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Inhaled Nitric Oxide/INOpulse DS for Pulmonary Arterial Hypertension (PAH)

Information source: INO Therapeutics
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Arterial Hypertension; Pulmonary Hypertension

Intervention: Nitric Oxide (Drug); Placebo (Other); Nitric Oxide (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: INO Therapeutics

Official(s) and/or principal investigator(s):
Brahm Goldstein, MD, Study Director, Affiliation: Ikaria Holdings Inc.

Overall contact:
Jason Banks, PhD, Phone: 908-238-6387, Email: jason.banks@ikaria.com

Summary

This is a Phase 2, Placebo Controlled, Double-Blind, Randomized, Clinical Study to Determine Safety, Tolerability and Efficacy of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo as Add-on Therapy in Symptomatic Subjects with Pulmonary Arterial Hypertension (PAH).

Clinical Details

Official title: A Phase 2, Placebo Controlled, Double-Blind, Randomized, Clinical Study to Determine Safety, Tolerability and Efficacy of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo as Add-On Therapy in Symptomatic Subjects With Pulmonary Arterial Hypertension (PAH)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: The primary endpoint is change in pulmonary vascular resistance (PVR) (dynes. sec/cm-5) from baseline to EOS Part 1.

Secondary outcome:

Change in 6 minute walk distance (6MWD) from baseline to EOS Part 1

Time (in days) to first clinical worsening event (TTCW) from randomization to EOS Part 1

Change in World Health Organization (WHO) Functional Class from baseline to EOS Part 1

Change in Borg Dyspnea Score (BDS) from baseline to EOS Part 1

Change in patient reported outcome (PRO) scores by the SF-36 short form version 2 and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) from baseline to EOS Part 1

Detailed description: Study to determine if inhaled nitric oxide (iNO) given through a special delivery device (INOpulse DS) is safe and efficacious in treating Pulmonary Arterial Hypertension (PAH). Medical literature and clinical experience suggests that iNO at pulsed doses of 0. 013 to 0. 1 mg/kg per hour for 1 month to 2+ years appears safe and suggests efficacy for the treatment of pulmonary hypertension.

There are two parts to this study. In Part 1 (week 0 to week 16), the objectives are to determine the safety, tolerability, efficacy, and exploratory objectives of two different doses of iNO delivered by a pulsed delivery device in symptomatic subjects with PAH who remain symptomatic due to PAH on approved PAH monotherapy or combination approved PAH therapy. In Part 2 (week 17 to end of study Part 2 [EOS Part 2]), the objective is to compile data on the long-term effects of iNO on safety, tolerability, clinical and hemodynamic measures.

Eligibility

Minimum age: 16 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Signed informed consent form (ICF) (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments

2. A confirmed diagnosis of Pulmonary Hypertension Group 1 (PAH) who have either idiopathic PAH (IPAH), heritable PAH, anorexigen-induced PAH, associated PAH (APAH) with connective tissue disease (CTD), APAH with repaired simple congenital systemic to pulmonary shunt (i. e., atrial septal defect [ASD], ventricular septal defect [VSD] and/or patent ductus arteriosus [PDA]; complete repair at least 1 year prior to Screening) or APAH with human immunodeficiency virus (HIV)

3. Confirmation of PAH diagnosis at the time of Baseline RHC according to the following definition: mPAP ≥ 25 mmHg at rest, with a concomitant mean pulmonary capillary wedge pressure (mPCWP), mean left atrial pressure (mLAP), or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg and a PVR ≥ 240 dynes. sec/cm-5

4. 6MWD at least 100 meters and no greater than 450 meters

5. The subject is receiving at least one approved PAH therapy and is clinically symptomatic from PAH (e. g., onset or increased dyspnea on exertion, dizziness, near-syncope, syncope, chest pain or peripheral edema)

6. Background PAH medication doses (including calcium channel blockade if being used to treat PAH) must be stable for at least 12 weeks prior to Screening

7. If on background conventional therapy (e. g., digoxin, diuretics, supplemental oxygen, anticoagulation), it must have been started at least 30 days prior to Screening and be on a stable dose for at least 30 days except for anticoagulation dose

8. If previously treated with an endothelin receptor antagonist (ERA), phosphodiesterase-5 (PDE-5) inhibitor, prostacyclin or a prostacyclin analog and is no longer on said treatment at Screening (per inclusion criteria as above), subject must have been off said treatment for > 90 days at Screening

9. If previously treated with a calcium channel blocker as treatment for PAH and is no longer on the calcium channel blocker treatment at Screening (per inclusion criteria as above), subject must have been off the calcium channel blocker treatment for > 90 days at Screening

10. Age between 16 and 80 years (inclusive)

11. Male height ≤ 200 cm (6'7") or Female height ≤ 210 cm (6'11")

12. Subjects are willing and considered in the judgment of the Investigator able to use the INOpulse DS device continuously for up to 24 hours per day

13. Females of childbearing potential must have a negative pre-treatment serum pregnancy test and must be on a reliable method of contraception (including double protection if appropriate, e. g., for subjects concurrently treated with bosentan therapy)

Exclusion Criteria:

1. Subjects with known HIV infection within the past 2 years who have a history of or show any clinical or laboratory evidence of any opportunistic pulmonary disease (e. g., tuberculosis, Pneumocystis carinii pneumonia, or other pneumonias) at the time of Screening

2. PAH associated with portal hypertension, untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy

3. Any subject with unrepaired congenital heart disease or repaired congenital heart disease other than the simple congenital to systemic shunts specified in the inclusion criteria, i. e., PAH associated with non-corrected simple congenital systemic-to-pulmonary shunts, corrected simple congenital systemic-to-pulmonary shunt with residual shunt post repair, or complex systemic-to- pulmonary shunts, corrected or non-corrected, or any other complex congenital heart disease, corrected or non-corrected

4. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis

5. Any subject with WHO PH Groups 2, 3, 4 or 5

6. Left ventricular systolic dysfunction, i. e., left ventricular ejection fraction (LVEF) < 40% or left ventricular shortening fraction (LVSF) < 22%

7. Left ventricular diastolic dysfunction, i. e., PCWP > 15 mmHg at rest or with exercise, acute volume loading or pharmacologic testing

8. History of clinically significant cardiomyopathy or valvular heart disease (i. e., moderate or greater aortic insufficiency; moderate or greater aortic stenosis; or moderate or greater mitral valve disease)

9. Clinically significant cardiac ischemic disease requiring use of nitrates, or hospital admission for acute coronary syndrome or intervention (percutaneous coronary intervention, coronary artery stent, coronary artery bypass surgery) within the past 90 days

10. Down syndrome

11. Any subject who develops a PCWP > 20 mmHg during AVT with iNO

12. Systemic hypertension defined as systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg persistent at Screening after a period of rest (treated or untreated)

13. Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period of rest

14. Moderate to severe obstructive lung disease defined as both a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value (bronchodilator administration prior to testing is optional; the test should be done within 3 years for all subjects with the exception of APAH/CTD which needs to be done within 6 months prior to Screening)

15. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted; if TLC 60% to 70% predicted, a high resolution CT scan showing diffuse disease or more than mild patchy disease (done within 3 years for all subjects with the exception of APAH/CTD which needs to be done within 6 months prior to Screening)

16. Moderate to severe hepatic impairment, i. e., Child-Pugh Class B or C

17. Estimated creatinine clearance < 30 mL/min (Cockcroft-Gault formula)

18. Hemoglobin < 10 gm/dL at Screening or Baseline

19. Acute or chronic physical impairment (other than dyspnea due to PAH) that would limit the ability to comply with study procedures or adherence to therapy, including carrying and wearing the INOpulse device per study protocol

20. Pregnant or breast-feeding at Screening

21. Administered L-arginine within 30 days prior to Screening

22. Known concomitant life-threatening disease with a life expectancy less than 1 year

23. Recently started (< 12 weeks prior to randomization) or planned cardiopulmonary rehabilitation program to start within the 16 week controlled study

24. Atrial septostomy within 3 months of randomization

25. Any subject with PAH who is treatment naïve or receiving any unapproved therapy as their only PAH treatment (including calcium channel blockade if the calcium channel blockade is the only treatment for the PAH)

26. Any subject who requires the use of a continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), or other positive pressure devices to treat obstructive sleep apnea

27. Medical problem(s) likely to preclude completion of Part 1

28. Use of investigational drugs or devices within 30 days prior to enrollment into the study (other than acute vasodilator testing with iNO or IV epoprostenol)

29. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study

30. Any condition other than the subject's PAH that, in that opinion of the investigator, affects their ability to perform the 6MWT

31. Refusal to follow the protocol, including the two RHCs in Part 1 and one RHC in Part 2

32. Unable to travel to the investigational site for all required study visits and for all additional visits per the judgment of the Investigator or Sponsor

33. Known need to travel by air during the 16 week study period for Part 1

Locations and Contacts

Jason Banks, PhD, Phone: 908-238-6387, Email: jason.banks@ikaria.com

Peter Lougheed Center, Calgary, Alberta T1Y614, Canada; Recruiting
Naushad Hirani, MD, Principal Investigator

ABACUS - University of Alberta Hospitals, Edmonton, Alberta T6G 2B7, Canada; Recruiting
Evangelos Michelakis, MD, Principal Investigator

Allianz Research Institute, Inc., Fountain Valley, California 92708, United States; Recruiting
David Pham, MD, Principal Investigator

University of California, San Francisco-Fresno, Fresno, California 93721, United States; Recruiting
Vijay Balasubramanian, MD, Principal Investigator

West Los Angeles VA Healthcare Center, Los Angeles, California 90073, United States; Recruiting
Shelley Shapiro, MD, PhD, Principal Investigator

David Geffen School of Medicine at UCLA, Los Angeles, California 90095, United States; Recruiting
David J. Ross, MD, Principal Investigator

Los Angeles Biomedical Research Institute at Harbor-UCLA Med Ctr, Torrance, California 90509, United States; Recruiting
Ronald J Oudiz, MD, Principal Investigator

University of Colorado Denver, Aurora, Colorado 80045, United States; Recruiting
David B. Badesch, MD, Principal Investigator

Children's Hospital Colorado, Aurora, Colorado 80045, United States; Recruiting
David D. Ivy, MD, Principal Investigator

South Denver Cardiology Associates P.C., Littleton, Colorado 80120, United States; Recruiting
Ira Dauber, MD, Principal Investigator

Christiana Care Health System, Newark, Delaware 19713, United States; Recruiting
Gerald O'Brien, MD, Principal Investigator

University of Florida College of Medicine, Jacksonville, Florida 32209, United States; Recruiting
Adil Shujaat, MD, Principal Investigator

Cleveland Clinic Florida, Weston, Florida 33331, United States; Recruiting
Franck F. Rahaghi, MD, Principal Investigator

University of Iowa Hospitals & Clinics, Iowa City, Iowa 52242, United States; Recruiting
Sif Hansdottir, MD, Principal Investigator

University of Kansas Medical Center, Kansas City, Kansas 66160, United States; Recruiting
Lewis Satterwhite, MD, Principal Investigator

Kentuckiana Pulmonary Associates, Louisville, Kentucky 40202, United States; Recruiting
John W. McConnell, MD, Principal Investigator

LSUHSC-New Orleans, New Orleans, Louisiana 70112, United States; Recruiting
Bennett deBoisblanc, MD, Principal Investigator

University of Maryland Medical Center, Baltimore, Maryland 21201, United States; Recruiting
Myung H Park, MD, Principal Investigator

Tufts Medical Center, Boston, Massachusetts 02111, United States; Recruiting
Nicholas S. Hill, MD, Principal Investigator

University of Michigan, Ann Arbor, Michigan 48109, United States; Recruiting
Vallerie McLaughlin, MD, Principal Investigator

University of Minnesota, Cardiovascular Division, Minneapolis, Minnesota 55455, United States; Recruiting
Marc R. Pritzker, MD, Principal Investigator

Washington University School of Medicine, St. Louis, Missouri 63110, United States; Recruiting
Murali M. Chakinala, MD, Principal Investigator

Barnabas Health Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States; Recruiting
Sean M Studer, MD, Principal Investigator

Montefiore Medical Center, Bronx, New York 10461, United States; Recruiting
Ronald Zolty, MD, PhD, Principal Investigator

Beth Israel Medical Center, New York, New York 10003, United States; Recruiting
Roxana Sulica, MD, Principal Investigator

UC Health/University of Cincinnati, Cincinnati, Ohio 45267, United States; Recruiting
Jean Elwing, MD, Principal Investigator

Cleveland Clinic, Cleveland, Ohio 44195, United States; Recruiting
Gustavo Heresi, MD, Principal Investigator

University Hospitals Case Medical Center, Cleveland, Ohio 44106, United States; Recruiting
Robert Schilz, DO, PhD, Principal Investigator

Ohio State University Martha Morehouse Medical Pavillion, Columbus, Ohio 43221, United States; Recruiting
Namita Sood, MD, Principal Investigator

London Health Sciences Centre, London, Ontario N6A 5W9, Canada; Recruiting
Sanjay Mehta, MD, Principal Investigator

Legacy Medical Group - Pulmonary Clinic, Portland, Oregon 97210, United States; Recruiting
Catherine J. Markin, MD, Principal Investigator

Temple University Hospital, Philadelphia, Pennsylvania 19140, United States; Recruiting
Gerard J. Criner, MD, Principal Investigator

Allegheny Singer Research Institute/Allegheny General Hospital, Pittsburgh, Pennsylvania 15212, United States; Recruiting
Raymond L. Benza, MD, Principal Investigator

Rhode Island Hospital, Providence, Rhode Island 02903, United States; Recruiting
James R Klinger, MD, Principal Investigator

University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States; Recruiting
Sonja Bartolome, MD, Principal Investigator

Baylor College of Medicine, Houston, Texas 77030, United States; Recruiting
Adaani Frost, MD, Principal Investigator

Intermountain Medical Center, Murray, Utah 84157, United States; Recruiting
Lynette Brown, MD PhD, Principal Investigator

Aurora St. Luke's Medical Center, Milwaukee, Wisconsin 53215, United States; Recruiting
Dianne L Zwicke, MD, Principal Investigator

Additional Information

Starting date: April 2012
Last updated: February 6, 2013

Page last updated: February 07, 2013

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