Inhaled Nitrite in Subjects With Pulmonary Hypertension

NCT01431313 | Completed Phase 2 Results DMC

• 1 other identifier: PRO11080686
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-center, open label phase II study to evaluate the effect of inhaled nitrite delivered in a dose escalation manner on the change in pulmonary vascular resistance (PVR) in subjects with pulmonary hypertension undergoing right heart catheterization. A total of 50 subjects with a confirmed diagnosis of pulmonary hypertension and meet all inclusion/exclusion criteria will be enrolled in the study which will entail a single right heart catheterization and nebulized nitrite dose of 45mg with one subsequent dosage of 90 mg.

Conditions

Pulmonary Hypertension; Heart Failure, Diastolic

Keywords

pulmonary hypertension; heart failure

Outcome Measures

Primary Outcomes (1)

• Change in Pulmonary Vascular Resistance (PVR)

  Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since pulmonary vascular resistance (PVR) was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of PVR over all subsequent times and doses (beta from the mixed effects model, converted back from natural log to Woods units), and is reported as the mean and 95% confidence interval.

  Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Secondary Outcomes (7)

• Time to Maximum Pulmonary Vascular Resistance (PVR) Decrease

  0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose

• Change in Systemic Blood Pressure (Mean Arterial Pressure, MAP)

  Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

• Change in Systemic Vascular Resistance (SVR)

  Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

• Change in Pulmonary Vascular Impedance / Wave Intensity

  Pre dose and 60 minutes post last dosage inhaled

• Change in Plasma Nitrite Concentrations in Mixed Venous Blood

  Pre-dose, 15 minutes post 45mg and 90mg inhalation

Study Arms (1)

Inhaled Nitrite

EXPERIMENTAL

Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.

Drug: Inhaled Nitrite

Interventions

Inhaled Nitrite DRUG

Each patient will receive a starting dose of 45 mg of inhaled nitrite, with one planned subsequent planned dose of 90 mg of inhaled nitrite

Also known as: Sodium Nitrite

Inhaled Nitrite

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of RHC confirmed WHO Group I PAH n=20
• Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases:
• PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil Stable PAH for at least 3 months if on therapy This patient population is closed to enrollment. Target enrollment of 20 subjects has been met
• WHO Group II Pulmonary Hypertension n=20 Pulmonary capillary wedge pressure PWCP greater than 15 AND Transpulmonary Gradient TPG greater than12
• WHO Group III PH n = 10
• Has WHO functional class II through IV symptoms
• Had the diagnosis of PH confirmed by a cardiac catheterization Both WHO Group I PAH and WHO Group III PH
• WHO GROUP I PAH, II and III PH Age 18 and older Able to participate in right heart catheterization Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

You may not qualify if:

• Age less than 18 years
• Baseline systemic hypotension, defined as MAP less than 50 mmHg
• Required intravenous inotropes within 30 days prior to study participation;
• Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure greater than160 mm Hg or sitting diastolic blood pressure greater than100 mm Hg at screening
• Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C with evidence of recent infection and/or active virus replication defined as moderate to severe hepatic impairment Child-Pugh Class B-C
• Has chronic renal insufficiency as defined by serum creatinine greater than 2.5 mgdL at screening or requires dialytic support
• Has a hemoglobin concentration less than 9 gdL at Screening
• History of atrial septostomy within 6 months prior to Day 1 visit
• Repaired or unrepaired congenital heart disease CHD
• Pericardial constriction
• Confirmed diagnosis of restrictive or congestive cardiomyopathy;
• Left ventricular ejection fraction 40 percent by multiple gated acquisition scan MUGA, angiography or echocardiography
• Symptomatic coronary disease with demonstrable ischemia;
• 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
• 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 30 days prior to study screening Day 0and for the duration of the study

Sponsors & Collaborators

• Schmidhofer, Mark, MD: lead

Study Sites (1)

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (14)

• DeMartino AW, Kim-Shapiro DB, Patel RP, Gladwin MT. Nitrite and nitrate chemical biology and signalling. Br J Pharmacol. 2019 Jan;176(2):228-245. doi: 10.1111/bph.14484. Epub 2018 Oct 3.

  PMID: 30152056 BACKGROUND

• Gladwin MT. How Red Blood Cells Process Nitric Oxide: Evidence for the Nitrite Hypothesis. Circulation. 2017 Jan 10;135(2):177-179. doi: 10.1161/CIRCULATIONAHA.116.024752. No abstract available.

  PMID: 28069711 BACKGROUND

• Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT. SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation. 2016 Feb 23;133(8):717-31. doi: 10.1161/CIRCULATIONAHA.115.018935. Epub 2016 Jan 26.

  PMID: 26813102 BACKGROUND

• Hon YY, Lin EE, Tian X, Yang Y, Sun H, Swenson ER, Taveira-Dasilva AM, Gladwin MT, Machado RF. Increased consumption and vasodilatory effect of nitrite during exercise. Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L354-64. doi: 10.1152/ajplung.00081.2015. Epub 2015 Dec 18.

  PMID: 26684248 BACKGROUND

• Vanderpool R, Gladwin MT. Harnessing the nitrate-nitrite-nitric oxide pathway for therapy of heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):334-6. doi: 10.1161/CIRCULATIONAHA.114.014149. Epub 2014 Dec 22. No abstract available.

  PMID: 25533965 BACKGROUND

• Rix PJ, Vick A, Attkins NJ, Barker GE, Bott AW, Alcorn H Jr, Gladwin MT, Shiva S, Bradley S, Hussaini A, Hoye WL, Parsley EL, Masamune H. Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects. Clin Pharmacokinet. 2015 Mar;54(3):261-72. doi: 10.1007/s40262-014-0201-y.

  PMID: 25421879 BACKGROUND

• Bueno M, Wang J, Mora AL, Gladwin MT. Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics. Antioxid Redox Signal. 2013 May 10;18(14):1797-809. doi: 10.1089/ars.2012.4833. Epub 2012 Oct 15.

  PMID: 22871207 BACKGROUND

• Totzeck M, Hendgen-Cotta UB, Luedike P, Berenbrink M, Klare JP, Steinhoff HJ, Semmler D, Shiva S, Williams D, Kipar A, Gladwin MT, Schrader J, Kelm M, Cossins AR, Rassaf T. Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation. Circulation. 2012 Jul 17;126(3):325-34. doi: 10.1161/CIRCULATIONAHA.111.087155. Epub 2012 Jun 9.

  PMID: 22685116 BACKGROUND

• Sparacino-Watkins CE, Lai YC, Gladwin MT. Nitrate-nitrite-nitric oxide pathway in pulmonary arterial hypertension therapeutics. Circulation. 2012 Jun 12;125(23):2824-6. doi: 10.1161/CIRCULATIONAHA.112.107821. Epub 2012 May 9. No abstract available.

  PMID: 22572912 BACKGROUND

• Zuckerbraun BS, George P, Gladwin MT. Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res. 2011 Feb 15;89(3):542-52. doi: 10.1093/cvr/cvq370. Epub 2010 Dec 22.

  PMID: 21177703 BACKGROUND

• Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008 Feb;7(2):156-67. doi: 10.1038/nrd2466.

  PMID: 18167491 BACKGROUND

• Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation. 2007 Oct 16;116(16):1821-31. doi: 10.1161/CIRCULATIONAHA.107.712133. Epub 2007 Sep 24.

  PMID: 17893272 BACKGROUND

• Vangeneugden T, Laenen A, Geys H, Renard D, Molenberghs G. Applying linear mixed models to estimate reliability in clinical trial data with repeated measurements. Control Clin Trials. 2004 Feb;25(1):13-30. doi: 10.1016/j.cct.2003.08.009.

  PMID: 14980746 BACKGROUND

• Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J 3rd, Parsley EL, Gladwin MT. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 2016 Nov 3;1(18):e89620. doi: 10.1172/jci.insight.89620.

  PMID: 27812547 RESULT

MeSH Terms

Conditions

Hypertension, Pulmonary; Heart Failure, Diastolic; Heart Failure

Interventions

Sodium Nitrite

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases; Heart Diseases

Intervention Hierarchy (Ancestors)

Nitrites; Nitrous Acid; Nitrogen Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

Small, early phase II pilot study, limited number of subjects. Exercise hemodynamics would be helpful in this population. Findings of acute changes in hemodynamics may or may not be translatable to chronic administration and longer-term outcomes.

Results Point of Contact

• Title: Marc A. Simon, MD
• Organization: University of Pittsburgh

SIMONMA@UPMC.EDU

4128023131

Study Officials

• Marc A. Simon, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDIV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: September 6, 2011
• First Posted: September 9, 2011
• Study Start: June 1, 2012
• Primary Completion: October 1, 2017
• Study Completion: October 1, 2017
• Last Updated: March 28, 2019
• Results First Posted: March 12, 2019

Record last verified: 2019-03

Locations

US (1)