Inhaled Nitrite in Subjects With Pulmonary Hypertension

March 15, 2019 updated by: Marc A. Simon, Schmidhofer, Mark, MD

A Dose Escalation Study to Evaluate the Effect of Inhaled Nitrite on Cardiopulmonary Hemodynamics in Subjects With Pulmonary Hypertension

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Screening Visit:Initial screening evaluations including physical examination, medical history, and clinical laboratory assessments will be conducted to determine study eligibilities during a routine clinic visit at the UPMC HVI, CLC or inpatient at UPMC Presbyterian. Subjects who meet the inclusion criteria and none of the exclusion criteria will be entered into the study.

Day 1: This study visit will occur on the same day subjects are scheduled for their clinically indicated right heart catheterization or who volunteer for a research right heart catheterization for this specific study. Subjects on oral background PAH therapy (ETRA or PDE5I) will be instructed to hold their regimen on the day of the study visit.

Subjects will receive nebulized AIR001 doses escalated based upon safety and tolerability. The dose of inhaled nitrite will be delivered via electronic nebulizer. During the study right heart/pulmonary artery hemodynamics will be measured as well as noninvasive systemic blood pressure monitoring. Subjects will be tested for the changes in pulmonary vascular resistance (PVR) using standard clinical protocol hemodynamic recordings of right atrial, right ventricular, and pulmonary artery pressures, in addition to cardiac output at time zero,

3 Day phone follow up

30 Day follow up visit: All subjects enrolled in the study will be followed for 30 days (+/- 5 day window) after completion of the study treatment. A physical exam and clinical labs will be obtained at this visit.

Study Type

Interventional

Enrollment (Actual)

48

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213
        • University of Pittsburgh

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Inhaled Nitrite
Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Drug: Inhaled Nitrite
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
Other Names:
  • Sodium Nitrite

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Pulmonary Vascular Resistance (PVR)
Time Frame: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to Maximum Pulmonary Vascular Resistance (PVR) Decrease
Time Frame: 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose
Time in minutes to maximum PVR decrease. During study procedure, hemodynamics were measured at 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose. The time point at which each patient's maximal decrease in PVR occurred was recorded and reported as the mean and standard deviation in each cohort.
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 Frame: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose
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. The reported mean is the change from baseline of MAP over all subsequent times and doses (beta from the mixed effects model), 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
Change in Systemic Vascular Resistance (SVR)
Time Frame: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose
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 systemic vascular resistance was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of SVR over all subsequent times and doses (beta from the mixed effects model), 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
Change in Pulmonary Vascular Impedance / Wave Intensity
Time Frame: Pre dose and 60 minutes post last dosage inhaled
Characteristic impedance (Zc) which may be related to compliance effects in the large, conduit arteries.
Pre dose and 60 minutes post last dosage inhaled
Change in Plasma Nitrite Concentrations in Mixed Venous Blood
Time Frame: Pre-dose, 15 minutes post 45mg and 90mg inhalation
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. The reported mean is the change from baseline of plasma nitrite concentrations in mixed venous blood over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval.
Pre-dose, 15 minutes post 45mg and 90mg inhalation
Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite
Time Frame: Pre-dose, 15 minutes post 45mg and 90mg inhalation
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. The reported mean is the change from baseline of pulmonary artery occlusion (capillary) pullback nitrite concentration over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval.
Pre-dose, 15 minutes post 45mg and 90mg inhalation
Change in Mitochondrial Oxygen Consumption Compared to Baseline After Each Dose of Nitrite
Time Frame: Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose
Basal platelet oxygen consumption measured in isolated platelets by extracellular flux analysis (XF24, Seahorse Biosciences, Billerica, MA).
Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Schmidhofer, Mark, MD

Investigators

  • Principal Investigator: Marc A. Simon, MD, University of Pittsburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 1, 2012

Primary Completion (ACTUAL)

October 1, 2017

Study Completion (ACTUAL)

October 1, 2017

Study Registration Dates

First Submitted

September 6, 2011

First Submitted That Met QC Criteria

September 8, 2011

First Posted (ESTIMATE)

September 9, 2011

Study Record Updates

Last Update Posted (ACTUAL)

March 28, 2019

Last Update Submitted That Met QC Criteria

March 15, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO11080686

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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