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Trial record 1 of 1 for:    nct 01086540
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Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

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ClinicalTrials.gov Identifier: NCT01086540
Recruitment Status : Completed
First Posted : March 15, 2010
Last Update Posted : January 29, 2020
Sponsor:
Collaborator:
Autoimmunity Centers of Excellence
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE March 11, 2010
First Posted Date  ICMJE March 15, 2010
Last Update Posted Date January 29, 2020
Actual Study Start Date  ICMJE June 24, 2011
Actual Primary Completion Date June 5, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2019)
Change from Baseline in Six Minute Walk Distance (6MWD) at Week 24 [ Time Frame: Baseline, Week 24 ]
The 6MWD is a 6 minute walk test. This test, a measure of exercise capacity, assesses the distance that a subject can walk in a period of 6 minutes.
Original Primary Outcome Measures  ICMJE
 (submitted: March 11, 2010)
Change in pulmonary vascular resistance measured by right heart catheterization [ Time Frame: 24 weeks after treatment initiation ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2019)
  • Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 24 [ Time Frame: Baseline, Week 24 ]
    Change in PVR measured by right heart catheterization.
  • Change from Baseline in 6-minute walk distance (6MWD) Through Week 48 [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    The 6MWD is a 6 minute walk test. This test, a measure of exercise capacity, assesses the distance that a subject can walk in a period of 6 minutes.
  • Time to Clinical Worsening [ Time Frame: Baseline through Week 48 ]
    Any outcome measure that indicates the participant is clinically worse, defined as first occurrence of:
    • 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 6MWD by > 20% and a decrease in functional class.
  • Percent of Participants Who Either Changed or Added Pulmonary Arterial Hypertension (PAH) Therapeutic Agents [ Time Frame: Week 24, Week 48 ]
    Percent of participants who changed or added PAH therapeutic agents at Weeks 24 and Week 48 status post treatment initiation.
  • Change from Baseline in Participant Quality of Life Using the SF-36 [ Time Frame: Baseline, Week 24, Week 48 ]
    The SF-36 is a quality of life assessment that that will be performed at Baseline, Week 24 and Week 48. Eight scale scores are derived from responses to the 36 items of the SF-36 questionnaire which are combined to produce the Physical Component Score and the Mental Component Score. The Physical Component Score is based on the Physical Functioning Scale (10 items), the Role-Physical Scale (4 items), the Bodily Pain Scale (2 items), and the General Health Scale (5 items). The Mental Component Score is based upon the Vitality Scale (4 items), the Social Functioning Scale (2 items), the Role-Emotional Scale (3 items) and the Mental Health Scale (5 items). Each component score is transformed into a 0-100 scale, with higher numbers indicating greater quality of life.
  • Change from Baseline in Participant Quality of Life Using the Scleroderma Health Assessment Questionnaire-Disability Index [ Time Frame: Baseline, Week 24, Week 48 ]
    This is a patient self-administered health assessment questionnaire. The SHAQ-DI assesses five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant's disease. These items were developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant's daily activities. Each VAS item is rated separately (0−100 millimeters [mm]), with higher scores indicating more severe disease. The five items are: 1) intestinal disease, 2) breathing problem, 3) Raynaud syndrome, 4) finger ulcers, and 5) overall disease. The measure produces a discrete value that can change through time and in response to medication.
  • Change in Number of New Digital Ulcers (DUs) Up to Week 48 [ Time Frame: Baseline,Week 24, Week 48 ]
    Number of new digital ulcers assessed longitudinally, from Baseline to Week 24 and Week 48.
  • Change in Severity of Raynaud Phenomenon Using the Self-Administered Health Assessment Questionnaire (SHAQ) [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    Severity of Raynaud phenomenon, as measured by the Visual Analog Scale (VAS) scale of the SHAQ.
  • Change From Baseline in Diffusion in Liters of Carbon Monoxide (DLCO) [ Time Frame: Baseline,Week 24, Week 48 ]
    Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function.
  • Percentage Change From Baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: Baseline, Week 24 ]
    Pulmonary vascular resistance (PVR) is the general pressure which the right ventricle must counteract to pump blood through the lungs. PVR is measured by right heart catheterization performed at Baseline and Week 24. Percentage change in PVR from Baseline at Week 24 is calculated as [(Baseline-Week 24)/Baseline]. Standard deviation is reported as a percentage.
  • Change From Baseline in Oxygen Saturation [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    Oxygen saturation at rest with room air, as a measure of lung function.
  • Number of Participants With Regimen-Related Toxicities [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    Regimen-related toxicities are defined as Grade 3 or higher adverse events reported by site physicians as possibly, probably, or definitely related to study therapy. The study will grade the severity of adverse events experienced by study participants according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version (CTCAE) 4.0.
  • Number of NCI-CTCAE Grade 3 to 5 Adverse Events [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    The study will grade the severity of adverse events experienced by study participants according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version (CTCAE) 4.0.
  • Number of Infection Related Events [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    Infectious complications include any events that code to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class of "Infections and infestations" or events that a site has classified as an infectious event. These can include bacteremia, septicemia, fungemia, fever associated with infection, infectious pneumonia, idiopathic pneumonia syndrome, clinical infection (i.e. infection diagnosed with clinical features without identification of an organism) and other local/organ site-specific infections.
  • Treatment-Related Mortality [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    Death, occurring at any time between randomization and Week 48 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.
  • Mean Count of CD19 Positive B Cells [ Time Frame: Baseline, Week 2, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    Assessment of the number of peripheral blood CD19+ B cells by flow cytometry.
  • Evaluation of Biomarkers as Indicators of Change in Disease Status [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    To assess pre-specified laboratory assessment for change over time with treatment (i.e., CD19 assessments, autoantibodies, immunoglobulins, cytokines).
  • Change from Baseline in Right Ventricular End Diastolic Volume Index (RVEDVI) at Week 24 [ Time Frame: Baseline, Week 24 ]
    A measure of right ventricle (RV) function, RVEDVI is a measure of the volume of blood in the right ventricle at the end of diastole, normalized over body surface area, measured using Cardiac Magnetic Resonance imaging (CMRI). RVEDVI is calculated as the right ventricular end diastolic volume (RDEDV) divided by the body surface area (BSA). This outcome will include the ≤20 participants per arm (i.e., 20 in the rituximab intervention arm and 20 in the placebo intervention) who undergo cardiac Magnetic Resonance Imaging (CMRI) evaluations at Baseline and Week 24.
  • Change From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24 [ Time Frame: Baseline, Week 24 ]
    A measure of right ventricle (RV) function. This outcome will include the ≤20 participants per arm (i.e., 20 in the rituximab intervention arm and 20 in the placebo intervention) who undergo cardiac Magnetic Resonance Imaging (CMRI) evaluations at Baseline and Week 24.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2010)
  • Safety and tolerability of rituximab therapy using the NCI-CTCAE [ Time Frame: Longitudinally over 48 weeks after treatment initiation ]
  • Assessment of time to clinical worsening [ Time Frame: Censored at 48 weeks after treatment initiation ]
  • DLCO and oxygen saturation at rest on room air [ Time Frame: Longitudinally over 48 weeks after treatment initiation ]
  • Number of new digital ulcers [ Time Frame: Longitudinally over 48 weeks after treatment initiation ]
  • Severity of Raynaud phenomenon [ Time Frame: Longitudinally over 48 weeks after treatment initiation ]
  • Exercise capacity determined by 6 minute walking distance [ Time Frame: Longitudinally over 48 weeks after treatment initiation ]
  • Evaluation of biomarkers as indicators of disease progression [ Time Frame: Baseline and longitudinally over 48 weeks after treatment initiation ]
  • Change in quality of life from baseline [ Time Frame: 24 weeks and 48 weeks after treatment initiation ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
Official Title  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Systemic Sclerosis-Associated PAH
Intervention  ICMJE
  • Biological: Rituximab

    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.

    Other Name: Rituxan®
  • Other: Placebo

    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.

    Other Name: Placebo for rituximab
  • Diagnostic Test: CMRI
    Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.
    Other Names:
    • cardiac MRI
    • cardiac Magnetic Resonance Imaging
  • Drug: prednisone
    Prednisone dose of 40 mg (or equivalent) by mouth administered the night before and the morning of each study drug infusion.
    Other Names:
    • prednisone tablets
    • Rayos®
  • Drug: methylprednisolone
    Methylprednisolone (or equivalent corticosteroid) administered intravenously 30 minutes prior to each study drug infusion.
    Other Name: corticosteroid
  • Drug: diphenhydramine

    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.

    Other Name: Benadryl®
  • Drug: acetaminophen

    Acetaminophen 650 mg (or equivalent) administered by mouth approximately thirty to sixty minutes prior to each study drug infusion.

    Dose may be repeated every four hours, as needed.

    Other Name: Tylenol®
Study Arms  ICMJE
  • Experimental: Rituximab+PAH SOC

    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).

    Interventions:
    • Biological: Rituximab
    • Diagnostic Test: CMRI
    • Drug: prednisone
    • Drug: methylprednisolone
    • Drug: diphenhydramine
    • Drug: acetaminophen
  • Placebo Comparator: Placebo + 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).

    Interventions:
    • Other: Placebo
    • Diagnostic Test: CMRI
    • Drug: prednisone
    • Drug: methylprednisolone
    • Drug: diphenhydramine
    • Drug: acetaminophen
Publications * 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). pii: eaan8289. doi: 10.1126/sciimmunol.aan8289.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 6, 2019)
58
Original Estimated Enrollment  ICMJE
 (submitted: March 11, 2010)
80
Actual Study Completion Date  ICMJE December 15, 2019
Actual Primary Completion Date June 5, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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/mm3; Platelet count < 100,000/mm3; 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01086540
Other Study ID Numbers  ICMJE DAIT ASC01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Autoimmunity Centers of Excellence
Investigators  ICMJE
Study Chair: Mark Nicolls, M.D. Stanford University Medical Service/VA Palo Alto Health Care System
Study Chair: David B. Badesch, M.D. University of Colorado, Denver
Study Chair: Thomas A. Medsger, Jr., M.D. University of Pittsburgh
Study Chair: Lorinda Chung, MD Stanford University
Study Chair: Robyn Domsic, MD University of Pittsburgh
Study Chair: Aryeh Fischer, MD National Jewish Health/University of Colorado School of Medicine
Study Chair: Roham Zamanian, MD Stanford University
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP