E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Symptomatic Pulmonary Arterial Hypertension |
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E.1.1.1 | Medical condition in easily understood language |
PAH is a progressive and life-threatening disease which is characterized by high blood pressure in the lungs caused by abnormal constriction and remodeling of the arteries in the lungs. |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
Assess the safety, tolerability, and effect on pulmonary vascular resistance (PVR) of dose titrated levels of PB1046 administered subcutaneously once-weekly for 16 weeks in subjects with symptomatic pulmonary arterial hypertension (PAH) |
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E.2.2 | Secondary objectives of the trial |
• To investigate the effect of PB1046 on exercise capacity following treatment in PAH subjects
• To investigate the effect of PB1046 on change in N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP)
• To investigate the effect of PB1046 on cardiopulmonary hemodynamics
• To evaluate the multi-dose pharmacokinetic profile of individually dose-titrated PB1046 administered once-weekly for 16 weeks
• To evaluate the immunogenicity profile of PB1046 PAH subjects |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects will be eligible for inclusion in the study if they meet all the following criteria at screening and up to the time of first dose as indicated:
1. Male and female subjects with PAH, ≥18 and ≤ 79 years of age, who are symptomatic and have reduced exercise capacity due primarily to their PAH diagnosis and have been assessed by a qualified individual (i.e. physician, physician assistant, nurse practitioner) to be in NYHA/WHO functional class II or III
2. Willing and able to sign a written informed consent prior to all study-related procedures
3. Subjects with PAH belonging to one of the following subgroups of the NICE Clinical Classification of Pulmonary Hypertension Group 1:
a. Idiopathic
b. Heritable
c. Drug or toxin-induced
d. Associated with connective tissue disease, HIV infection, portal hypertension, congenital heart disease (pulmonary-to-systemic shunt, e.g., atrial septal defect (ASD) or patent ductus arteriosus (PDA), at least 1 year after surgical repair)
4. Two 6MWT results > 50 m and < 550 m prior to randomization with results +/- 10% of each other. Note: Up to four tests may be conducted between Screening and Randomization for eligibility purposes (no more than two 6MWT may be performed on the same day, and must be completed at least two hours apart)
5. Hemodynamic assessment of PAH by right heart catheterization (RHC) demonstrating elevated mPAP and PVR as indicated below during the Screening Period
a. mPAP of ≥ 25 mmHg; and
b. PVR ≥ 400 dyne•sec/cm5; and
c. PCWP or left ventricular end diastolic pressure (LVEDP) of ≤ 12 mmHg if PVR ≥ 400 and < 500 dynes•sec/cm5; or PCWP/LVEDP ≤ 15 mmHg if PVR ≥ 500 dynes•sec/cm5
6. Body mass index (BMI) ≥ 18 kg/m2 and ≤ 40 kg/m2 at screening
7. Meet the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to screening
a. Forced expiratory volume in one second (FEV1) ≥ 55% of predicted normal
b. FEV1: FVC (forced vital capacity) ratio ≥ 0.60
8. Agrees to use a medically acceptable method of contraception (both male and female patients) throughout the entire study period and continuing for 30 days after their last dose of study drug if the possibility of conception exists. Medically acceptable methods of contraception include the following: abstinence (not having sex), vasectomy (with confirmed negative sperm counts), condoms and partner using vaginal spermicide and/or cervical cap with spermicide or sponge; oral, implantable, or injectable contraceptives (starting >2 months before dosing), diaphragm with vaginal spermicide, intrauterine device,, surgical sterilization (>6 months after surgery). Female subjects < 45 years of age of non-childbearing potential are defined as being surgically sterile by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy. Female subject 45 to 60 years of age, inclusive, who is post-menopausal for at least 1 year and have a follicle-stimulating hormone (FSH) level confirmation indicating post-menopausal status, will be considered to be of non-childbearing potential. Female subjects >60 years of age are considered post-menopausal and of non-childbearing potential
9. Stable background medical regimen of up to 3 PAH disease-specific therapies for at least 3 months comprised of any combination of oral and/or inhaled or IV therapy and at stable doses for at least 30 days prior to Screening
10. If a subject has historical diagnosis (prior to screening visit) of being positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV), must be clinically stable and if on therapy, must be on stable therapy for HIV or HCV for at least 3 months
11. Willing and able to understand and follow instructions; return to the study unit for specified study visits; and able to participate in the study for the entire period |
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E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if they meet any of the following criteria:
1. Concomitant medical disorder, condition, or history, that in the opinion of the Investigator would impair the subject’s ability to participate in or complete the requirements of the study
2. Concomitant medical disorder that is expected to limit the subject’s life-expectancy to ≤ 1 year
3. Pregnant or lactating female subjects
4. First positive result from serology testing at Visit 1 (screening labs) for HIV, HBsAg, or HCV prior to randomization
5. Participation in another investigational drug study within 30 days prior to screening or participating in a non-medication study which, in the opinion of the Investigator, would interfere with the study compliance or outcome assessments
6. Use of subcutaneous prostanoid/prostacyclin therapy for PAH within 30 days prior to the screening visit
7. More than mild mitral or aortic valve disease, left ventricular ejection fraction < 50%, or left ventricular regional wall motion abnormality suggestive of active coronary artery disease on documented 2D-echocardiography occurring within 12 months of Screening
8. Sustained SBP < 95 mmHg and/or diastolic blood pressure (DBP) < 50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive readings (self-monitored or office) at screening and prior to dosing, or overt symptomatic hypotension
9. Sustained resting heart rate >110 beats per minute (BPM) (confirmed by duplicate assessments of office vital signs or consecutive ECG assessments) on at least 3 consecutive readings at screening and prior to dosing
10. Clinically significant renal dysfunction based on Screening labs as measured by the estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73m2 as calculated by the IDMS-Traceable MDRD equation: eGFR = (mL/min/1.73 m2) = 175 x (serum creatinine in mg/dL) – 1.154 x (Age) – 0.203 x (0.742 if female) x (1.212 if African American) (conventional units)
11. Significant liver dysfunction as measured by any one of the following at screening:
a. alanine aminotransferase (ALT) >3.0 times ULN or
b. aspartate aminotransferase (AST) >3.0 times ULN or
c. serum bilirubin ≥ 1.6 mg/dL
12. Known history of substance abuse within the past 1 year that in the opinion of the Investigator would impair the subject’s ability to participate in or complete the requirements of the study
13. Any major surgical procedure within 90 days prior to screening or planned surgical procedure during the study period
14. Any in-patient hospitalization (defined as greater than 23 hours) within 30 days of subject screening
15. Enrollment within the past 3 months prior to screening or plans to enroll during the study into a cardiopulmonary rehabilitation program
16. Other medical or psychiatric condition which, in the opinion of the Investigator, would place the subject at increased risk or would preclude obtaining voluntary consent or would confound the objectives of study
17. Known hypersensitivity to study drug or any of the excipients of the drug formulation;
18. Three or more of the following:
a. BMI >35
b. Current atrial fibrillation
c. Current Diabetes Mellitus
d. Current Hypertension
e. History of clinically significant coronary artery disease in prior 3 years |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Change from Baseline to end of assessment in Pulmonary Vascular Resistance (PVR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Right Heart Catherization (RHC) performed between Screening and Baseline and between Visits 17 (End of Treatment) and 18, preferably 48 to 72 hours after the last dose. |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
1. Change from Baseline to end of assessment in:
• Six Minute Walk Test (6MWT)
• NT-proBNP
• Cardiac index (CI), mean pulmonary artery pressure (mPAP), mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP), mixed venous oxygen saturation (SvO2), including pulmonary artery compliance
2. Safety Endpoints
• Incidence and severity of AEs and their relationship to study drug
• Vital signs, laboratory parameters, electrocardiograms (ECGs) and their relationship to PB1046
• Immunogenicity
3. Pharmacokinetic Endpoints:
• Plasma PB1046 concentration at each time point and PK parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From Baseline (V2) to end of assessment (V18)
2. From Baseline (V2) to the day of enrollment in the open-label extension (OLE) study PB1046-PT-CL-0006 (V18)
or
2. For those not opting to continue into the OLE, safety endpoints will continue to be collected for 28 days after the final dose of PB1046 (V18). Moreover, approximately 56 days after the final dose (V18) a blood sample will be also drawn for immunogenicity testing. If anti-drug antibodies are still present at 56 days post last dose, then subjects will be followed further until resolution of the antibody status.
3. From Baseline to end of assessment |
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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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | No |
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 |
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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 | 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 |
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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 | Yes |
E.8.2.3.1 | Comparator description |
different treatment schedule of the same IMP |
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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 | 30 |
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 |
Serbia |
United States |
Austria |
Belgium |
Czechia |
Germany |
Greece |
Hungary |
Italy |
Poland |
Bulgaria |
Romania |
Spain |
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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
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LVLS - Visit 18 (Week 17)/End of Treatment Visit |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 16 |