Clinical Study of Inhaled GB002 for the Treatment of WHO Group 1 Pulmonary Arterial Hypertension (PAH)

• Register: EUCTR
• Last refreshed on: 9 January 2023
• Main ID: EUCTR2019-002669-37-CZ
• Date of registration: 22/10/2020
• Prospective Registration: Yes
• Primary sponsor: GB002, Inc.
• Public title: Clinical Study of Inhaled GB002 for the Treatment of WHO Group 1 Pulmonary Arterial Hypertension (PAH)
• Scientific title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Clinical Study to Evaluate the Efficacy and Safety of Oral Inhalation of GB002 for the Treatment of WHO Group 1 Pulmonary Arterial Hypertension (PAH)
• Date of first enrolment: 21/01/2021
• Target sample size: 80
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-002669-37
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Canada, Czech Republic, Czechia, France, Germany, Israel, Serbia, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trials Information Website
• Affiliation: GB002, Inc.

• Name: Clinical Trials Information Website
• Affiliation: GB002, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Adult female subjects aged 18 to 75 years, inclusive, or adult male subjects aged 50 to 75 years, inclusive, at the time of signing the ICF prior to initiation of any study specific activities/procedures.

2. A current diagnosis of symptomatic PAH classified by one of the following:
a. Idiopathic PAH (IPAH) or heritable pulmonary arterial hypertension (HPAH).
b. PAH associated with connective tissue diseases (CTD-APAH):
- Systemic sclerosis,
- Mixed CTD or overlap syndrome,
- Systemic lupus erythematosus.
- Other CTD established by ACR/EULAR guidelines
c. PAH associated with anorexigen or methamphetamine use.
d. Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after surgical repair.
3. 6MWD = 150 meters and = 550 meters at screening. The lower of 2 distances should be within 15% of the higher distance.
4. WHO FC II or III symptomatology.
5. Treatment with standard of care PAH background therapies. Medications should remain stable for the past 4 weeks prior to consent and throughout screening period.
Exception: As needed (PRN) diuretics for intermittent weight gain and/or edema are allowed and will be considered a stable dose for this study.
6. Documentation of cardiac catheterization within the screening period consistent with the diagnosis of PAH and meeting following criteria, to be confirmed by the central hemodynamic core laboratory:
a. mPAP = 25 mmHg (at rest), AND
b. PVR = 400 dyne·s/cm5, AND
c. PCWP or LVEDP =12 mm Hg if PVR =400 to <500 dyne·sec/cm5 OR
d. PCWP or LVEDP =15 mmHg if PVR =500 dyne·sec/cm5

7. Pulmonary function tests (PFTs) a at screening with following criteria met:
a. Forced expiratory volume in 1 second (FEV1) divided by the forced vital capacity (FVC) =70%;
b. Total lung capacity (TLC) or FVC = 70% predicted
If the subject uses continuous oxygen therapy, they must be able to complete PFTs without oxygen. Subjects who are unable to complete PFTs without oxygen therapy are not eligible for the study.

Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
8. Women of childbearing potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin[hCG]) at screening and a negative urine pregnancy test on Day 1 before first administration of IP. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required and results must be negative.
9. Women of nonchildbearing potential: Evidence of post-menopausal status. Women will be considered post-menopausal if ave been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, tubal ligation, or hysterectomy).
- Women =50 years of age would be considered post-menopausal if have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year
Exclusion criteria:
1.Evidence of chronic thromboembolic disease or acute pulmonary embolism as assessed by ventilation-perfusion(V/Q)scan, computed tomography (CT)-angiogram, or pulmonary angiogram prior to screening. If not available previously, then test should be performed during the screening period.
2.Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure >100mmHg during screening visit after a period of rest
3.Systolic blood pressure<90mmHg during screening and baseline visits.
4.WHO Pulmonary Hypertension Group 2–5
5.HIV-associated PAH
6.History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
a.Aortic or mitral valve disease(stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis (AS), mild mitral stenosis (MS), moderate mitral regurgitation (MR)
b.Mechanical cardiac valve requiring anticoagulation
c.Pericardial constriction or pericardial effusion with tamponade physiology
d.Restrictive cardiomyopathy
e. Left ventricular ejection fraction (LVEF) = 50% by echocardiography (ECHO) within 6 weeks prior to screening; if ECHO from the prior 6 weeks is not available, the screening ECHO results may be used to establish this criterion
f. Left Atrial Area greater than 29cm2 by ECHO within 6 weeks prior to screening; if ECHO from the prior 6 weeks is not available, screening ECHO results may be used to establish this criterion.
g. Documented uncontrolled symptomatic coronary disease (ie, unstable angina or percutaneous coronary intervention or coronary artery bypass graft within 12 months prior to screening, or planned coronary intervention or coronary artery bypass surgery).
7.Untreated severe obstructive sleep apnea
8.History of atrial septostomy within 180 days prior to screening.
9.Pulmonary venous occlusive disease (PVOD)
10.Subjects with a history of portopulmonary hypertension or portal hypertension due to cirrhosis classified as Child-Pugh Class A or higher; or baseline ALT or AST > 2 x ULN or Total Bilirubin = 2 X ULN.
11.History of malignancy within 5 years prior to screening, with the exception of localized non-metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix
12.History of a potentially life-threatening cardiac arrhythmia with an ongoing risk
13.Uncontrolled bacterial, viral, or fungal infections which require systemic therapy
14.Severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP administration (eg. history of intracranial hemorrhage)or absolute neutrophil count (ANC) < 1x109/L or platelet count < 50x109/L
15.Any musculoskeletal disease or any other disease that limits evaluation of 6MWT
16.Pregnant or nursing or intends to become pregnant during the duration of the study
17.Body weight<40 kg at screening
18.Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR)<45 mL/min/1.73m2 via CKD-epi at screening or requires dialytic therapy or hemofiltration
19.Hemoglobin(Hgb) concentration <8.5g/dL at screening
20.Evidence of active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infections.
21.Inhaled prostanoids; these drugs may be withdrawn = 4 weeks prior to screening, if clinically indicated
22.Use of oral anticoagulants (ie, warfarin or novel oral anticoagulants [NOAC]) at randomi

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Pulmonary Arterial Hypertension (PAH)
MedDRA version: 20.0 Level: LLT Classification code 10077739 Term: Pulmonary arterial hypertension WHO functional class I System Organ Class: 100000004855

Intervention(s)

Product Name: GB002 Capsules
Product Code: GB002
Pharmaceutical Form: Inhalation powder, hard capsule
INN or Proposed INN: Seralutinib
CAS Number: 1619931-27-9
Current Sponsor code: GB002
Other descriptive name: (S)-3-((3-(1-((6-(3,4-DIMETHOXYPHENYL)PRYAZIN-2-YL)AMINO)ETHYL)PHENYL)CARBAMOYL)-5-METHYLPRIDIN-1-IUM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Inhalation powder, hard capsule
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Main Objective: Determine the effect of GB002 on improving pulmonary hemodynamics in subjects with WHO Group 1 PAH who are WHO FC II and III.

Primary end point(s): Determine the effect of GB002 on improving pulmonary hemodynamics in subjects with WHO Group 1 PAH who are WHO FC II and III:
• Change in Pulmonary Vascular Resistance (PVR) using Right Heart Catheterization (RHC)

RHC will be done to assess the severity of hemodynamic impairment and to subsequently help to identify risk status of subjects with a diagnosis of PAH. These data will also be used to evaluate the efficacy of GB002.

Secondary Objective: Determine the effect of GB002 on improving exercise capacity in this population.

Safety:
Evaluate the safety of GB002 in this population.

Exploratory:
• Evaluate the effect of GB002 on right heart function measures in this population
• Evaluate the effect of GB002 on other measures of efficacy
• Evaluate the safety of GB002 on other measures of tolerability
• Evaluate the pharmacokinetics (PK) of GB002
• Evaluate the pharmacodynamics (PD) of GB002 in this population
• Heart Rate Expenditure during Six Minute Walk Test (6MWT) – Substudy at select participating sites
• Evaluate the effects of GB002 on Heart Rate Expenditure and Heart Rate Recovery during Six Minute Walk Test (6MWT) – Substudy at select participating sites.
• Evaluate changes in the pulmonary vasculature by High-resolution CT – Substudy at select participating sites.
• Determine the effect of GB002 on Risk Score Category.

Timepoint(s) of evaluation of this end point: Baseline to Week 24

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Secondary Endpoint:
Baseline to Week 24

Secondary end point(s): SECONDARY
Determine the effect of GB002 on improving pulmonary hemodynamics in subjects with WHO Group 1 PAH who are WHO FC II and III:
• Change in distance achieved on the six-minute walk test (6MWT), (?6MWD) from Baseline to Week 24.

SAFETY
Evaluate the safety of GB002 in this population:
• Incidence of treatment-emergent adverse events (TEAEs), serious TEAEs (SAEs), and treatment-emergent adverse event of special interests (AESIs).

EXPLORATORY
Evaluate the effect of GB002 on right heart function measures in this population:
• Change from Baseline in tricuspid annular peak systolic velocity (TAS’), right ventricular (RV) Tei index and right ventricular free wall strain (RVFWS) by echocardiogram (ECHO).

Evaluate the effect of GB002 on other measures of efficacy:
• Changes in:
- WHO FC
- European QOL - 5 Dimensions - 5 Levels (EQ-5D-5L)
- Right ventricle (RV) function by imaging (echocardiography)
- Sub-study: Functional respiratory imaging (FRI) by computed tomography (CT) scan (in subjects with prior CT imaging).
• Time from first dose of GB002 to first event of protocol-defined clinical worsening event, assessed by measuring the first occurrence of any one of the following events:
- Death (all causes)
- Hospital admission for worsening PAH, as a result of any of the following:
o Non-elective hospitalization caused by clinical conditions directly related to PAH and/or right heart failure;
o Need for intravenous (IV) diuretics (more than a single dose in 24 hours);
o Lung or heart/lung transplantation;
o Atrial septostomy;
o Initiation of parenteral (IV infusion or subcutaneous injection) therapy with a prostacyclin (if not previously utilizing parenteral prostacyclin therapy).
- Disease progression, defined as:
o Worsening symptoms of right heart failure requiring initiation of a new PAH disease-specific medication or an increase in dose, or change in disease-specific background PAH medications or initiation of chronic
oxygen therapy (i.e., requires oxygen for >24 hours with the intent of long-term use); or
o A decrease in distance on 6MWT (6MWD) of at least 15% from Baseline, directly related to PAH progression, confirmed by 2 assessments of 6MWD performed at 2 consecutive visits and worsening
in WHO FC for subjects with WHO FC I/II/III; or
o Worsening Risk Score Category. Defined as a change in two components of the Risk Assessment to a worse risk category

Evaluate the safety of GB002 on other measures of tolerability:
• Change from Baseline in clinical laboratory parameters, ECG parameters, pulmonary function and vital signs.

Evaluate the PK of GB002:
• Plasma concentrations of GB002 and its metabolites, if appropriate.

Evaluate the pharmacodynamics (PD) of GB002 in this population:
• Change from Baseline in N-terminal pro b-type natriuretic peptide (NTproBNP).
• Changes from Baseline in biomarkers measured in blood samples

Evaluate the effects of GB002 on Heart Rate Expenditure and Heart Rate Recovery during 6MWT – Substudy at select participating sites:
• Change from Baseline in heart rate expenditure and heart rate recovery as measured by continuous heart rate monitoring during the 6MWT.

Evaluate changes in the pulmonary vasculature by High-resolution CT – Substudy at select participating sites:
• Change from Baseline in pulmonary vasculature blood volume, pulmonary blood volume as a percent of total lung volume, fibrosis
score, and image-based ventilation to perfusion score.

Determine the effect of GB002 on Risk Score Category:
• Change from Baseline in Risk Score Category based on REVEAL v2.0 and European Society of Cardiology (ESC)/European Respiratory Society (ERS).

Secondary ID(s)

NCT04456998

GB002-2101

2019-002669-37-GB

Source(s) of Monetary Support

GB002, Inc.

Ethics review

Status: Approved
Approval date: 21/01/2021
Contact: