Clinical trial NCT01725256: A Phase 2 Study to Determine the Safety and Efficacy of AIR001 in Subjects With Pulmonary Arterial Hypertension (PAH)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Keywords: AIR001
sodium nitrite
PAH
Pulmonary Arterial Hypertension
inhaled sodium nitrite
Lead sponsor: Aires Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2012-11-12
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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

Primary outcomes:
measure: Change in pulmonary vascular resistance (PVR)from baseline to week 16 assessed at peak AIR001
timeFrame: 16 weeks
Secondary outcomes:
measure: Time to Clinical Worsening (TTCW), other hemodynamics, and safety
timeFrame: 16 weeks
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD Medical Center
state: California
city: Torrance
country: United States
facility: UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center
state: Wisconsin
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Budapest
country: Hungary
facility: Gottsegen Gyorgy Hungarian
city: Budapest
country: Hungary
facility: Semmelweis Karlocai
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Szeged
country: Hungary
facility: University of Szeged
Study officials:
affiliation: Baylor College of Medicine
name: Adaani E Frost, M.D.
role: PRINCIPAL_INVESTIGATOR
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