A Randomized, Double-blind, Placebo-Controlled, Dose Escalation Study to Assess Safety, Efficacy and Pharmacokinetics of GMA301 in Subjects With Pulmonary Arterial Hypertension
Phase: PHASE1
Conditions: Pulmonary Arterial Hypertension
Sponsor: Gmax Biopharm LLC.

Protocol Amendment 2 
CONFIDENTIAL 
Covance Study: 000000180905 
Sponsor Reference: GETA_MAD_01 
 
Final Protocol Amendment 2, 17 March 2020 
Page 1 of 10 
Summary of Amended Protocol Changes 
A Randomized, Double-blind, Placebo-Controlled, Dose Escalation Study to 
Assess Safety, Efficacy and Pharmacokinetics of GMA301 in Subjects with 
Pulmonary Arterial Hypertension 
Protocol Version 3.0 Status: Final 
Original Protocol Date: 14 August 2019 
Protocol Date: 17 March 2020 
Study Drug: GMA301 Injection 
 
Sponsor Reference Number: GETA_MAD_01 
Covance Study Number: 000000180905 
 
 
 
Sponsor: 
Gmax Biopharm LLC. 
Room 302, Building No. 2, 288 Qiuyi Road 
Binjiang District, Hangzhou, 310052, China 
 
 
 
Sponsor Signatory: 
Shuqian JING 
 
Principal Investigators: 
Raymond L. Benza M.D 
Zhicheng JING M.D 
 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the Sponsor. 
________________________________________ 
 
 

Protocol Amendment 2 
CONFIDENTIAL 
Covance Study: 000000180905 
Sponsor Reference: GETA_MAD_01 
 
Final Protocol Amendment 2, 17 March 2020 
Page 2 of 10 
The primary changes in this amendment, along with the rationale for the changes as 
appropriate, are: 
1. To update the English protocol based on Chinese protocol version 4.0 (dated 25Feb2020). 
• To update the version of Registry to Evaluate Early and Long-term Pulmonary 
Arterial Hypertension Disease Management (REVEAL) calculator to be used in 
the study 
• To clarify exclusion criteria regarding echocardiogram 
• To clarify drug concentration will be determined in serum 
• To clarify the dose delivery method should be IV injection 
2. To clarify that pregnancy test will be done in females of reproductive potential. 
3. To specify Baseline REVEAL score should be collected at randomization. 
Minor changes: 
1. The synopsis was updated according to the changes in the protocol body, as applicable. 
2. The amendment/version number and date were updated throughout the protocol. 
3. Typographical errors and formatting errors were corrected, as necessary. 
4. Abbreviations were added and/or removed, as appropriate. 
A detailed summary of changes is presented below: 
Section 2.2.2 
Previously read: 
• Pharmacokinetics 
o Area under the plasma concentration- time curve from time zero to the last 
measurable concentration (AUC0-t) 
o Area under the plasma concentration- time curve over a dosing interval (AUC0-tau) 
o Observed maximum serum concentration (Cmax) 
o Time to maximum Area under the serum concentration-time curve from time zero to 
infinity (AUC0-inf) 
o serum concentration (Tmax) 
o Terminal elimination half-life (t1/2) 
o Volume of distribution  
o Trough concentration  
o Clearance  
o Accumulation ratio  

Protocol Amendment 2 
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Final Protocol Amendment 2, 17 March 2020 
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Now reads: 
• Pharmacokinetics 
o Area under the serum concentration- time curve from time zero to the last measurable 
concentration (AUC0-t) 
o Area under the serum concentration- time curve over a dosing interval (AUC0-tau) 
o Observed maximum serum concentration (Cmax) 
o Area under the serum concentration-time curve from time zero to infinity (AUC0-inf) 
o Time to maximum serum concentration (Tmax) 
o Terminal elimination half-life (t1/2) 
o Volume of distribution  
o Trough concentration  
o Clearance  
o Accumulation ratio  
 
Section 3.1 
Previously read: 
Subjects will be sequentially recruited into 3 ascending dose treatment cohorts with GMA301-
assigned subjects receiving either 300, 600 or 1000 mg injections of the study drug depending on 
their assigned cohort. Each cohort will contain 12 subjects, 9 of whom will be administered 
active GMA301 and 3 of whom will be administrated placebo. All subjects will undergo IV 
infusion at baseline, Week 4, and Week 8. 
Now reads: 
Subjects will be sequentially recruited into 3 ascending dose treatment cohorts with GMA301-
assigned subjects receiving either 300, 600 or 1000 mg injections of the study drug depending on 
their assigned cohort. Each cohort will contain 12 subjects, 9 of whom will be administered 
active GMA301 and 3 of whom will be administrated placebo. All subjects will undergo IV 
injection at baseline, Week 4, and Week 8. 
 
Section 3.3 
Previously read: 

Protocol Amendment 2 
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Sponsor Reference: GETA_MAD_01 
 
Final Protocol Amendment 2, 17 March 2020 
Page 4 of 10 
The selection of the GMA301 dosing frequency of Q4W via IV infusion at baseline and then at 4 
and 6 weeks was based on the available clinical safety, tolerability and PK data obtained from 
healthy human subjects.18 
Now reads: 
The selection of the GMA301 dosing frequency of Q4W via IV injection at baseline and then at 
Week 4 and Week 8 was based on the available clinical safety, tolerability and PK data obtained 
from healthy human subjects.18 
 
Section 4.1 
Previously read: 
5. Right heart catheterization (RHC) result meets below criteria when screening. 
a. Mean pulmonary arterial pressure (PAP) ≥25 mmHg 
b. Pulmonary vascular resistance (PVR) >3 Woods units  
c. PA wedge pressure (PAWP) ≤15 mmHg 
if subject has undergone RHC within 3 months before screening, the waveform results will serve 
as baseline data if they meet entry criteria and the baseline RHC will not be repeated. 
6. Has been taking at least one oral PAH targeted drug that has been approved by local 
guidelines for at least 3 months before screening with a stable dosage and associated 
PAH symptoms in this period.  
Now reads: 
5. Has been taking at least one oral PAH targeted drug that has been approved by local 
guidelines for at least 3 months before screening with a stable dosage and the disease did 
not worsen during this period.  
6. Right heart catheterization (RHC) result meets below criteria when screening. 
d. Mean pulmonary arterial pressure (PAP) ≥25 mmHg 
e. Pulmonary vascular resistance (PVR) >3 Woods units  
f. PA wedge pressure (PAWP) ≤15 mmHg 
if subject has undergone RHC within 3 months before screening, the waveform results will serve 
as baseline data if they meet entry criteria and the RHC at Screening will not be repeated. 
 
Section 4.2 
Previously read: 
5. Pulmonary function test: FEV1<60%, TLC<60%, DLCO<60%; 
[…] 
10. Echocardiogram (ECHO) demonstrating at least 1 of the following:  

Protocol Amendment 2 
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Final Protocol Amendment 2, 17 March 2020 
Page 5 of 10 
a. LVEF <50% 
b. Mean end-diastolic left ventricular septal and posterior wall thickness of >12 mm 
and one of the following: 
i. 
Left atrial (LA) area on apical 4 chamber view >20 cm2 
ii. 
LA volume by biplane modified Simpsons or area-length methods >55 mL 
iii. 
LA volume index >29 mL/m2 
c. Significant valvular heart disease including moderate or severe mitral or aortic 
stenosis with an aortic valve area <1.0 cm2 or mitral valve area <1.5 cm2), greater 
than moderate aortic or mitral regurgitation, greater than moderate tricuspid or 
pulmonic stenosis 
Now reads: 
5. Pulmonary function test: FEV1<60% of predicted, TLC<60% of predicted, DLCO<60% 
of predicted; 
[…] 
10. Echocardiogram (ECHO) demonstrating at least 1 of the following:  
a. LVEF <50% 
b. Mean end-diastolic left ventricular septal and posterior wall thickness of >12 mm 
c. Left atrial (LA) area on apical 4 chamber view >20 cm2 
d. LA volume by biplane modified Simpsons or area-length methods >55 mL 
e. LA volume index >29 mL/m2 
f. 
Significant valvular heart disease including moderate or severe mitral or aortic 
stenosis with an aortic valve area <1.0 cm2 or mitral valve area <1.5 cm2), greater 
than moderate aortic or mitral regurgitation, greater than moderate tricuspid or 
pulmonic stenosis 
 
Section 5.2 
Previously read: 
The 300 (5 mg/kg), 600 (10 mg/kg), and 1000 mg (16.6 mg/kg) doses of GMA301 and matching 
placebo will be administered Q4W via IV injection by slow push for 12 weeks.  
Now reads: 
The 300, 600, and 1000 mg doses of GMA301 and matching placebo will be administered Q4W 
via IV injection by slow push for 12 weeks. 
 
Section 7.1.2 
Previously read: 
Plasma concentrations of GMA301 will be determined using validated analytical procedures. 
Specifics of the analytical methods will be provided in separate documents. 

Protocol Amendment 2 
CONFIDENTIAL 
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Final Protocol Amendment 2, 17 March 2020 
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Now reads: 
Serum concentrations of GMA301 will be determined using validated analytical procedures. 
Specifics of the analytical methods will be provided in separate documents. 
 
Section 7.2.2 
Previously read: 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, and 
will undergo an alcohol breath test at the times indicated in the Schedule of Assessments in 
Appendix 6. For all female subjects, a pregnancy test will be performed at the times indicated in 
the Schedule of Assessments in Appendix 6. 
Now reads: 
For females of reproductive potential, a pregnancy test will be performed at the times indicated 
in the Schedule of Assessments in Appendix 6. 
 
Section 7.3.3 
Previously read: 
The 6MWT will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. The operation details of 6MWT is described in the Site Operation Menu. 
Now reads: 
The 6MWT will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. The operation details of 6MWT is described in the Site Operation Menu. Borg 
index score will be collected immediately after 6MWTs. 
 
Section 8.5 
Previously read: 
Non-compartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of GMA301 
and PK parameters will be listed and summarized using descriptive statistics. Individual and 
mean GMA301 concentration-time profiles will also be presented graphically. 

Protocol Amendment 2 
CONFIDENTIAL 
Covance Study: 000000180905 
Sponsor Reference: GETA_MAD_01 
 
Final Protocol Amendment 2, 17 March 2020 
Page 7 of 10 
Now reads: 
Non-compartmental PK analysis will be performed on individual serum concentration data, using 
commercial software such as Phoenix® WinNonlin®. Serum concentrations of GMA301 and PK 
parameters will be listed and summarized using descriptive statistics. Individual and mean 
GMA301 concentration-time profiles will also be presented graphically. 
 
Section 8.6 
Previously read: 
AEs will be coded by System Organ Class and Preferred Term using the current version of the 
MedDRA dictionary. Safety parameters will be listed and summarized using descriptive 
statistics. No formal statistical analysis of safety data is planned. Safety data will be summarized 
by dose group. Incidences of TEAEs (those events that started after exposure to study drug or 
worsened in severity after dosing) will be presented by dose group as well. Incidences of TEAEs 
will be presented by maximum severity and relationship to study medication. AEs will be 
classified according to whether they are covered by the Standardized MedDRA Query of 
Pulmonary Hypertension, and incidences will be presented by maximum severity. 
Now reads: 
AEs will be coded by System Organ Class and Preferred Term using the current version of the 
MedDRA dictionary. Safety parameters will be listed and summarized using descriptive 
statistics. No formal statistical analysis of safety data is planned. Safety data will be summarized 
by dose group. Incidences of TEAEs (those events that started after exposure to study drug or 
worsened in severity after dosing) will be presented by dose group as well. Incidences of TEAEs 
will be presented by maximum severity and relationship to study medication. 
 
Appendix 6: Schedule of Assessments 
Changes to the Schedule of Assessments: 
• Footnote d was added to clarify that Week 12 tests can also be done on the last day of 
Week 11. If a subject discontinues the visit in advance, it would be better to ask the 
subject to complete the Week 12 examinations. 
• Baseline REVEAL risk score will be collected at randomization. 
 

Protocol Amendment 2 
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Covance Study: 000000180905 
Sponsor Reference: GETA_MAD_01 
 
Final Protocol Amendment 2, 17 March 2020 
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Appendix 6: Pharmacokinetics sampling 
Previously read: 
Pharmacokinetics sampling: 
Pharmacokinetics plasma samples will be obtained for PK assessments at the following 
timepoints (±Time window): 
Now reads: 
Pharmacokinetics sampling: 
Pharmacokinetics serum samples will be obtained for PK assessments at the following 
timepoints (±Time window): 
 
 

Protocol Amendment 2 
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Covance Study: 000000180905 
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Final Protocol Amendment 2, 17 March 2020 
Page 9 of 10 
Appendix 7 
Previously read: 
 
Calculated risk scores can range from 0 (lowest risk) to 22 (highest risk). If N-terminal proBNP is available and BNP is not, 
listed cut points are replaced with, 300 pg/mL and 1500 pg/mL. APAH 5 associated pulmonary arterial hypertension; BNP 5 
brain natriuretic peptide; BPM 5 beats per minute; CTD 5 connective tissue disease; DLco 5 diffusing capacity of lung for carbon 
monoxide; FPAH 5 familial pulmonary arterial hypertension; HR 5 heart rate; mRAP 5 mean right atrial pressure; NYHA 5 New 
York Heart Association; PAH 5 pulmonary arterial hypertension; PoPH 5 porto pulmonary hypertension; PVR 5 pulmonary 
vascular resistance; REVEAL Registry 5 Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease 
Management; SBP 5 systolic BP; WHO 5 World Health Organization. 

Protocol Amendment 2 
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Covance Study: 000000180905 
Sponsor Reference: GETA_MAD_01 
 
Final Protocol Amendment 2, 17 March 2020 
Page 10 of 10 
Now reads: 
Calculated risk scores can range from 0 (lowest risk) to 23 (highest risk). BNP = brain natriuretic peptide; BPM = beats per 
minute; CTD-PAH = PAH associated with connective tissue disease; DLco = diffusing capacity of the lungs for carbon 
monoxide; eGFR = estimated glomerular filtration rate; FC = functional category; HR = heart rate; mRAP = mean right atrial 
pressure; NT-proBNP = N-terminal fragment of pro-brain natriuretic peptide; NYHA = New York Heart Association; 
PAH = pulmonary arterial hypertension; PoPH = pulmonary hypertension associated with portopulmonary hypertension; 
PVR = pulmonary vascular resistance; REVEAL Registry = Registry to Evaluate Early and Long-term Pulmonary Arterial 
Hypertension Disease Management; SBP = systolic BP; WHO = World Health Organization. 

Protocol 
A Randomized, Double-blind, Placebo-Controlled, Dose Escalation Study 
to Assess Safety, Efficacy and Pharmacokinetics of GMA301 in Subjects 
with Pulmonary Arterial Hypertension  
Protocol Status: Final 
Protocol Date: 17 Mar 2020 
Protocol Version: 3.0 
Investigational Product: GMA301 Injection  
 
Protocol Reference Number: GETA_MAD_01 
 
 
 
 
Sponsor: 
Gmax Biopharm LLC. 
Room 302, Building No. 2, 288 Qiuyi Road 
Binjiang District, Hangzhou, 310052, China 
 
 
 
 
Sponsor Signatory: 
Shuqian JING 
 
Principal Investigators: 
Raymond L. Benza M.D 
Zhicheng JING M.D 
 
 
 
This protocol may not be reproduced or communicated to a third party without the written 
permission of Gmax Biopharm LLC. 

Protocol No.: GETA_MAD_0l 
SPONSOR APPROVAL SIGNATURE 
r have read the protocol and approve it to be conducted in compliance with the 
International Council for Harmonisation guidelines for Good Clinical Practice and 
applicable regulatol) requirements. 
Shuqian JIBG 
Chief Executive Officer, Gmax Biopharm LLC. 
Protocol Version 3.0 
Page 2 of 57 

Protocol No.: GETA_MAD_OI
INVESTIGATOR APPROVAL SIGNATURE
This study will be conducted in compliance with the clinical study protocol (and
amendments), the International Council for Hannonisation guidelines for current
Good Clinical Practice and applicable regulatory requirements.
Zhicheng JING M.D. 
Protocol Version 3.0 
Page 3 of57 

Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
Page 4 of 57 
INVESTIGATOR APPROVAL SIGNATURE 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), the International Council for Harmonisation guidelines for current 
Good Clinical Practice and applicable regulatory requirements. 
Raymond L. Benza M.D. 
Date 
May 22, 2020 

 
Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
Page 5 of 57 
STUDY PERSONNEL 
Sponsor 
Gmax Biopharm LLC.  
Room 302, Building No. 2, 288 Qiuyi Road 
Binjiang District, Hangzhou, 310052, China 
Sponsor Contact (Project) 
Quanyu SU,  
Project Director  
Gmax Biopharm LLC.  
Room 308, Building No.1, 288 Qiuyi Road 
Binjiang District, Hangzhou, 310052, China  
Sponsor Contact (Medical) 
Chuan YOU. 
Medical Director 
Gmax Biopharm LLC.  
Room 308, Building No. 1, 288 Qiuyi Road 
Binjiang District, Hangzhou, 310052, China 
Principal Investigators 
Zhicheng JING M.D. 
Peking Union Medical College Hospital 
No.1 Shuaifuyuan Wangfujing Dongcheng 
District, Beijing, China 100730 
Tel: (0086) 10-69156114 
 
Dr. Raymond L. Benza M.D.  
Allegheny General Hospital 
20 East North Avenue 16th Floor – South Tower 
Pittsburgh, Pennsylvania, 15212, US 
Tel: (001) 412-359-3584 
Clinical Laboratory  
Covance Pharmaceutical Research and 
Development (Shanghai) Co., Ltd 
Bioanalytical Laboratory 
Covance Pharmaceutical Research and 
Development (Shanghai) Co., Ltd 
Statistical Analysis 
Covance Pharmaceutical Research and 
Development (Beijing) Co., Ltd Shanghai Branch 

 
Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
Page 6 of 57 
SYNOPSIS 
Title of Study: A Randomized, Placebo-Controlled, Double-blind, Dose Escalation Study 
to Assess Safety, Efficacy and Pharmacokinetics of GMA301 Injection in Subjects with 
Pulmonary Arterial Hypertension 
Objectives:  
The primary objective is: 
• To assess the safety and tolerability of GMA301 following repeated intravenous 
(IV) doses in subjects with World Health Organization (WHO) Group 1 pulmonary 
arterial hypertension (PAH) 
The secondary objectives are: 
• To determine the pharmacokinetics (PK) and dose/exposure-response relationships 
of GMA301  
• To evaluate the effects of GMA301 on hemodynamics 
• To evaluate the effects of GMA301 on exercise tolerance 
• To evaluate the effects of GMA301 on relevant PAH biomarkers 
 
The exploratory objectives are: 
• To evaluate the effects of GMA301 on REVEAL 2.0 risk score 
Study Design: 
This is a randomized, placebo-controlled, double-blind, dose escalation study to assess the 
safety, efficacy and PK of GMA301 in PAH subjects with WHO functional class II to III 
who are taking approved targeted therapy other than endothelin receptor antagonists 
(ERAs). Treatment will include 3 sequential dose-ascending cohorts, each with 9 subjects 
receiving GMA301 injection and 3 subjects receiving GMA301 matching placebo injection 
(total of 36 subjects; in the ratio of 3:1). Patients in the ascending dose cohorts who are 
assigned to active GMA301 will be administered 300, 600, or 1000 mg of GMA301 based 
on their assigned cohort as described above.  
 
Subjects will undergo a Screening Period of up to 4 weeks and those proceeding to 
randomization will receive GMA301 or placebo at baseline, Week 4 and Week 8 visits. 
Subjects will be evaluated for safety, efficacy and pharmacokinetics at Weeks 4, 8, and 12 
visits.  
 
Dose escalation criteria for each cohort will be assessed by a Safety Review Committee 
(SRC) prior to escalating to the next higher dose cohort. The initial SRC meeting will 
review safety data from the initial 8 subjects in Cohort 1 who have completed 3 doses of 
the study drug and have been followed for 28 days following the third dose. If no safety 
issues are identified, Cohort 2 will be opened for recruitment once the residual 4 subjects 
have been randomized in Cohort 1. The second meeting of the SRC will review safety data 
from the initial 8 subjects in Cohort 2 and the 4 residual subjects from Cohort 1 who 
were not yet reviewed. If no safety issues are identified, once the residual 4 subjects in 
Cohort 2 are randomized, there will be notification to sites that Cohort 3 can be initiated for 
recruitment. If fewer than 8 subjects (including 8) in a cohort, with some drop-outs, have 

 
Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
Page 7 of 57 
completed administration and follow-up regimen, their safety data will be reviewed by SRC 
aiming to determine whether the next cohort with a higher dose can be started. 
Number of Subjects: 
A total of 36 subjects will be recruited from approximately 7 PAH sites in China and 3 in 
the United States (US). 
Subject Eligibility: 
The subject eligibility will be determined by the following inclusion and exclusion criteria: 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. Male or female, aged 18 to 75 years inclusive 
2. WHO Group 1 PAH related to one of the following conditions: 
a. Idiopathic  
b. Heritable  
c. Drugs or toxins-induced  
d. Associated with connective tissue disease  
e. Associated with congenital heart disease if subjects underwent surgical 
correction more than 12 months before Screening  
3. Symptoms due to PAH are consistent with WHO functional class II- III; 
4. Have not taken endothelin receptor antagonists (ERAs) within 3 months before 
randomization. 
5. Has been taking at least one oral PAH targeted drug that has been approved by local 
guidelines for at least 3 months before screening with stable dosage and the disease 
did not worsen during this period. 
6. Right heart catheterization (RHC) result meets below criteria when screening. 
a. Mean pulmonary arterial pressure (PAP) ≥25 mmHg 
b. Pulmonary vascular resistance (PVR) >3 Woods units  
c. PA wedge pressure (PAWP) ≤15 mmHg 
* if a subject has undergone RHC within 3 months before screening, the waveform results 
will serve as baseline data if they meet entry criteria; and the RHC at Screening will not be 
repeated.  
7. Has a six-minute walk test (6MWT) with distance between 150 to 450 meters at 
Screening.  
8. The dosage of digitalis drugs or L-arginine supplementation must be stable for at 
least 1 month before Screening, if applicable. 
9. No new use of an IV diuretic, cardiotonic or vasoactive drug within 30 days before 
screening.  
10. Both male and female subjects agree to use a medically acceptable method of 
contraception throughout the entire study period from informed consent signing to 
90 days after last dose, if the possibility of conception exists. Medically acceptable 
methods of contraception include oral, implantable, or injectable contraceptives 
(starting 2 months before dosing); diaphragm with vaginal spermicide; intrauterine 
device; condom and partner using vaginal spermicide; and surgical sterilization (6 
months after surgery). Women who are surgically sterile or those who are 
postmenopausal for at least 2 years are not considered to be of childbearing 
potential. Eligible male and female subjects must agree not to participate in a 

 
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Protocol Version 3.0 
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conception process (i.e. active attempt to become pregnant or to impregnate, sperm 
donation, in vitro fertilization) during the study and for 90 days after the last dose of 
study drug. 
11. Body weight no less than 40 kg at Screening. 
12. Able to understand and willing to sign the Informed Consent Form (ICF) and 
comply with the study procedures. 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be allowed to participate in this 
study: 
1. Diagnosed with WHO Group II, III, IV, V of PH;  
2. Using calcium channel blockers when Screening; 
3. BP>160/100mmHg at Screening; 
4. Systolic BP <90 mmHg at Screening; 
5. Pulmonary function test: FEV1<60% of predicted, TLC<60% of predicted, 
DLCO<60% of predicted; 
6. One of the following tests with confirmed pulmonary embolism and/or chronic 
thrombo-embolic pulmonary hypertension (CTEPH) following initial diagnosis of 
PAH: 
a. Pulmonary ventilation/perfusion scan 
b. CT pulmonary angiogram 
c. Contrast dye pulmonary angiogram 
7. History of sleep apnea.  
8. Limited full participation in the 6MWT due to arthritic, neuromuscular, vascular or 
other diseases unrelated to PAH. 
9. History of acute cardiovascular and/or cerebrovascular events within 6 months 
before screening.  
10. Echocardiogram (ECHO) demonstrating at least one of the following: 
a. LVEF <50% 
b. Mean end-diastolic left ventricular septal and posterior wall thickness of 
>12 mm 
c. Left atrial (LA) area on apical 4 chamber view >20 cm2 
d. LA volume by biplane modified Simpsons or area-length methods >55 mL 
e. LA volume index >29 mL/m2 
f. Significant valvular heart disease including moderate or severe mitral or 
aortic stenosis with an aortic valve area <1.0 cm2 or mitral valve area 
<1.5 cm2), greater than moderate aortic or mitral regurgitation, greater than 
moderate tricuspid or pulmonic stenosis 
11. Restrictive, dilated or hypertrophic cardiomyopathy or constrictive pericarditis 
12. Using non-oral prostacyclin when screening;  
13. Laboratory parameters during screening: 
a. Baseline aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥2 times the upper limit of normal (ULN) or total bilirubin ≥1.5 
times ULN 
b.  Estimated glomerular filtration rate (eGFR) <60 mL/min by Cockcroft-
Gault formula 
c. Hemoglobin concentration ≤100 g/L at screening 
14. QTc interval by Fridericia’s criteria (QTcF) ≥500 msec at screening 

 
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15. Malignancy within 5 years before screening visit (with the exception of localized 
non-metastatic basal cell carcinoma of the skin, non-metastatic carcinoma of the 
prostate or in-situ carcinoma of the cervix excised with curative results) 
16. Alcohol or drug abuse within 1 year before screening 
17. A psychiatric, addictive or other disorder that compromises the ability to give 
informed consent for participating in this study 
18. History of organ transplantation 
19. Pregnant or nursing females 
20. History of HIV 
21. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), or 
HIV antibody (HIV-ab). 
22. Enrolled in another interventional study within 30 days before screening.  
23. Any condition that, in the opinion of the investigator, prevents a potential subject 
from safely participating in the study. 
Investigational products, dose, and mode of administration: 
Test products: GMA301  
Proposed dose levels: 300, 600, and 1000 mg every 4 weeks (Q4W) for 12 weeks  
Administration route: IV  
Duration of subject participation in the study: 
Planned Screening duration: up to 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 22 weeks. 
Endpoints: 
Primary Endpoints 
The incidence of Treatment Emergent Adverse Events (TEAE) after the start of GMA301 
dosing compared with placebo. 
Secondary Endpoints 
• Pharmacokinetics 
o Area under the serum concentration- time curve from time zero to the last 
measurable concentration (AUC0-t) 
o Area under the serum concentration- time curve over a dosing interval (AUC0-
tau) 
o Observed maximum serum concentration (Cmax) 
o Area under the serum concentration-time curve from time zero to infinity 
(AUC0-inf) 
o Time to maximum serum concentration (Tmax) 
o Terminal elimination half-life (t1/2) 
o Volume of distribution  
o Trough concentration  
o Clearance  
o Accumulation ratio  
 

 
Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
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• Comparison of GMA301 treatment effect at Week 12 versus baseline regarding the 
hemodynamic parameters based on RHC. Parameters include:  
o Pulmonary vascular resistance (PVR)  
o Mean PAP 
o Cardiac index 
 
• Comparing the following treatment effect metrics: 
o 6MWT distance (Week 12 versus screening) 
o NT-pro BNP level (Weeks 4, 8, and 12 versus baseline) 
o WHO functional class (Weeks 8 and 12 versus baseline) 
 
Exploratory Endpoints 
• Changes in REVEAL 2.0 risk score at Week 12 compared with baseline 
Statistical methods: 
 
Safety: 
Adverse events (AEs) will be coded by System Organ Class and Preferred Term using the 
current version of the MedDRA dictionary. Safety parameters will be listed and 
summarized using descriptive statistics. No formal statistical analysis of safety data is 
planned. Safety data will be summarized by dose group. Incidences of TEAEs (those events 
that started after exposure to study drug or worsened in severity after dosing) will be 
presented by dose group as well. Incidences of TEAEs will be presented by maximum 
severity and relationship to study medication. 
 
Laboratory test results, ECG results, vital sign results and their changes from baseline will 
be summarized using descriptive statistics. Shift tables comparing baseline results to the 
worst post baseline results will be presented for laboratory results and ECG overall 
interpretation. Other safety measurements like physical examinations will be presented in 
listings. 
 
Pharmacokinetics: 
Individual serum concentrations of GMA301 will be listed and summarized using 
descriptive statistics. Individual and mean GMA301 concentration-time profiles will be 
presented graphically.  
 
Where data are available, GMA301 dose proportionality will be examined across the dose 
level. The PK parameters will be analyzed for dose proportionality using a power model 
approach or analysis of variance (ANOVA) model as appropriate.  
 
Efficacy: 
Efficacy endpoints include hemodynamic parameters, 6-minute walk distance, NT-pro BNP 
levels, WHO functional class, and their change from baseline will be listed and summarized 
by treatment group using descriptive statistics as appropriate at each collection timepoint. 

 
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Exploratory Analyses: 
REVEAL 2.0 risk score and their change from baseline will be listed and summarized 
descriptively by treatment group at each collection timepoint. 
 
 

 
Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
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TABLE OF CONTENTS 
SPONSOR APPROVAL SIGNATURE .................................................................. 2 
INVESTIGATOR APPROVAL SIGNATURE ...................................................... 3 
INVESTIGATOR APPROVAL SIGNATURE ...................................................... 4 
STUDY PERSONNEL ............................................................................................ 5 
SYNOPSIS ............................................................................................................... 6 
Primary Endpoints ....................................................................................... 9 
Secondary Endpoints ................................................................................... 9 
TABLE OF CONTENTS ....................................................................................... 12 
LIST OF TABLES AND FIGURES ..................................................................... 14 
LIST OF ABBREVIATIONS ................................................................................ 15 
1. 
INTRODUCTION ......................................................................................... 17 
1.1. 
Overview .............................................................................................. 18 
1.2. 
Summary of Nonclinical Pharmacology .............................................. 18 
1.3. 
Summary of Safety Pharmacology ...................................................... 19 
1.4. 
Summary of Nonclinical Pharmacokinetics......................................... 19 
1.5. 
Summary of Clinical Experience ......................................................... 20 
1.5.1. 
Safety ......................................................................................... 20 
1.5.2. 
Pharmacokinetics ....................................................................... 20 
1.6. 
Study Rationale .................................................................................... 20 
1.7. 
Benefit-risk Assessment ...................................................................... 21 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 21 
2.1. 
Objectives ............................................................................................ 21 
2.1.1. 
Primary Objective ...................................................................... 21 
2.1.2. 
Secondary Objectives ................................................................ 21 
2.1.3. 
Exploratory Objectives .............................................................. 21 
2.2. 
Endpoints ............................................................................................. 22 
2.2.1. 
Primary Endpoints ..................................................................... 22 
2.2.2. 
Secondary Endpoints ................................................................. 22 
2.2.3. 
Exploratory Endpoints ............................................................... 22 
3. 
INVESTIGATIONAL PLAN ........................................................................ 23 
3.1. 
Overall Study Design and Plan ............................................................ 23 
3.2. 
Study Start and End of Study Definitions ............................................ 25 
3.3. 
Discussion of Study Design, Including the Choice of Control 
Groups .................................................................................................. 25 
3.4. 
Dose selection in the Study .................................................................. 26 
3.5. 
Safety Review Committee (SRC) ........................................................ 27 
3.6. 
Stopping and Subjects withdraw Criteria ............................................ 28 
4. 
SELECTION OF STUDY POPULATION ................................................... 29 
4.1. 
Inclusion Criteria ................................................................................. 29 
4.2. 
Exclusion Criteria ................................................................................ 30 

 
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4.3. 
Subject Number and Identification ...................................................... 31 
5. 
STUDY DRUGS ............................................................................................ 32 
5.1. 
Description, Storage, Packaging, and Labeling ................................... 32 
5.2. 
Study drug Administration ................................................................... 32 
5.3. 
Randomization ..................................................................................... 32 
5.4. 
Blinding ............................................................................................... 32 
5.5. 
Treatment Compliance ......................................................................... 32 
5.6. 
Drug Accountability ............................................................................ 33 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS .............. 33 
6.1. 
Concomitant Therapies ........................................................................ 33 
6.2. 
Diet ....................................................................................................... 33 
6.3. 
Smoking ............................................................................................... 33 
6.4. 
Exercise ................................................................................................ 33 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................... 34 
7.1. 
Pharmacokinetic Assessments ............................................................. 34 
7.1.1. 
Sample Collection and Processing ............................................. 34 
7.1.2. 
Analytical Methodology ............................................................ 34 
7.2. 
Safety and Tolerability Assessments ................................................... 34 
7.2.1. 
Adverse Events .......................................................................... 34 
7.2.2. 
Clinical Laboratory Evaluations ................................................ 35 
7.2.3. 
Vital Signs .................................................................................. 35 
7.2.4. 
Electrocardiogram ...................................................................... 35 
7.2.5. 
Physical Examination ................................................................ 36 
7.2.6. 
Body Weight .............................................................................. 36 
7.2.7. 
Immunogenicity (ADA) ............................................................. 36 
7.2.8. 
Pregnancy test ............................................................................ 36 
7.3. 
Efficacy Assessments: ......................................................................... 36 
7.3.1. 
Right heart catheterization (RHC) ............................................. 36 
7.3.2. 
Echocardiogram (ECHO) .......................................................... 36 
7.3.3. 
Six-minute walk test (6MWT) ................................................... 36 
7.3.4. 
NT-pro-BNP .............................................................................. 37 
7.3.5. 
WHO functional class ................................................................ 37 
7.3.6. 
The REVEAL risk score ............................................................ 37 
8. 
SAMPLE SIZE AND DATA ANALYSIS .................................................... 37 
8.1. 
General Analysis .................................................................................. 37 
8.2. 
Determination of Sample Size ............................................................. 37 
8.3. 
Analysis Populations ............................................................................ 37 
8.3.1. 
Pharmacokinetic Population ...................................................... 37 
8.3.2. 
Safety Population ....................................................................... 38 
8.4. 
Demographics and Other Baseline Characteristics .............................. 38 
8.4.1. 
Baseline demographics .............................................................. 38 

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8.4.2. 
Medical History ......................................................................... 38 
8.5. 
Pharmacokinetic Analyses ................................................................... 38 
8.6. 
Safety Analysis .................................................................................... 38 
8.7. 
Efficacy Analyses ................................................................................ 39 
8.8. 
Exploratory Analyses ........................................................................... 39 
8.9. 
Interim Analysis ................................................................................... 39 
9.
REFERENCES .............................................................................................. 39
10. APPENDICES ............................................................................................... 42
Appendix 1: Adverse Event Reporting ............................................................ 42 
Appendix 2: Clinical Laboratory and other Evaluations ................................. 45 
Appendix 3: Total Blood Volume ................................................................... 46 
Appendix 4: Contraception Guidance .............................................................. 47 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations .......... 49 
Appendix 6: Schedule of Assessments ............................................................ 52 
Appendix 7: The REVEAL Risk Score ........................................................... 56 
LIST OF TABLES AND FIGURES 
Table 1: Pharmacokinetics Parameters of GMA301 in monkeys .................... 20 
Table 2: Proposed Investigational Medicinal Product Dose Levels ................ 27 
Figure 1: Study Schematic ............................................................................... 24 
Figure 2: Planned Dose Levels ........................................................................ 25 

 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
6MWT 
6-Minute Walk Test  
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
AUC0-Inf 
Area Under the Serum Concentration-Time Curve from Time 
Zero to Infinity 
AUC0-T 
Area Under the Serum Concentration-Time Curve from Time 
Zero to the Last Measurable Concentration T Time  
AUC0-Tau 
 
Area Under the Serum Concentration- Time Curve Over a Dosing 
Interval  
BP 
Blood Pressure 
CFR 
cGMP 
Code of Federal Regulations 
Cyclic Guanosine Monophosphate 
CHO 
Chinese Hamster Ovary  
Cmax 
Observed Maximum Serum Concentration 
CRO 
Contract Research Organization 
CSA 
Clinical Study Agreement 
SRC 
Safety Review Committee  
EC 
Ethics Committee 
ECG 
ECHO 
Electrocardiogram 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
eGFR 
Electronic Data Capture 
estimated glomerular filtration rate 
ERA 
Endothelin Receptor Antagonist 
ET 
Endothelin 
ETA 
Endothelin Receptor Type A 
ETB 
Endothelin Receptor Type B 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
Gmax 
Gmax Biopharm Australia Pty Ltd 
GMP 
HIV 
Good Manufacturing Practice 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 

 
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INR 
International Normalized Ratio  
IRB 
Institutional Review Board 
IV 
Intravenous  
IWRS 
Interactive Web Response System 
LA 
Left Atrial 
MedDRA  
Medical Dictionary for Regulatory Activities  
NOAEL 
No Observed Adverse Effect Level 
PAH 
Pulmonary Arterial Hypertension  
PAP 
Pulmonary Artery Pressure 
PH 
PI 
Pulmonary Hypertension 
Primary Investigator 
PK 
Pharmacokinetic 
PVR 
Pulmonary Vascular Resistance 
Q4W 
Every Four Weeks 
QTc 
QT Interval Corrected for Heart Rate 
QTcF 
REMS 
QT Interval Corrected for Heart Rate Using Fridericia’s Method 
Risk Evaluation Mediation Strategy 
RHC 
Right Heart Catheterization 
RVSP 
Right Ventricular Systolic Pressure 
SAE 
SAP 
Serious Adverse Event 
Statistical Analysis Plan 
t1/2 
Terminal Elimination Half-Life 
Tmax 
Time to aximum serum concentration 
TMF 
Trial Master File 
ULN 
Upper Limit of Normal  
WHO 
World Health Organization  
 
 

 
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1. INTRODUCTION 
Pulmonary arterial hypertension (PAH) is a rare, progressive, life-threatening disease 
caused by obliteration of the small, peripheral pulmonary arteries by endothelial and 
smooth muscle cell proliferation and in-situ thrombosis. Progressive obstruction of the 
distal arteries leads to increasing pulmonary vascular resistance (PVR), pulmonary 
artery pressure, right heart failure, severe debilitation and, eventually death.1 Of the 
5 categories of pulmonary hypertension described at the 5th World Symposium on 
Pulmonary Hypertension held in Nice, France, in 2013, PAH is classified as Group 1 
indicating that it is a primary vascular disease and not caused by post-capillary pressure 
backup from left heart disease, parenchymal lung disease or pre-capillary chronic 
thromboembolic disease. PAH most commonly has no clear cause or association 
(idiopathic) but can be genetically based, drug or toxin-induced or associated with 
collagen vascular disease, congenital heart disease, human immunodeficiency virus 
(HIV), portal hypertension or schistosomiasis.2 While an imbalance of vasoconstrictive 
and vasorelaxant factors is felt to be an underlying cause of progressive disease in all 
forms of PAH, the end results in all cases include pulmonary arteriolar constriction, in-
situ thrombosis and pulmonary vascular remodeling.3  
An array of pharmacotherapeutic approaches for PAH have been developed over the 
past two decades and provide dramatic improvement in PAH-associated symptoms and 
quality of life. 4 Most of these molecules have been approved based on short-term (12 
to 24 week) studies demonstrating improvement in exercise tolerance primarily 
demonstrated by increasing distance on the 6MWT. More recently, reduction of disease 
progression with the mixed endothelin receptor antagonist macitentan and the selective 
prostacyclin receptor agonist selexipag has been reported. 5,6 
Based on data obtained over three decades ago by the US National Institutes of Health, 
patients with untreated PAH have a median survival of 2.8 years. To date, no single 
therapy, with the possible exception of intravenous epoprostenol,7 has been clearly 
associated with increased survival. This may be due to the small sample sizes and 
limited follow-up of individual studies. Indeed, there are clear trends in improved 
survival. Meta-analysis combining studies averaging 14.8 weeks of follow-up suggest 
that current treatment modalities may have had a substantial impact on survival though 
this has yet to be clearly documented in a long-term outcome study. 8  
Current pharmacologic treatment of PAH leverages imbalances in vasoconstrictive/ 
vasodilatory pathways including the endothelin, nitric oxide and prostacyclin systems. 
Based on some studies showing improvement in clinical outcomes, there is an 
increasing use of initial combined therapy.9 The actual sequencing of treatment 
additions is not entirely clear though prostanoids are not usually prescribed as initial 
therapy.9 Treatment options currently include prostanoids, synthetic analogues of 
prostacyclin, and the prostacyclin receptor agonist, selexipag, which have vasodilatory 
as well as antiproliferative effects. Vasodilator drugs work by increasing cyclic 
guanosine monophosphate (cGMP) downstream and include the phosphodiesterase-5 
inhibitors (e.g. sildenafil and tadalafil), which reduce cGMP degradation and the 
soluble guanylate cyclase agonists (e.g. riociguat) which both stimulate soluble 
guanylyl cyclase production and sensitize cGMP to nitric oxide. 
Endothelin-1 (ET-1) is a 21 amino acid endothelial cell-derived polypeptide and one of 
the most potent vasoconstrictors known. Stimulation of the endothelin type A and B 

 
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g-protein-coupled receptors (ETA and ETB) causes vascular smooth muscle contraction 
and stimulates smooth muscle proliferation. Thus, blockade of ET-1 may have both 
vasodilatory and antiproliferative effects which could blunt or even reverse pulmonary 
vascular remodeling. While principally found in endothelial cells, a range of other cells 
types have also been shown to express endothelin including cardiac myocytes, lung 
epithelium, glomerular kidney cells, mesangial cell, leukocytes, and macrophages. 
ETA receptors, found largely in smooth muscle cells, play an important vasoconstrictive 
role in PAH. In contrast, the ETB receptors which are found mostly in smooth muscle, 
primarily promote vasodilation by mediating ET-1 clearance as well as endothelial 
production of nitric oxide and prostacyclin..10,11,12 Current endothelin receptor 
antagonists (ERAs) employed in PAH are designed to selectively block the ETA 
receptor but are incompletely selective. Bosentan, the first of the ERAs approved for 
clinical use, is relatively non-selective and has an affinity for the ET-A receptor which 
is 20 times that of the ET-B receptor. In contrast, ambrisentan has over 4000-fold higher 
the affinity for the ETA receptor.13,14 Macitentan is a modification of bosentan designed 
to reduce side effects. While generally considered a dual ERA, it actually has greater 
selectivity for the ETA receptor. Also, macitentan is more tissue specific. 15 
Despite having a strong therapeutic track record since bosentan first became clinically 
available in 2002, the ERAs have some safety concerns. Anemia, headache and nasal 
congestion are common in all of the ERAs. Bosentan has the risk for hepatotoxicity and 
the Food and Drug Administration (FDA) requires monthly monitoring of liver function 
tests in patients taking this drug. While ambrisentan and macitentan have not shown 
strong evidence of hepatotoxicity in clinical trials the FDA still considers this a possible 
class effect and requires baseline liver function testing and warning to patient about 
possible hepatotoxicity symptoms. 
Due to concerns about fetal toxicity in all ERAs, the FDA has mandated risk evaluation 
mediation strategy (REMS) programs which require female patients of child-bearing 
potential to undergo a formal education in the ERA risks. 
Gmax Biopharm LLC. has invented GMA301 as a potential new drug for the treatment 
of PAH. 
1.1. 
Overview 
GMA301 is an anti-endothelin receptor type A humanized monoclonal antibody. The 
molecular weight is around 148kDa. 
1.2. 
Summary of Nonclinical Pharmacology 
The completed nonclinical studies of GMA301 include in vitro potency testing, in vivo 
efficacy study in cynomolgus monkeys, single and repeat doses pharmacokinetics (PK) 
and toxicity studies also in cynomolgus monkeys.  
An in vitro study of the biological activity of GMA301 was conducted in Chinese 
hamster ovary (CHO) cells with rats, monkey and human ETA expressed. Ambrisentan 
was used as a positive control. Results showed that GMA301 has a similar IC50 value 
on monkey and human ETA (67.55 and 57.50 nM) but does not bind to rat ETA, which 
proved that GMA301 has a species specificity in ETA binding. The positive control, 

 
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ambrisentan, showed similar inhibitory potency in 3 cell lines with IC50 of 1.61, 2.84, 
and 8.07 nM on rat, monkey, and human ETA. 18 
In an efficacy study of GMA301 administered intravenously twice per week for 
6 weeks in a monocrotaline-induced PAH model in cynomolgus monkeys, right 
ventricular systolic pressure (RVSP) of GMA301 decreased by 13.6%, 45.7%, and 
54.0% in 1.5, 5, and 15 mg/kg dose groups (p<0.01 in 5 and 15 mg/kg groups compared 
to the model group) and Fulton’s index (weight of right ventricular/(weight of left 
ventricular plus weight of interventricular septum)*100%) decreased by 31% in the 
5 mg/kg group. 18  
The results indicated that the efficacy of 5 mg/kg GMA301 was similar to ambrisentan. 
The dose of ambrisentan used in this study is 1 mg/kg, which is administrated once a 
day for 6 weeks by oral gavage.  
1.3. 
Summary of Safety Pharmacology 
Although mice are not relevant species to GMA301, a single dose toxicity study was 
still conducted. Both GMA301 injection and placebo result in some death after IV 
injection at a very high dosage (equal to 6.9-gram GMA301injected in a 60 kg human). 
The cause of death may need further study, however, according to International Council 
for Harmonisation (ICH) S6, “Toxicity studies in non-relevant species may be 
misleading and are discouraged”. Therefore, the results of acute toxicity study in mice 
may not be relevant for the preclinical safety evaluation of GMA301. 
The preclinical toxicity studies included single and repeat doses of GMA301 were 
conducted in cynomolgus monkeys.  
In single dose toxicity study, cynomolgus monkeys were administrated at 75, 250, and 
750 mg/kg, No GMA301-related changes were noted in clinical observations, body 
weight, hematology and clinical chemistry tests. The no observed adverse effect level 
(NOAEL) was 750 mg/kg.  
In a multiple dose toxicity study in cynomolgus monkeys, GMA301 was administrated 
at 25, 75, and 250 mg/kg twice weekly for 4 weeks and 25, 75, and 250 mg/kg once 
weekly for 13 weeks followed by a six-week recovery period. No changes were noted 
in clinical observations, body weight, body temperature, hematology and clinical 
chemistry. No GMA301-related histopathology abnormality was found. 18  
1.4. 
Summary of Nonclinical Pharmacokinetics 
A total of 24 naive cynomolgus monkeys (3 males and 3 females in each group) were 
used in a single and repeat dose PK study. In the single dose study, GMA301 was 
injected at 5, 15, 50 mg/kg and in the multiple dose study, injected at 15 mg/kg once 
weekly for 4 consecutive weeks. Blood was collected at different timepoints and PK 
parameters were calculated. GMA301 showed a long half-life of approximately 
244.74, 173.15, and 173.41 hours in 5, 15, and 50 mg/kg group after single dose 
injection. After a total of 4 injections, the AUC of the last dose of 15 mg/kg was 1.96 
times higher than that of the first dose, at 47.96 and 24.50 h·mg/mL, respectively. 18 

 
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Table 1: Pharmacokinetics Parameters of GMA301 in monkeys 
Group 
Dose 
(mg/kg) 
t1/2 
Cmax 
AUCinf 
(h) 
(μg/mL) 
(h·mg/mL) 
Single 
dose 
5 
244.74±30.29
98.22±16.81 
16.10±2.31 
15 
173.15±63.14 317.57±38.19 
40.26±15.21 
50 
173.41±24.65 1014.96±73.63 
137.50±23.34 
Group 
Dose 
t1/2 
Cmax 
AUC (0-168 h) 
F 
(h) 
(μg/mL) 
(h·mg/mL) 
Repeat 
dose* 
15mg/kg- 
first dose 
182.81±46.82 326.27±41.49 
24.50±2.75 
15mg/kg-last 
dose 
263.54±38.67 481.76±59.05 
47.96±3.59 
1.96 
*：15 mg/kg once per week for 4 weeks. F=AUClast/AUCfirst; t1/2=Terminal Elimination Half Life; 
Cmax=Maximum Observed Serum Concentration 
1.5. 
Summary of Clinical Experience 
1.5.1. 
Safety 
A single-center, double-blind, placebo-controlled, dose escalation study to assess the 
safety, tolerability, and PK of GMA301 in healthy subjects was performed in 
Australia. Four sequential dosing cohorts, each with 6 subjects receiving GMA301 
and 2 subjects receiving placebo (total of 32 subjects), were given increasing single 
doses of GMA301. The administered doses were 75, 200, 500, and 1000 mg, or 
matching placebo. The most frequent Treatment Emergent Adverse Events (TEAEs) 
across the 4 groups were headache (39.4%), nausea (12.1%) and pharyngitis (12.1%). 
All of these TEAEs were well tolerated without further medical intervention needed.  
1.5.2. 
Pharmacokinetics 
Pharmacokinetic results were obtained from the same study that was performed in 
Australia. All individuals in the study exhibited quantifiable plasma GMA301 
concentrations at the first timepoint of 4 hours. Most individuals appeared to exhibit 
mono-exponential pharmacokinetics, with a slow decline in plasma concentrations 
after attainment of Maximum Observed Serum Concentration (Cmax). Terminal half-
life was long with average values ranging from 503.75 hours to 565.63 hours. 
Other pharmacokinetic values of GMA301 refer to clinical study report of GMA301 
Australia study. 19 
1.6. 
Study Rationale 
The selection of GMA301 doses and dosing frequency was based on the available 
clinical safety, tolerability and PK data obtained from healthy human subjects19. The 
dose level of 1000 mg GMA301 observed in the previous Phase Ia study has been 
proven safe for human subjects. Based on that, we believe that GMA301 dosed at 
300, 600, and 1000 mg every 4 weeks (Q4W) should be safe for human subjects.  

 
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The principal aim of this study is to obtain safety and tolerability data when GMA301 
is administered as multiple doses in subjects with PAH. This information, together 
with the PK data, will help establish the doses and dosing regimen for future studies. 
The efficacy parameters of GMA301 will also be investigated. 
1.7. 
Benefit-risk Assessment 
Subjects enrolled in this study will receive no known benefit from the study drug. 
Subjects will undergo additional testing (e.g. right heart catheterization [RHC], 
echocardiography, 6MWT and biomarkers) that may help their practitioner better 
characterize their disease. The risks of participation are primarily those associated 
with adverse reactions to the investigational medicinal product (IMP). In addition, 
there may also be some discomfort or morbidity from the RHC and collection of 
blood samples and other study procedures. 
More information about the known and expected benefits, risks, and reasonably 
anticipated adverse events (AEs) associated with GMA301 may be found in the 
Investigator’s Brochure 18. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
• To assess the safety and tolerability of GMA301 following repeated 
intravenous (IV) dosing in subjects with World Health Organization (WHO) 
Group-1 PAH 
 
2.1.2. 
Secondary Objectives 
• To determine the PK and dose/exposure-response relationships of GMA301  
• To evaluate the effects of GMA301 on hemodynamics 
• To evaluate the effects of GMA301 on exercise tolerance 
• To evaluate the effects of GMA301 on relevant PAH biomarkers 
 
2.1.3. 
Exploratory Objectives 
• To evaluate the effects of GMA301 on REVEAL 2.0 risk score (See 
Appendix 7) 
 

 
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2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The incidence of TEAEs in subjects assigned to GMA301 compared with those 
assigned to placebo 
2.2.2. 
Secondary Endpoints 
• Pharmacokinetics 
o Area under the serum concentration- time curve from time zero to the last 
measurable concentration (AUC0-t) 
o Area under the serum concentration- time curve over a dosing interval 
(AUC0-tau) 
o Observed maximum serum concentration (Cmax) 
o Area under the serum concentration-time curve from time zero to infinity 
(AUC0-inf) 
o Time to maximum serum concentration (Tmax) 
o Terminal elimination half-life (t1/2) 
o Volume of distribution  
o Trough concentration  
o Clearance  
o Accumulation ratio  
 
• Comparison of GMA301 treatment effect at Week 12 versus baseline regarding 
the hemodynamic parameters based on RHC. Parameters include but are not 
limited to:  
o Pulmonary vascular resistance (PVR)  
o Mean pulmonary arterial pressure (mPAP) 
o Cardiac index 
 
• Comparing the following treatment effect metrics: 
o 6MWT distance (Week 12 versus Screening) 
o NT-pro BNP level (Weeks 4, 8, and 12 versus baseline) 
o WHO functional class (Weeks 8 and 12 versus baseline) 
 
2.2.3. 
Exploratory Endpoints 
• Changes in REVEAL 2.0 risk score at Week 12 compared with baseline 

 
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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a Phase 1b randomized, double-blind, placebo-controlled, on top of 
background therapy, dose escalation study to assess safety, efficacy and PK of 
GMA301 in subjects with PAH. The study will be carried out at sites in China and the 
US.  
After signing informed consent, subjects will participate in a Screening Phase. The 
subjects’ medical history will be obtained through interview and a chart review before 
the subject undergoes a physical examination.  
Subjects will be selected and enrolled from the PAH population who are taking local-
approved, non-ERA agents, including but not limited to calcium channel blockers, 
phosphodiesterase type 5 inhibitors, guanylate cyclase stimulators, non-intravenous 
prostacyclin receptor agonists and prostacyclin analogues. 
The dosage of PAH medication must be stable for 3 months before Screening.  
Subjects who underwent RHC within the 3 months prior to Screening will not be 
required to repeat another RHC if the investigators accept the quality of the saved 
waveforms and pressure measurements and these meet study entry criteria. 
Subjects meeting screening criteria for baseline metrics will then be randomized by 
Interactive Web Response System (IWRS). Each treatment cohort will be randomized 
at a 3:1 ratio of active treatment to placebo in each cohort. Subjects will be 
randomized to receive either: 
• Q4W GMA301 IV injections 
or 
• Q4W placebo IV injections (indistinguishable from GMA301). 
Subjects will be sequentially recruited into 3 ascending dose treatment cohorts with 
GMA301-assigned subjects receiving either 300, 600 or 1000 mg injections of the 
study drug depending on their assigned cohort. Each cohort will contain 12 subjects, 9 
of whom will be administered active GMA301 and 3 of whom will be administrated 
placebo. All subjects will undergo IV injection at baseline, Week 4, and Week 8. 
Dosing will proceed in a cohort-based dose escalation sequence from 300 mg 
GMA301 in the initial cohort. Pre-specified criteria for dose escalation based on 
subjects’ safety will be assessed by a Safety Review Committee (SRC) before 
progressing to the next higher dose level as described below. The efficacy parameters 
will include disease-relevant hemodynamic parameters derived from RHC, REVEAL 
2.0 risk score, WHO functional class, ECG, 6MWT, biomarkers and 
echocardiography measures of right ventricular function.  
All key efficacy parameters will be assessed at 4, 8, and 12 weeks following baseline 
evaluation and an ECG will be performed as scheduled. The protocol will include a 

 
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6-week follow-up (from Week 12 to Week 18) at which time subjects will be assessed 
to identify any AEs and conducting the PK assessment.  
Routine clinical and laboratory parameters including antigenicity and AE reporting 
will be examined.  
Overall, 36 subjects, with 3 cohorts each composed of 12 subjects, will participate in 
a multiple-dose, sequential-group fashion. An overview of the study design is shown 
in Figure 1 and the planned dose levels in Figure 2. 
The total duration of the study for an individual subject will be approximately 22 weeks 
including up to 4 weeks of screening, 12 weeks of double-blind treatment period, and 
6 weeks of follow-up. During the double-blind treatment period (12 weeks), the 
subjects will receive the IV injections at Week 0 (baseline), Week 4, and Week 8, 
respectively.  
 
 
Figure 1: Study Schematic 

 
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Figure 2: Planned Dose Levels  
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
Study Start and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of the subject number 
allocation. The end of the study is defined as the date of the last subject’s last 
assessment (scheduled or unscheduled). 
3.3. 
Discussion of Study Design, Including the Choice of Control Groups 
A sequential-group, ascending-dose design has been chosen for safety reasons as 
GMA301 is in the early stage of clinical development. Intravenous doses have been 
chosen for the study, as this is the intended clinical route of administration.  
Based upon the nonclinical data, the duration of each treatment period is considered 
adequate to achieve the study objectives. Details of the dosing regimen and duration 
used for the study will be documented in the trial master file (TMF). 

 
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The selection of the GMA301 dosing frequency of Q4W via IV injection at baseline 
and then at Week 4 and Week 8 was based on the available clinical safety, tolerability 
and PK data obtained from healthy human subjects.18 
To estimate and determine the levels and frequency of GMA301 dosing for the 
upcoming Phase Ib study, a simulation of GMA301 for a Q4W repeated dosing in 
human subjects has been established based on all previous observations in 
cynomolgus monkeys and healthy human volunteers. The simulation indicated that a 
steady state could be achieved after the 3rd dose, and the Q4W dose interval has been 
deemed safe for human subjects.  
3.4. 
Dose selection in the Study 
GMA301 300, 600 and 1000 mg IV injection Q4W for 3 months was based on the 
available clinical safety, tolerability and PK data obtained from healthy human 
subjects. 
The proposed GMA301 dose levels are shown in Table 2. 
 
 

 
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Table 2: Proposed Investigational Medicinal Product Dose Levels  
Cohort 
Intervention 
Treatment 
1 
300 mg GMA301 
(N=9) 
Drug:     GMA301, 300 mg IV Q4W at Week 0 
(baseline), Weeks 4 and 8  
Placebo (N=3)  
Drug:      Placebo, IV, Q4W at Week 0 
(baseline), Weeks 4 and 8 
2 
600 mg GMA301 
(N=9) 
Drug:     GMA301 600 mg IV, Q4W at Week 0 
(baseline), Weeks 4 and 8 
Placebo (N=3) 
Drug:     Placebo IV, Q4W at Week 0 
(baseline), Weeks 4 and 8 
3 
1000 mg GMA301 
(N=9) 
Drug:     GMA301 1000 mg IV, at Week 0 
(baseline), Weeks 4 and 8  
Placebo(N=3) 
Drug:     Placebo IV, Q4W at Week 0 
(baseline), Weeks 4 and 8  
Details of all doses administered in the study will be documented in the TMF. 
3.5. 
Safety Review Committee (SRC) 
A SRC will be established to assess safety profile for each cohort to determine dose 
escalation. The SRC will be composed of 3 investigators, the Covance Lead Project 
Physician, the Gmax Lead Project Physician, and another unblinded physician who is 
not involved in this study.  
SRC Operation. The SRC will meet after 8 of 12 subjects have received 3 doses of 
the study drug with a 28-day follow-up and the entire cohort of 12 subjects has been 
randomized.   
The initial SRC meeting will review safety data from the initial 8 subjects in Cohort 1 
who have completed 3 doses of the study drug and have been followed for 28 days 
following the third dose. Upon SRC’s approval, Cohort 2 will be opened for 
recruitment once the residual 4 subjects have been randomized in Cohort 1. The 
second meeting of the SRC will review safety data from the initial 8 subjects in 
Cohort 2 and the 4 residual subjects from Cohort 1 who were not yet reviewed. 
Upon SRC’s approval, once the residual 4 subjects in Cohort 2 are randomized, 
Cohort 3 can be initiated for recruitment. If fewer than 8 subjects (including 8) in a 
cohort have completed administration and follow-up regimen, with some drop-outs, 
their safety data will be reviewed by SRC aiming to determine whether the next 
cohort with a higher dose can be started. Additionally, ad hoc meetings will be 
organized in case of any SAE or adverse event with maximum severity that could be 
drug-related. 
SRC reviews will include, but not limited to, clinical findings, vital signs, hematology 
and biochemistry results, ECG, AEs, and SAEs. The composition, operation, and 
management of the SRC will be described in detail in the SRC charter. 

 
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3.6. 
Stopping and Subjects withdraw Criteria 
The following criteria will result in immediate discontinuation of the subject dosing: 
• An SAE that is related to GMA301; 
• QTcF >500 msec or extension 60 msec against baseline. 
• Liver function test abnormalities for severe liver injury (based upon US 
FDA “Guidance for Industry, Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation”, July 2009): 
o Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST)>3x upper limits of normal (ULN) with total bilirubin > 2X ULN 
(Hy’s Law)  
o ALT or AST >3x ULN with international normalized ratio (INR)>1.5  
o ALT or AST >8X ULN  
o ALT or AST >5X ULN persisting for more than 2 weeks 
o ALT or AST >3x ULN or 3 times baseline value with the appearance 
of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash and/or eosinophilia (>5%)  
 
Close follow-up of subjects must be organized in any of the above cases 
including: 
• Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or the trial drug has been discontinued and the subject is 
asymptomatic.  
• Obtaining a more detailed history of symptoms and prior or concurrent 
diseases 
• Obtaining a history of concomitant drug use (including non-prescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets.  
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; non-alcoholic steatohepatitis; hypoxic/ischemic 
hepatopathy; and biliary tract disease.  
• Obtaining a history of exposure to environmental chemical agents.  
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, 
direct bilirubin) 
• Obtaining gastroenterology or hepatology consultations 
If a treatment-related SAE is suspected by investigators, immediate discontinuation of 
study drug must occur and medical care must be applied and the case immediately 
reported to the SRC. An ad hoc SRC meeting will be organized to make decisions for 
the study accordingly.   

 
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A subject is free to withdraw from the study at any time. A subject is requested to 
withdraw by the investigators if any of the following criteria are met: 
• Subjects’ non-compliance with the study procedure that might affect subject 
safety or study assessments/objectives, by the investigators  
• Any clinically relevant sign or symptom (eg, Class IV heart failure) that, in the 
opinion of the Investigator (or designee), warrants subject withdrawal. 
Subject who didn’t get IMP treatment within protocol defined timeline with any 
reason can get back to the IMP treatment with investigator or SRC’s evaluation and 
agreement.  
All the discontinuation must be documented accordingly. If a subject is withdrawn, 
the Sponsor will be notified in 24 hours and the date and reason(s) for the withdrawal 
will be documented in electronic Case Report Form (eCRF). In this case, efforts in 
any ways must be made to complete the follow up assessments. (Appendix 6). Other 
medical procedures may be performed at the Investigator’s discretion. The 
Investigator may also request subjects to return for additional Follow-up visits. All 
AEs will be followed until recovery or stabilization. 
Cohort discontinuation and study termination  
The SRC will discontinue or stop the cohort or even the study in case of ： 
• Two cases discontinuations in a cohort due to events related to the study drug 
under the diagnosis of the investigators; 
• Single case with severe allergic event related to study drug;  
• Known and expected AEs are with increased frequency, severity and or long 
lasting.  
The sponsor can terminate the study with notification to the investigators. 
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. Male or female, aged 18 to 75 years inclusive 
2. WHO Group 1 PAH related to one of the following conditions: 
a. Idiopathic  
b. Heritable  
c. Drugs or toxins-induced  
d. Associated with connective tissue disease  
e. Associated with congenital heart disease if subjects underwent surgical 
correction more than 12 months before Screening  
3. Symptoms due to PAH are consistent with WHO functional class II- III 
4. Have not taken endothelin receptor antagonists (ERAs) within 3 months 
before randomization. 
5. Has been taking at least one oral PAH targeted drug that has been approved by 
local guidelines for at least 3 months before screening with a stable dosage 
and the disease did not worsen during this period.  

 
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6. Right heart catheterization (RHC) result meets below criteria when screening. 
a. Mean pulmonary arterial pressure (PAP) ≥25 mmHg 
b. Pulmonary vascular resistance (PVR) >3 Woods units  
c. PA wedge pressure (PAWP) ≤15 mmHg 
if subject has undergone RHC within 3 months before screening, the waveform results 
will serve as baseline data if they meet entry criteria and the RHC at Screening will 
not be repeated. 
7. Has a six-minute walk test (6MWT) with distance between 150 to 450 meters 
at Screening.  
8. The dosage of digitalis drugs or L-arginine supplementation, if applicable, 
must be stable for at least 1 month before Screening. 
9. No new use of an IV diuretic, cardiotonic, or vasoactive drug within 30 days 
before screening.  
10. Both male and female subjects agree to use a medically acceptable method of 
contraception throughout the entire study period from informed consent 
signing to 90 days after last dose, if the possibility of conception exists. 
Medically acceptable methods of contraception include oral, implantable, or 
injectable contraceptives (starting 2 months before dosing); diaphragm with 
vaginal spermicide; intrauterine device; condom and partner using vaginal 
spermicide; and surgical sterilization (6 months after surgery). Women who 
are surgically sterile or those who are postmenopausal for at least 2 years are 
not considered to be of childbearing potential. Eligible male and female 
subjects must agree not to participate in a conception process (i.e. active 
attempt to become pregnant or to impregnate, sperm donation, in vitro 
fertilization) during the study and for 90 days after the last dose of study drug. 
11. Body weight no less than 40 kg at Screening. 
12. Able to understand and willing to sign the Informed Consent Form (ICF) and 
comply with the study procedures. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be allowed to participate in 
this study: 
1. Diagnosed with WHO Group II, III, IV, V of PH.  
2. Using calcium channel blockers when screening.  
3. BP >160/100 mmHg at Screening 
4. Systolic BP <90 mmHg at Screening 
5. Pulmonary function test: FEV1<60% of predicted, TLC<60% of predicted, 
DLCO<60% of predicted 
6. One of the following tests with confirmed pulmonary emboli and chronic 
thromboembolic pulmonary hypertension (CTEPH) following initial diagnosis 
of PAH: 
a. Pulmonary ventilation/perfusion scan 
b. CT pulmonary angiogram 
c. Contrast dye pulmonary angiogram 
7. History of sleep apnea  
8. Limited full participation in the 6MWT due to arthritic, neuromuscular, 

 
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vascular or other diseases unrelated to PAH 
9. History of acute cardiovascular and cerebrovascular events within 6 months 
before screening.  
10. Echocardiogram (ECHO) demonstrating at least 1 of the following:  
a. LVEF <50% 
b. Mean end-diastolic left ventricular septal and posterior wall thickness of 
>12 mm 
c. Left atrial (LA) area on apical 4 chamber view >20 cm2 
d. LA volume by biplane modified Simpsons or area-length methods 
>55 mL 
e. LA volume index >29 mL/m2 
f. 
Significant valvular heart disease including moderate or severe mitral or 
aortic stenosis with an aortic valve area <1.0 cm2 or mitral valve area 
<1.5 cm2), greater than moderate aortic or mitral regurgitation, greater 
than moderate tricuspid or pulmonic stenosis 
11. Restrictive, dilated or hypertrophic cardiomyopathy or constrictive pericarditis 
12. Using non-oral prostacyclin when screening; 
13. Laboratory parameters during screening: 
a. Baseline aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) ≥2 times the upper limit of normal (ULN) or total bilirubin ≥1.5 
times ULN. 
b. Estimated glomerular filtration rate (eGFR) <60 mL/min by Cockcroft-
Gault formula 
c. Hemoglobin concentration ≤100 g/L at screening 
14. QTc interval by Fridericia’s criteria (QTcF) ≥500 msec at screening 
15. Malignancy within 5 years before screening visit (with the exception of 
localized non-metastatic basal cell carcinoma of the skin, non-metastatic 
carcinoma of the prostate or in-situ carcinoma of the cervix excised with 
curative results) 
16. Alcohol or drug abuse within 1year before screening 
17. A psychiatric, addictive or other disorder that compromises the ability to give 
informed consent for participating in this study 
18. History of organ transplantation 
19. Pregnant or nursing females 
20. History of HIV 
21. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), 
or HIV antibody (HIV-ab). 
22. Enrolled in another interventional study within 30 days before screening.  
23. Any condition that, in the opinion of the investigator, prevents a potential 
subject from safely participating in the study 
 
4.3. 
Subject Number and Identification 
Subjects will have unique identification numbers used at Screening and 
randomization. Assignment of subject numbers will be in ascending order and no 
numbers will be omitted.  
All study documentation will be identified by Screening number only. A list 
identifying the subjects by subject number will be kept in the Site Master File. 

 
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5. STUDY DRUGS 
5.1. 
Description, Storage, Packaging, and Labeling 
The IMPs (300, 600, and 1000 mg GMA301 Injection) and their matching placebos 
will be supplied by the Sponsor, along with the batch/lot numbers and Certificate of 
Analysis. The IMP will be provided in glass vial and stored according to the 
instructions on the label. 
The placebo treatment will be composed of the same ingredients as the GMA301. The 
appearance of the placebos should be identical to either GMA301, to ensure the study 
is blinded. 
All IMPs will be stored at the study site in a location that is locked with restricted 
access. 
The bulk drug container and unit dose containers will be labeled in accordance with 
national laws and regulations. The IMPs will be transferred from bulk supplies into 
the subject’s dose container by qualified clinical staff. 
GMA301 and placebo injections should be stored at 2～8°C and protected from direct 
sunlight. Protection from light is not required during preparation and injection. 
5.2. 
Study drug Administration 
The 300, 600, and 1000 mg doses of GMA301 and matching placebo will be 
administered Q4W via IV injection by slow push for 12 weeks.  
The study drug will be injected at an approximate rate of no more than 4 mL/min. The 
syringes should be connected to the previously inserted cannula for administration. 
5.3. 
Randomization 
An IWRS will be used to randomly assign subjects to treatments. Nine subjects per 
cohort will be randomly assigned to active GMA301 and three subjects per cohort 
will be randomly assigned to receive placebo. 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the 
study: 
The placebo will be identical in appearance to the GMA301.  
The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
All doses will be administered by suitably qualified study site staff. 

 
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At each dosing occasion, a pre-dose and post-dose inventory of IMP will be 
performed.  
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the 
study supplies received. In addition, an accurate drug dispensation record will be kept, 
specifying the amount dispensed to each subject and the date of dispensing. This drug 
accountability record will be available for inspection at any time. At the completion 
of the study, the original drug accountability record will be available for review by the 
Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded 
upon satisfactory completion of the compliance and accountability procedures. Any 
unused assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or nonprescription 
medications/products during the study until the Follow-up visit, unless the 
Investigator (or designee) and/or Sponsor have given their prior consent.  
 The administration of any concomitant medications during the study is prohibited 
without prior approval of the investigator. Any medication taken by a subject during 
the study and the reason for its use will be documented in the source data.  
6.2. 
Diet 
Subjects will be fasted at least 8 hours and cannot drink water for 2 hours before any 
blood sample collections for safety examination purpose. 
Consumption of alcohol will not be permitted from 48 hours prior to Screening to the 
last follow-up visit.  
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 
3 months prior to Screening until the last follow-up visit. 
6.4. 
Exercise 
Subjects are required to refrain from intensifying strenuous exercise from 7 days 
before screening until the Follow-up visit, but will otherwise maintain their normal 
level of physical activity during this time (ie, will not begin a new exercise program 
nor participate in any unusually strenuous physical exertion). 

 
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7. STUDY ASSESSMENTS AND PROCEDURES 
Where activities at a given timepoint coincide, consideration must be given to ensure 
that the following order of activities is maintained: ECGs, vital signs, and blood 
drawings. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated 
in the Schedule of Assessments in Appendix 6.  
Up to 3 additional blood samples may be taken from each subject per treatment 
period, with the maximum volume of blood withdrawn per subject not exceeding the 
limit detailed in Appendix 3. Any changes to the scheduled times of PK assessments 
will be agreed with the Sponsor and documented in the TMF. 
7.1.2. 
Analytical Methodology 
Serum concentrations of GMA301 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate 
documents. 
7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events 
AE definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to 
final discharge from the study. Subjects will be observed for any signs or symptoms 
and asked about their condition by open questioning, such as “How have you been 
feeling since you were last asked?”, at least once each day while resident at the study 
site and at each study visit. Subjects will also be encouraged to spontaneously report 
AEs occurring at any other time during the study. 
All non-serious AEs, whether reported by the subject voluntarily or upon questioning, 
or noted on physical examination, will be recorded from initiation of study drug until 
study completion. Serious AEs will be recorded from the time the subject signs the 
ICF until study completion. The nature, time of onset, duration, and severity will be 
documented, together with an Investigator’s (or designee’s) opinion of the 
relationship to study drug. 
AEs recorded during the course of the study will be followed up, where possible, until 
resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
The Adverse Event(s) related to RHC is listed in the separated document.   

 
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7.2.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations 
(including clinical chemistry, hematology, urinalysis, and serology) at the times 
indicated in the Schedule of Assessments in Appendix 6.  
Clinical laboratory evaluations are listed in Appendix 2. Additional clinical laboratory 
evaluations will be performed at other times if judged to be clinically appropriate or if 
the ongoing review of the data suggests a more detailed assessment of clinical 
laboratory safety evaluations is required. 
For females of reproductive potential, a pregnancy test will be performed at the times 
indicated in the Schedule of Assessments in Appendix 6.  
An Investigator (or designee) will perform a clinical assessment of all clinical 
laboratory data. 
7.2.3. 
Vital Signs 
Seated blood pressure, seated pulse rate, respiratory rate, and body temperature will 
be assessed at the times indicated in the Schedule of Assessments in Appendix 6. 
Vital signs may also be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of vital signs 
is required. 
Day 1 pre-dose blood pressure, pulse rate, and respiratory rate will be measured in 
triplicate at approximately 2-minute intervals. The mean value will be used as the 
baseline value in the data analysis. All subsequent measurements will be performed 
singly and repeated once if outside the relevant clinical reference ranges. Body 
temperature will be measured singly. 
Subjects must be seated or lie for at least 5 minutes before blood pressure and pulse 
rate measurements. 
7.2.4. 
Electrocardiogram 
7.2.4.1. 
12-Lead Electrocardiogram 
A resting 12-lead ECG will be recorded after the subject has been supine and be 
seated or lie for at least 5 minutes at the times indicated in the Schedule of 
Assessments in Appendix 6.  
ECGs will be recorded at screening, Week 4, Week 8, and Week 12. 
The 12-lead ECGs will be repeated 3 times, and an average taken of the 3 readings. 
The QTcF will be averaged and any subject meeting the following criteria will have 
study medication held and will be followed up: 
• QTcF value >500 msec 
• QTcF change from the baseline (predose) >60 msec. 
• Second- or third-degree heart block or bundle branch block  

 
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Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the data suggests a more detailed assessment of ECGs is required. 
The investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 pre-dose 12-lead ECGs will serve as the baseline assessment. The mean values 
of PR, QRS, and QTcF will be entered into the eCRF. Averaged values for 
subsequent ECG intervals should also be entered into the eCRF.  
7.2.5. 
Physical Examination 
A full physical examination or symptom-directed physical examination will be 
performed at the timepoints specified in the Schedule of Assessments in Appendix 6. 
Full physical examination will usually only be performed at Screening or Day-1. 
7.2.6. 
Body Weight 
Body weight will be recorded at the timepoints indicated in the Schedule of 
Assessments in Appendix 6. 
7.2.7. 
Immunogenicity (ADA) 
Blood samples for immunogenicity (anti-drug antibodies [ADA]) will be collected at 
the times indicated in the Schedule of Assessments in Appendix 6. 
Neutralization activity will be evaluated if ADA is positive. 
7.2.8. 
Pregnancy test 
Females of reproductive potential will be tested at the times indicated in the Schedule 
of Assessments in Appendix 6. 
7.3. 
Efficacy Assessments: 
7.3.1. 
Right heart catheterization (RHC) 
The data will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. 
7.3.2. 
Echocardiogram (ECHO)  
Echocardiogram will be recorded at the times indicated in the Schedule of 
Assessments in Appendix 6. 
7.3.3. 
Six-minute walk test (6MWT) 
The 6MWT will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. The operation details of 6MWT is described in the Site Operation Menu. 
Borg index score will be collected immediately after 6MWTs. 

 
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7.3.4. 
NT-pro-BNP 
The data will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. 
7.3.5. 
WHO functional class 
The data will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. 
7.3.6. 
The REVEAL risk score 
The data will be collected at the times indicated in the Schedule of Assessments in 
Appendix 6. 
 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
General Analysis 
Statistical analyses will be descriptive only, with no hypothesis testing. Analyses will 
be performed in SAS®. Summary tables will present results for each of the three 
GMA301 doses. Descriptive statistics including the number (n), the arithmetic mean 
(Mean), standard deviation (SD), median, the minimum value (Min), and the 
maximum value (Max) will be presented for continuous variables, and the number of 
subjects (n) and the percentage (%) will be presented for categorical and ordinal 
variables. All study data will also be presented in by subject data listings. The details 
of the statistical analysis will be described in the Statistical Analysis Plan (SAP). 
8.2. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted. 
Approximately 36 subjects will be randomized into 3 treatment cohorts with 
GMA301-assigned subjects receiving either 300, 600, or 1000 mg injections of the 
study drug depending on their assigned cohort. Each cohort will include 12 subjects, 9 
of whom will be administered active GMA301 and 3 of whom will receive placebo. 
The number of subjects in each cohort of the present study is common in early clinical 
pharmacology studies and is considered sufficient to achieve the objectives of the 
study. 
8.3. 
Analysis Populations 
8.3.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of study drug 
(GMA301) and have at least 1 evaluable PK data.  

 
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8.3.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
drug. The safety population will be analyzed according to treatment actually received. 
Any subject who did not receive the treatment randomly assigned will be listed, but 
will be included in all analyses according to the treatment actually received. 
8.4. 
Demographics and Other Baseline Characteristics 
8.4.1. 
Baseline demographics 
Demographic and baseline characteristics will be listed and summarized by treatment 
group and overall for the Safety Population. Characteristics will include but not 
limited to age, weight, height, body mass index, sex, and race. No formal statistical 
comparisons will be made between treatment groups. 
8.4.2. 
Medical History 
Medical History will be coded according to the current version of MedDRA. The 
Medical Histories will be listed and numbers and percentages of any medical history 
will be summarized for the safety population by system organ class and preferred 
term for each treatment group, and overall. 
8.5. 
Pharmacokinetic Analyses 
Non-compartmental PK analysis will be performed on individual serum concentration 
data, using commercial software such as Phoenix® WinNonlin®. Serum 
concentrations of GMA301 and PK parameters will be listed and summarized using 
descriptive statistics. Individual and mean GMA301 concentration-time profiles will 
also be presented graphically. 
In the study, where data are available, GMA301 dose proportionality will be 
examined across dose groups. The PK parameters will be analyzed for dose 
proportionality using a power model approach or analysis of variance (ANOVA) 
model as appropriate.  
Other parameters may be added as appropriate. Final PK parameters reported will be 
detailed in the SAP. 
8.6. 
Safety Analysis 
All safety analyses will be performed on the Safety Population. No formal statistical 
analysis of safety data is planned. 
AEs will be coded by System Organ Class and Preferred Term using the current 
version of the MedDRA dictionary. Safety parameters will be listed and summarized 
using descriptive statistics. No formal statistical analysis of safety data is planned. 
Safety data will be summarized by dose group. Incidences of TEAEs (those events 
that started after exposure to study drug or worsened in severity after dosing) will be 
presented by dose group as well. Incidences of TEAEs will be presented by maximum 
severity and relationship to study medication. 

 
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Laboratory test results, ECG results, vital sign results and their changes from Baseline 
will be summarized by dose group using descriptive statistics. Shift tables (low, 
normal, high) comparing baseline results to the worst post baseline results will be 
presented by parameters and dose group for laboratory results. Shift tables (normal, 
abnormal not clinically significant, abnormal clinically significant) comparing 
baseline results to the worst post baseline results will be presented by parameters and 
dose group for ECG results. Other safety measurements like physical examinations 
will be presented in listings.  
Prior and Concomitant Medications will be classified according to the WHO Drug 
Dictionary. All usage will be listed. The current version of the WHO Drug Dictionary 
will be used. The frequency of usage of each medication class will be summarized 
using the WHO Drug hierarchy. The percentage of subjects in each dose using each 
class of medication after baseline will be presented. 
The number and percentage of positive ADA and the positive neutralizing antibody at 
each timepoint will be summarized descriptively. 
8.7. 
Efficacy Analyses 
The Safety Population will be used for efficacy analyses. 
Efficacy endpoints including hemodynamic parameters, 6-minute walk distance, 
NT-proBNP levels, WHO functional class, and their change from baseline will be 
listed and summarized by treatment group using descriptive statistics as appropriate at 
each collection timepoint. 
8.8. 
Exploratory Analyses 
REVEAL 2.0 risk score and their change from baseline will be listed and summarized 
descriptively by treatment group at each collection timepoint.  
8.9. 
Interim Analysis 
Not applicable. 
 
9. REFERENCES 
1. Maron BA, Galie N. Diagnosis, Treatment, and Clinical Management of 
Pulmonary Arterial Hypertension in the Contemporary Era: A Review. JAMA 
Cardiol 2016;1:1056-1065. 
2. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of 
pulmonary hypertension. Journal of the American College of Cardiology 
2013;62:D34-41. 
3. Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of 
pulmonary hypertension: state of the art and research perspectives. Eur Respir J 
2019;53. 

 
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4. Hahn SS, Makaryus M, Talwar A, et al. A review of therapeutic agents for the 
management of pulmonary arterial hypertension. Ther Adv Respir Dis 
2017;11:46-63. 
5. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and 
mortality in pulmonary arterial hypertension. The New England journal of 
medicine 2013;369:809-818. 
6. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary 
Arterial Hypertension. N Engl J Med 2015;373:2522-2533. 
7. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous 
epoprostenol (prostacyclin) with conventional therapy for primary pulmonary 
hypertension. N Engl J Med 1996;334:296-301. 
8. Galie N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials 
in pulmonary arterial hypertension. European heart journal 2009;30:394-403. 
9. Hoeper MM, McLaughlin VV, Dalaan AM, et al. Treatment of pulmonary 
hypertension. Lancet Respir Med 2016;4:323-336. 
10. Benigni A, Remuzzi G. Endothelin antagonists. Lancet 1999;353:133-138. 
11. Rodriguez-Pascual F, Busnadiego O, Lagares D, et al. Role of endothelin in the 
cardiovascular system. Pharmacol Res 2011;63:463-472. 
12. Aversa M, Porter S, Granton J. Comparative safety and tolerability of endothelin 
receptor antagonists in pulmonary arterial hypertension. Drug Saf 
2015;38:419-435. 
13. Carrington M, Murphy NF, Strange G, et al. Prognostic impact of pulmonary 
arterial hypertension: a population-based analysis. Int J Cardiol 
2008;124:183-187. 
14. Ambrisentan Label, FDA 2015 
15. Davenport AP, Hyndman KA, Dhaun N, et al. Endothelin. Pharmacol Rev 
2016;68:357-418. 
16. Simonneau C, Gatzoulis MA, Adatia I, et al, Updated Clinical Classification of 
Pulmonary Hypertension, JACC 2013,62(25) suppl D: 34-41 
17. Wei A et al, Clinical adverse effects of endothelin receptor antagonists: insights 
from the meta-analysis of 4894 subjects from 24 randomized double-blind 
placebo- controlled clinical trials, J Am Heart Assoc, 2016; 5(11):1-16 
18. GMAX Biopharm Australia Pty Ltd. GMA301 – Investigator’s Brochure. 
(Version 02). 24 Nov 2017. 
19. GMAX Biopharm Australia Pty Ltd. GMA301 – Clinical Study Report. A Phase 
1, Placebo-Controlled, Double-Blind, Dose Escalation Study to Investigate the 

 
Protocol No.: GETA_MAD_01 
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Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Dose of 
Getagozumab in Healthy Volunteers. 14 Nov 2018. 
20. US FOOD AND DRUG ADMINISTRATION, et al. Guidance for industry 
drug-induced liver injury: premarketing clinical evaluation. Drug Safety 
[Internet]. 28 Jul 2009 
 
 

 
Protocol No.: GETA_MAD_01 
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10. APPENDICES 
Appendix 1: Adverse Event Reporting 
Definitions 
An AE is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable 
and/or unintended sign (including a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a study drug, 
whether or not related to the study drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE 
using the following categories:  
• Mild: event is medically significant but produces no disruption to daily 
activity;  
• Moderate: event is medically significant and reduces or affects normal daily 
activity;  
• Severe: event is medically significant and results in inability to work or 
perform normal daily activity. 
Relationship to Study drug 
The Investigator will make a determination of the relationship of the AE to the study 
drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the 
study procedure/conditions. 
• Unlikely Related: The temporal association between the AE and the drug is 
such that the drug is not likely to have any reasonable association with the AE. 
• Possibly Related: The AE follows a reasonable temporal sequence from the 
time of drug administration but could have been produced by the subject’s 
clinical state or the study procedures/conditions. 
• Related: The AE follows a reasonable temporal sequence from administration 
of the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears when the 
drug is reintroduced.  
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any 
subject who has an ongoing AE that is possibly related or related to the IMP or study 
procedures at the Follow-up visit will be followed up, where possible, until resolution 
or until the unresolved AE is judged by the Investigator (or designee) to have 
stabilized. This will be completed at the Investigator’s (or designee’s) discretion. Any 

 
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subject who has an ongoing AE that is not related or unlikely related to the IMP or 
study procedures at the Follow-up visit can be closed out as ongoing at the 
Investigator’s discretion.  
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship 
between an IMP and an AE is at least a reasonable possibility) related to any dose 
should be considered adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and 
unintended and which occurs at doses normally used in man for prophylaxis, 
diagnosis, or therapy of diseases or for modification of physiological function is to be 
considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or 
severity of which is not consistent with the applicable product information (eg, 
Investigator’s Brochure for an unapproved IMP). 
Serious Adverse Events 
A SAE is defined as any untoward medical occurrence that at any dose either: 
• results in death 
• is life-threatening 
• requires in subject hospitalization or prolongation of existing 
hospitalization 
• results in persistent or significant disability/incapacity (disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the 
Investigator at any time after cessation of the study drug and considered by the 
Investigator to be possibly related to the study drug, will be reported to the Sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event 
as it occurred (ie, does not include a reaction that might have caused death if it had 
occurred in a more serious form). For instance, drug-induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life-threatening even 
though drug-induced hepatitis can be fatal. 

 
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Definition of Hospitalization 
AEs requiring hospitalization should be considered serious. In general, hospitalization 
signifies that the subject has been detained (usually involving an overnight stay) at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the 
result of an AE, need not be considered AEs and should be recorded on a Clinical 
Assessment Form and added to the electronic Case Report Form. If anything 
untoward is reported during the procedure, this must be reported as an AE and either 
‘serious’ or ‘nonserious’ attributed according to the usual criteria. 
Serious Adverse Event Reporting 
FDA-reportable SAEs are AEs that are associated with the use of the drug and are 
serious and unexpected. Food and Drug Administration-reportable AEs will be 
reported by the study site to the Sponsor, and the responsible Institutional Review 
Board (IRB). 
The Sponsor and Medical Monitor will be notified in writing (eg, facsimile) within 
24 hours when a SAE that is FDA-reportable is firstly recognized or reported. 
Subsequently, a written confirmation or summary of the AE (using FDA Form 3500A 
or equivalent) will be sent to the Sponsor within 3 working days of the original 
notification.  
The IRB will be notified of any FDA-reportable AEs within the timeframe required 
by the IRB. The IRB Serious and Unexpected Adverse Experience Submission Form 
will be completed and submitted with the copy of the written confirmation or 
summary of the AE. 
The responsibility for reporting SAEs will be transferred to the Sponsor 30 days after 
the end of the study. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition 
of an AE. However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother 
and fetus. 
All the female subjects of child-bearing potential will be educated formally before 
they sign the ICF in order to be compliance with FDA’s requirements.  
 
 

 
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Appendix 2: Clinical Laboratory and other Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen  
Calcium 
Chloride 
Cholesterol 
Creatinine 
Gamma-glutamyl transferase 
Glucose 
Potassium  
Sodium  
Total bilirubina 
Total protein 
Uric acid 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Coagulation profile: 
Activated partial thromboplastin 
time 
International normalized ratio 
Prothrombin time 
 
Bilirubin  
Blood 
Color and appearance  
Glucose 
Ketones 
Leukocyte esterase  
Nitrite  
pH 
Protein 
Specific gravity 
Urobilinogen 
  
Serologyb: 
Drug screen 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human 
immunodeficiency - antibodies  
 Not applicable 
Follicle-stimulating hormoneb 
(postmenopausal females 
only) 
 
Serum or Urine pregnancy 
test c 
 
a Direct and indirect bilirubin will be analyzed if total bilirubin is elevated  
b Only analyzed at Screening. 
c All females will perform pregnancy test in serum at Screening and in urine at all other times.  

 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Hematology, clinical 
chemistry, and 
coagulation 
10 
5 
50 
Serology 
5 
1 
5 
GMA301 
pharmacokinetics 
2 
21 
42 
ADA 
6 
6 
36 
NT-proBNP 
2.5 
4 
10 
FSH and pregnancy 
test  
5 
1 
5 
Blood volumes for clinical chemistry, hematology, coagulation, serology test, FSH, 
and pregnancy test will meet local laboratory requirement. The volumes in above 
table are only for reference. 

 
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Appendix 4: Contraception Guidance 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically 
and physiologically capable of becoming pregnant following menarche. 
Women of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported 
medical history and/or medical records. Surgical sterilization to have 
occurred a minimum of 6 weeks, or at the Investigator’s discretion, prior 
to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 
months without an alternative medical reason with confirmatory 
follicle-stimulating hormone (FSH) levels of ≥40 mIU/mL. The 
amenorrhea should not be induced by a medical condition such as anorexia 
nervosa, hypothyroid disease or polycystic ovarian disease, or by extreme 
exercise. It should not be due to concomitant medications that may have 
induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators.  
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use an 
acceptable method of birth control from the time of signing the informed consent 
form until 90 days after the Follow-up visit. Acceptable methods of contraception 
include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as 
prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit: 
o 
bilateral tubal ligation 
o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
• hormonal implant 

 
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• hormonal or non-hormonal intrauterine device 
• male condom with spermicide 
• female condom with spermicide 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to 
the Screening visit, with verbal confirmation of surgical success, and the 
sole partner for the female subject.  
Female subjects of childbearing potential should refrain from donation of ova from 
Check-in (Day -1) until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects will be surgically sterile for at least 90 days, with documented 
azoospermia, or when sexually active with female partners of childbearing potential 
will be required to use a male condom with spermicide (even if participant has a 
history of vasectomy) from Check-in until 90 days after the Follow-up visit. Sexual 
intercourse with female partners who are pregnant or breastfeeding should be avoided 
unless condoms are used from the time of the first dose until 90 days after the 
Follow-up visit. Male subjects are required to refrain from donation of sperm from 
Check-in until 90 days after the Follow-up visit.  
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the 
subject should not become abstinent just for the purpose of study participation), are 
exempt from contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. If a subject who is abstinent at the time of signing the ICF becomes 
sexually active they must agree to use contraception as described previously.  
For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. If a subject who is in a same-sex relationship at the time of 
signing the ICF becomes engaged in a heterosexual relationship, they must agree to 
use contraception as described previously. 

 
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Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
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 ICH Good Clinical Practice (GCP) Guidelines. 
Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents must be submitted to an IRB/Ethics Committee (EC) by the Investigator 
and reviewed and approved by the IRB/EC before the study is initiated.  
Any amendments to the protocol will require IRB and regulatory authority (as locally 
required) 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/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC. 
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures. 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a 
study-specific ICF giving details of the study drugs, procedures, and potential risks of 
the study. Subjects will be instructed that they are free to obtain further information 
from the Investigator (or designee) and that their participation is voluntary, and they 
are free to withdraw from the study at any time. Subjects will be given an opportunity 
to ask questions about the study prior to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will 
sign 2 copies of the ICF in the presence of a suitably trained member of staff to 
indicate that they are freely giving their informed consent. One copy will be given to 
the subject, and the other will be maintained in the subject’s records. 

 
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Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in 
eCRFs, study-related forms, study reports, or any related publications. Subject and 
Investigator personal data will be treated in compliance with all applicable laws and 
regulations. In the event the study protocol, study report, or study data are included in 
a public registry, all identifiable information from individual subjects or Investigators 
will be redacted according to applicable laws and regulations.  
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. The level of disclosure must 
also be explained to the subject. The subject must also be informed that his/her 
study-related data may be examined by Sponsor or CRO auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected 
and/or documented during the course of the study, will be regarded as confidential. 
The Investigator (or designee) agrees not to disclose such information in any way 
without prior written permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the Sponsor or Covance electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF.  
The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The Sponsor or Covance is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a 
risk management register. Additional details of quality checking to be performed on 
the data may be included in a Data Management Plan.  
A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable 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 all applicable 
regulatory requirements. 

 
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Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) (US site) 
unless local regulations or institutional policies require a longer retention period. 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.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely 
fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to the Sponsor or Covance electronically, will be integrated with the 
subject’s eCRF data in accordance with the Data Management Plan.  
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, 
will review the supporting source documentation against the data entered into the 
eCRFs to verify the accuracy of the electronic data. The Investigator will ensure that 
corrections are made to the eCRFs and that data queries are resolved in a timely 
fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic 
signature procedure. These signatures will indicate that the Investigator reviewed and 
approved the data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may 
publish the results in recognized (refereed) scientific journals subject to the provisions 
of the clinical study agreement (CSA). Unless otherwise specified in the CSA, the 
following process will occur: 
If the Investigator expects to participate in the publication of data generated from this 
site, the institution and Investigator will submit reports, abstracts, manuscripts, and/or 
other presentation materials to the Sponsor for review before submission for 
publication or presentation. The Sponsor will have 60 days to respond with any 
requested revisions including, without limitation, the deletion of confidential 
information. The Investigator will act in good faith upon requested revisions, except 
the Investigator will delete any confidential information from such proposed 
publications. The Investigator will delay submission of such publication or 
presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed.

 
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Appendix 6: Schedule of Assessments 
 
Screening 
a 
Randomizati
on b 
Treatment period  
Follow-up 
Week 
-4 
Day -1  
0 c 
1 
2 
3 
4 
8 
9 
10 
11 
12d 
14 
16 
18 
Day (range) 
 
-1 
1 
8 
15±1 
22±1 
29±1 
57±1 
64±1 
71±2 
78±2 
85±3 
99±3 
113±3 
127±3 
Visit 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Vital signs 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
Height 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
Physical examination 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
Serology tests e 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, clinical 
chemistry, and 
coagulation 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
Urinalysis 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 

 
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Screening 
a 
Randomizati
on b 
Treatment period  
Follow-up 
Week 
-4 
Day -1  
0 c 
1 
2 
3 
4 
8 
9 
10 
11 
12d 
14 
16 
18 
Day (range) 
 
-1 
1 
8 
15±1 
22±1 
29±1 
57±1 
64±1 
71±2 
78±2 
85±3 
99±3 
113±3 
127±3 
Visit 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Pregnancy test f 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
FSH g 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
 
 
Injection of GMA301 or 
placebo 
 
 
× 
 
 
 
× 
× 
 
 
 
 
 
 
 
Pharmacokinetics 
sampling 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Immunogenicity (ADA) h 
 
 
× 
 
× 
 
× 
× 
 
 
 
× 
 
 
× 
NT-proBNP 
 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
AE recording 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
12-lead ECG 
× 
× 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
RHC 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
 
 
Echocardiogram  
× 
 
 
 
 
 
 
× 
 
 
 
× 
 
 
 
6MWT (Borg dyspnea 
scale) 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
 
 
WHO function 
classification 
× 
× 
 
 
 
 
 
× 
 
 
 
× 
 
 
 

 
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Screening 
a 
Randomizati
on b 
Treatment period  
Follow-up 
Week 
-4 
Day -1  
0 c 
1 
2 
3 
4 
8 
9 
10 
11 
12d 
14 
16 
18 
Day (range) 
 
-1 
1 
8 
15±1 
22±1 
29±1 
57±1 
64±1 
71±2 
78±2 
85±3 
99±3 
113±3 
127±3 
Visit 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
REVEAL risk score 
 
× 
 
 
 
 
 
 
 
 
 
× 
 
 
 
 
Abbreviations: 6MWT = six-minute walk test; ADA = Anti-drug antibodies; ECG = electrocardiogram; FSH= follicle stimulating hormone; RHC = right heart catheterization.  
 
a. 
Screening period will be up to 4 weeks. If a Screening test was performed within 3 days prior to Week 0, the results can be used as baseline (Week 0) results. No need to repeat the test at 
Week 0. 
b. 
Day -1 the randomization day can also be the first day of Week 0, ie, the baseline blood sampling and information collection can be conducted just before the first dosing.  
c. 
The samples at Week 0 will be collected on Day 1 of Week 0 before the first dosing. 
d. 
Tests can also be done on the last day of Week 11. If a subject discontinues the visit in advance, it would be better to ask the subject to complete the Week 12 examinations. 
e. 
Serology tests refer to Hepatitis B surface antigen, Hepatitis C antibody, and Human Immunodeficiency Virus antibodies (Appendix 2). 
f. 
Women of childbearing potential will perform pregnancy test in serum at Screening and in urine at randomization and Weeks 4, 8, and 12.  
g. 
FSH test will be performed at the same time with serum pregnancy test at Screening. 
h. 
ADA will be collected at: Week 0 (pre-dose of the 1st dose), Week 2, Week 4 (prior to 2nd dose), Week 8 (prior to 3rd dose), Week 12 and Week 18 (end of follow-up). 
 
 

 
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Pharmacokinetics sampling: 
Pharmacokinetics serum samples will be obtained for PK assessments at the following timepoints (±Time window): 
Dose 1st: predose, 4 (±15 min), 8 (±30 min), 24 (±120 min), 72 (±240 min), 168 (Day 8; ±480 min), 336 (Day 15; ±1 day), 504 (Day 22; ±1 day), 
and 672 (Day 29; ±1 day) hours post dose.  
Dose 3rd: predose, 4 (±15 min), 8 (±30 min), 24 (±120 min), 72 (±240 min), 168 (Day 8; ±480 min), 336 (Day 15; ±1 Day), 504 (Day 22; ±1 day), 
672 (Day 29; ±1 day), 1008 (Day 43; ±2 day), 1344 (Day 57; ±3 day), 1680 (Day 71; ±3 day) hours postdose.  
The samples of the 672h post 1st dose will be collected before the 2nd dose. 
 
 

 
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Appendix 7: The REVEAL Risk Score 
The REVEAL risk score can be implemented to identify predictors of short- and long-
term survival in the context of current treatment and clinical variables. The calculator 
is as follows. 
Calculated risk scores can range from 0 (lowest risk) to 23 (highest risk).  BNP = brain natriuretic peptide; BPM = 
beats per minute; CTD-PAH = PAH associated with connective tissue disease; DLco = diffusing capacity of the 
lungs for carbon monoxide; eGFR = estimated glomerular filtration rate; FC = functional category; HR = heart 
rate; mRAP = mean right atrial pressure; NT-proBNP = N-terminal fragment of pro-brain natriuretic peptide; 
NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PoPH = pulmonary hypertension 
associated with portopulmonary hypertension; PVR = pulmonary vascular resistance; REVEAL = Registry to 
Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management; SBP = systolic BP; WHO 

 
Protocol No.: GETA_MAD_01 
Protocol Version 3.0 
Page 57 of 57 
= World Health Organization.