ASC01 - A Randomized, Double-Blind, Placebo-Controlled, Phase II Multicenter Trial of a Monoclonal Antibody to CD20 (Rituximab) for the Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a serious, life-threatening manifestation of systemic sclerosis (SSc), an autoimmune disease of the connective tissue characterized by scarring (fibrosis) and atrophy of the skin, joints and tendons, skeletal muscles, and internal organs, and immunological disturbances. One-year survival for patients with SSc-PAH ranges from 50-81%. There is currently no cure for SSc-PAH and treatment is limited to vasodilator therapy used in all forms of PAH. In recent studies, immunotherapy was shown to be effective in treating SSc-interstitial lung disease, another serious, life-threatening manifestation of SSc. In addition, there are compelling pre-clinical data and anecdotal clinical reports that suggest modulation of the immune system may be an effective strategy for treating SSc-PAH. To test this approach, this trial will determine if rituximab, an immunotherapy, has a marked beneficial effect on clinical disease progression, with minimal toxicity, in patients with SSc-PAH when compared to placebo.
Factors that allow someone to participate in a clinical trial.
- Subject has provided written informed consent.
- Subject must be between the ages of 18 and 75.
- 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 ≥ 30 mmHg at entry.
- Mean PVR of > 3 Wood units.
- Baseline 6MWD of at least 100 meters.
- 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, and/or PDE-5 inhibitor)
- for a minimum of 3 months and have been on stable dose medical therapy for at least 4 weeks prior to randomization.
Factors that do not allow someone to participate in a clinical trial.
- Documented PAH for greater than 5 years at the time of randomization defined as:
- Measurement of a mean 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.
- Treatment with biologic or chemical immunosuppressive agents within 3 months prior to treatment initiation, except for hydroxychloroquine and penicillamine.
- Previous exposure to any lymphocyte 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.
- 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.
- Presence of positive PPD.
- Significant renal insufficiency.
- Active, untreated SSc renal crisis at the time of enrollment.
- Recent administration of a live vaccine.
- History of anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component of rituximab.
- 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.
- A recent history of alcohol or drug abuse.
- Participation in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit.
- Inability to perform the 6-minute walk test.
- 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/mm3; Platelet count < 100,000/mm3; Hemoglobin < 9 g/dL.
- Concurrent treatment in a clinical research study using a non-FDA approved agent.
- Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a participant in the trial.