Inhaled Nitrite in Subjects With Pulmonary Hypertension
Condition: Pulmonary Hypertension; Heart Failure, Diastolic
MeSH terms: Hypertension, Pulmonary; Hypertension; Heart Failure; Heart Failure, Diastolic
Intervention: Inhaled Nitrite
Intervention description: 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
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pulmonary hypertension; heart failure

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.
    

Eligibility criteria:

        Inclusion Criteria:

        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

        Exclusion Criteria

        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

        Poorly controlled asthma defined by active wheezing and or cough with FEV1 less than 70
        percent predicted, responsive to inhaled BD greater than 15 percent increase in FEV1 with
        BD

        Investigators, study staff or their immediate families

        Clinically significant intercurrent illness (including lower respiratory tract infection)
        or clinically significant surgery within 4 weeks before the administration of study drug

        Personal or family history of congenital or acquired methemoglobinemia

        Personal or family history of RBC CYP B5 reductase deficiency

        Known or suspected hypersensitivity or allergic reaction to sodium nitrite Personal history
        of glucose-6-phosphate dehydrogenase G6PD deficiency or any contraindication to receiving
        methylene blue

        If female, is pregnant or breast feeding, or has a positive pregnancy test result predose

        Receipt of an investigational product or device, or participation in a drug research study
        within a period of 15 days or 5 half-lives of the drug, whichever is longer before the
        first dose of study drug

        Blood loss or blood donation greater than 550 mL within 90 days or plasma donation greater
        than 500 mL within 14 days before administration of study drug

        RHC less than 2 weeks from treatment visit unless clinically indicated