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

This prospective, double-blind, placebo-controlled, multi-center, randomized trial will evaluate the effect of rituximab on disease progression in subjects with SSc-PAH receiving concurrent stable-dose standard medical therapy with a prostanoid, endothelin receptor antagonist, and/or phosphodiesterase 5 (PDE-5) inhibitor. The study will focus on assessment of clinical response and safety measures longitudinally. In addition, the effects of treatment with rituximab on the underlying immune mechanisms associated with B-cell dysregulation and pathogenic autoantibody response in this disease will be investigated. 1000 mg of rituximab or placebo will be administered as two IV infusions given two weeks apart. Clinical assessments and sample collection will occur at monthly visits through Week 48. If a participant has not recovered B cells by Week 48, B cell studies will be conducted quarterly until reconstitution is documented or for 2 years after initial treatment.

This trial will include a sub-study, entitled "Right Ventricular Response to Rituximab in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension - A Magnetic Resonance Imaging Sub-study" (RESTORE Sub-study). The objective of the RESTORE sub-study is to evaluate the therapeutic effect of rituximab on the right ventricle of patients with SSc-PAH. Changes in right ventricular end diastolic volume index (RVEDVI) and stroke volume (SV) determined by cardiac MRI will be used as surrogates of right ventricle function and prognosis. Enrollment for the RESTORE sub-study will parallel that of main trial. Twenty patients from each treatment arm, distributed among all participating sites, will be recruited for this sub-study. Each patient will be studied at baseline (i.e. prior to initiation of study drug) and after 24 weeks or at time of discontinuation. In addition to the data collection and testing specified in the main trial, participants in RESTORE will undergo comprehensive cardiac MRI evaluation. All main trial study inclusion and exclusion criteria apply, as well as additional exclusion criteria that pertain only to the RESTORE sub-study: 1) known hypersensitivity to Gadolinium; 2) inability to tolerate or cooperate with MRI; 3) morbid obesity; and 4) presence of metallic objects or pacemakers.

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.