Clinical trial NCT01086540: Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Systemic Sclerosis-Associated PAH
Keywords: Pulmonary Arterial Hypertension (PAH)
Autoimmune Disease
Systemic Scleroderma
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Autoimmunity Centers of Excellence
name: Rho Federal Systems Division, Inc.
First posted: 2010-03-15
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Primary outcomes:
measure: Change From Baseline in Distance Walked During a Six Minute Walk Test
timeFrame: Baseline (Pre Treatment Initiation) to Week 24
Secondary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization at Week 24
timeFrame: Baseline (Pre Treatment Initiation) to Week 24
measure: Change From Baseline in Distance Walked During a Six Minute Walk Test at Week 24 and Week 48
timeFrame: Baseline (Pre Treatment Initiation) to Week 24 and Week 48
measure: Time to Clinical Worsening
timeFrame: Baseline (Pre Treatment Initiation) to Week 48
measure: Time to the Change or Addition of New Pulmonary Arterial Hypertension (PAH) Therapeutic Medications
timeFrame: Baseline (Pre Treatment Initiation) to Week 48
measure: Change From Baseline in Quality of Life as Measured by the Short Form Health Survey (SF-36): Mental Component Summary Score
timeFrame: Baseline (Pre Treatment Initiation) to Week 24 and Week 48
measure: Change From Baseline in Quality of Life as Measured by the Short Form Health Survey (SF-36): Physical Component Summary Score
timeFrame: Baseline (Pre Treatment Initiation) to Week 48
measure: Change in Quality of Life as Measured by the Disability Index of the Scleroderma Health Assessment Questionnaire (HAQ-DI)
timeFrame: Baseline (Pre Treatment Initiation) to Week 24 and Week 48
measure: Number of New Digital Ulcers
timeFrame: Baseline (Pre Treatment Initiation) to Week 24 and Week 48
measure: Change in Severity of Raynaud's Phenomenon
timeFrame: Baseline (Pre Treatment Initiation) to Week 24 and Week 48
measure: Change in Carbon Monoxide Diffusing Capacity (DLCO)
timeFrame: Baseline (Pre Treatment Initiation) to Week 24 and Week 48
measure: Oxygen Saturation Levels at Week 24 and Week 48
timeFrame: Week 24 , Week 48
measure: Percent Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization
timeFrame: Baseline (Pre Treatment Initiation) to Week 24
measure: Number of Infusion-Related Toxicities
timeFrame: Day 0 (Treatment Randomization) to Week 48
measure: Number of Grade 3 or Higher Adverse Events (AEs) Through Week 48
timeFrame: Baseline (Pre Treatment Initiation) to Week 48
measure: Number of Infection-Related Adverse Events (AEs) Through Week 48
timeFrame: Day 0 (Treatment Randomization) to Week 48
measure: Treatment-Related Mortality: From Treatment Initiation to Week 48
timeFrame: Day 0 (Treatment Randomization) to Week 48
measure: All-Cause Mortality: From Treatment Initiation to Week 48
timeFrame: Day 0 (Treatment Randomization) to Week 48
measure: All-Cause Mortality: From Treatment Initiation to Week 104
timeFrame: Day 0 (Treatment Randomization) to Week 104
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Health Care
state: California
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University, Pulmonary and Critical Care Medicine
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Health Clinics and Surgery Center
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill: UNC Hospitals
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center-William P. Clements University Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas: Memorial Herman Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Stanford University
name: Mark Nicolls, M.D.
role: STUDY_CHAIR
affiliation: University of Colorado Health Sciences Center (Aurora, CO)
name: David B. Badesch, M.D.
role: STUDY_CHAIR
affiliation: University of Pittsburgh
name: Thomas A. Medsger, Jr., M.D.
role: STUDY_CHAIR
affiliation: Stanford University
name: Lorinda Chung, MD
role: STUDY_CHAIR
affiliation: University of Pittsburgh: Division of Rheumatology and Clinical Immunology
name: Robyn Domsic, MD
role: STUDY_CHAIR
affiliation: National Jewish Health: University of Colorado School of Medicine
name: Aryeh Fischer, MD
role: STUDY_CHAIR
affiliation: Stanford University
name: Roham Zamanian, MD
role: STUDY_CHAIR
References:
citation: Zamanian RT, Badesch D, Chung L, Domsic RT, Medsger T, Pinckney A, Keyes-Elstein L, D'Aveta C, Spychala M, White RJ, Hassoun PM, Torres F, Sweatt AJ, Molitor JA, Khanna D, Maecker H, Welch B, Goldmuntz E, Nicolls MR. Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Randomized, Placebo-controlled Trial. Am J Respir Crit Care Med. 2021 Jul 15;204(2):209-221. doi: 10.1164/rccm.202009-3481OC.
citation: Zhang Y, Michelakis ED. A Phase-2 NIH-sponsored Randomized Clinical Trial of Rituximab in Scleroderma-associated Pulmonary Arterial Hypertension Did Not Reach Significance for Its Endpoints: End of Story? Not So Fast! Am J Respir Crit Care Med. 2021 Jul 15;204(2):123-125. doi: 10.1164/rccm.202103-0612ED. No abstract available.
citation: Andreasson K, Bengtsson MF, Bostrom C, Hesselstrand R, Volkmann ER. Multiple Manifestations of Systemic Sclerosis Affect Walk Distance. Am J Respir Crit Care Med. 2021 Aug 1;204(3):359. doi: 10.1164/rccm.202104-0938LE. No abstract available.
citation: Zamanian RT, Pinckney A, Domsic RT, Medsger T, Keyes-Elstein L, Sweatt AJ, Welch B, Goldmuntz E, Nicolls MR, Chung L. Reply to Andreasson et al.: Multiple Manifestations of Systemic Sclerosis Affect Walk Distance. Am J Respir Crit Care Med. 2021 Aug 1;204(3):377-378. doi: 10.1164/rccm.202104-1023LE. No abstract available.
citation: de Bourcy CFA, Dekker CL, Davis MM, Nicolls MR, Quake SR. Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis. Sci Immunol. 2017 Sep 29;2(15):eaan8289. doi: 10.1126/sciimmunol.aan8289.