A Study of GMA301 in Subjects With Pulmonary Arterial Hypertension

A Randomized, Double-blind, Placebo-Controlled, Dose Escalation Study to Assess Safety, Efficacy and Pharmacokinetics of GMA301 in Subjects With Pulmonary Arterial Hypertension

A Randomized, Placebo-Controlled, Double-blind, Dose Escalation Study to Assess Safety, Efficacy and Pharmacokinetics of GMA301 Injection in Subjects with Pulmonary Arterial Hypertension

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Q4W GMA301 IV injections (300 mg); Other: Q4W placebo IV injections; Drug: Q4W GMA301 IV injections (600 mg); Drug: Q4W GMA301 IV injections (1000 mg); Drug: Q4W GMA301 IV injections (1800 mg)

Detailed Description

Drug: Q4W GMA301 IV injections (300 mg) Drug: Q4W GMA301 IV injections (600 mg) Drug: Q4W GMA301 IV injections (1000 mg) Drug: Q4W GMA301 IV injections (1800 mg) Other: Q4W placebo IV injections

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jianjun Wu; Phone Number: +8618358737112; Email: jianjunwu@gmaxbiopharm.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Peking Union Medical College Hospital - Dongcheng District
  • Changsha, China
    • Recruiting
    • Xiangya Hospital, Central South University
  • Chongqing, China
    • Recruiting
    • The First Affiliated Hospital of Chongqing Medical University
  • Guangzhou, China
    • Recruiting
    • Guangdong General Hospital
    • Contact: Hua Yao
  • Shanghai, China
    • Recruiting
    • Shanghai Pulmonary Hospital
    • Contact: Lan Wang
  • Xian, China
    • Recruiting
    • The First Affiliated Hospital Of Xi'an Jiaotong University
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Aaron Waxman

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

   1. Idiopathic
   2. Heritable
   3. Drugs or toxins-induced
   4. Associated with connective tissue disease
   5. 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 per Investigator's judgment

6. Right heart catheterization (RHC) result meets below criteria when Screening:

   1. Mean pulmonary arterial pressure (PAP) ≥25 mmHg
   2. Pulmonary vascular resistance (PVR) >3 Woods units
   3. 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 only if they meet the entry criteria and the RHC at Screening will not be repeated. In case PAWP cannot be well measured during RHC, left ventricular end diastolic pressure will be tested by left heart catheterization.

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 (positive inotropic agents), or vasoactive drug within 30 days before Screening
10. Both male and female subjects agree to use 2 medically acceptable methods of contraception (Appendix 4) 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.

Exclusion Criteria

Subjects who me et 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. Use of calcium channel blockers within 1 month prior to Screening
3. Systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg at Screening
4. SBP <90 mmHg at Screening
5. Pulmonary function test: FEV1 <60% of predicted, TLC <60% of predicted, DLCO <60% of predicted
6. History of pulmonary embolism as judged by the Investigator
7. Uncontrolled sleep apnea at the discretion of the Investigator
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 at Screening:

    1. LVEF <50%
    2. Mean end-diastolic left ventricular septal and posterior wall thickness of >12 mm
    3. Left atrial (LA) area on apical 4 chamber view >20 cm2
    4. LA volume >55 mL
    5. LA volume index >34 mL/m2
    6. 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:

    1. Baseline aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 times the upper limit of normal (ULN) or total bilirubin ≥1.5 times ULN

    2. Estimated glomerular filtration rate (eGFR) <60 mL/min by Cockcroft-Gault formula

       Online calculation available from https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc

       Cockcroft-Gault formula (1973):

       Male: CCr=((l40-Age) × Weight)/(72×SCr)

       Female: CCr={((l40-Age) × Weight)/(72×SCr)}× 0.85

       CCr (creatinine clearance rate) = mL/min

       Age = year

       Weight = Kg

       SCr (serum creatinine) = mg/dL

    3. 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 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
24. Start a new exercise program or participate in any unusually strenuous physical exertion within 6 weeks prior to Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Q4W GMA301 IV injections (300 mg); Drug: Q4W GMA301 IV injections (300 mg) Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo. Other: Q4W placebo IV injections Placebo is indistinguishable from GMA301	Drug: Q4W GMA301 IV injections (300 mg); Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo.; Other: Q4W placebo IV injections; Placebo is indistinguishable from GMA301.
EXPERIMENTAL: Q4W GMA301 IV injections (600 mg); Drug: Q4W GMA301 IV injections (600 mg) Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo. Other: Q4W placebo IV injections Placebo is indistinguishable from GMA301	Other: Q4W placebo IV injections; Placebo is indistinguishable from GMA301.; Drug: Q4W GMA301 IV injections (600 mg); Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo.
EXPERIMENTAL: Q4W GMA301 IV injections (1000 mg); Drug: Q4W GMA301 IV injections (1000 mg) Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo. Other: Q4W placebo IV injections Placebo is indistinguishable from GMA301	Other: Q4W placebo IV injections; Placebo is indistinguishable from GMA301.; Drug: Q4W GMA301 IV injections (1000 mg); Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo.
EXPERIMENTAL: Q4W GMA301 IV injections (1800 mg); Drug: Q4W GMA301 IV injections (1800 mg) Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo. Other: Q4W placebo IV injections Placebo is indistinguishable from GMA301	Other: Q4W placebo IV injections; Placebo is indistinguishable from GMA301.; Drug: Q4W GMA301 IV injections (1800 mg); Each cohort will contain 12 subjects, 9 of whom will be administered active GMA301 and 3 of whom will be administrated placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The incidence of Treatment-emergent Adverse Events (TEAE) in subjects assigned to GMA301 compared with those assigned to placebo.	Through study completion (up to 22 weeks)

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics (Area under the serum concentration- time curve from time zero to the last measurable concentration)	Through study completion (up to 22 weeks)
Comparison of GMA301 treatment effect at Week 12 versus baseline regarding the pulmonary vascular resistance (PVR) based on right heart catheterization (RHC)	Baseline to Week 12
Comparing 6MWT distance	Baseline to Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in REVEAL 2.0 risk score at Week 12 compared with baseline	Calculated risk scores can range from 0 (lowest risk) to 23 (highest risk).	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Gmax Biopharm LLC.
• Investigators: Principal Investigator: Hua Yao, Guangdong Provincial People's Hospital; Principal Investigator: Lan Wang, Shanghai Pulmonary Hospital, Shanghai, China; Principal Investigator: Wei Huang, First Affiliated Hospital of Chongqing Medical University; Principal Investigator: Zaixin Yu, Xiangya Hospital of Central South University; Principal Investigator: Fenling Fan, First Affiliated Hospital Xi'an Jiaotong University; Principal Investigator: Zhicheng Jing, Peking Union Medical College Hospital - Dongcheng District; Principal Investigator: Aaron Waxman, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 22, 2020
• Primary Completion (ANTICIPATED): October 26, 2022
• Study Completion (ANTICIPATED): June 10, 2023

Study Registration Dates

• First Submitted: July 24, 2020
• First Submitted That Met QC Criteria: August 5, 2020
• First Posted (ACTUAL): August 7, 2020

Study Record Updates

• Last Update Posted (ACTUAL): January 14, 2022
• Last Update Submitted That Met QC Criteria: December 29, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: GETA_MAD_01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No