| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
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| E.1.1.1 | Medical condition in easily understood language |
| High blood pressure in the blood vessels of the lungs |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 |
The primary objective of this study is to evaluate the efficacy of inhaled
nebulized AIR001 administered, for 16 weeks, according to 3 treatment arms (80 mg once daily, 46 mg 4 times daily, or 80 mg 4 times daily) in subjects with World Health Organization (WHO) Group 1 Pulmonary Arterial Hypertension (PAH), as determined by change in Pulmonary Vascular Resistance (PVR) from Baseline to Week 16 measured immediately post completion of AIR001 nebulization (as soon as feasible). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of inhaled nebulized AIR001 administered according to 3 treatment arms (80 mg once daily, 46 mg 4 times daily, or 80 mg 4 times daily) in subjects with WHO Group 1 PAH for 16 weeks, as determined by time to the first morbidity/mortality event as defined in TTCW assessments and change from Baseline to Week 16 in the following:
- PVR
- N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
- 6-Minute Walk Distance (6MWD) assessed immediately post completion of AIR001 nebulization (peak) , but no more than 40-minutes after completion of AIR001 nebulization
- 6MWD assessed prior to AIR001 nebulization (trough)
- CO, CI
- mRAP
- WHO/NYHA Functional Class (FC)
- QOL as measured by Short-Form 36 (SF-36) health survey instrument
- Borg Dyspnea Index
- mPAP
- PVR measured at greater than 5-hours after last dose of AIR001
nebulization (trough)
- To evaluate the safety and tolerability of AIR001 in subjects with WHO Group 1 PAH. |
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| 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 |
Cardiac catheterization, Pharmacokinetic (PK), and Endothelin 1 (ET-1) evaluations will be performed in those subjects who consent to participate at select study centers in this sub study. Attempts will be made to recruit approximately 15 subjects into the sub-study.
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| E.3 | Principal inclusion criteria |
1. 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 study-mandated procedures.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Has a current diagnosis of symptomatic PAH classified by one of the following:
a. Idiopathic (IPAH) or heritable pulmonary arterial hypertension (HPAH); or
b. PAH associated with one of the following CTD:
i. Systemic sclerosis (scleroderma);
ii. Limited scleroderma;
iii. Mixed connective tissue disease;
iv. Systemic lupus erythematosus;
v. Overlap syndrome.
c. PAH associated with:
i. HIV infection;
ii. Simple, congenital systemic-to-pulmonary shunts at least one year post surgical repair.
iii. Exposure to legal drugs, chemicals and toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil or L-tryptophan. Subjects with PAH associated with illegal drug use, such as methamphetamine, are excluded.
4. Has a cardiac catheterization prior to Screening that is consistent with the diagnosis of PAH meeting all of the following criteria:
a. mPAP ≥ 25 mmHg (at rest);
b. PCWP ≤ 15 mmHg; and
c. If PCWP is not available, then mean left atrial pressure (mLAP) or left ventricular-end diastolic pressure (LVEDP) ≤ 15 mmHg in the absence of left atrial obstruction;
c. PVR > 3 mmHg/Liter (L)/minute (min) or 240 dyn.sec/cm.
5. A qualification cardiac catheterization is required, to confirm the persistence and severity of PAH, if the diagnostic catheterization was performed more than 1 month (30 days) prior to Baseline/Day 1 (see criteria in Inclusion Criteria #4). This catheterization will serve to
provide Baseline hemodynamic values for further efficacy analysis. A cardiac catheterization performed within 1 month (30 days) prior to Baseline/Day 1, per the subject standard medical care (not for the purposes of this study) can be used in lieu of repeating the test, if all
the following criteria are met:
a. Confirms diagnosis as per the required data points (PVR, CO, CI, mPAP, mRAP, PCWP, SVR, and SvO 2 );
b. The subject has a PVR above 300 dyn.sec/cm on the catheterization used to qualify the subject for the study; and
c. No change in disease-specific PAH therapy has occurred since the catheterization used to qualify the subject for the study.
6. Newly diagnosed PAH on no disease-specific PAH therapy or previously diagnosed with PAH on stable (i.e. 3 months (90 days) prior to the Baseline qualification cardiac catheterization) oral disease-specific PAH therapy with either an ETRA and/or PDE-5i. Every attempt should be made to maintain the dose of these agents throughout the study. The use of PDE-5i as needed for erectile dysfunction (ED) is permitted as long as the subject has not taken a dose within 48-hours of any Baseline or study related efficacy assessment. In addition, the subject must not take more than 8 sildenafil tablets, 6 vardenafil, or 4 tadalafil tablets per month for ED.
7. Has PFTs within 6 months (180 days) prior to Baseline/Day 1 with no evidence of significant parenchymal lung disease. Parenchymal lung disease is defined as:
• Forced expiratory volume in 1 second (FEV 1 ) ≤ 70% (predicted);
• Forced expiratory volume in 1 second/forced vital capacity ratio
(FEV 1 /FVC) ≤ 70% (pre-bronchodilators); or
• Total lung capacity (TLC) < 70% (predicted).
8. Has WHO/NYHA functional class II- IV symptomatology.
9. Male or female ≥ 18 and ≤ 75 years of age at Screening.
10. Has a body weight ≥ 40 kg at Screening.
11. Has a 6MWT distance ≥ 50 meters at Screening. If the distance walked is not within the required range, the test may be repeated 1 time. The distance walked during the 2nd assessment must be in the required range, with the test conducted on a separate day, and must
be within 15% of the first distance walked.
12. Had a ventilation-perfusion (V/Q) lung scan or pulmonary angiogram prior to Screening that shows no evidence of thromboembolic disease. V/Q scanning is preferred, but if unavailable, spiral/helical/electron beam computed tomography (CT) angiography is acceptable in subjects with NO history of venous thromboembolic disease.
13. If on the following therapies, which may affect PAH: vasodilators (including calcium channel blockers), digoxin, spironolactone, or L-Arginine supplementation; the subject must be on a stable dose for at least 1 month (30 days) prior to Baseline/Day 1 and the dosage maintained throughout the study.
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| E.4 | Principal exclusion criteria |
1.Participation in a device or other interventional clinical studies, with the exception of studies utilizing AIR001, within 1 month (30 days) of Baseline/Day 1 and/or during study participation.
2. Participation in a cardio-pulmonary rehabilitation program based upon exercise within 1 month (30 days) prior to Baseline/Day 1 and/or during study participation.
3. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic blood pressure >100 mmHg during Screening.
4. Sitting systolic BP < 90 mmHg at Screening or Baseline/Day 1.
5. History of orthostatic hypotension or at the time of Screening demonstrates orthostatic hypotension defined as a drop in systolic BP by ≥ 20 mmHg or diastolic BP of ≥ 10 mmHg or the development of significant postural symptoms (syncope, near syncope, lightheadedness, or vertigo) when going from the supine to the standing position as assessed during Screening assessment.
6.Has 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;
b.Pericardial constriction;
c. Restrictive or congestive cardiomyopathy;
d. Left ventricular ejection fraction < 40% by multiple gated acquisition scan (MUGA), angiography or echocardiography (ECHO) prior to Screening;
e. Left ventricular shortening fraction < 22% by ECHO prior to Screening;
f. Symptomatic coronary disease.
7. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation.
8. Acutely decompensated heart failure within 1 month (30 days) prior to Baseline/Day 1.
9. History of atrial septostomy within 6 months (180 days) prior to Baseline/Day 1.
10. History of obstructive sleep apnea (treated, untreated or resolved).
11. Diagnosis of Down syndrome.
12. Moderate to severe hepatic impairment classified as a Child-Pugh Class B or C at Screening.
13. Has chronic renal insufficiency as defined by serum creatinine > 2.5 mg/dL or has an estimated Glomular Filtration Rate (eGFR) < 30 mL/min at Screening, or requires dialytic support.
14. Has a hemoglobin (Hgb) concentration < 8.5 g/dL at Screening.
15. Personal or family history of the following:
a. Congenital or acquired methemoglobinemia;
b. RBC CYPB5 reductase deficiency.
16. History of glucose-6-phosphate dehydrogenase (G6PD) deficiency or any contraindication to receiving methylene blue.
17. For subjects with HIV associated PAH, any of the following:
• Concomitant active opportunistic infections within 6 months (180 days) prior to Screening;
• Detectable viral load within 3 months (90 days) of Screening;
• Cluster designation 4 (CD4+) T-cell count < 200 mm within 3 months of Screening;
• Changes in antiretroviral regimen within 3 months of Screening;
• Using inhaled pentamidine.
18. Receiving chronic treatment with prostacyclin/prostacyclin analogue within 2 months of Baseline/Day 1. Use of prostacyclin for acute vasodilator testing during cardiac catheterization is allowed.
19. Requirement of intravenous inotropes within 1 month (30 days) prior to Baseline/Day 1.
20. The use of oral or topical nitrates (nitroglycerin, glyceryl trinitrate (GTN), isosorbide dinitrate, and isosorbide mononitrate) within 1 month (30 days) prior to Baseline/Day 1 or throughout the AIR001-CS05 study until EOS or Termination visit. Note: Intravenous GTN in an emergency setting may be administered by starting with a low dose and titrating
upward, while the subject is being monitored closely for changes in blood pressure and heart rate.
21. Known or suspected hypersensitivity or allergic reaction to sodium nitrite or sodium nitrate.
22. History of malignancy within 5-years prior to Baseline/Day 1, with the exception of localized non-metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix.
23. Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product 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.
24. Has a psychiatric, addictive or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs 1 month (30 days) prior to study Baseline/Day 1 and for the duration
of the study.
25. Is currently pregnant or breastfeeding or intends to become pregnant (or intends to father a child) during the study.
26. Investigators, study staff or their immediate families. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in PVR from Baseline to Week 16 as assessed by
Cardiac Catheterization measured immediately post completion of AIR001 nebulization (as soon as feasible). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Assessments of TTCW and change from Baseline to Week 16 in the following:
• PVRI
• NT-proBNP
• 6MWD assessed immediately post completion of AIR001 nebulization (peak) , but no more than 40-minutes after completion of AIR001 nebulization
• 6MWD assessed prior to AIR001 nebulization (trough)
• CO, CI
• mRAP
• WHO/NYHA FC
• QOL as measured by SF-36 health survey instrument
• BORG Dyspnea Score
• mPAP
• PVR measured at greater than 5-hours after last dose of AIR001 nebulization (trough)
• PVR/systemic vascular resistance (SVR) ratio at greater than 5 hours
after the last dose of AIR001 nebulization (trough) and immediately
post completion of AIR001 nebulization (peak) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Different dosage of the same product |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Serbia |
| United States |
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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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| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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