Evaluation of Seralutinib Efficacy and Safety in Pulmonary Arterial Hypertension: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-503614-80-00
- Protocol
- GB002-3101
- Sponsor
- GB002 Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of **seralutinib** compared to placebo on exercise capacity after 24 weeks of treatment in patients with **Pulmonary Arterial Hypertension (PAH)**. This is clinically relevant as improving exercise capacity is a critical outcome for patients with PAH, potentially enhancing their quality of life and overall functional status.
Secondary objectives include:
- Evaluating the effect of seralutinib compared to placebo on time to Clinical Worsening (TTCW).
- Assessing the effect on clinical improvement.
- Measuring the impact on NT-proBNP levels.
- Evaluating the effect on PAH risk assessment.
- Assessing the safety and tolerability of seralutinib.
Participants
The clinical trial for **Pulmonary Arterial Hypertension** involves a total of 215 participants, comprising both male and female subjects. The study population includes adults aged between 18 to 75 years, with a body mass index ranging from 17 kg/m² to 40 kg/m². Participants were selected based on specific criteria, including a confirmed diagnosis of idiopathic, heritable, or associated forms of pulmonary arterial hypertension, and a 6-minute walk distance between 150 and 475 meters. The trial does not include vulnerable populations. Participants are required to be on a stable regimen of at least one background PAH disease-specific medication prior to screening. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to certain health and medication stability requirements. The trial aims to evaluate the effect of seralutinib compared to placebo on exercise capacity over a 24-week period.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of oral inhalation of **seralutinib** for the treatment of **Pulmonary Arterial Hypertension** (PAH). The trial aims to assess the effect of seralutinib compared to placebo on exercise capacity after 24 weeks of treatment, in addition to background PAH disease-specific medication. The study is expected to commence recruitment on January 31, 2024, and conclude by October 31, 2025.
Participants will be randomly assigned to receive either seralutinib or a placebo, both administered as an inhalation powder in hard capsules. The trial will involve a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, body mass index, and specific PAH diagnostic parameters. Eligible participants will then proceed to the baseline visit, where initial assessments will be conducted, including the six-minute walk test (6MWT) to establish baseline exercise capacity.
Subsequent visits will occur at regular intervals throughout the 24-week treatment period to monitor safety, efficacy, and any adverse events. These visits will include assessments such as the 6MWT, measurement of NT-proBNP levels, and evaluation of clinical worsening or improvement. The primary endpoint is the change in distance achieved on the 6MWT from baseline to Week 24. Secondary endpoints include time to first event of clinical worsening, proportion of subjects achieving clinical improvement, and changes in NT-proBNP levels.
The end-of-study visit will occur at the conclusion of the 24-week treatment period, where final assessments will be conducted to evaluate the overall impact of the treatment. Participant involvement is expected to last approximately 48 weeks, including the screening, treatment, and follow-up phases. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures.
Treatment
The clinical trial involves the administration of **seralutinib**, an experimental medication formulated as an **inhalation powder, hard capsule**. The active substance, seralutinib, is of chemical origin and is provided by GB002, INC. The medication is administered via inhalation using a device that has received CE marking from IMQ S.p.A. The maximum daily dose of seralutinib is 180 mg, with a total treatment period extending up to 48 weeks. The dosing schedule is designed to ensure consistent delivery of the medication, and participant compliance is monitored throughout the study to ensure adherence to the prescribed regimen.
The study also includes a **placebo** treatment, which is an inhalation powder contained in a capsule identical in size, shape, and color to the seralutinib drug product. The placebo contains lactose monohydrate and is administered in the same manner as the active drug, using the same inhaler device. This design ensures blinding and allows for a direct comparison of the effects of seralutinib against the placebo. The placebo serves as a control to evaluate the efficacy and safety of seralutinib in the treatment of **pulmonary arterial hypertension** (PAH).
Efficacy
The efficacy of the investigational product, **seralutinib**, in the treatment of Pulmonary Arterial Hypertension (PAH) will be assessed through a series of predefined endpoints. The primary endpoint is the change in distance achieved on the six-minute walk test (6MWT) from baseline to Week 24. This test is a widely accepted measure of exercise capacity in patients with PAH and will be conducted at specified intervals to evaluate the improvement in physical endurance.
Secondary endpoints include the time to the first event of clinical worsening from the first dose of the investigational product through the end of the study, and the proportion of subjects achieving all components of a composite endpoint of clinical improvement at Week 24, in the absence of clinical worsening. Additionally, changes in NT-proBNP levels from baseline to Week 24 will be measured as a biomarker of cardiac stress. The proportion of subjects with a decrease of at least one point from baseline in the REVEAL Lite 2 Risk Score at Week 24 will also be evaluated. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs (SAEs), and treatment-emergent adverse events of special interest (AESIs) will be monitored to assess safety alongside efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1-9 1.Adult subjects aged 18 to 75 years. 2. Body mass index (BMI) ≥ 15 kg/m2 and ≤ 40 kg/m2. 3. Diagnosis of PAH classified by one of the following: a. Idiopathic PAH (IPAH) or heritable PAH (HPAH). b. PAH associated with connective tissue disease (CTD-APAH); c. PAH associated with anorexigen or PAH associated with methamphetamine use. d. Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after surgical repair. 4. 6MWDs ≥ 150 meters and ≤ 475 meters during Screening prior to randomization. 5. WHO FC II or III. 6. US Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score ≥ 5 OR NT-proBNP ≥ 300 ng/L OR PVR ≥ 800 dyne∙s/cm5. 7. Cardiac catheterization within the screening period, or a standard of care RHC (with pressure wave forms available for review) up to 48 weeks prior to Screening: a. Mean pulmonary arterial pressure (mPAP) > 20 mmHg (at rest), AND b. Pulmonary vascular resistance (PVR) ≥ 400 dyne∙s/cm5, AND c. Pulmonary capillary wedge pressure (PCWP) or left ventricle end-diastolic pressure (LVEDP) ≤ 15 mmHg 8. Treatment with at least one allowed background PAH disease-specific medication(s) prior to Screening, a. Subjects receiving treatment with endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, guanylate cyclase stimulators, and/or prostacyclin analogues or prostacyclin receptor agonists are eligible only if on a stable dose for at least 12 weeks prior to and throughout Screening. b. Subjects receiving treatment with sotatercept are eligible only if on a stable dose of sotatercept for at least 24 weeks prior to and throughout Screening, with a RHC performed during Screening (or within 2 weeks prior to Screening).9. Pulmonary function tests (PFTs) at Screening or completed no more than 12 weeks prior to Screening.
- 10-12 10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening and on Day 1 before first administration of Investigational Product (IP). 11. WOCBP who are not abstinent and intend to be sexually active with a non-sterilized male partner must be willing to use a highly effective method of contraception from consent through 30 days following the last administration of IP12. Women of nonchildbearing potential (WONCBP), classified by one of the following: a. Surgical sterilization. b. Evidence of post-menopausal status. 13. Male subjects: Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom from consent through 90 days after the last dose of IP.
Exclusion Criteria
- 1.-20. 1. Evidence of chronic thromboembolic disease or acute pulmonary embolism. 2. Uncontrolled systemic hypertension as evidenced by systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg. 3. Systolic blood pressure < 90 mm Hg during Screening. 4. WHO Pulmonary Hypertension Group 2 – 5. 5. Human immunodeficiency virus (HIV)-associated PAH, schistosomiasis-associated PAH, PAH associated with portal hypertension, or pulmonary veno-occlusive disease (PVOD). 6. Recent history of left-sided heart disease and/or clinically significant cardiac disease within 48 weeks of Screening. 7. Left ventricular ejection fraction (LVEF) ≤ 50% within 24 weeks of Screening. 8. Hemodynamically significant valvular heart disease or uncontrolled symptomatic coronary disease. 9. History of atrial septostomy. 10. Uncontrolled atrial fibrillation or paroxysmal atrial fibrillation. 11. Three or more of the following risk factors for left ventricular disease: a. BMI > 32 kg/m2 b. Diagnosis of essential hypertension that is actively treated c. Diabetes mellitus d. Atrial fibrillation. 12. Untreated severe obstructive sleep apnea. 13. Hepatic dysfunction defined as Child-Pugh Class A or higher, or as evidenced by one of the following at Screening: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 2 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 2 x ULN . 14. History of malignancy with 5 years prior to Screening, with the exception of localized non-metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix. 15. History of a potentially life-threatening cardiac arrhythmia with an ongoing risk. 16. Uncontrolled bacterial, viral, or fungal infections which require ongoing systemic therapy 17. Severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP administration (eg, history of intracranial hemorrhage, recurrent syncope). 18. Any musculoskeletal disease, injury, or any other disease that limits evaluation of 6MWT. 19. Initiation of an exercise program for cardiopulmonary rehabilitation within 12 weeks prior to Screening or planned during the study. 20. Pregnant or nursing or intends to become pregnant during the duration of the study.
- 21.-35. 21. Body weight < 37 kg at Screening. 22. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2. 23. Hemoglobin (Hgb) concentration < 8.5 g/dL at Screening. 24. Evidence of active or latent Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infection at Screening. 25. Tyrosine kinase inhibitors within 12 weeks prior to Screening. Prior/concurrent treatment with tyrosine kinase or activin signaling inhibitors: a. Tyrosine kinase inhibitors, other than Janus kinase inhibitors approved for systemic autoimmune rheumatic diseases, within 12 weeks prior to Screening; b. Activin signaling inhibitors within 5 half-lives prior to Screening 26. Requirement of IV inotropes (ie, levosimendan, dopamine, dobutamine, milrinone, norepinephrine) or IV diuretics for more than 24 hours within 4 weeks prior to Screening. 27. Subjects currently receiving oral anticoagulants (ie, warfarin/other vitamin K antagonists or direct-acting oral anticoagulants [DOACs]) if any of the following criteria are met: a. History within 24 weeks of Screening of: i. Syncope, or ii. Symptomatic bleeding in a critical area or organ iii. Intramuscular with compartment syndrome, or iv. Bleeding causing a fall in hemoglobin levels of 1.24 mmol/L (20 g/L or greater) or more, or v. Bleeding to a transfusion of 2 U or more of whole blood or red blood cells. b. History of central nervous system pathology. c. History of clinically significant (massive) hemoptysis. d. If on warfarin/other vitamin K antagonist, uncontrolled International normalized ratio (eg, INR > 3) as assessed. e. Platelet count < 150 x 109/L at Screening. f. Concomitant use of antiplatelet agents. g. CTD-APAH. h. Concomitant use of sotatercept. 28. Prior participation in seralutinib studies and/or prior treatment with seralutinib. 29. Currently participating in or has participated in a study of an investigational agent or has used an investigational device for the treatment of PAH within 8 weeks or 5 half-lives of the investigational agent, whichever is longer, prior to Screening. 30. Current use of inhaled tobacco- or nicotine-containing products (including e-vapor products) and/or inhaled marijuana. 31. Current alcohol use disorder based on the opinion of the Investigator, and/or a positive test for drugs of abuse. 32. Subjects with a history of severe milk protein allergy or known intolerance to lactose. 33. QT interval corrected for heart rate using Fridericia’s formula (QTcF) of > 500 msec. 34. Have any other condition or reason that, in the opinion of the Investigator or in the opinion of the Sponsor’s Medical Monitor (MM) (or designee) in consultation with the Investigator, would prohibit the subject from participating in the study 35. Subjects performing mandatory military service, subjects deprived of liberty, subjects who, due to a judicial decision, cannot take part in clinical studies, or subjects in residential care institutions, according to local/national regulations
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 31 Jan 2024 | 4 |
 Belgium | Not Recruiting | 31 Jan 2024 | 4 |
 Czechia | Not Recruiting | 31 Jan 2024 | 4 |
 Denmark | Not Recruiting | 31 Jan 2024 | 4 |
 France | Not Recruiting | 31 Jan 2024 | 18 |
 Germany | Not Recruiting | 31 Jan 2024 | 53 |
 Greece | Not Recruiting | 31 Jan 2024 | 8 |
 Ireland | Not Recruiting | 31 Jan 2024 | 2 |
 Italy | Not Recruiting | 31 Jan 2024 | 6 |
 Latvia | Not Recruiting | 31 Jan 2024 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GB002 | Test | INHALATION POWDER, HARD CAPSULE | INHALATION | 180 | 48 | PRD7871021 |
The placebo is an inhalation powder, comprised in a capsule identical in size, shape, and color to the drug product and contains lactose monohydrate.
The placebo is administered the same way as the drug product via an inhaler device. | Placebo | N/A | — | — | — | N/A |