| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| WHO Group 1 pulmonary arterial hypertension is associated with raised blood pressure in the pulmonary artery due to abnormalities in the small branches of the pulmonary artery, the arterioles. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077739 |
| E.1.2 | Term | Pulmonary arterial hypertension WHO functional class I |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Determine the effect of GB002 on improving pulmonary hemodynamics in subjects with WHO Group 1 PAH who are WHO FC II and III. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
• Heart Rate Expenditure during 6MWT – Substudy at select participating sites.
Change from Baseline in heart rate expenditure as measured by continuous heart rate monitoring during the 6MWT. |
|
| E.3 | Principal inclusion criteria |
1. Adult female subjects aged 18 to 80 years, inclusive, or adult male subjects aged 50 to 80 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 one of the following connective tissue diseases (CTDs):
− Systemic sclerosis,
− Mixed CTD or overlap syndrome,
− Systemic lupus erythematosus.
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 consecutive 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 all following criteria, to be confirmed by a central hemodynamic core laboratory:
a. mPAP ≥ 25 mmHg (at rest);
b. Pulmonary capillary wedge pressure ≤ 15 mmHg, or mean left atrial pressure (mLAP) or left ventricular-end diastolic pressure (LVEDP) ≤ 15 mmHg in the absence of left atrial obstruction;
c. PVR ≥ 400 dyne•s/cm5.
7. Pulmonary function tests (PFTs) and diffusing capacity of the lungs for carbon monoxide (DLCO) at screening with following criteria met:
a. Forced expiratory volume in 1 second (FEV1) ≥60% (predicted);
b. DLCO ≥40% predicted except for subjects with PAH associated with systemic sclerosis (SSc-APAH) where DLCO ≥30% is required.
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 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 ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
10. Women of childbearing potential who are not abstinent and intend to be sexually active with a non-sterilized male partner must be willing to use a highly effective method of contraception (defined in Appendix 4 in Section 10.4 of the protocol) from consent through 30 days following the last administration of IP; acceptable methods include hormonal contraception (oral contraceptives – as long as on stable dose, patch, implant, or injection), intrauterine devices, or other form of highly effective contraception.
11. Male subjects: Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom from consent through 90 days after the last dose of IP. Male subjects should refrain from sperm donation throughout this period, except for the purpose of fertility analysis as part of this protocol.
12. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any subject-mandated procedures. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the study if he/she meets any of the following:
Medical Conditions
1. Evidence of chronic thromboembolic disease or acute pulmonary embolism as assessed by ventilation-perfusion (V/Q) scan, computed tomography (CT)-angiogram, or pulmonary angiogram prior to screening. If not available previously, then test should be performed during the screening period.
2. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during screening visit after a period of rest.
3. Systolic blood pressure < 90 mm Hg during screening and baseline visits.
Other Exclusion Criteria
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 ECHO within 12 weeks prior to screening;
Note: If ECHO images are not adequate to provide an accurate estimate of LVEF then a multigated acquisition (MUGA) or cardiac magnetic resonance imaging (cMRI) scan or single photon emission computed tomography (SPECT) imaging can be used to obtain an accurate LVEF.
f. Documented symptomatic coronary disease (i.e., angina or previous myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft), previous or planned coronary artery bypass surgery).
7. Untreated obstructive sleep apnea.
8. History of atrial septostomy within 180 days prior to screening.
9. Pulmonary venous occlusive disease (PVOD).
10. Moderate-to-severe hepatic impairment classified as Child-Pugh Class B or C at screening.
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. Active and/or 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).
15. Any musculoskeletal disease or any other disease that limits evaluation of 6MWT.
16 Pregnant or nursing or intends to become pregnant during the duration of the study.
Diagnostic Assessments
17 Body weight < 40 kg at screening.
18. Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) ≤ 30 mL/min via CKD-epi at screening or requires dialytic therapy or hemofiltration.
19. Hemoglobin (Hgb) concentration < 8.5 g/dL at screening.
20. Evidence of active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infections.
Prior Therapy
21. Inhaled prostanoids; these drugs must be withdrawn prior to or at screening.
22. Use of anticoagulants (ie, coumadin or novel oral anticoagulants [NOAC]) at randomization; if on coumadin or a NOAC, these drugs can be withdrawn, if clinically appropriate, during the screening period, and subjects should have normal coagulation parameters prior to the randomization (see Section 10.6 for examples of prohibited anticoagulants).
23. Requirement of intravenous (IV) inotropes (ie, levosimendan, dopamine, dobutamine, milrinone, norepinephrine) other than an IV prostanoid within 4 weeks of screening.
Prior/Concurrent Clinical Study Experience
24. Prior participation in GB002 studies and/or prior treatment with GB002.
25. Currently participating in or has participated in a study of an investigational agent or has used an investigational device for the treatment of PAH within 4 weeks prior to screening.
Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks or at least 5 half-lives (whichever is greater) after the last dose of the previous investigational agent.
Other Exclusion Criteria
26. Current use of inhaled tobacco.
27. A positive test for drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine [PCP]). Retest may be performed for potential false positive results. Certain drugs may be allowed if prescribed for medical conditions (i.e., opioids for pain, benzodiazepines for anxiety) and approved by the medical monitor. Ingestible or topical marijuana is allowed. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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), (Δ6MWD) from Baseline to Week 24.
SAFETY
Evaluate the safety of GB002 in this population:
• Incidence of treatment-emergent adverse events (TEAEs), serious TEAEs (SAEs), and treatment-emergent adverse event of special 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:
• Change from Baseline in European QOL – 5 dimensions – 5 levels (EQ-5D-5L).
• Change from Baseline in WHO FC.
• Time to clinical worsening (TTCW) defined as any of the following:
− death by any cause
− non-elective hospitalization for PAH, including atrial septostomy;
− reduction from Baseline in the 6MWD by ≥ 15%;
− worsening WHO FC;
− signs or symptoms of right-sided heart failure.
• Change from Baseline in pulmonary right atrial pressure (RAP), cardiac output (CO), cardiac index (CI), stroke volume (SV), and mean pulmonary arterial pressure (mPAP).
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 (NT-proBNP)
• Changes from Baseline in biomarkers measured in blood samples, circulating cells, mucosal fluid samples.
Heart Rate Expenditure during 6MWT – Substudy at select participating sites:
• Change from Baseline in heart rate expenditure as measured by continuous heart rate monitoring during the 6MWT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoint:
Baseline to Week 24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Israel |
| Serbia |
| Singapore |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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