A Phase 2, Multi-Centre, unblinded, parallel dose, safety and effectiveness study of AIR001 in subjects with high blood pressure in the blood vessels in the lungs

• Register: EUCTR
• Last refreshed on: 10 March 2014
• Main ID: EUCTR2012-000166-37-PL
• Date of registration: 28/01/2013
• Prospective Registration: Yes
• Primary sponsor: Aires Pharmaceuticals Inc
• Public title: A Phase 2, Multi-Centre, unblinded, parallel dose, safety and effectiveness study of AIR001 in subjects with high blood pressure in the blood vessels in the lungs
• Scientific title: A Phase 2, Multi-Center, Open-label, Randomized, Parallel-Dose Study to Determine the Safety and Efficacy of AIR001 in Subjects with WHO Group 1 Pulmonary Arterial Hypertension
• Date of first enrolment: 17/04/2013
• Target sample size: 90
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-000166-37
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Different dosage of the same product Number of treatment arms in the trial: 3

Countries of recruitment

Australia, Czech Republic, France, Germany, Hungary, Italy, Poland, Serbia, United States

Contacts

• Name: Ed Parsley
• Affiliation: Aires Pharmaceuticals, Inc

• Name: Ed Parsley
• Affiliation: Aires Pharmaceuticals, Inc

Key inclusion & exclusion criteria

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 capacit
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 througho

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: AIR001 Inhalation Solution
Product Code: AIR001
Pharmaceutical Form: Nebuliser solution
INN or Proposed INN: sodium nitrite
CAS Number: 7632-00-0
Current Sponsor code: AIR001
Other descriptive name: SODIUM NITRITE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 80-

Primary Outcome(s)

Main Objective: 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).

Timepoint(s) of evaluation of this end point: Baseline to week 16

Secondary Objective: 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.

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).

Secondary Outcome(s)

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)

Timepoint(s) of evaluation of this end point: Baseline to week 16

Secondary ID(s)

2012-000166-37-HU

77272

AIR001-CS05

Source(s) of Monetary Support

Aires Pharmaceuticals, Inc