| Eligibility |
Inclusion Criteria:
Subjects will be eligible for inclusion in the study if they meet all of the following
criteria:
1. Subject must be willing and able to sign a written informed consent prior to any
study-related procedures and able to understand and follow instructions; return to the
study unit for specified study visits; and able to participate in the study for the
entire period.
2. Subject is male or female, aged 18 to 80 years.
3. Subject must have a body mass index (BMI) 18 to 40 kg/m2 at Screening. If BMI is >35
kg/m2, subject chest circumference should be <65 inches (165 cm).
4. Subject with PAH belonging to 1 of the following subgroups of NICE Clinical
Classification of PAH category:
1. Idiopathic PAH.
2. Heritable PAH.
3. Drug or toxin-induced (anorexigen or methamphetamine use).
4. PAH associated with connective tissue disease.
5. Subject with PAH who are symptomatic and have reduced exercise capacity due primarily
to their PAH diagnosis, having been assessed by qualified individual, ie, physician,
physician assistant, or nurse practitioner, to be in NYHA/WHO functional class II or
III and having an RRS 2.0 of 6 to 10.
6. PAH therapy at stable doses of standard-of-care therapies for at least 90 days prior
to screening.
7. Subject has most recent (within the last 36 months) hemodynamic assessment of PAH by
RHC demonstrating a persistent resting mPAP =25 mm Hg and resting mean pulmonary
vascular resistance (PVR) =5 Wood Units with Pulmonary Capillary Wedge Pressure =15
mmHg.
8. Subject is willing to undergo CardioMEMS PA Sensor implantation and RHC prior to
randomization or has had the CardioMEMS PA Sensor implanted previously.
9. Subject has a 6-minute walk distance (6MWD) =150 meters (m) and <550 m at Screening.
10. Female subject of childbearing potential must be willing and able to practice
effective contraception during the study and continuing contraception for 30 days
after their last dose of study drug. A female subject of non-childbearing potential is
defined as being surgically sterilized by bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy. A female subject 45 to 60 years of age, who is
post-menopausal for at least 1 year, and has a follicle-stimulating hormone level
confirmation indicating post menopausal status will be considered of non-childbearing
potential. A female subject >60 years of age is considered post menopausal and of non
childbearing potential.
Exclusion Criteria:
Subjects will be excluded from the study if they meet any of the following criteria:
1. Subject has pulmonary hypertension category 2 to 5.
2. Subject has adult congenital heart disease (ACHD).
3. Subject has concomitant medical or psychiatric disorder, condition, history, or any
other condition that in the opinion of the Investigator would either put the subject
at risk or impair the subject's ability to participate in or complete the requirements
of the study or confound the objectives of the study.
4. Subject has a concomitant medical disorder that is expected to limit the subject's
life-expectancy to =1 year.
5. Subject has RRS 2.0 score of =5 or =11.
6. Subject has heart fai
7. lure with preserved ejection fraction defined as those with >50% ejection fraction
(with signs and symptoms of heart failure) or left atrial volume (LAV) >34 mL/ m2.
8. Subject is not able to have CardioMEMS PA Sensor implanted due to:
1. An active, ongoing infection defined as being febrile, an elevated white blood
cell count, on intravenous antibiotics, and/or positive cultures (blood, sputum,
or urine).
2. History of current or recurrent (=2 episodes within 5 years prior to consent)
pulmonary emboli and/or deep vein thromboses.
3. Cannot tolerate RHC.
4. PA branch inner diameter <7 mm in a descending branch within the left or right
lower lung lobe (target implant vessel).
5. Unable to take dual antiplatelet or anticoagulation therapy for 1 month after
CardioMEMS PA Sensor implantation.
9. Subject is likely to undergo lung transplantation within the next 6 months.
10. Subject has untreated, moderate to severe obstructive sleep apnea.
11. Subject has evidence of significant chronic thromboembolic disorder as determined by
the Investigator or recent pulmonary embolism within 6 months prior to Screening (see
also exclusion criterium 7b).
12. Subject has uncontrolled hypertension (?160/100 mmHg, confirmed by duplicate seated
readings) at 2 or more historical visits within 3 months prior to Screening.
13. Subject has sustained systolic blood pressure <95 mmHg and/or diastolic blood pressure
<50 mmHg (confirmed by duplicate seated readings) on at least 3 consecutive occasions
(self monitored or office) prior to or at Screening, or overt symptomatic hypotension.
14. Subject has sustained resting heart rate >120 beats per minute (confirmed by duplicate
assessments of office vital signs) or consecutive electrocardiogram (ECG) assessments
on at least 3 consecutive occasions prior to or at Screening.
15. Subject has a history of a bleeding disorder.
16. Subject has thrombocytopenia: platelets <150,000/mm3.
17. Subject has known porphyria, mitochondrial, or urea cycle disease.
18. Subject has a history of chronic pancreatic disease.
19. Subject is a pregnant or lactating female.
20. Subject has a positive result from serology testing at Screening for human
immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus
(HCV); but if the subject has a historical diagnosis (prior to Screening) of being
positive for HIV, HBsAg, or HCV, must be clinically stable and if on therapy, be on
stable therapy for at least 3 months prior to Screening. A subject should not have
active coronavirus disease 19 (COVID-19); however, those with previous COVID 19 are
permitted.
21. Subject has participated in another investigational drug study within 30 days prior to
Screening or is participating in a non medication study which, in the opinion of the
Investigator, would interfere with the study compliance or outcome assessments.
22. Subject is on regular treatment with sodium valproate/valproic acid (VPA), other
anti-epilepsy drugs, or other prohibited medications that cannot be discontinued at
the Screening Visit (V1).
23. Subject is on regular anticoagulation or on dual antiplatelet therapy (DAPT) that
cannot be discontinued at the Screening Visit (V1); however, during the Baseline
Period following CardioMEMS PA Sensor implantation, DAPT is allowed according to
clinical practice for up to 4 weeks. A low daily dose aspirin (<125 mg) is allowed,
ie, "baby" aspirin.
24. Subject has more than mild mitral or aortic valve disease, left ventricular ejection
fraction (LVEF) <50%, or left ventricular regional wall motion abnormality suggestive
of active coronary artery disease on 2D-echocardiogram at Screening.
25. Subject has a forced expiratory volume in 1 second (FEV1)/forced vital capacity <70%
(absolute), FEV1 =50% or total lung capacity (TLC) <70% predicted on pulmonary
function testing (PFT); for potential subjects with TLC 60 to 69% predicted, non
contrasted computerized tomography (CT) scan must be performed to exclude subjects
with more than mild interstitial lung disease. PFTs should have been obtained within 3
years prior to Screening.
26. Subject has clinically significant renal dysfunction as measured by the estimated
Glomerular Filtration Rate (eGFR) of <30 mL/min/1.73m2 as calculated by Modification
of Diet in Renal Disease (MDRD) at Screening.
27. Subject has significant liver dysfunction as measured by any one of the following at
Screening (including subjects with acute or chronic hepatitis as well as subjects with
own or family history of serious hepatitis, especially drug related):
1. Alanine aminotransferase (ALT) >2.0 × upper limit of normal (ULN).
2. Aspartate aminotransferase (AST) >2.0 × ULN.
3. Serum bilirubin =1.6 mg/dL or >2.0 × ULN.
28. Subject has a known history of substance abuse including alcohol abuse within the 1
year prior to Screening that in the opinion of the Investigator would impair the
subject's ability to participate in or complete the requirements of the study.
29. Subjects with any major surgical procedure or trauma within 30 days prior to Screening
or planned surgical procedure during the study period.
30. Subject with any inpatient hospitalization (defined as >23 hours) within 30 days prior
to Screening.
31. Subject enrolled within 90 days prior to Screening or plans to enroll during the study
into a cardiopulmonary rehabilitation program.
32. Subject has known hypersensitivity to study drug or any of the excipients of the drug
formulation.
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