Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

Inclusion Criteria

• Subject has provided written informed consent.
• Clinical diagnosis of systemic sclerosis (either limited or diffuse cutaneous disease).
• Diagnosis of SSc-PAH within the past 5 years, with a mean pulmonary arterial pressure of ≥ 25 mmHg at entry.
• Mean Pulmonary Vascular Resistance (PVR) of > 3 Wood units.
• Screening 6-minute Walking Distance (6MWD) of at least 100 meters.
• New York Heart Association (NYHA) Functional Class II, III, or IV.
• Subject must be able to maintain O2 saturation ≥ 90% at rest (with or without oxygen);

--Oxygen use is permitted.

• Subject must be vaccinated with the pneumococcal vaccine at least one month prior to initiation of therapy, unless subject was vaccinated within 5 years of study entry.
• Subject must have been treated with background medical therapy for PAH (prostanoid, endothelin receptor antagonist, PDE-5 inhibitor, and/or guanylate cyclase stimulators) for a minimum of 8 weeks and have been on stable dose medical therapy for at least 4 weeks prior to randomization with no expectation of change for 24 weeks after randomization.

Exclusion Criteria

• Documented PAH for greater than 5 years at the time of randomization defined as:
• Measurement of a mean Pulmonary Artery Pressure (PAP) > 25 mmHg by right heart catheterization at least 5 years previously, OR
• Treatment with targeted background PAH therapy for > 5 years.
• Pulmonary Capillary Wedge Pressure > 15 mmHg or Left Ventricular End Diastolic Pressure > 15 mmHg.
• Persistent hypotension with Systolic Blood Pressure (SBP) 10mg daily are excluded.
• Previous exposure to any lymphocyte or B cell depleting agent.
• PAH for any reason other than SSc.
• History of coronary artery disease, significant ventricular tachy-arrhythmia, stent placement, coronary artery bypass surgery, and/or myocardial infarction.
• Moderate or severe interstitial lung disease.
• Chronic infections.
• Positive serology for infection with hepatitis B or C.
• A deep space infection within the past 2 years.
• Evidence of active infection within 2 weeks of randomization
• Presence of a positive tuberculosis (TB) skin test (e.g., PPD test) or positive QuantiFERON®-TB blood test, an indeterminate QuantiFERON®-TB blood test, or latent tuberculosis (TB).
• Significant renal insufficiency.
• Active, untreated SSc renal crisis at the time of enrollment.
• Recent administration of a live vaccine ( 2x the upper limit of normal (ULN) and/or bilirubin > 2x ULN; Absolute neutrophil count < 1,500/mm^3; Platelet count < 100,000/mm^3; Hemoglobin < 9 g/dL.
• Concurrent treatment in a clinical research study using a non-FDA approved agent with the exception of an open-label study/study extension of investigational prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors, and guanylate cyclase stimulators, provided the open-label investigational drug will be available and dose will remain stable through the trial's primary outcome time point of 24 weeks after randomization in this study, ASC01 (NCT01086540).
• Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a participant in the trial.