Inclusion Criteria:
- - Age ≥ 18 years, ≤ 80 years.
- - Established diagnosis of PAH due to the following:
- Idiopathic or heritable PAH;
- Scleroderma associated PAH (limited or diffuse);
- Drugs (anorexigens) or toxins;
- Congenital heart defects (atrial septal defects, ventricular septal defects, and
patent ductus arteriosus) repaired ≥ 1 years.
- - WHO functional class II, III, or IV on appropriate stable therapy for PAH for at least
3 months prior to the screening period and up until randomization, apart from
modification of anticoagulant or diuretic dosages, or small adjustments in
prostaglandin dose that are considered by the Investigator to be consistent with
stable parenteral therapy.
- - Able to walk unassisted (oxygen use allowed).
Aids for carrying oxygen (such as a
wheel chair or walker) are permitted provided they are not also required as mobility
aids.
- - An average 6-Minute Walk Distance (6MWD) of ≥ 125 meters and ≤ 440 meters on two
consecutive tests during the Screening period.
- - Previous diagnostic right heart cardiac catheterization (RHC) at the time of PAH
diagnosis with findings consistent with PAH: specifically, mean pulmonary arterial
pressure (mPAP) ≥ 25 mmHg (at rest); pulmonary vascular resistance (PVR) ≥ 3 WU;
pulmonary capillary wedge pressure (PCWP) (or left ventricular end diastolic pressure)
≤12 mmHg if PVR ≥ 3 to < 5 WU, or pulmonary capillary wedge pressure (PCWP) (or left
ventricular end diastolic pressure) ≤ 15 mmHg if PVR ≥ 5 WU.
If repeat testing has
occurred since initial diagnosis, the most recent results should be used.
- - Echocardiography performed within 12 months prior to the Screening Period confirming a
left atrial volume index (LAVI) of ≤ 34 ml/m2 and the absence of any clinically
significant left heart disease including evidence of more than mild left-sided
valvular heart disease, systolic or diastolic left ventricular dysfunction.
- - Ventilation and perfusion (VQ) nuclear scan performed as part of the initial workup to
establish the diagnosis of PAH showing absence (i.e. low probability) of pulmonary
embolism.
If repeat testing has occurred since initial diagnosis, the most recent
results should be used. In the absence of a VQ scan to establish eligibility, a CT
angiogram that has been reviewed by a radiologist with expertise in the work up for
pulmonary endarterectomy and deemed negative for chronic thromboembolic disease may be
used instead.
- - Pulmonary function tests conducted within 2 years prior to the Screening Period to
confirm: total lung capacity (TLC) ≥ 65% the predicted value; and forced expiratory
volume at one second (FEV1) of ≥ 65% the predicted value.
- - Must have a resting arterial oxygen saturation (SaO2) ≥88% with or without
supplemental oxygen as measured by pulse oximetry at the Screening Visit.
- - Must not be enrolled in an exercise training program for pulmonary rehabilitation
within 3 months prior to the Screening Visit and must agree not to enroll in an
exercise training program for pulmonary rehabilitation during the Screening Period and
the first 6 months of the study.
Participants enrolled in an exercise program for
pulmonary rehabilitation 3 months prior to screening may enter the study if they agree
to maintain their current level of rehabilitation for the first 6 months of the study.
- - Women of child-bearing potential (defined as less than 1 year post-menopausal and not
surgically sterile) must be practicing abstinence or using two highly effective
methods of contraception (defined as a method of birth control that results in a low
failure rate, i.e., less than 1% per year, such as approved hormonal contraceptives,
barrier methods [such as a condom or diaphragm] used with a spermicide, or an
intrauterine device).
Subjects must have a negative ß-hCG pregnancy test during the
Screening period and negative urine pregnancy test results at all other study visits.
- - Must be willing and able to comply with study requirements and restrictions.
Exclusion Criteria:
- - PAH related to any condition not covered under inclusion criteria, including but not
limited to pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary
capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension.
- - Evidence of more than mild interstitial lung disease on Chest CT within the last 5
years (last 3 years for patients with scleroderma associated PAH)
- Treatment with an investigational drug, device or therapy within 3 months prior to the
screening period or is scheduled to receive an investigational drug, device or therapy
during the course of the study.
- - Any musculoskeletal disease or any other disease that would significantly limit
ambulation.
- - Unrepaired or recently repaired (< 1 year) congenital systemic-to-pulmonary shunt
other than patent foramen ovale.
- - Patients having three or more of the following four AMBITION study HFpEF risk factors
will be excluded:
- BMI ≥ 30 kg/m2,
- History of essential hypertension,
- Diabetes mellitus (any type)
- Historical evidence of significant coronary artery disease (CAD) by ANY ONE of
the following:
- History of MI.
- - Prior coronary angiography evidence of CAD (>50% stenosis in ≥1 vessel)
- Previous positive Stress Test.
- - Creatinine clearance <30 ml/min (using the Cockroft-Gault formula) or requires
hemodialysis.
- - Inability to undergo the apheresis procedure due to poor venous access or laboratory
tests that are not within acceptable ranges (not including INR for patients on
Coumadin)
- Childs-Pugh class C liver cirrhosis.
- - Previous atrial septostomy.
- - Any other clinically significant illness or abnormal laboratory values (measured
during the screening period) that, in the opinion of the Investigator, might put the
subject at risk of harm during the study or might adversely affect the interpretation
of the study data.
- - Anticipated survival less than 1 year due to concomitant disease.
- - History of cancer in the past 5 years (except for low grade and fully resolved
non-melanoma skin cancer)
- Results during screening consistent with current infection with HIV, Hepatitis B(HBV)
or C(HCV), human T-cell lymphotropic virus (HTLV- I/II) or syphilis.
- - Systemic arterial systolic blood pressure < 85 mm Hg.
- - Known allergy to gentamicin or amphotericin.
- - Patients who have participated in any gene therapy study or an angiogenic growth
factor protein study.
- - Patients unable to provide informed consent and comply with the visit schedule.
