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
Intervention: Rituximab; Placebo; CMRI; prednisone; methylprednisolone; diphenhydramine; acetaminophen
Intervention description: 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.
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Prednisone; Methylprednisolone; Rituximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 57.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pulmonary Arterial Hypertension (PAH); Autoimmune Disease; Systemic Scleroderma

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.
    

Eligibility criteria:

        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.