002 
on Heart Rate Expenditure and 
Heart Rate Recovery during 
6MWT – Substudy at select 
participating sites 
• Change from Baseline in heart rate expenditure and heart 
rate recovery as measured by continuous heart rate 
monitoring during the 6MWT 
• Evaluate changes in the 
pulmonary vasculature by High-
resolution CT – Substudy at 
select participating sites 
• Change from Baseline in pulmonary vasculature blood 
volume, pulmonary blood volume as a percent of total lung 
volume, fibrosis score, and image-based ventilation to 
perfusion score 
• Determine the effect of GB002 
on Risk Score Category 
• Change from Baseline in Risk Score Category based on 
REVEAL v2.0 and European Society of Cardiology 
(ESC)/European Respiratory Society (ERS) 
2.2. 
Overall Study Design and Plan 
This is a double-blind, placebo-controlled, randomized study of oral inhalation of GB002 in 
adult subjects with WHO Group 1 PAH who are WHO FC II and III and have a PVR ≥ 400 
dyne•s/cm5. 
This study will consist of 3 periods: the screening period (up to 5 weeks), the treatment period 
(24 weeks), and the follow-up period (4 weeks) for a total study participation time of up to 
33 weeks per subject.  Subjects who complete the treatment period of this study and qualify for a 
separate open-label extension (OLE) study may enroll directly into the OLE study following the 
treatment period and those who do will not participate in the follow-up period of this study. 
Subjects will initiate dosing with GB002 60 mg (4 inhalations) or placebo BID and, after 2 
weeks, will up titrate to GB002 90 mg (6 inhalations) or placebo BID. Dose modifications 
downward to a minimum of 45 mg (3 inhalations) BID based on tolerability are permitted.  
The first dose of study drug will be administered via oral inhalation using a dry powder inhaler 
(DPI) in the clinic on Day 1 (Visit 2).  Subsequent doses will be taken via oral inhalation using a 
DPI twice daily at home. 
Subjects who permanently discontinue study drug will be encouraged to complete any remaining 
study visits as per the protocol Schedule of Activities. 
An Independent Data Monitoring Committee (IDMC) will regularly monitor overall safety and 
emerging efficacy results, as well as general aspects of study conduct, to ensure that the benefits 
and risks of study participation remain acceptable.   
The study schema is shown in Appendix 13.1. 


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2.3. 
Study Population  
This study will enroll adult female subjects aged 18-75 years, inclusive, and adult male subjects 
aged 50-75 years, inclusive, at the time of signing the Informed Consent Form (ICF). Key 
eligibility criteria include: 
• Current diagnosis of symptomatic PAH with WHO FC II or III symptomatology 
• 
Six-minute walk distance (6MWD) ≥ 150 meters and ≤ 550 meters at Screening 
• Stable treatment (≥ 4 weeks) with standard of care PAH background therapies 
• PVR ≥ 400 dyne•s/cm5 via RHC 
• Forced expiratory volume in 1 second (FEV1) ≥ 70% and either total lung capacity 
(TLC) or forced vital capacity (FVC) ≥ 70% predicted 
2.4. 
Randomization and Blinding 
On Day 1 of the treatment period, subjects who meet the eligibility criteria will be randomized 
1:1 to 1 of 2 treatment groups using interactive response technology (IRT): 
• GB002 BID (40 subjects) 
• Placebo BID (40 subjects) 
Randomization will be stratified by PVR (< 800 dyne•s/cm5, ≥ 800 dyne•s/cm5). 
This is a double-blind study.  Subjects, investigators, other site personnel, and Sponsor (and/or 
designee) personnel who are directly involved in the conduct of the study, collection of the data, 
and analysis of the final safety and efficacy results will remain blinded to treatment assignments 
until after completion of the study and the database has been locked. 
2.5. 
Sample Size Determination 
Based on the results from a Phase 2 study with the PDGFR inhibitor imatinib (Ghofrani, 2010), 
the mean (standard deviation [SD]) decrease from Baseline in PVR over 24 weeks is assumed to 
be 300 (340) dyne•s/cm5 for the GB002 group and 79 (270) dyne•s/cm5 for the placebo group, 
resulting in a GB002 treatment effect (SD) of 221 (305) dyne•s/cm5.  Assuming this treatment 
effect, 40 subjects per treatment group has approximately 90% power to detect a statistically 
significant difference between GB002 and placebo using Satterthwaite’s t-test with α = 0.05, 
two-sided. 
  


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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
3.1. 
General Considerations 
 
Continuous data will be presented using descriptive statistics: number of subjects (n), mean, SD, 
median, minimum, and maximum. Descriptive statistics on selected efficacy measures may also 
include the standard error (SE). Categorical data will be summarized by the number and percent 
of subjects. In general, data will be displayed in listings sorted by treatment group, subject 
number, and visit/study day. When count data are presented, the percent will be suppressed when 
the count is zero. A row denoted “Missing” will be included in count tabulations where 
necessary to account for dropouts and missing values. The denominator for all percentages will 
be the number of subjects in that treatment group within the population of interest, unless 
otherwise stated. Non-zero percentages will be rounded to one decimal place, except 100% will 
be displayed without any decimal places. Additional rounding rules are as follows: 
• If the original value has 0 decimal places: mean and median will have one decimal 
place and SD and SE will have 2 decimal places 
• If the original value has 1 decimal place: mean and median will have 2 decimal places 
and SD and SE will have 3 decimal places 
• If the original value has 2 or more decimal places: mean, median, SD, and SE will all 
have 3 decimal places 
Minimum and maximum will always have the same decimal places as the original measure, up to 
a maximum of 3 decimal places. The above rounding rules will not be applied to original 
measures displayed in listings. 
Values that are collected with “<” or “>” signs will be analyzed as the numerical value without 
the sign in tables and figures. In listings, these data will be reported as collected with the sign. 
All safety and efficacy data will be collected electronically. Datasets will be created using the 
Study Data Tabulation Model (SDTM) v. 1.7 or higher, conforming to the SDTM 
Implementation Guide (SDTMIG) v. 3.3 or higher. Datasets, tables, listings, and figures will be 
programmed using SAS® v 9.4 or higher (SAS Institute Inc., Cary, NC). All safety and efficacy 
data will be listed via the SDTM datasets and selected safety and efficacy data will be listed via 
programmed listings. 
The following treatment groups will be presented: 
• Placebo 
• GB002 
All subjects will be pooled into one of these 2 treatment groups regardless of how much they 
titrate up and/or down or how long they remain on a particular dose. 
Selected tables will also present the following: 
• Total (placebo and GB002 pooled together), for disposition, demographics, baseline 
characteristics, medical history, prior medications, and protocol deviation tables only 


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Protocol No. GB002-2101 
 
 
 
 
 
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The order of columns presented in tables and figures will be as follows: Placebo first, GB002 
second, and where applicable, Total third. 
3.2. 
Definition of Baseline 
Baseline data are defined as the last observed measurements collected, whether scheduled or 
unscheduled, prior to the start of the first dose of study drug (GB002 or placebo) administration 
on Day 1.  
3.3. 
Calculation of Change and Percent Change from Baseline 
Change from Baseline to any timepoint t (Ct) is calculated as follows: 
• Ct = Mt – MB, where: 
o Mt is the measurement of interest at timepoint t 
o MB is the measurement of interest at Baseline 
Percent change from Baseline to any timepoint t (Pt) is calculated as follows: 
• Pt = 100*(Ct/MB) 
3.4. 
Study Day Calculation for Reporting Purposes 
The following convention will be used to calculate study day for reporting purposes: 
• The study day of the first dose of study drug administration (SDA) is Day 1 
For measurements that are on or after the date of the first dose of SDA:  
• Day = date of measurement – date of SDA + 1 
For measurements that are prior to the date of the first dose of SDA: 
• Day = date of measurement – date of SDA 
There is no Day 0. 
3.5. 
Visit Windowing 
The designation of visits (or timepoints) will generally be based on the actual day of evaluation 
relative to the date of first dose of study drug (Day 1), rather than the nominal visit, for any 
analysis that are conducted by visit. 
Mutually exclusive windows containing no gaps will generally be utilized to assign visits for by-
visit analyses and will correspond to post-Baseline visits in the protocol.  Visits for analysis will 
be assigned using the windowing scheme shown below. 




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Protocol No. GB002-2101 
 
 
 
 
 
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If 2 or more evaluations occur in the same visit window, the evaluation closest to the target day 
will be selected for inclusion in the analysis.  If 2 or more evaluations are equally close to the 
target day, then the latest evaluation will be selected for inclusion in the analysis.  If multiple 
evaluations occur on the same day, the average of these evaluations will be used for analysis 
excluding maximum post-Baseline, abnormality, and outlier analyses. 
 
 


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4. 
ANALYSIS POPULATIONS 
4.1. 
Enrolled Population  
All subjects with a non-missing date of informed consent will be included in the Enrolled 
Population.  This population will be used for summaries of disposition.  The subset of subjects 
who enroll and fail screening will additionally be used in demographics reporting. 
4.2. 
Intent-to-Treat Population 
All subjects who are randomized will be included in the Intent-to-Treat (ITT) Population.  This 
population will be used as the primary analysis population for all efficacy endpoints.  Subjects 
will be grouped in this population according to their randomized treatment assignment 
4.3. 
Safety Population 
All subjects who receive any amount of study drug will be included in the Safety Population.  
This population will be used for all summaries of safety data.  Subjects will be grouped as 
follows: any subject that receives only placebo doses will be in the placebo group.  Any subject 
that receives at least one dose of GB002 will be in the GB002 group. 


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Protocol No. GB002-2101 
 
 
 
 
 
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5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects 
A summary of disposition of subjects for the Enrolled Population will include the number and 
percentage of subjects in the following categories except where noted: 
• Subjects enrolled (signed the ICF) 
• Subjects who failed screening with reasons for screen failure 
• Subjects randomized 
• Subjects dosed 
• Subjects completing dosing of study drug 
• Subjects not completing dosing of study drug with reasons for discontinuation 
• Subjects completing study overall and through Week 24 and Week 28 
• Subjects not completing study with reasons for withdrawal 
Only one reason for study drug discontinuation and only one reason for study withdrawal may be 
recorded for each subject. 
Subjects enrolled will display the number only in the Total column. Subjects who failed 
screening will have percentages based on the number of subjects enrolled as the denominator. 
Subjects randomized will display the number only across the treatment group columns and the 
number and percentage in the Total column based on the number of subjects enrolled.  The 
number and percentage of subjects in the ITT Population and in the Safety Population will be 
reported, based on the number of subjects randomized.  Percentages in all other categories will 
be based on the ITT Population. 
A listing of screen failures and a listing of disposition for all randomized subjects will be 
provided.  The randomization scheme will also be listed. 
5.2. 
Protocol Deviations 
Protocol deviations will be identified and reviewed on an ongoing basis by the study team and 
entered into a Clinical Trial Management System (CTMS).  Important protocol deviations are 
defined as those that can affect efficacy and/or safety assessments, the safety of a subject, or the 
scientific value of the study.  Protocol deviations will be classified as important or non-important 
and will be assigned a protocol deviation type prior to unblinding the study.  The number and 
percent of subjects with at least 1 important protocol deviation overall and for each protocol 
deviation type will be summarized for the ITT Population.  In addition, Coronavirus Disease 2019 
(COVID-19) related and non-COVID-19 related important protocol deviations will be 
summarized.   
Protocol deviations will also be listed. 


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Protocol No. GB002-2101 
 
 
 
 
 
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6. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS, AND 
MEDICAL HISTORY 
6.1. 
Demographic and Baseline Characteristics 
Demographics will consist of the following parameters:  
• Age (years) 
• Age category (≥ 18-49, ≥ 50-64, ≥ 65) 
• Sex (female, male) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
Baseline characteristics will consist of the following parameters: 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) [kg/m2] 
• Country (Australia, Belgium, Czech Republic, France, Germany, Spain, United 
Kingdom, United States) 
• Region (North America [United States], Western Europe [Belgium, France, Germany, 
Spain, United Kingdom], Eastern Europe [Czech Republic], Asia Pacific [Australia]) 
Demographics and baseline characteristics will be summarized by treatment group and Total for 
the ITT Population. Demographics only will separately be summarized in a single column for 
screen failure subjects.  Demographics and baseline characteristics will also be listed. 
6.2. 
Baseline Disease Characteristics 
Baseline disease characteristics will be summarized for the ITT Population and include the 
following variables: 
• Age at PAH diagnosis (years) – derived as follows: 
o Age – floor (time since PAH diagnosis) 
• Time since PAH diagnosis (years) – derived as follows: 
o (date IC signed – date of PAH diagnosis)/365.25  
• PAH classification (idiopathic, heritable, associated with connective tissue disease 
[CTD], associated with anorexigen use, associated with methamphetamine use, 
associated with congenital heart disease with simple systemic to pulmonary shunt) 
• Type of connective tissue disease (if applicable – systemic sclerosis, mixed CTD, 
overlap syndrome, systemic lupus erythematosus [SLE]) 
• Time since CTD diagnosis (years) – derived as follows: 


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o (date IC signed – date of CTD diagnosis)/365.25 
• WHO functional classification at Screening and Baseline (Class II, Class III) 
• PVR  
o randomized (< 800 dyne•s/cm5, ≥ 800 dyne•s/cm5) 
o actual (< 800 dyne•s/cm5, ≥ 800 dyne•s/cm5) 
o continuous (dyne•s/cm5) 
o continuous (wood units) 
• 6MWD at Screening #1, Screening #2, and Baseline (m) 
• NT-proBNP (ng/L) 
• Number of PAH disease-specific background medications (< 3, ≥ 3)  
• PAH disease-specific background medications category: 
1. Endothelin receptor antagonists (ERA) 
2. Phosphodiesterase type 5 inhibitors (PDE-5i) 
3. Soluble guanylate cyclase (sGC) stimulators 
4. Prostacyclins or prostacyclin receptor agonist (PRA) 
For the background medications portion of the summary, the number and percent of subjects on 
each of those 4 categories alone (monotherapy) will be presented, along with the number and 
percent of subjects on the following combination therapies: 
• ERA + PDE-5i 
• ERA + PDE-5i + Prostacyclins/PRA 
• ERA + sGC 
• ERA + sGC + Prostacyclins/PRA 
• PDE-5i + Prostacyclins/PRA 
• sGC + Prostacyclins/PRA 
See Appendix 13.2 for a list of PAH disease-specific background medications by category. 
Baseline disease characteristics will also be listed. 
6.3. 
Medical History 
General medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24.0 or later. General medical history will be summarized by System Organ 
Class (SOC) and Preferred Term (PT) for the ITT Population.  General medical history will also 
be listed. 


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7. 
TREATMENTS AND MEDICATIONS 
7.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring before Day 1. 
Concomitant medications are defined as medications that are ongoing on Day 1 or with a start 
date occurring on or after Day 1. Medications with start and stop dates which bracket Day 1, or 
for which missing information makes it impossible to determine the prior or concomitant status, 
will be summarized as concomitant medications. 
All medications will be coded with the World Health Organization Drug Classification 
Dictionary (WHODrug), March 2021 or later. 
Incidence of prior and concomitant medications will be summarized separately for the Safety 
Population by drug class and PT. In addition, incidence of prior PAH disease-specific therapies, 
PAH disease-specific background medications, and concomitant PAH disease-specific 
medications will be summarized separately for the ITT Population by drug class and PT.  At 
each level of summarization, a subject is counted once if that subject reports 1 or more 
medications at that level. Drug class will correspond to the Anatomical Therapeutic Chemical 
(ATC) Level 2 term. 
All prior and concomitant medications, prior PAH disease-specific therapies, and background 
and concomitant PAH disease-specific medications will also be listed.  In addition, all 
concomitant procedures and therapies will be listed 
7.2. 
Extent of Time on Study, Study Drug Exposure, and Compliance 
Duration of study treatment and time on study in subject-days, subject-weeks (subject-days/7), 
and subject-years (subject-days/365.25) will be summarized for the Safety Population.  A 
subject’s duration of study treatment in days will be calculated as last dose date – first dose date 
+ 1.  Drug holidays will be ignored for the purposes of calculating treatment duration.  A 
subject’s time on study in days will be calculated as last assessment date – first dose date + 1. 
Dosing and time on study will also be summarized by the number of weeks completed for the 
following categories: 
•   < 12 weeks 
• 12-15 weeks 
• 16-19 weeks 
• 20-23 weeks 
•   ≥ 24 weeks 
For the purposes of this categorical summary, the duration in subject-weeks will be rounded to 
the nearest integer to determine the category for each subject.   
For each dose level, the expected number of capsules taken per dose is as follows (15 mg active 
pharmaceutical ingredient [API] per capsule): 
• 45 mg: 3 capsules 


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• 60 mg: 4 capsules 
• 75 mg: 5 capsules 
• 90 mg: 6 capsules 
The study is designed such that each subject starts on 60 mg BID and then titrates to 90 mg BID 
after 14 days.  Therefore, the expected number of capsules for a subject that completes dosing on 
schedule (168 days) without further titration is as follows: 
• (4 capsules x 2 [BID] x 14 days) + (6 capsules x 2 [BID] x 154 days) = 1,960 capsules 
For subjects that discontinue early or that titrate the dose other than scheduled will have their 
expected number of capsules adjusted accordingly. 
Note: Protocol v2 specified a maximum dose of 60 mg BID. Any subjects enrolled under that 
amendment and not titrating to 90 mg BID will have their expected number of capsules adjusted 
accordingly. 
Compliance 100*(capsules taken/expected), average BID dose in mg, and total cumulative dose 
in mg will be summarized.  Compliance will also be summarized for the following categories: 
• < 80% 
• 80-100% 
• > 100% 
Extent of time on study, study drug exposure, and compliance will be listed.  Study treatment 
administration, titrations, and lot numbers will also be listed. 


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8. 
EFFICACY EVALUATION 
All analyses of efficacy data will be conducted using the ITT Population.  Unless specified 
otherwise, all statistical analyses will be performed using 2-sided hypothesis tests at the 5% level 
of significance.  Confidence intervals (CI) will be 95% and 2-sided, unless otherwise stated.  All 
efficacy data will be summarized by randomized treatment group and visit, where applicable. 
8.1. 
Primary Endpoint 
8.1.1. 
Statistical Hypothesis and Estimand 
The superiority of GB002 over placebo will be evaluated by testing the following null hypothesis 
(H0) vs. the alternative hypothesis (Ha): 
• H0: There is no difference in ΔPVR after 24 weeks in PAH subjects treated with 
GB002 compared to placebo 
• Ha: There is a difference in ΔPVR after 24 weeks in PAH subjects treated with 
GB002 compared to placebo 
The primary estimand to address the statistical hypothesis is the change in PVR from Baseline to 
Week 24 for each subject in the ITT Population with missing Week 24 PVR values imputed 
using multiple imputation (MI) techniques under the assumption that missing PVR values at 
Week 24 are missing at random (MAR), comparing the estimated least squares mean differences 
(LSMDs) between the GB002 group and the placebo group using an analysis of covariance 
(ANCOVA) model adjusted for treatment, Baseline PVR, and Baseline WHO FC.  Possible 
intercurrent events that could affect whether a post-Baseline PVR value is missing not at random 
(MNAR) or that could affect an observed post-Baseline value itself are initiation of a new PAH 
disease-specific medication or increase in dose of a background PAH disease-specific 
medication, death, or discontinuation due to disease progression.  Intercurrent events affecting 
Week 24 PVR values will be classified and documented prior to DBL. 
8.1.2. 
Primary Efficacy Analysis 
PVR in units of dyne•s/cm5 is calculated as: 
𝑃𝑃𝑃𝑃𝑃𝑃= 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚−𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
𝐶𝐶𝐶𝐶
 𝑥𝑥 80 
where mPAP = mean pulmonary arterial pressure in millimeters of mercury (mmHg), PCWP = 
pulmonary capillary wedge pressure in mmHg, and CO = cardiac output in L/min.  In cases 
where PCWP is missing, left ventricular-end diastolic pressure (LVEDP) in mmHg will be used 
instead. 
RHC from which PVR is collected is scheduled at Baseline and Week 24.  The primary analysis 
of change in PVR from Baseline to Week 24 will be carried out using an ANCOVA model 
adjusted for treatment, Baseline PVR, and Baseline WHO FC.  Results will be expressed as least 
squares (LS) mean changes in PVR and associated SEs, LSMDs and SEs with associated 95% 
CI, and p-values.  Missing PVR values at Week 24 and observed PVR values affected by 
intercurrent events will be imputed using MI.  Fifty imputations will be performed, and the 
resulting 50 complete datasets will be combined to produce a single inference that incorporates 


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uncertainty due to missing data (Rubin, 1987).  Values that are affected by intercurrent events 
and therefore subject to imputation in the primary analysis will be documented prior to DBL. 
A bar graph showing the LS mean and SE for each treatment group along with the LSMD and 
associated p-value will be produced.  PVR results will also be listed. 
The normality of the primary analysis model will be assessed using the Shapiro-Wilk test.  If the 
test indicates that the assumption of normality is violated, then the primary analysis of PVR 
effects will be repeated in 2 ways: first by repeating the primary analysis model on the difference 
in log transformed PVR values and second by using a Wilcoxon rank sum test on non-
transformed PVR changes.   
8.1.3. 
Sensitivity and Supplemental Analyses 
Sensitivity and supplemental analyses will include the following: 
• Repeating the primary analysis on percent change in PVR 
• Repeating the primary analysis (without MI) on the subgroup of subjects with 
observed post-Baseline PVR values 
• Repeating the primary analysis (without MI) on the subgroup of subjects who 
complete at least 20 weeks of treatment and have an observed Week 24 PVR 
• Repeating the primary analysis on the following subgroups: 
o Females 
o Number of PAH disease-specific background medications (< 3, ≥ 3) 
o Presence of Prostacyclins at Baseline (yes, no) 
o Age groups (< median, ≥ median; < 65, ≥ 65) 
o Race (white, non-white) 
o Region (North America, rest of world [ROW]) 
o PVR strata (< 800 dyne•s/cm5, ≥ 800 dyne•s/cm5) 
o WHO FC at Baseline (II, III) 
o CTD (yes, no) 
o Risk Score using REVEAL 2.0 (< 6, ≥ 6) 
A forest plot showing the primary analysis result along with each of the subgroup results will be 
produced.   
Note: the expected number of males enrolled in the study is ≤ 12 (15%), so no supplemental 
analysis is planned on males.  If the actual male enrollment is ≥ 8 per group, then an analysis of 
ΔPVR in males will also be performed. 
8.1.4. 
Other Analyses of RHC Results 
Changes from Baseline to Week 24 in the following parameters will be analyzed using an 
ANCOVA model adjusted for treatment, Baseline value of the parameter of interest, PVR strata, 


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and Baseline WHO FC.  Results will be expressed as LS mean changes and associated SEs, 
LSMDs and SEs with associated 95% CI, and p-values.  Missing values will not be imputed. 
• Mean right atrial pressure (mRAP) 
• RV systolic pressure 
• PCWP or LVEDP 
• Pulmonary artery (PA) systolic pressure 
• PA diastolic pressure 
• mPAP 
• CO 
• Cardiac index 
• PVR index (PVRi) 
• Stroke volume (SV) (calculated as 1000*CO/heart rate) 
• PA pulsatility index (PAPi) (calculated as [PA systolic pressure – PA diastolic 
pressure]/mRAP) 
• PA compliance (PAC) (calculated as SV/[PA systolic pressure – PA diastolic 
pressure]) 
• Systemic vascular resistance index (SVRi) 
Other RHC results will also be listed.  A bar graph showing the LS mean and SE for each 
treatment group along with the LSMD and associated p-value will be produced for mPAP and 
CO. 
8.2. 
Secondary Endpoint 
The 6MWT is scheduled at Screening, Baseline, Week 12, and Week 24. If the 6MWT is not 
done at a post-Baseline visit due to PAH disease progression, the change from Baseline value 
will be imputed to the worst observed value across all subjects. The secondary endpoint of 
change from Baseline to Week 24 in 6MWD will be analyzed using a mixed-effects model with 
repeated measures (MMRM) with treatment, Baseline 6MWD, Baseline WHO FC, PVR strata, 
visit, Baseline 6MWD by visit interaction, and treatment by visit interaction as fixed effects. 
MMRM will be performed using a restricted maximum-likelihood (REML) based approach with 
unstructured covariance to model within-subject error.  Parameters will be estimated via REML 
using the Newton-Raphson algorithm.  Results will be expressed as LS mean changes in 6MWD 
and associated SEs, LSMDs and SEs with associated 95% CI and p-values with the Kenward-
Roger adjustment (Kenward, 1997).  If the model fails to converge due to the complexity of the 
model specification, alternative methods to enable model convergence will be explored, such as 
employing a log transformation of the 6MWT results.   


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Sensitivity and supplemental analyses will include the following: 
• Performing MI for missing 6MWT results and repeating the primary analysis of 
6MWD on the full dataset (MMRM with MI) 
• Running ANCOVA on both the Week 12 and Week 24 6MWD results adjusted for 
treatment, Baseline 6MWD, Baseline WHO FC, and PVR strata on the full dataset 
after performance of MI (ANCOVA with MI) 
• Repeating the ANCOVA model (without MI) on the subset of subjects with observed 
post-Baseline values at, or carried forward to, each timepoint 
• Repeating the primary analysis on the subset of subjects who complete at least 20 
weeks of treatment and have an observed Week 24 6MWT 
• Repeating the primary analysis on the same subgroups listed in Section 8.1.3  
A forest plot showing the primary analysis result along with each of the subgroup results will be 
produced.  A bar graph showing the LS mean and SE for each treatment group along with the 
LSMD and associated p-value will also be produced. 
6MWT results will also be listed. 
8.3. 
Exploratory Endpoints 
Sensitivity and supplemental/subgroup analyses indicated for the primary and secondary 
endpoints are not planned to be performed on any of the exploratory endpoints.   
8.3.1. 
Echocardiography Endpoint 
ECHO is performed at Screening, Week 12, and Week 24.  ECHO endpoints include the 
following: 
• Change from Baseline in: 
o TAS’ 
o RVFWS 
o Right ventricular fractional area change (RVFAC) 
o Tricuspid annular plane systolic excursion (TAPSE) 
o Tricuspid regurgitation (TR) velocity 
o Right atrial size (RAA) 
o Pericardial effusion 
o estimated systolic PA pressure (sPAP) 
o TAPSE:sPAP Ratio 
o RV:left ventricular (LV) Basal Diameter Ratio 
o Left ventricular ejection fraction (LVEF) 




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Subjects who do not progress to clinical worsening during the study will be censored on the date 
of their last study visit.   
TTCW will be compared between treatment groups via a Cox proportional hazards model using 
the exact method to handle ties in event times, adjusted for treatment, PVR strata, and Baseline 
WHO FC.  The estimated hazard ratio with corresponding 95% CI and p-values will be reported.  
The percent reduction in hazard and corresponding 95% CI will also be reported.  A Kaplan-
Meier analysis will be run to report the median TTCW, 25th and 75th percentiles (if estimable), 
along with associated 95% CI.  Kaplan-Meier curves will be produced, and the logrank test 
stratified by PVR strata and Baseline WHO FC will be used to compare differences in the 
curves. 
The number and percentage of subjects who progress to clinical worsening in each treatment 
group along with the 95% binomial CI (or exact CI if the number of subjects is small) will be 
reported.  The difference in proportion between the treatment groups, 95% CI, and p-value will 
be reported using the Cochran-Mantel-Haenszel (CMH) method adjusted for treatment, PVR 
strata, and Baseline WHO FC, using modified ridit scores. The number and percentage of 
subjects meeting each one of the clinical worsening components will also be presented in a table, 
with subjects counted only once for the component first met.   
Clinical worsening results will also be listed. 
Note: if the number of clinical worsening events is so low that the 25th percentile cannot be 
estimated, TTCW analyses will not be performed and will be listed only. 
8.3.3. 
WHO Functional Class  
WHO FC is assessed at Screening, Baseline, Week 12, and Week 24.  For the analysis of change 
in WHO FC, subjects will be assigned to one of the 3 categories as follows: 
1. Improved: II → I; III → II; III → I 
2. No Change: II → II; III → III 
3. Worsened: II → III; III → IV; II → IV 
The distribution of subjects in each category by visit will be analyzed using the CMH method 
adjusted for treatment, PVR strata, and Baseline WHO FC, using modified ridit scores.  The 
number and percentage of subjects in each category will be reported, along with p-values.  The 
number and percentage of subjects by WHO FC will also be reported.  Missing values will not be 
imputed.  
WHO FC results will also be listed. 
8.3.4. 
EQ-5D-5L 
The EQ-5D-5L is collected at Baseline, Week 12, and Week 24.  This questionnaire is designed 
to profile a subject’s current health state across 5 dimensions:  
• Mobility 
• Self-Care 
• Usual Activities 


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• Pain/Discomfort 
• Anxiety/Depression 
Each dimension is comprised of a single question with 5 possible responses that are scored 1-5 
(EQ-5D-5L User Guide v 3.0, Sept. 2019). In addition, there is a 6th question asking the subject 
to assess their overall health on a visual analogue scale (VAS) with a range of 0-100. 
Change from Baseline for each dimension will be analyzed using an ANCOVA model adjusted 
for treatment, Baseline dimension response, PVR strata, and Baseline WHO FC.  Results will be 
expressed as LS mean changes and associated SEs, LSMDs, and SEs with associated 95% CI, 
and p-values.  Missing values will not be imputed. 
Change from Baseline in overall health VAS responses will be analyzed using an ANCOVA 
model adjusted for treatment, Baseline VAS response, PVR strata, and Baseline WHO FC.  
Results will be expressed as LS mean changes and associated SEs, LSMDs, and SEs with 
associated 95% CI, and p-values.  Missing values will not be imputed. 
EQ-5D-5L results will also be listed. 
8.3.5. 
NT-proBNP 
NT-proBNP is measured at Baseline and Weeks 4, 8, 12, 24 and Follow-up. Change from 
Baseline in NT-proBNP will be analyzed using a MMRM similar to that described in 
Section 8.2, with treatment, Baseline NT-proBNP, Baseline WHO FC, PVR strata, visit, 
Baseline NT-proBNP by visit interaction, and treatment by visit interaction as fixed effects.  
Mean and SE for actual values and changes from Baseline over time will be plotted.   
The distribution of NT-proBNP will be analyzed by visit using the CMH method adjusted for 
treatment, Baseline NT-proBNP, PVR strata, and Baseline WHO FC, using modified ridit scores.  
The categories are as follows: 
• Low: < 300 ng/L 
• Medium: 300 – <1100 ng/L 
• High: ≥ 1100 ng/L 
The number and percentage of subjects in each category will be reported, along with p-values.  
Missing values will not be imputed.  
NT-proBNP results will also be listed. 
8.3.6. 
Risk Score 
Components of the Risk Score are assessed at Baseline, Week 12, and Week 24.  Risk Score will 
be evaluated 2 ways: the first using REVEAL 2.0 criteria (Benza, 2019), and the second using 
the REVEAL Lite 2 criteria (Benza, 2021). 
Risk Score using the REVEAL 2.0 criteria is calculated using 13 variables across 11 categories 
(see Appendix 13.3) resulting in a score that ranges from 0-23, with a minimum of 7 of 13 


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variables required to generate a score.  Risk of clinical worsening is then assigned to one of 
3 categories based on the score: 
1. 0-6: Low Risk 
2. 7-8: Intermediate Risk 
3. ≥ 9: High Risk 
Risk Score using REVEAL 2.0 includes components of the RHC and as such will only be 
analyzed at Baseline and Week 24.  The distribution of subjects across the 3 categories will be 
reported at both Baseline and Week 24.  The exploratory endpoint of change from Baseline in 
Risk Score will be analyzed using an ANCOVA model adjusted for treatment, Baseline Risk 
Score, PVR strata, and Baseline WHO FC.  Results will be expressed as LS mean changes and 
associated SEs, LSMDs and SEs with associated 95% CI, and p-values.  
Risk Score using the REVEAL 2.0 Lite criteria is calculated using 6 variables (see 
Appendix 13.4) resulting in a score that ranges from 1 to 14, with a minimum of 3 variables 
required to generate a score where at least 2 are of the most predictive variables (NT-proBNP, 
6MWT, WHO FC).  Risk of clinical worsening is then assigned to one of 3 categories based on 
the score: 
1. ≤ 5: Low Risk 
2. 6-7: Intermediate Risk 
3. ≥ 8: High Risk 
Risk Score using REVEAL 2.0 Lite can be calculated at Baseline, Week 12, and Week 24.  The 
distribution of subjects across the 3 categories will be reported at all 3 visits.  The exploratory 
endpoint of change from Baseline in Risk Score will be analyzed using a MMRM similar to that 
described in Section 8.2, with treatment, Baseline Risk Score, Baseline WHO FC, PVR strata, 
visit, Baseline Risk Score by visit interaction, and treatment by visit interaction as fixed effects. 
Risk Score results will also be listed. 


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9. 
SAFETY EVALUATION 
All analyses of safety data will be conducted using the Safety Population.  No statistical 
hypothesis testing of any safety results will be performed.  All safety data will be summarized by 
actual treatment group as described in Section 4.3. 
9.1. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
study subject, whether considered related to the study drug or not. A SAE is an AE occurrence 
that results in death, is life-threatening, requires inpatient hospitalization or prolongation of 
existing inpatient hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital abnormality/birth defect. Important medical events that may not be immediately life-
threatening or result in death, or require hospitalization may be considered SAEs when, based 
upon medical judgment, they may jeopardize the subject or may require intervention to prevent 
one of the outcomes listed above. 
For an event to be a TEAE, it must meet one of the following conditions: 
• Begins on Day 1, during or after administration of the first dose of study drug 
• Begins after Day 1 
• Begins before Day 1 and worsens in severity during or after the administration of the 
first dose of study drug 
AEs with unknown start dates or unknown end dates will be counted as TEAEs unless the event 
resolves before Day 1.  
AEs will be coded using MedDRA version 24.0 or higher. Only TEAEs will be presented in AE 
tables, according to the SOC and/or PT. Any AEs that occur and resolve prior to Day 1 or are 
ongoing but do not worsen on or after Day 1 will be considered pretreatment AEs and will 
appear in the AE listing but not in TEAE tables. 
9.1.1. 
Treatment-Emergent Adverse Events 
The incidence of TEAEs table will include only 1 occurrence of a PT per subject. If a subject 
reports the same PT multiple times, then that PT will only be incremented by 1 since subject 
counts will be presented. As with the PT, if a subject reports multiple TEAEs within the same 
SOC, then that SOC will only be incremented by 1 since subject counts will be presented. For 
tables showing incidence by SOC and PT, SOCs will be sorted by the internationally agreed 
order (see Appendix 13.6) and PTs will be sorted within SOC in descending order of incidence 
in the GB002 column. For tables showing incidence by PT only, the PTs will be sorted in 
descending order of incidence in the GB002 column.  
An overall summary of TEAEs will be presented, and will include the following: 
• Number of TEAEs 
• Number and percent of subjects with:  
o at least 1 TEAE 


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o  at least 1 severe TEAE 
o  at least 1 related TEAE 
o at least 1 TEAE leading to study drug discontinuation 
o at least 1 TEAE leading to study withdrawal 
o at least 1 AESI 
• Number of SAEs 
• Number and percent of subjects with: 
o at least 1 SAE 
o at least 1 related SAE 
o a fatal TEAE 
The following additional adverse event summaries will be presented: 
• Incidence of TEAEs by SOC and PT 
• Incidence of TEAEs by PT 
• Incidence of Severe TEAEs by SOC and PT 
• Incidence of Related TEAEs by SOC and PT 
• Incidence of TEAEs leading to study drug discontinuation by SOC and PT 
• Incidence of TEAEs leading to study withdrawal by SOC and PT 
• Incidence of AESIs by SOC and PT 
• Incidence of SAEs by SOC and PT 
AESIs fall into 2 categories based on safety concerns seen in the class of PDGFR kinase 
inhibitors: bleeding and cardiac effects and are collected directly on the eCRF. 
All AEs will be presented in a listing.  TEAEs leading to study drug discontinuation and/or study 
withdrawal, AESIs, SAEs and fatal TEAEs will be presented in separate listings. 
9.2. 
Clinical Laboratory Evaluation 
Summary tables for serum chemistry, hematology, coagulation, and quantitative and qualitative 
urinalysis values including actual values and change from Baseline values will be presented for 
clinical laboratory tests with numeric results. These tables will include each visit (Baseline, 
Weeks 4, 8, 12, 18, 24, Follow-up), highest postdose value, and lowest postdose value. For 
urinalysis results with categorical values, summary tables will present the number and 
percentage of subjects in each category at each visit.  All laboratory values will be reported in 
standard international (SI) units, where available. 
Shift tables will be presented for serum chemistry, hematology, and coagulation parameters 
showing shifts from Baseline to highest and lowest post-Baseline values, whether scheduled or 
unscheduled, based on laboratory normal ranges.  


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Listings of laboratory values will include flags for values outside the central laboratory normal 
ranges that indicate how far out of the normal range an abnormal value is. For example, a value 
that is ≥ 3 times the upper limit of normal (ULN) but below 4 times the ULN will have a “3H” 
flag. Flag multipliers will show values that are 1, 2, 3, 4, 5, 8, 10, and 20 times relative to the 
ULN if high (> for all ULNs except ≥ 3). Values that are below the lower limit of normal (LLN) 
will be flagged simply with “L”.  Normal ranges from the central laboratories will also be listed.  
9.2.1. 
Serum Chemistry 
The following parameters will be included in the serum chemistry summary tables: alanine 
aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase 
(AST), bicarbonate, blood urea nitrogen (BUN), calcium, chloride, cholesterol, creatinine, direct 
bilirubin, gamma-glutamyl transferase (GGT), glucose, lactate dehydrogenase (LDH), lipids, 
magnesium, phosphorus, potassium, sodium, total bilirubin, total protein, triglycerides, and uric 
acid. 
Associated serum chemistry parameters such as hepatic profile (ALT, albumin, ALP, AST, direct 
bilirubin, GGT, total bilirubin), electrolytes (bicarbonate, calcium, chloride, magnesium, 
phosphorus, potassium, sodium), lipid profile (cholesterol, lipids, and triglycerides), renal profile 
(BUN, creatinine), and other (glucose, LDH, total protein, uric acid) will be sorted/grouped 
together in table and listing presentations.  
A summary table of maximum post-Baseline values for hepatic profile serum chemistry 
parameters by ULN category will be presented.  Evaluation of drug-induced serious 
hepatotoxicity (eDISH) scatterplots of the highest postdose ALT vs. total bilirubin observed at 
the same draw as the high ALT value, of the highest postdose AST vs. total bilirubin observed at 
the same draw as the high AST value, and of the highest of either ALT/AST vs. total bilirubin 
observed at the same draw as the high value will also be produced. 
9.2.2. 
Hematology 
The following parameters will be included in hematology summary tables: hematocrit, 
hemoglobin, platelet count, red blood cell (RBC) count with mean corpuscular volume (MCV) 
and mean corpuscular hemoglobin (MCH), and total and differential white blood cell (WBC) 
count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
9.2.3. 
Coagulation 
The following laboratory tests will be included in coagulation summary tables: partial 
thromboplastin time (PTT), prothrombin time, and international normalized ratio (INR). 
9.2.4. 
Urinalysis 
The following laboratory tests will be included in urinalysis summary tables: pH and specific 
gravity (numeric summary), and appearance, bilirubin, blood, color, glucose, ketones, leukocyte 
esterase, nitrite, protein, and urobilinogen (categorical summary). 




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9.4. 
12-Lead ECGs 
ECG parameters include heart rate (beats/min), PR interval (ms), QRS duration (ms), QT interval 
(ms), and Fridericia’s correction formula for QT interval (QTcF) interval (ms) and will be collected 
at Screening, Baseline, Weeks 4, 8, 12, 18, and 24. Overall interpretations of ECG results are 
also included.  
A summary table including actual values and changes from Baseline will be presented for ECG 
results. ECG results will also be listed. 
The number and percentage of subjects with the following clinically relevant abnormalities will 
be summarized at each visit and overall. 
• QTcF values: 
o > 450 ms 
o > 480 ms 
o > 500 ms 
• Change from Baseline in QTcF values: 
o > 30 ms 
o > 60 ms 
Clinically relevant ECG abnormalities will be flagged in the listing. 
9.5. 
Pulmonary Function Tests 
PFTs will be performed at Screening and Week 24. The following PFTs will be collected: 
• FVC 
• FEV1 
• Diffusing capacity of the lungs for carbon monoxide (DLCO) 
• FEV1/FVC ratio 
• Percent predicted for each of the above parameters 
A summary table including actual values and changes from Baseline will be presented for PFTs.  
PFT results will also be listed. 


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10. 
INTERIM ANALYSES AND DATA MONITORING 
No formal interim analyses will be performed. 
An IDMC, comprised of 2 independent external expert physicians and an independent 
biostatistician will regularly monitor overall safety and emerging efficacy results, as well as 
general aspects of study conduct, to ensure that the benefits and risks to subjects of study 
participation remain acceptable.  Based on these regular reviews of emerging results, the IDMC 
will recommend to the Sponsor continuation, modification, or termination of the study.  Makeup 
of the IDMC, meeting structure, schedule, and procedures, including communication between 
the Sponsor and the IMDC, the content and format of IDMC reports, and other relevant details 
can be found in the IDMC Charter and the IDMC SAP. 


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Protocol No. GB002-2101 
 
 
 
 
 
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11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
The formal interim analysis described in the protocol will not be performed.  The estimand and 
primary analysis model specified in the protocol inadvertently left out the WHO FC covariate; it 
has been added to the SAP.  The tipping point analysis specified in the protocol has been 
eliminated due to the anticipated low amount of missing RHC data.  The endpoint regarding 
change from Baseline in risk score category will be analyzed using REVEAL 2.0 and the 
REVEAL Lite 2, as opposed to REVEAL 2.0 and the ESC/ERS criteria.  RV Tei index was not 
collected and therefor the endpoint regarding change from Baseline in RV Tei index will not be 
performed.  As of the writing of this SAP there are no other changes to the analyses and 
endpoints disclosed in the protocol. 
 


GB002, Inc. 
 
Statistical Analysis Plan, v1.0 
Protocol No. GB002-2101 
 
 
 
 
 
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CONFIDENTIAL 
 
 
Page 40 of 47 
12. 
REFERENCES 
Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting survival in patients with 
pulmonary arterial hypertension: The REVEAL Risk Score Calculator 2.0 and comparison with 
ESC/ERS-based risk assessment strategies. Chest. 2019;156(2):323-337. 
Benza RL, Kanwar MK, Raina A, et al. Development and validation of an abridged version of 
the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for use in patients with pulmonary 
arterial hypertension. Chest. 2021;159(1):337-346. 
Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension 
patients with inadequate response to established therapy. Am J Respir Crit Care Med. 
2010;182(9):1171-1177. 
Kenward, MG. Small sample inference for fixed effects from restricted maximum likelihood. 
Biometrics. 1997;53:983-997. 
Leuchte HH, Ten Freyhaus H, Gall H, et al. Risk stratification strategy and assessment of disease 
progression in patients with pulmonary arterial hypertension: Updated recommendations from 
the Cologne Consensus Conference 2018. Int J Cardiol. 2018;272S:20-29. 
Rubin DB. Multiple imputation for response in surveys. New York: John Wiley & Sons, Inc.; 
1987.  
US Federal Register. International Conference on Harmonisation; Guidance for Industry: 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration, Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register. International Conference on Harmonisation; Guidance for Industry: 
Structure and Content of Clinical Study Reports. Department of Health and Human Services: 
Food and Drug Administration, Federal Register Vol. 61, July 17, 1996, page 37320.  


GB002, Inc. 
 
Statistical Analysis Plan, v1.0 
Protocol No. GB002-2101 
 
 
 
 
 
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CONFIDENTIAL 
 
 
Page 41 of 47 
13. 
APPENDICES 
13.1. 
Study Schema 
 
Abbreviations: 1° EP, primary endpoint; BID, twice daily; ECHO, echocardiogram; BL, Baseline; PVR, pulmonary 
vascular resistance; RHC, right heart catheterization; Scr, Screening; 6MWT, six-minute walk test; WK, week. 
* After 2 weeks, all subjects should be dose escalated, as tolerated, to 90 mg BID. Should a dose reduction be 
required, after discussion with the Sponsor’s Medical Monitor (or designee), dose reduction to 60 mg BID, and if 
not tolerated, further dose reduction to 45 mg BID will be allowed.  
* A 4-week safety follow up will not be required for subjects transitioning to OLE.    




GB002, Inc. 
 
Statistical Analysis Plan, v1.0 
Protocol No. GB002-2101 
 
 
 
 
 
 27 October 2022 
CONFIDENTIAL 
 
 
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13.3. 
REVEAL 2.0 Risk Score Calculator 
 
Source: Benza, 2019 


GB002, Inc. 
 
Statistical Analysis Plan, v1.0 
Protocol No. GB002-2101 
 
 
 
 
 
 27 October 2022 
CONFIDENTIAL 
 
 
Page 44 of 47 
13.4. 
REVEAL Lite 2 Risk Score Calculator 
 
Source: Benza, 2021