A Phase 2 Study to Determine the Safety and Efficacy of AIR001 in Subjects With Pulmonary Arterial Hypertension (PAH)

Pulmonary Arterial Hypertension Clinical Trial

Official 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 (PAH)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01725256
• Other study ID #: AIR001-CS05
• Status: Terminated
• Phase: Phase 2
• First received: November 8, 2012
• Last updated: April 7, 2014
• Start date: November 2012
• Est. completion date: February 2014

Study information

• Verified date: April 2014
• Source: Aires Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationEuropean Union: European Medicines AgencyAustralia: Department of Health and Ageing Therapeutic Goods Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and effectiveness of an investigational/experimental drug called AIR001.

To test the effectiveness, the study will evaluate how AIR001 affects the blood vessels in the lungs and the function of the heart. This will be done by monitoring changes in Pulmonary Vascular Resistance (PVR); from Baseline/Day 1 (start of study drug) to Week 16 of the study. PVR measures the resistance to flow in the blood vessels of the lungs. The study will include other assessments to evaluate the effect of the study drug on PAH, including measurements of exercise ability and evaluations of PAH disease symptoms.

Description:

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 29
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Signed and dated informed consent document

2. Able to comply with study procedures

3. Diagnosis of PAH as classified by:

1. Idiopathic (IPAH) or heritable(HPAH); or

2. PAH associated with CTD; Systemic Sclerosis, Limited Scleroderma, Mixed, SLE, or overlap syndrome;

3. PAH associated with HIV ii. Simple, congenital shunts at least one year post repair. iii. Exposure to legal drugs, chemicals and toxins

4. Cardiac catheterization prior to Screening with:

1. mPAP = 25 mmHg (at rest);

2. PCWP = 15 mmHg; and

3. PVR > 3 mmHg/L/min or 240 dyn.sec/cm5

5. A qualification cardiac catheterization, to confirm the persistence and severity of PAH, if the diagnostic catheterization was performed more than 30 days prior to Baseline

1. Confirms diagnosis;

2. PVR above 300 dyn.sec/cm5 to demonstrate the persistence and severity of PAH; and

3. No change in disease-specific PAH therapy since the qualification catheterization used

6. Newly diagnosed PAH on no disease-specific PAH therapy or previously diagnosed on oral disease-specific PAH therapy for 90 days prior with either an ETRA and/or PDE-5i

7. Has PFTs within 180 days prior to Baseline with no evidence of significant parenchymal lung disease defined as:

• FEV1 = 70% (predicted) (pre-bronchodilators);

• FEV1/FVC = 70% (pre-bronchodilators); or

• Total lung capacity < 70% (predicted).

8. Has WHO/NYHA FC II- IV.

9. = 18 and = 75 years.

10. Weight = 40 kg.

11. Has 6MWT distance at least 50 meters.

12. Had a V/Q scan or pulmonary angiogram prior to Screening that shows no evidence of thromboembolic disease

13. If on the following: vasodilators (including calcium channel blockers), digoxin, spironolactone, or L-Arginine; must be on a stable dose 30 days prior to Baseline and maintained throughout the study

14. If on corticosteroids, has been receiving a stable dose of = 20 mg/day of prednisone (or equivalent dose, if other corticosteroid) for at least 30 days

15. Women of childbearing potential must be using at least one form of medically acceptable contraception. Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential. Men who are not sterile must also agree to use contraception

Exclusion Criteria:

1. Participation in a device or other interventional clinical studies, within 30 days of Baseline and during study participation

2. Participation in a cardio-pulmonary rehabilitation program based upon exercise within 30 days prior to Baseline and/or during the study

3. Has uncontrolled systemic hypertension: SBP > 160 millimeter of mercury (mmHg) or DBP > 100 mmHg during Screening

4. SBP < 90 mmHg at Screening or Baseline

5. History of orthostatic hypotension or at the time of Screening; defined as a drop in SBP by = 20 mmHg or DBP of = 10 mmHg during Screening

6. History of left-sided heart disease and/or clinically significant cardiac disease, including:

1. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild;

2. Pericardial constriction;

3. Restrictive or congestive cardiomyopathy;

4. Left ventricular ejection fraction < 40%

5. Left ventricular shortening fraction < 22% by ECHO prior to Screening;

6. Symptomatic coronary disease

7. Significant (2+ for regurgitation) valvular disease other than TR or PR

8. Acutely decompensated heart failure within 30 days prior to Baseline

9. History of atrial septostomy within 180 days prior to Baseline

10. History of obstructive sleep apnea (treated, untreated or resolved)

11. Diagnosis of Down syndrome

12. Moderate to severe hepatic impairment

13. Has chronic renal insufficiency as defined by serum creatinine > 2.5 mg/dL or has an eGFR < 30 mL/min at Screening, or requires dialysis

14. Has a Hgb concentration < 8.5 g/dL at Screening

15. Personal or family history of the following:

1. Congenital or acquired methemoglobinemia;

2. RBC CYPB5 reductase deficiency

16. G6PD deficiency or any contraindication to receiving methylene blue

17. For subjects with HIV any of the following:

• Concomitant active opportunistic infections 180 days prior to Screening;

• Detectable viral load within 90 days of Screening;

• T-cell count < 200 mm3 within 90 days of Screening;

• Changes in antiretroviral regimen within 90 days of Screening;

• Using inhaled pentamidine

18. Receiving chronic treatment with prostacyclin/prostacyclin analogue within 60 days of Baseline

19. Requirement of intravenous inotropes within 30 days prior to Baseline

20. The use of oral or topical nitrates (nitroglycerin, glyceryl trinitrate (GTN), isosorbide dinitrate, and isosorbide mononitrate) within 30 days prior to Baseline and until EOS or Termination

21. Known or suspected hypersensitivity or allergic reaction to sodium nitrite or sodium nitrate

22. History of malignancy within 5-years prior to Baseline

23. Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation

24. Has a disorder that compromises the ability to give informed consent

25. Is currently pregnant or breastfeeding or intends to become pregnant

26. Investigators, study staff or their immediate families

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• AIR001 (sodium nitrite inhalation solution)
Dose arms specify dose loaded into the I-neb AAD System nebulizer

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	St. Vincent's Hospital	Darlinghurst	New South Wales
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	The Alfred Hospital	Melbourne	Victoria
Hungary	Gottsegen Gyorgy Hungarian	Budapest
Hungary	Semmelweis Karlocai	Budapest
Hungary	University of Debrecen	Debrecen
Hungary	University of Szeged	Szeged
United States	University of Colorado Denver	Aurora	Colorado
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	University of Cincinnati	Cincinnati	Ohio
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Baylor College of Medicine	Houston	Texas
United States	UCSD Medical Center	La Jolla	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	St. Louis	Missouri
United States	UCLA Medical Center	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Aires Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Hungary, 

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* Note: There are 61 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in pulmonary vascular resistance (PVR)from baseline to week 16 assessed at peak AIR001	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).	16 weeks	Yes
Secondary	Time to Clinical Worsening (TTCW), other hemodynamics, and safety	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 Time to Clinical Worsening (TTCW) assessments and change from Baseline to Week 16 in the following: Pulmonary Vascular Resistance Index (PVRI), N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP), 6-Minute Walk Distance (6MWD) assessed at peak, 6MWD assessed prior to AIR001 nebulization (trough), Cardiac Output (CO), Cardiac Index (CI), Mean Right Atrial Pressure (mRAP), WHO/NYHA Functional Class (FC), Quality of Life (QOL) as measured by Short-Form 36 (SF-36), Borg Dyspnea Index, Mean pulmonary artery pressure (mPAP), PVR measured at trough, PVR/systemic vascular resistance (SVR) ratio at trough and peak,; To evaluate the safety and tolerability of AIR001 in subjects with WHO Group 1 PAH.	16 weeks	Yes