| 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 |
Main Study:
To evaluate the safety and tolerability of orally inhaled GB002 in subjects with WHO Grade 1 PAH.
Open-Label Extension (OLE) Study:
To evaluate the long-term safety and tolerability of orally inhaled GB002 in subjects with WHO Group 1 PAH who have completed the Main Study. |
|
| E.2.2 | Secondary objectives of the trial |
Main Study:
To evaluate PK of orally inhaled GB002.
Open-Label Extension (OLE) Study:
Evaluate the long-term effect of orally inhaled GB002 on exercise capacity, functional class, NT-proBNP, cardiac function and quality of life in subjects with WHO Group 1 PAH who have completed the Main Study. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Main Study
1 Evidence of a personally signed and dated informed consent document indicating the subject has been informed of all pertinent aspects of the study prior to initiation of any subject-mandated procedures. Willingness & ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
2 Adult (males & females) aged 18-75 years (incl) with WHO Gp 1 PAH
3 A current diagnosis of symptomatic PAH classified by one of the following:
a Idiopathic or heritable PAH
b PAH associated with one of the following connective tissue diseases:
i Systemic sclerosis
ii Rheumatoid arthritis
iii Mixed CTD or overlap syndrome
iv Systemic lupus erythematosus
c PAH associated with anorexigen or methamphetamine use
4 A WHO/NYHA functional class II–IV symptomatology
5 Documentation of right heart catheterization prior to screening consistent with the diagnosis of PAH and meeting all following criteria:
a Mean pulmonary arterial pressure (mPAP) ≥25 mmHg (at rest)
b Pulmonary capillary wedge pressure (PCWP) ≤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 Pulmonary vascular resistance (PVR) ≥4 mmHg/L/min or 320 dyn×sec/cm5
A qualifying cardiac catheterization is required during screening period if results of previous assessments are not documented
6 Treatment with single or combination therapy from classes of phosphodiesterase type 5 (PDE-V) inhibitors, guanylate cyclase (GC) stimulators, endothelin receptor antagonists, and prostanoids including prostacyclins and small molecule prostacyclin receptor agonists, eg, selexipag (with exception of inhaled prostanoids) is allowed. For this study, single or combination therapy with one or more of these drugs is considered PAH background therapy. Subjects who are intolerant of all PAH background therapy may be allowed to be randomized on a case-by-case basis in consultation with the Medical Monitor. PAH background medications should remain stable and unchanged for the past 30 days prior to screening. In addition, diuretic doses should be stable for the past 30 days prior to Screening. Diuretics (as needed) for intermittent weight gain (if prescribed 30 or more days prior to screening and unchanged within 30 days prior to Screening) will be considered a stable dose for this study.
7 Pulmonary function tests (PFTs) and diffusing capacity of the lungs for carbon monoxide (DLCO) at screening with the following criteria met:
a Forced expiratory volume in 1 second (FEV1) ≥70% (predicted)
b FEV1/forced vital capacity ratio (FEV1/FVC) >70%
c DLCO ≥40% predicted except for subject 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 study
8 Body weight >40 kg at screening
9 6 Minute Walk Test (6MWT) distance >100 m at screening; if distance walked is not >100 m, test may be repeated once; the distance walked during second assessment must be >100 m, with test conducted on a separate day)
10 No evidence of CTEPH or acute pulmonary embolism as assessed by ventilation-perfusion (V/Q) lung scan, CT-angiogram, or pulmonary angiogram (i.e., should note “normal” or “low probability” for pulmonary embolism) prior to screening, or at screening if: a) not performed prior or b) if clinical course suggests possibility of a pulmonary embolus as determined by the principal investigator since the last time study was performed
11 Women of childbearing potential must use one contraceptive method (one additional non hormonal contraceptive method if using combined hormonal contraceptive or progestogen-only hormonal contraceptive) that is highly effective (failure rate of <1% per year), preferably with low user dependency during the intervention period and for at least 28 days after the last dose of IP, and have a negative pregnancy test at Screening and Day 1. To be considered as “not of childbearing potential” females must be either: postmenopausal for at least 1 year as confirmed by an elevated FSH level (≥30 mIU/mL) at Screening and 1 year of amenorrhea OR have been irreversibly surgically sterilized by hysterectomy, oophorectomy, or bilateral tubal ligation at least 3 months prior to the first dose of IP. Men who are not sterile (ie, have not had a vasectomy) must also agree to use contraception and not donate sperm during the intervention period through at least 3 months after the last dose of IP
OLE Study (abbrv.)
1 Adult female subjects aged 18-75 years, inclusive, or adult male subjects aged 50-75 years, inclusive.
2 Willing to Comply with Protocol/Informed Consent Signed
3 Prior study completion
4 Contraception
For subjects with gap ≥1 day between the Main study and OLE
5 PAH Diagnosis
6 Background PAH therapy |
|
| E.4 | Principal exclusion criteria |
Main Study
1 Participation in a device or other interventional clinical study within 1 month (30 days; or within 5 half-lives of the medication, whichever is longer) of Day 1
2 Clinically significant systemic hypertension or hypotension
3 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 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% ECHO performed within 84 days prior to Screening will be accepted with availability of results documentation. If ECHO results within 84 days prior to Sceening are not available, then ECHO will be performed as part of Sceening
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 screening
i History of untreated obstructive sleep apnea
4 History of Atrial Septostomy
5 History of decompensated right heart failure within 30 days of screening (e.g., hospitalization for PAH or the need to add an additional PAH medication)
6 Use of inhaled prostanoids
7 Moderate to severe hepatic impairment classified as a Child-Pugh Class B or C at screening
8 An estimated glomerular filtration rate (eGFR) < 45 mL/min via CKD-epi at Screening or requires chronic renal replacement therapy for any cause
9 Requirement of intravenous (IV) inotropes (eg levosimendan, dopamine, dobutamine, milrinone; norepinephrine) other than a prostanoid within 1 month (30 days) of screening
10 A positive result for hepatitis B or C infection indicating prior infection (excluding hepatitis B antibody due to prior vaccination), human immunodeficiency virus (HIV) antibody, or tuberculosis (TB)
11 Pulmonary venous occlusive disease
12 Anemia: Hgb concentration <8.5 g/dL at Screening
13 Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP 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 Screening, 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; history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage; thyroid disease requiring treatment, gastrointestinal (GI) bleed requiring blood transfusion, history of pulmonary embolus or deep vein thrombosis (DVT), history of vasovagal syncope with phlebotomy
14 Currently pregnant or breastfeeding or intends to become pregnant during the duration of the study
15 Atrial fibrillation (AFIB), atrial flutter, or history of AFIB/flutter within 1 year prior to Screening. History of a potentially life-threatening cardiac arrhythmia; prior ablation for AFIB/atrial flutter
16 Use of 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 IP.
17 Any over-the-counter (OTC) medication use specifically including acetaminophen (up to 2 g per day, not to exceed 4g per week during the 14 days prior to administration of the first dose of GB002) will be allowed
18 Inability to perform maneuvers required for adequate inhalation using a dry powder inhaler (DPI) after instruction
19 Inability to generate a flow rate of at least 60 L/min with an inhalation testing device after instruction at screening
20 Prior treatment with a kinase inhibitor
21 Use of inhaled Tobacco or Marijuana
22 A positive test for drugs of abuse (amphetamines, methamphetamines, barbiturates, cocaine, phencyclidine [PCP], methadone, and opioids [narcotics]) or cotinine. Retest may be performed for potential false positive results with approval from the medical monitor
OLE Study (abbrv.)
1 Male subjects <50 years of age
2 Other Clinical Study Participation
3 Any other condition or any other reason
4 Systemic Hypertension or Hypotension
5 Left Heart Disease
6 Atrial septostomy
7 Hepatic Impairment
8 Renal Impairment
9 Anemia
10 Malignancy
11 Pregnancy
12 Cardiac Arrythmia
13 Anticoagulation
14 IV Inotropes
15 Other Medical or Lab Abnormality
16 Inhaled Tobacco or Marijuana
17 Drugs of Abuse |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Main Study
The incidence of adverse events (AEs) and changes from baseline in oxygenation, pulmonary function, clinical laboratory parameters, electrocardiogram (ECG) parameters, vital sign parameters, and assessment of cardiac function by echocardiogram (ECHO).
OLE Study
Incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs).
Changes from baseline in clinical laboratory parameters, ECG parameters, pulmonary function, and vital signs. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main Study
Adverse events: from Day 1 to Day 42
EKG, pulmonary function and clinical laboratory parameters: screening; treatment period Day 1, 8, 14; early withdrawal visit
Assessment of left ventricular ejection fraction (LVEF) by cardiac MRI: screening; treatment period Day 14; early withdrawal visit
OLE Study
Every 4 weeks (Study days 29, 57, 85, 113, 141 and 169); early withdrawal visit.
|
|
| E.5.2 | Secondary end point(s) |
Main Study
The PK parameters of GB002 and metabolite(s), if applicable.
Open Label Extension (OLE) Study
Changes from baseline in:
− Six minute walk test (6MWT)
− WHO Functional class (FC)
− NT-proBNP
− Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) quality of life (QOL) questionnaire
Changes from baseline in right ventricular (RV) function by ECHO |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Main Study
Treatment period Day 1, 2, 8, 14.
OLE Study
Every 4 weeks (Study days 29, 57, 85, 113, 41 and 169); early withdrawal visit.
ECHO at Day 85 only and early withdrawal visit.
NT-proBNP collected pre-dose. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Main Study
Tolerability
Open-Label Extension (OLE) Study
The multi-center, OLE study investigates the long-term safety, tolerability, and efficacy of orally inhaled GB002 after extended dosing of up to 24 weeks in subjects with WHO Group 1 PAH who previously completed the Main study. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 8 |
| 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 |
| Denmark |
| France |
| Netherlands |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The End of Study is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, whichever occurs later. |
|
| 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 | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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