| 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 |
| Evaluate the long-term safety and tolerability of orally inhaled GB002 in subjects with World Health Organization (WHO) Group 1 PAH. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
• Evaluate the long-term effect of orally inhaled GB002 on exercise capacity.
Exploratory:
• Evaluate the pharmacodynamics (PD) of orally inhaled GB002;
• Evaluate additional long-term effects of orally inhaled GB002;
• Determine the effect of GB002 on Risk Score Category;
• Evaluate additional long-term safety of orally inhaled GB002. |
|
| 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 |
Functional Respiratory Imaging (Sub-study)
Functional respiratory imaging (FRI) by high resolution computed tomography (CT) scan will be conducted in subjects with prior CT imaging in the parent study at designated timepoints in the SoA. The study will use specialized software to determine 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. |
|
| E.3 | Principal inclusion criteria |
Subjects must meet ALL the following inclusion criteria to be enrolled into the extension:
Age and Sex
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 informed consent form (ICF).
Type of Subject and Disease Characteristics
2. Subjects must have completed a prior GB002 PAH study and, in the opinion of the Investigator and Sponsor, have been compliant with study procedures and have completed treatment with IP through parent study EOT visit.
3. Treatment with standard of care PAH disease-specific background therapies (stable dose).
Contraception
Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
4. Women of childbearing potential must have a negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at extension enrolment visit before first administration of GB002 in this study. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required, and results must be negative.
5. Women of nonchildbearing potential: Evidence of post-menopausal status. Women will be considered post-menopausal if they have 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 they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
− Women ≥ 50 years of age would be considered post-menopausal if they 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).
6. 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 from consent through 30 days following the last administration of GB002; 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.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable.
Note: A vasectomized partner is acceptable.
7. 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 GB002. Male subjects should refrain from sperm donation throughout this period (except for male subjects participating in fertility analysis as part of this protocol).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable.
Informed Consent
8. 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 protocol-mandated procedures.
9. 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. Persistent and clinically significant systemic hypertension or hypotension.
2. Interval history of newly developed left-sided heart disease with onset or severity increased after participation in the parent or lead in-study, and/or clinically significant cardiac disease, unless reviewed and approved as eligible to participate in the study by Sponsor’s Medical Monitor (or designee), 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 or bioprosthetic cardiac valve;
c. Pericardial constriction or pericardial effusion with tamponade physiology;
d. Restrictive or congestive cardiomyopathy;
e. Left ventricular ejection fraction (LVEF) ≤50%.
f. Symptomatic coronary disease;
g. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation;
h. Acutely decompensated left heart failure within 1 month (30 days) of extension enrolment visit;
i. History of severe and untreated obstructive sleep apnoea.
3. Potentially life-threatening cardiac arrhythmia with an ongoing risk.
4. Uncontrolled bacterial, viral, or fungal infections which require systemic therapy.
5. Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or GB002 administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study; including but not necessarily limited to the following: malignancy within 5 years of extension enrolment visit, with the exception of effectively treated or excised localized non-metastatic basal cell carcinoma of the skin and in situ carcinoma of the cervix; psychiatric disorder that compromises ability to give informed consent, substance abuse, coagulopathy, history of stroke, transient ischemic attack (TIA) requiring concurrent oral coagulation therapy, or intracranial haemorrhage; history of pulmonary embolus or deep vein thrombosis (DVT), history of vasovagal syncope with phlebotomy.
6. Currently pregnant or breastfeeding or intends to become pregnant during the duration of the study.
7. History of portopulmonary hypertension or portal hypertension classified as Child-Pugh Class A or higher.
8. Subjects with a history of severe milk protein allergy. In addition, subjects with known intolerance or hypersensitivity to lactose who, in the opinion of the investigator, may experience severe symptoms following the ingestion of lactose.
9. Current use of inhaled tobacco and/or inhaled marijuana. Ingestible or topical marijuana is allowed, per local restrictions and regulations.
10. Documented history of alcohol abuse and/or history of utilizing drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine [PCP]).
11. Have any other condition or reason that, in the opinion of the Investigator and/or the Sponsor’s Medical Monitor (or designee), would prohibit the subject from participating in the study.
Diagnostic Assessments
The most recent laboratory assessment from the parent study may be used to evaluate laboratory-associated exclusion criterion, if performed within 6 weeks (± 2 days) of the extension enrolment visit.
12. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) or total bilirubin ≥ 2 × ULN.
13. Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2 via CKD-EPI at extension enrolment visit or requires dialytic therapy or hemofiltration.
14. Haemoglobin (Hgb) concentration <8.5 g/dL.
15. Absolute neutrophil count (ANC) < 1 x 109/L.
16. Platelet count <50 x 109/L.
17. Body weight ≤40 kg at extension enrolment visit.
Prior Therapy
18. Use of inhaled prostanoids.
19. Chronic use of oral anticoagulants (i.e., coumadin or novel oral anticoagulant [NOAC]); if on coumadin or a NOAC it is clinically acceptable to be withdrawn 1 month prior to start of GB002.
20. Chronic use of any prohibited medication. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Incidence and frequency of treatment-emergent adverse events (TEAEs). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline, 2, 4, 8, 12, 16, 24, 32, 40, 48, 60 and 72 weeks and 4 weeks post last GB002 dose. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoint
• Change in the distance achieved on six-minute walk test (6MWT), (Δ6MWD).
Exploratory Endpoints
Pharmacodynamics
• Changes in N-terminal pro b-type natriuretic peptide (NT-proBNP).
• Changes in various biomarkers measured in blood samples and/or circulating cells from baseline to end of treatment.
Long-term Effects
• 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 extension enrolment visit, 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.
Risk Score category
• Change from Baseline in Risk Score Category.
Additional Long-Term Safety
• Incidence and frequency of serious TEAEs (SAEs) and AESIs;
• Changes in clinical laboratory parameters, ECG parameters, and vital signs.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoint: Baseline, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72 and 4 weeks post last GB002 dose.
Exploratory Endpoints: Baseline to Week 76 as specified in protocol. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Canada |
| Israel |
| Serbia |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Spain |
| United Kingdom |
| Czechia |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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