A Phase 2, Open-Label, Dose-Escalation Study in Subjects with Pulmonary Arterial Hypertension, (PAH, WHO Group 1) and Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis, (PH-IPF WHO Group 3) Using Inhaled NITROsyl (GeNO P2010-002)
This is a Phase 2, open-label, dose-escalation study to test various dose levels of nitric oxide for up to 150 minutes.
Up to 75 subjects undergoing RHC are planned in this study, and shall include subjects meeting eligibility criteria classified as WHO Group 1 PAH or WHO Group 3 IPF-PH. Subjects will receive inhaled nitric oxide from the GeNO NITROSYL System to characterize the hemodynamic response and evaluate safety and tolerability.
Dose cohorts of approximately 5, 15, 30, and 80 ppm nitric oxide in air will be studied. Different dose levels will be achieved by varying the flow rate of the drug substance (80 ppm NO2 in balance air) and changing the delivery device, (cannula or mask). Each subject will receive two different doses of inhaled nitric oxide separated by a placebo (medical grade air) washout. Eligible subjects will be assigned to a dosing cohort in an escalating manner to receive study drug (up to 80 ppm nitric oxide in air) in the following order:
* Study drug dose 1: 1 LPM via nasal cannula for 15 minutes.
* Placebo washout for 15 minutes
* Study drug dose 2: cohort assignment for 15 minutes as follows:
o 1 LPM via nasal cannula
o 2 LPM via nasal cannula
o 6 LPM via ventimask
o 12-15 LPM via non-rebreather
* 120 minutes inhalation of assigned cohort following clinical and safety assessments.
Subjects will be assigned to one of the selected dosing cohorts for the second dose of nitric oxide in ascending order until the maximum effective dose (MaxED) is achieved. The MaxED is the dose beyond which no further effect on PVR has been identified (as determined by comparison between the mean change from baseline in PVR for study drug dose 1 and dose 2). Each cohort will enroll 15 subjects (PAH:PH-IPF-2:1 ratio).
All subjects will remain on the second dose for an additional period of 120 minutes followed by hemodynamic and safety assessments.
Following the completion of the 2 LPM and 6 LPM dosing cohorts, the Safety Review committee (comprised of the Medical Monitor and the Sponsor) will review the mean difference in PVR between each dose level and placebo to determine if a downward adjustment, or intermediate dose(s), are appropriate in order to identify the MinED/MaxED.
Once the MaxED is established, an additional cohort of 15 subjects (PAH:PH-IPF-2:1 ratio) will be enrolled.
At the PI[AND]amp;apos;s discretion each subject will be asked to participate in the PK portion of the study until we have the required six subjects. Blood for pharmacokinetic (PK) analysis of total nitrates/nitrites and methemoglobin will be collected from 6 subjects (4 PAH, 2 PH-IPF) at each dose level based on the following schedule: treatment baseline (predose [?] Day 1), after placebo washout prior to initiation of the next nitric oxide dose, and at 0.5, 1, 1.5, 2.25 (immediately prior to stopping nitric oxide), 3, 4, 6, 8, 12, and 24 hours after initiating nitric oxide therapy. Samples for total nitrates/nitrites will be analyzed at a central laboratory, whereas methemoglobin will be analyzed at the sites local laboratory.
General health status will be assessed at Day 30.
The results from this study will help provide the information required to design the first study of the ambulatory GeNO NITROSYL System, using a small ambulatory liquid nitric oxide device that will allow chronic ambulatory administration of nitric oxide.
Inclusion Criteria: PAH and PH-IPF
An Institutional Review Board (IRB) approved informed consent is signed dated
and timed prior to any study-related activities.
* Male or female.
* WHO Functional Class (or equivalent classification) II x IV.
* Subjects using supplemental oxygen must be receiving a stable course of therapy
for a minimum of 14 days prior to study drug administration.
* All Subjects[Single Quote] oxygen saturation should be > 88% at time of treatment.
* Echocardiogram within 6 months of screening/enrollment shows no signs of
clinically significant left sided heart disease.
* Females of child-bearing potential with a negative urine pregnancy test, or a
documented surgical sterilization, or is post-menopausal prior to administration of
investigational product. Females of childbearing potential must be practicing
adequate birth control to be eligible. It is the Investigator[Single Quote]s responsibility to
determine and document whether the Subject has adequate birth control for study
* Subject has the ability to understand the requirements of the study.
* Subject willing to comply with all study procedures.
WHO Group 1-Eligibility Criteria
In addition to the Eligibility Criteria listed subjects with the diagnosis of PAH shall be required to meet all of the following Inclusion Criteria.
PAH (WHO Group 1) ONLY-Inclusion
* Documented diagnosis of WHO Group 1 PAH, (including idiopathic, heritable, drug-toxin induced, associated with connective tissue disease, portal hypertension, repaired congenital heart disease); documented by a previous RHC and hemodynamics consistent with PAH, WHO Group 1 as follows:
o PAPm > 25 mmHg (at rest),
o PCWP or left ventricular end diastolic pressure (LVEDP) < 15 mmHg,
o PVR > 3 Wood Units
* Pulmonary Function Testing within 6 months prior to screening/enrollment shows
no evidence of:
o interstitial lung disease, unless Total Lung Capacity >= 70 % of predicted is
o obstructive lung disease, unless a forced expiratory volume in 1
second/forced vital capacity (FEV1/FVC) ratio of >= 50% is demonstrated.
* Must be receiving a stable course of approved PAH oral mono therapies for a minimum of 14 days prior to treatment period.
* Age 18-80 years inclusive.
WHO Group 3-Eligibility Criteria
In addition to the Eligibility Criteria listed subjects with the diagnosis of PH-IPF shall be required to meet all of the following Inclusion Criteria.
PH-IPF (WHO Group 3) ONLY Inclusion
* Documented diagnosis of probable or definite IPF using ATS/ERS criteria:
o Previous open or video-assisted thoracoscopic (VATS) lung biopsy showing definite or probable unsual interstitial pneumonia (UIP).
o In the absence of a surgical lung biopsy, previous HRCT showing
* Previous transbronchial biopsy, if performed, shows no features to support a definitive alternative diagnosis.
* Previous bronchoalveolar lavage (BAL), if performed, shows no features that provides an alternative diagnosis.
* FVC > 40% within 6 months of baseline visit.
* Diagnosis of PH based on the following hemodynamic requirements:
o PAPm > 25 mmHg (at rest)
o PCWP or LVED < 15 mmHg, and
o PVR >3 Wood Units
* Age 40-85 years inclusive.
* Diagnosis of IPF > 3 months prior to study drug administration.