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) < 90 mmHg.

   - Treatment with cyclophosphamide within 4 weeks of randomization.

   - Treatment with immunocompromising biologic agents within 4 weeks prior to treatment
   initiation or treatment with infliximab within 8 weeks prior to treatment initiation.

   - If being treated with a non-biologic immunosuppressive or immunomodulating drug,
   changes in dosage within 4 weeks prior to randomization. Subjects taking prednisone or
   equivalent corticosteroid > 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 (< 8 weeks) or any other immunization within 4
   weeks of treatment.

   - History of anaphylaxis or Immunoglobulin E (IgE) -mediated hypersensitivity to murine
   proteins or any component of rituximab.

   - Pregnancy.

   - Lactation.

   - History of malignancy within the last 5 years, except for resected basal or squamous
   cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer Grade
   I.

   - A woman of childbearing potential who is unwilling to use a medically acceptable form
   of birth control

   - History of non-compliance with other medical therapies.

   - History of alcohol or drug abuse within 1 year of randomization.

   - Receipt of any investigational drug or device within 4 weeks before the Screening
   Visit, with the exception of investigational prostanoids, endothelin receptor
   antagonists, and PDE-5 inhibitors, and guanylate cyclase stimulators.

   - Recipient of lung transplant.

   - Laboratory parameters at the screening visit showing any of the following abnormal
   results: Transaminases > 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.