Back to resultsRituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
Primary Purpose
Systemic Sclerosis-Associated PAH
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Placebo
CMRI
prednisone
methylprednisolone
diphenhydramine
acetaminophen
Sponsored by
About this trial
This is an interventional treatment trial for Systemic Sclerosis-Associated PAH focused on measuring Pulmonary Arterial Hypertension (PAH), Autoimmune Disease, Systemic Scleroderma
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.
Sites / Locations
- Stanford Health Care
- University of Colorado Health Sciences Center
- University of Iowa
- Johns Hopkins University, Pulmonary and Critical Care Medicine
- Boston University Medical Center
- University of Michigan
- University of Minnesota Health Clinics and Surgery Center
- Columbia University Medical Center
- Weill Cornell Medical College
- University of Rochester Medical Center
- University of North Carolina at Chapel Hill: UNC Hospitals
- Ohio State University
- University of Pittsburgh Medical Center
- Medical University of South Carolina
- University of Texas Southwestern Medical Center-William P. Clements University Hospital
- University of Texas: Memorial Herman Hospital
- University of Utah
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Rituximab+PAH SOC
Placebo + PAH SOC
Arm Description
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).
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).
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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.
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.
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.
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.
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.
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.
All-Cause Mortality: From Treatment Initiation to Week 48
Death from any cause occurring after randomization and ≤ Week 48.
All-Cause Mortality: From Treatment Initiation to Week 104
Death from any cause occurring after randomization and ≤ Week 104.
Full Information
NCT ID
NCT01086540
First Posted
March 11, 2010
Last Updated
January 24, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Autoimmunity Centers of Excellence, Rho Federal Systems Division, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01086540
Brief Title
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
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
June 24, 2011 (Actual)
Primary Completion Date
June 5, 2018 (Actual)
Study Completion Date
December 15, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Autoimmunity Centers of Excellence, Rho Federal Systems Division, Inc.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Systemic Sclerosis-Associated PAH
Keywords
Pulmonary Arterial Hypertension (PAH), Autoimmune Disease, Systemic Scleroderma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
57 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rituximab+PAH SOC
Arm Type
Experimental
Arm Description
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).
Arm Title
Placebo + PAH SOC
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan®
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo for rituximab
Intervention Description
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.
Intervention Type
Diagnostic Test
Intervention Name(s)
CMRI
Other Intervention Name(s)
cardiac MRI, cardiac Magnetic Resonance Imaging
Intervention Description
Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.
Intervention Type
Drug
Intervention Name(s)
prednisone
Other Intervention Name(s)
prednisone tablets, Rayos®
Intervention Description
Prednisone dose of 40 mg (or equivalent) by mouth administered the night before and the morning of each study drug infusion.
Intervention Type
Drug
Intervention Name(s)
methylprednisolone
Other Intervention Name(s)
corticosteroid
Intervention Description
Methylprednisolone (or equivalent corticosteroid) administered intravenously 30 minutes prior to each study drug infusion.
Intervention Type
Drug
Intervention Name(s)
diphenhydramine
Other Intervention Name(s)
Benadryl®
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
acetaminophen
Other Intervention Name(s)
Tylenol®
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change From Baseline in Distance Walked During a Six Minute Walk Test
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24
Secondary Outcome Measure Information:
Title
Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization at Week 24
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24
Title
Change From Baseline in Distance Walked During a Six Minute Walk Test at Week 24 and Week 48
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24 and Week 48
Title
Time to Clinical Worsening
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 48
Title
Time to the Change or Addition of New Pulmonary Arterial Hypertension (PAH) Therapeutic Medications
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 48
Title
Change From Baseline in Quality of Life as Measured by the Short Form Health Survey (SF-36): Mental Component Summary Score
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24 and Week 48
Title
Change From Baseline in Quality of Life as Measured by the Short Form Health Survey (SF-36): Physical Component Summary Score
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 48
Title
Change in Quality of Life as Measured by the Disability Index of the Scleroderma Health Assessment Questionnaire (HAQ-DI)
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24 and Week 48
Title
Number of New Digital Ulcers
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24 and Week 48
Title
Change in Severity of Raynaud's Phenomenon
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24 and Week 48
Title
Change in Carbon Monoxide Diffusing Capacity (DLCO)
Description
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)
Time Frame
Baseline (Pre Treatment Initiation) to Week 24 and Week 48
Title
Oxygen Saturation Levels at Week 24 and Week 48
Description
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.
Time Frame
Week 24 , Week 48
Title
Percent Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 24
Title
Number of Infusion-Related Toxicities
Description
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.
Time Frame
Day 0 (Treatment Randomization) to Week 48
Title
Number of Grade 3 or Higher Adverse Events (AEs) Through Week 48
Description
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.
Time Frame
Baseline (Pre Treatment Initiation) to Week 48
Title
Number of Infection-Related Adverse Events (AEs) Through Week 48
Description
Number of adverse events classified as infections. Reference: National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0.
Time Frame
Day 0 (Treatment Randomization) to Week 48
Title
Treatment-Related Mortality: From Treatment Initiation to Week 48
Description
Death occurring after randomization and ≤ Week 48, and possibly, probably, or definitely resulting from assigned study treatment.
Time Frame
Day 0 (Treatment Randomization) to Week 48
Title
All-Cause Mortality: From Treatment Initiation to Week 48
Description
Death from any cause occurring after randomization and ≤ Week 48.
Time Frame
Day 0 (Treatment Randomization) to Week 48
Title
All-Cause Mortality: From Treatment Initiation to Week 104
Description
Death from any cause occurring after randomization and ≤ Week 104.
Time Frame
Day 0 (Treatment Randomization) to Week 104
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Nicolls, M.D.
Organizational Affiliation
Stanford University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
David B. Badesch, M.D.
Organizational Affiliation
University of Colorado Health Sciences Center (Aurora, CO)
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Thomas A. Medsger, Jr., M.D.
Organizational Affiliation
University of Pittsburgh
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Lorinda Chung, MD
Organizational Affiliation
Stanford University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Robyn Domsic, MD
Organizational Affiliation
University of Pittsburgh: Division of Rheumatology and Clinical Immunology
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Aryeh Fischer, MD
Organizational Affiliation
National Jewish Health: University of Colorado School of Medicine
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Roham Zamanian, MD
Organizational Affiliation
Stanford University
Official's Role
Study Chair
Facility Information:
Facility Name
Stanford Health Care
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
University of Colorado Health Sciences Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Johns Hopkins University, Pulmonary and Critical Care Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Boston University Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
University of Minnesota Health Clinics and Surgery Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
University of North Carolina at Chapel Hill: UNC Hospitals
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15261
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
University of Texas Southwestern Medical Center-William P. Clements University Hospital
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
University of Texas: Memorial Herman Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
33651671
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.
Results Reference
result
PubMed Identifier
33856964
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.
Results Reference
result
PubMed Identifier
34107236
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.
Results Reference
result
PubMed Identifier
34107229
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.
Results Reference
result
PubMed Identifier
28963118
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.
Results Reference
derived
Links:
URL
https://www.niaid.nih.gov
Description
The National Institute of Allergy and Infectious Diseases (NIAID)
URL
https://www.niaid.nih.gov/about/dait
Description
The Division of Allergy, Immunology, and Transplantation (DAIT)
Learn more about this trial
Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
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