Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Systemic Sclerosis-Associated PAH

Intervention / Treatment
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* Biological: Rituximab
* Other: Placebo
* Diagnostic Test: CMRI
* Drug: prednisone
* Drug: methylprednisolone
* Drug: diphenhydramine
* Drug: acetaminophen


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab+PAH SOC<br>Rituximab (1000 mg) will be administered as 2 intravenous infusions given 2 weeks apart. Concurrent stable-dose Pulmonary Arterial Hypertension (PAH) medical therapy will be continued/managed as per standard of care (PAH SOC). | Biological: Rituximab<br>* 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.<br>* Other names: Rituxan®;Diagnostic Test: CMRI<br>* Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.<br>* Other names: cardiac Magnetic Resonance Imaging;Drug: prednisone<br>* Prednisone dose of 40 mg (or equivalent) by mouth administered the night before and the morning of each study drug infusion.<br>* Other names: Rayos®;Drug: methylprednisolone<br>* Methylprednisolone (or equivalent corticosteroid) administered intravenously 30 minutes prior to each study drug infusion.<br>* Other names: corticosteroid;Drug: diphenhydramine<br>* 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.<br>* Other names: Benadryl®;Drug: acetaminophen<br>* 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.<br>* Other names: Tylenol®;|
| Placebo Comparator: Placebo + PAH SOC<br>Placebo will be administered as 2 intravenous infusions given 2 weeks apart. Concurrent stable-dose Pulmonary Arterial Hypertension (PAH) medical therapy will be continued/managed as per standard of care (PAH SOC). | Other: Placebo<br>* 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.<br>* Other names: Placebo for rituximab;Diagnostic Test: CMRI<br>* Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.<br>* Other names: cardiac Magnetic Resonance Imaging;Drug: prednisone<br>* Prednisone dose of 40 mg (or equivalent) by mouth administered the night before and the morning of each study drug infusion.<br>* Other names: Rayos®;Drug: methylprednisolone<br>* Methylprednisolone (or equivalent corticosteroid) administered intravenously 30 minutes prior to each study drug infusion.<br>* Other names: corticosteroid;Drug: diphenhydramine<br>* 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.<br>* Other names: Benadryl®;Drug: acetaminophen<br>* 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.<br>* Other names: Tylenol®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Distance Walked During a Six Minute Walk Test | The six minute walk test measures the distance a participant is able to walk over a total of six minutes on a hard, flat surface. The goal is for the participant to walk as far as possible in six minutes. The participant is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. The total distance walked, in meters, was recorded for each participant. Longer distances indicate better outcomes. | Baseline (Pre Treatment Initiation) to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization at Week 24 | During a right heart catheterization, a catheter is guided to the right side of the heart and then into the pulmonary artery; blood flow through the heart is observed and is used to measure pressures in a participant's heart and lungs. The calculation of Pulmonary Vascular Resistance (PVR) is measured in Woods Units. Change is derived by measuring the difference between Baseline and Week 24 PVR (Week 24 minus Baseline). Higher PVR values indicate worse disease status. | Baseline (Pre Treatment Initiation) to Week 24 | 
| Change From Baseline in Distance Walked During a Six Minute Walk Test at Week 24 and Week 48 | The six minute walk test measures the distance a participant is able to walk over a total of six minutes on a hard, flat surface. The goal is for the participant to walk as far as possible in six minutes. The participant is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway. The total distance walked, in meters, was recorded for each participant. Longer distances indicate better outcomes. | Baseline (Pre Treatment Initiation) to Week 24 and Week 48 | 
| Time to Clinical Worsening | Assessment of time to clinical worsening, censored at Week 48, defined as the first occurrence of any of the following: death, hospitalization for Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH), lung transplantation, atrial septostomy, addition of other Pulmonary Arterial Hypertension (PAH) therapeutic agents, or worsening of the six minute walk distance by > 20% and an increase in New York Heart Association functional class. Time to clinical worsening was defined as the first date that met any of the above criteria and was calculated in study days as: date of first event minus (-) date of treatment randomization. If a participant did not experience any of the referenced events by Week 48 or, if the date of death was after the 48 week follow-up period, time to clinical worsening was equal to the participant's duration of follow-up in the study. | Baseline (Pre Treatment Initiation) to Week 48 | 
| Time to the Change or Addition of New Pulmonary Arterial Hypertension (PAH) Therapeutic Medications | Per protocol, from the time of study entry, participants were to remain on background PAH medical therapy with either a single agent or a combination of prostanoid, endothelin receptor antagonist, PDE-5 inhibitor, and/or guanylate cyclase stimulators as per the entry criteria. Doses should have remained stable through the Week 24 primary outcome/endpoint visit. If a dose of a background PAH medication was changed or a new PAH medication was added during the course of the trial, the date of the first dose change or additional medication was recorded. Time to the addition or modification of PAH medications was defined in study days as: date of the first time a PAH medication was modified or added minus (-) date of randomization. | Baseline (Pre Treatment Initiation) to Week 48 | 
| Change From Baseline in Quality of Life as Measured by the Short Form Health Survey (SF-36): Mental Component Summary Score | The SF-36 measures health-related quality of life. It has 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. The SF-36 Mental Health component summary score is comprised of the Vitality Scale, the Social Functioning Scale, the Role-Emotional Scale, and the Mental Health Scale. It is scaled from 0 to 100 with a score of 0 equivalent to maximum disability and a score of 100 is equivalent to no disability. A negative value indicates a decrease in quality of life from Baseline. | Baseline (Pre Treatment Initiation) to Week 24 and Week 48 | 
| Change From Baseline in Quality of Life as Measured by the Short Form Health Survey (SF-36): Physical Component Summary Score | The SF-36 measures health-related quality of life. It has 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. The SF-36 Physical component summary score is comprised of the Physical Functioning Scale, the Role-Physical Scale, the Bodily Pain Scale, and the General Health Scale. It is scaled from 0 to 100 with a score of 0 equivalent to maximum disability and a score of 100 is equivalent to no disability. A negative value indicates a decrease in quality of life from Baseline. | Baseline (Pre Treatment Initiation) to Week 48 | 
| Change in Quality of Life as Measured by the Disability Index of the Scleroderma Health Assessment Questionnaire (HAQ-DI) | The HAQ-DI is a self-reported questionnaire of functionality that includes questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities) and addresses scleroderma related manifestations that contribute to disability. The final score ranges from 0 to 3, where a higher HAQ-DI score indicates a worse outcome. | Baseline (Pre Treatment Initiation) to Week 24 and Week 48 | 
| Number of New Digital Ulcers | The total number of digital ulcers present on the dorsal and palmar surfaces for both the left and right fingers were captured at the Baseline study visit. The number of new digital ulcers since the last study visit (including any ulcers that had appeared and healed since the last study visit) on the dorsal and palmar surfaces for both the left and right fingers were captured at the post-Baseline study visits. The total number of digital ulcers on both hands was summed from the number present on the dorsal and palmar surfaces for both the left and right fingers. | Baseline (Pre Treatment Initiation) to Week 24 and Week 48 | 
| Change in Severity of Raynaud's Phenomenon | Severity of Raynaud's phenomenon was measured by a Visual Analog Scale (VAS) of the Scleroderma Health Assessment Questionnaire (SHAQ). The SHAQ VAS includes a question asking, In the past week, how much has your Raynaud's Phenomenon interfered with your activities? Participants were asked to place a mark on a 15 cm line, scaled from 0 (does not interfere) to 100 (very severe limitation), to describe the severity of their Raynaud's phenomenon in the past week. The distance from the left edge of the line to the vertical line placed by the participant was measured in centimeters; VAS scores were converted to a 0 to 100 scale. | Baseline (Pre Treatment Initiation) to Week 24 and Week 48 | 
| Change in Carbon Monoxide Diffusing Capacity (DLCO) | Carbon Monoxide Diffusing Capacity (DLCO) is a measure of lung function. Predicted values for DLCO were computed according to the Global Lung Function Initiative (GLI) all-age reference values and corrected for hemoglobin. Lower DLCO values indicate worse disease activity. DLCO (Diffusing Capacity of the Lungs for Carbon Monoxide) | Baseline (Pre Treatment Initiation) to Week 24 and Week 48 | 
| Oxygen Saturation Levels at Week 24 and Week 48 | Oxygen saturation is the amount of oxygen that is in your bloodstream and is measured as the percentage of blood hemoglobin that is carrying oxygen. Normal oxygen saturation levels are considered to be 95-100 percent; low oxygen saturation values indicate worse disease. Room air oxygen saturation by pulse oximetry and/or amount of supplemental oxygen used, if saturation <90%, were recorded. | Week 24 , Week 48 | 
| Percent Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization | During a right heart catheterization, a catheter is guided to the right side of the heart and then into the pulmonary artery; blood flow through the heart is observed and is used to measure pressures in a participant's heart and lungs. Pulmonary vascular resistance (PVR) is measured in Woods Units. Higher PVR values indicate worse disease status. Change in PVR is determined by Baseline value minus (-) Week 24 value. | Baseline (Pre Treatment Initiation) to Week 24 | 
| Number of Infusion-Related Toxicities | The number of Grade 3, 4, and 5 Adverse Events (AEs), which were defined as possibly, probably, or definitely related to rituximab or placebo infusion. This study graded the severity of adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. | Day 0 (Treatment Randomization) to Week 48 | 
| Number of Grade 3 or Higher Adverse Events (AEs) Through Week 48 | Total number of Grade 3, 4, and 5 AEs. Ref: National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. | Baseline (Pre Treatment Initiation) to Week 48 | 
| Number of Infection-Related Adverse Events (AEs) Through Week 48 | Number of adverse events classified as infections. Reference: National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. | Day 0 (Treatment Randomization) to Week 48 | 
| Treatment-Related Mortality: From Treatment Initiation to Week 48 | Death occurring after randomization and ≤ Week 48, and possibly, probably, or definitely resulting from assigned study treatment. | Day 0 (Treatment Randomization) to Week 48 | 
| All-Cause Mortality: From Treatment Initiation to Week 48 | Death from any cause occurring after randomization and ≤ Week 48. | Day 0 (Treatment Randomization) to Week 48 | 
| All-Cause Mortality: From Treatment Initiation to Week 104 | Death from any cause occurring after randomization and ≤ Week 104. | Day 0 (Treatment Randomization) to Week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension (PAH), Autoimmune Disease, Systemic Scleroderma