Research

ASCI: A Randomized, Double-blind, Placebo-controlled, Phase II Multicenter Trial of a Monoclonal Antibody to CD20 (Rituximab) for the Treatment of Systemic Scllerosis-Associated Pulonary Arterial Hypertension (SSc-PAH)

IRB Number: 13004

Institutional Review Board, Hospital for Special Surgery

April 02, 2014

The safety of study participants is our top priority. The trial is approved and periodically reviewed by an Institutional Review Board (IRB), which includes doctors, administrators, ethicists, and members of the general public. The safety of clinical trials is reviewed by the U.S. Food and Drug Administration.

Before enrolling in a clinical trial, the investigator will explain the purpose of the trial, its expected benefits, any possible risks or side effects, and what your role will be. This is the time to ask questions! If you want to join the trial, you must sign the informed consent documents. You can leave a clinical trial at any time without penalty.

For further information, see Understanding Clinical Trials.

Principal Investigator

Robert F. Spiera, MD

Co-Investigators

Jessica K. Gordon, MD
Evelyn Horn, MD
Irina Sobol, MD
Maria Karas, MD
Lindsay Lally, MD
Uzunma Udeh
Nina Paddu
Daniele Lerner
Madeline Yushak

Summary

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. Five patients will be recruited from this site

Inclusion/Exclusion Criteria

Inclusion Criteria:
 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.
Exclusion Criteria:
 Documented PAH for greater than 5 years at the time of randomization defined as:
o Measurement of a mean PAP > 25 mmHg by right heart catheterization at least 5 years previously, OR
o 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.
 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.
 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.

Contact Information

Uzunma Udeh
udehu@hss.edu
212.774.2123



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