Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
Condition: Systemic Sclerosis-Associated PAH
MeSH terms: Pulmonary Arterial Hypertension; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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.
      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.
    

Intervention name(s): Rituximab; Placebo; CMRI; prednisone; methylprednisolone; diphenhydramine; acetaminophen
Intervention type(s): Biological; Other; Diagnostic Test; Drug; Drug; Drug; Drug
Intervention description(s): Participants receive rituximab intravenous (IV) infusions, 1000 mg each, 14 days apart (Day 0 and Week 2).
Rituximab is supplied as a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials, which must be diluted before administration
Standard rituximab pre-medications will be provided in preparation for the rituximab infusions.; Participants receive placebo intravenous (IV) infusions 14 days apart (Day 0 and Week 2).
Standard pre-medications will be provided in preparation for the infusions.; Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.; Prednisone dose of 40 mg (or equivalent) by mouth administered the night before and the morning of each study drug infusion.; Methylprednisolone (or equivalent corticosteroid) administered intravenously 30 minutes prior to each study drug infusion.; Diphenhydramine 50 mg (or equivalent) administered by mouth approximately thirty to sixty minutes prior to each study drug infusion.
Dose may be repeated every four hours, as needed.; Acetaminophen 650 mg (or equivalent) administered by mouth approximately thirty to sixty minutes prior to each study drug infusion.
Dose may be repeated every four hours, as needed.
Other intervention name(s): Rituxan®; Placebo for rituximab; cardiac MRI; cardiac Magnetic Resonance Imaging; prednisone tablets; Rayos®; corticosteroid; Benadryl®; Tylenol®
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Prednisone; Methylprednisolone; Rituximab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pulmonary Arterial Hypertension (PAH); Autoimmune Disease; Systemic Scleroderma