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Study Design for NIAID/NIH Clinical Trial using Rituximab for the Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

Mark Nicolls


Thomas Medsger

David Badesch


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Mark R. Nicolls1*, Thomas Medsger2, David Badesch3

1. VA Palo Alto Health Care System/Stanford University
2. University of Pittsburgh Medical Center
3. University of Colorado at Denver Health Sciences Center
* Presenting Author.

BACKGROUNDSystemic 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.

STUDY DESIGNRandomized, double-blind, placebo-controlled, Phase II multicenter trial.

Eligibility: 18-75 years of age with SSc-PAH and without significant ILD

Primary Outcome Measures: Change in pulmonary vascular resistance measured by right heart catheterization at 6 months.

Secondary Outcome Measures: Safety and tolerability of rituximab therapy, assessment of time to clinical worsening, DLCO and oxygen saturation at rest on room air, number of new digital ulcers, severity of Raynaud phenomenon, exercise capacity determined by 6 minute walking distance, evaluation of biomarkers as indicators of disease progression longitudinally over 48 wks after treatment initiation, and change in quality of life from baseline

DETAILED DESCRIPTION: 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. This trial includes 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. This trial is currently enrolling. For further clinical trial information:http://clinicaltrials.gov/ct2/show/study/NCT01086540