Pulmonary HypertensionPhase 2NCT01431313
Inhaled Nitrite in Subjects With Pulmonary Hypertension
A Phase 2 study testing Inhaled Nitrite in people with Pulmonary Hypertension and Heart Failure, Diastolic, run by Schmidhofer, Mark, MD at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pulmonary Hypertension, Heart Failure, Diastolic
- What is being tested?
- Inhaled Nitrite
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2012to Oct 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 25Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
About this study
Official title: 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.
Read the 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.
- Conditions
- Pulmonary Hypertension, Heart Failure, Diastolic
- Being tested
- Inhaled Nitrite
- Keywords
- pulmonary hypertension, heart failure
- Medical subject headings
- Hypertension, Pulmonary, Heart Failure, Diastolic, Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Inhaled NitriteDrug
Also called Sodium 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
| Study group | Role | What they receive |
|---|---|---|
| Inhaled Nitrite | Experimental | Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. Receives: Drug: Inhaled Nitrite |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
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.
Measured: 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)
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.
Measured: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose
Change in Systemic Vascular Resistance (SVR)
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.
Measured: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose
Change in Pulmonary Vascular Impedance / Wave Intensity
Characteristic impedance (Zc) which may be related to compliance effects in the large, conduit arteries.
Measured: Pre dose and 60 minutes post last dosage inhaled
Change in Plasma Nitrite Concentrations in Mixed Venous Blood
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.
Measured: Pre-dose, 15 minutes post 45mg and 90mg inhalation
Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite
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.
Measured: Pre-dose, 15 minutes post 45mg and 90mg inhalation
Change in Mitochondrial Oxygen Consumption Compared to Baseline After Each Dose of Nitrite
Basal platelet oxygen consumption measured in isolated platelets by extracellular flux analysis (XF24, Seahorse Biosciences, Billerica, MA).
Measured: Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Sep 2011 (estimated)
- Study startJun 2012
- Primary completionOct 2017
- Study completionOct 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Pulmonary HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- Schmidhofer, Mark, MD
- Responsible party
- Principal investigator, Marc A. Simon, University of Pittsburgh
- Investigators
- Marc A. Simon, MD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01431313
- Sponsor's protocol ID
- PRO11080686
- Status last verified
- Mar 2019
- First submitted
- 6 Sep 2011
- Last updated
- 28 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 30152056Gladwin 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.
PubMed 28069711Lai 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.
PubMed 26813102Hon 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.
PubMed 26684248Vanderpool 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.
PubMed 25533965Rix 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.
PubMed 25421879Bueno 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.
PubMed 22871207Totzeck 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.
PubMed 22685116Sparacino-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.
PubMed 22572912Zuckerbraun 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.
PubMed 21177703Lundberg 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.
PubMed 18167491Dejam 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.
PubMed 17893272Vangeneugden 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.
PubMed 14980746Simon 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.
PubMed 27812547
Study at a glance
From the registry record, last updated by the sponsor on 28 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Dose Escalation Study to Evaluate the Effect of Inhaled Nitrite on Cardiopulmonary Hemodynamics in Subjects With Pulmonary Hypertension
- ClinicalTrials.gov ID
- NCT01431313
- Acronym / sponsor ID
- PRO11080686
- Conditions
- Pulmonary Hypertension, Heart Failure, Diastolic
- Keywords
- pulmonary hypertension, heart failure
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- Schmidhofer, Mark, MD
- Study start
- Jun 2012 (actual)
- Primary completion
- Oct 2017 (actual)
- Study completion
- Oct 2017 (actual)
- First posted
- 9 Sep 2011 (estimated)
- Results
- Posted 12 Mar 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Inhaled Nitrite | Experimental | Drug: Inhaled NitriteSodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inhaled NitriteAlso: Sodium NitriteEach patient will receive a starting dose of 45 mg of inhaled nitrite, with one planned subsequent planned dose of 90 mg of inhaled nitrite | Drug | Inhaled Nitrite |
Primary outcome
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.
7 secondary outcomes
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
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
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
Change in Pulmonary Vascular Impedance / Wave Intensity
Time frame: 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
Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 30152056DeMartino 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.
- Background: PubMed 28069711Gladwin 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.
- Background: PubMed 26813102Lai 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.
- Background: PubMed 26684248Hon 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.
- Background: PubMed 25533965Vanderpool 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.
- Background: PubMed 25421879Rix 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.
- Background: PubMed 22871207Bueno 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.
- Background: PubMed 22685116Totzeck 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.
- Background: PubMed 22572912Sparacino-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.
- Background: PubMed 21177703Zuckerbraun 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.
- Background: PubMed 18167491Lundberg 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.
- Background: PubMed 17893272Dejam 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.
- Individual participant dataSharing planned: Undecided
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Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
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Study of Treprostinil Administered Via Soft Mist Inhaler (SMI) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Active, not recruitingPhase 1
A Pilot Study of Microbiota Transplant With Antibiotic Preconditioning and Fiber Supplementation in Pulmonary Arterial Hypertension (GUT RESTORE-PAH)
Pulmonary Arterial Hypertension
RecruitingObservational study
Natural History Study of Biomarkers in Pulmonary Arterial Hypertension
Pulmonary Disease, Pulmonary Hypertension
Active, not recruitingPhase 1
Study of Intravenous ZMA001 in Healthy Subjects
Pulmonary Arterial Hypertension PAH
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marc A. Simon, MD principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Inhaled Nitrite in people with Pulmonary Hypertension and Heart Failure, Diastolic, run by Schmidhofer, Mark, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Mar 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01431313, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2019.