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

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT01086540

Purpose

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.

Condition	Intervention	Phase
Systemic Sclerosis-Associated Pulmonary Arterial Hypertension	Biological: Rituximab Other: Placebo	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
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)

Resource links provided by NLM:

Genetics Home Reference related topics: pulmonary arterial hypertension systemic scleroderma

MedlinePlus related topics: Autoimmune Diseases High Blood Pressure Scleroderma

Drug Information available for: Rituximab

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Change in pulmonary vascular resistance measured by right heart catheterization [ Time Frame: 24 weeks after treatment initiation ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Safety and tolerability of rituximab therapy using the NCI-CTCAE [ Time Frame: Longitudinally over 48 weeks after treatment initiation ] [ Designated as safety issue: Yes ]
Assessment of time to clinical worsening [ Time Frame: Censored at 48 weeks after treatment initiation ] [ Designated as safety issue: No ]
DLCO and oxygen saturation at rest on room air [ Time Frame: Longitudinally over 48 weeks after treatment initiation ] [ Designated as safety issue: No ]
Number of new digital ulcers [ Time Frame: Longitudinally over 48 weeks after treatment initiation ] [ Designated as safety issue: No ]
Severity of Raynaud phenomenon [ Time Frame: Longitudinally over 48 weeks after treatment initiation ] [ Designated as safety issue: No ]
Exercise capacity determined by 6 minute walking distance [ Time Frame: Longitudinally over 48 weeks after treatment initiation ] [ Designated as safety issue: No ]
Evaluation of biomarkers as indicators of disease progression [ Time Frame: Baseline and longitudinally over 48 weeks after treatment initiation ] [ Designated as safety issue: No ]
Change in quality of life from baseline [ Time Frame: 24 weeks and 48 weeks after treatment initiation ] [ Designated as safety issue: No ]

Estimated Enrollment:	80
Study Start Date:	August 2010
Estimated Primary Completion Date:	December 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Rituximab	Biological: Rituximab 2 infusions, 1000 mg. each, 14 days apart
Placebo Comparator: Control	Other: Placebo 2 infusions 14 days apart

Detailed Description:

This prospective, double-blind, placebo-controlled, multi-center, randomized trial will evaluate the effect of rituximab on disease progression in subjects with SSc-PAH receiving concurrent stable-dose standard medical therapy with a prostanoid, endothelin receptor antagonist, and/or phosphodiesterase 5 (PDE-5) inhibitor. The study will focus on assessment of clinical response and safety measures longitudinally. In addition, the effects of treatment with rituximab on the underlying immune mechanisms associated with B-cell dysregulation and pathogenic autoantibody response in this disease will be investigated. 1000 mg of rituximab or placebo will be administered as two IV infusions given two weeks apart. Clinical assessments and sample collection will occur at monthly visits through Week 48. If a participant has not recovered B cells by Week 48, B cell studies will be conducted quarterly until reconstitution is documented or for 2 years after initial treatment.

This trial will include a sub-study, entitled "Right Ventricular Response to Rituximab in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension - A Magnetic Resonance Imaging Sub-study" (RESTORE Sub-study). The objective of the RESTORE sub-study is to evaluate the therapeutic effect of rituximab on the right ventricle of patients with SSc-PAH. Changes in right ventricular end diastolic volume index (RVEDVI) and stroke volume (SV) determined by cardiac MRI will be used as surrogates of right ventricle function and prognosis. Enrollment for the RESTORE sub-study will parallel that of main trial. Twenty patients from each treatment arm, distributed among all participating sites, will be recruited for this sub-study. Each patient will be studied at baseline (i.e. prior to initiation of study drug) and after 24 weeks or at time of discontinuation. In addition to the data collection and testing specified in the main trial, participants in RESTORE will undergo comprehensive cardiac MRI evaluation. All main trial study inclusion and exclusion criteria apply, as well as additional exclusion criteria that pertain only to the RESTORE sub-study: 1) known hypersensitivity to Gadolinium; 2) inability to tolerate or cooperate with MRI; 3) morbid obesity; and 4) presence of metallic objects or pacemakers.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Subject has provided written informed consent.
Subject must be between the ages of 18 and 75.
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 ≥ 30 mmHg at entry.
Mean PVR of > 3 Wood units.
Baseline 6MWD of at least 100 meters.
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, and/or PDE-5 inhibitor) for a minimum of 3 months and have been on stable dose medical therapy for at least 4 weeks prior to randomization.

Exclusion Criteria:

Documented PAH for greater than 5 years at the time of randomization defined as:
- Measurement of a mean 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.
Treatment with biologic or chemical immunosuppressive agents within 3 months prior to treatment initiation, except for hydroxychloroquine and penicillamine.
Previous exposure to any lymphocyte 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.
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.
Presence of positive PPD.
Significant renal insufficiency.
Active, untreated SSc renal crisis at the time of enrollment.
Recent administration of a live vaccine.
History of anaphylaxis or 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.
A recent history of alcohol or drug abuse.
Participation in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit.
Inability to perform the 6-minute walk test.
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.
Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a participant in the trial.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01086540

Locations

United States, Alabama
University of Alabama at Birmingham	Recruiting
Birmingham, Alabama, United States, 35294
Contact: Rachel Culbreth 205-934-8767 chfnurse@cardiology.uab.edu
Principal Investigator: Robert C. Bourge, MD
Principal Investigator: Barri Fessler, MD, MSPH
United States, California
Stanford University	Recruiting
Palo Alto, California, United States, 94304
Contact: Val Scott 650-725-8082 valscott@stanford.edu
Principal Investigator: Mark Nicolls, MD
Principal Investigator: Roham Zamanian, MD
Principal Investigator: Lorinda Chung, MD
United States, Colorado
University of Colorado Health Sciences Center	Recruiting
Aurora, Colorado, United States, 80045
Contact: Gentle Arnez 720-848-6536 gentle.arnez@ucdenver.edu
Principal Investigator: David B. Badesch, MD
Principal Investigator: Aryeh Fischer, MD
United States, Maryland
Johns Hopkins University	Recruiting
Baltimore, Maryland, United States, 21205
Contact: Mohamed Gashouta 410-614-1316 mgashou1@jhmi.edu
Contact: Jude Aidam 410-614-1316 jaidam@jhmi.edu
Principal Investigator: Paul Hassoun, MD
Principal Investigator: Laura Hummers, MD
United States, New York
Feinstein Institute for Medical Research - North Shore - Long Island Jewish Health System	Recruiting
Manhasset, New York, United States, 11030
Contact: Andrew Shaw 516-562-2591 anshaw@nshs.edu
Principal Investigator: Meggan Mackay, MD
Principal Investigator: Arunabh Talwar, MD
University of Rochester Medical Center	Recruiting
Rochester, New York, United States, 14642
Contact: Kathleen Wessman 585-486-0147 ext 123 Kathleen_wessman@urmc.rochester.edu
Contact: Debbie Campbell (585) 275-1635 debbie_campbell@urmc.rochester.edu
Principal Investigator: R. James White, MD
Principal Investigator: R. John Looney, MD
United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27710
Contact: Marguerite Thomas 919-668-1770 thoma094@mc.duke.edu
Contact: Abby Poms 919-684-6237 Krich001@mc.duke.edu
Principal Investigator: Terry Fortin, MD
Principal Investigator: William St. Clair, MD
United States, Pennsylvania
Thomas Jefferson University	Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Elizabeth Grace 215-955-5778 elizabeth.grace@jefferson.edu
Principal Investigator: Sandra Weibel, MD
Principal Investigator: Sergio Jimenez, MD
University of Pittsburgh Medical Center	Recruiting
Pittsburgh, Pennsylvania, United States, 15261
Contact: Dana Ivanco 412-648-7040 des2@pitt.edu
Principal Investigator: Thomas A. Medsger, Jr, MD
Principal Investigator: Michael A. Mathier, MD
Allegheny General Hospital	Recruiting
Pittsburgh, Pennsylvania, United States, 15212
Contact: Susan Hebda 412-359-6894 shebda@wpahs.org
Contact: Joan Rossi 412-359-3293 Jrossi1@wpahs.org
Principal Investigator: Srinivas Murali, MD
Principal Investigator: David J. Helfrich, MD
United States, Texas
University of Texas Southwestern	Recruiting
Dallas, Texas, United States, 75390
Contact: Robert Patrizi 214-645-6092 Robert.patrizi@utsouthwestern.edu
Principal Investigator: Fernando Torres, MD
Principal Investigator: Andreas Reimold, MD
United States, Virginia
Virginia Commonwealth University	Recruiting
Richmond, Virginia, United States, 23298
Contact: Chris DeWilde 804-628-5710 dewildect@vcu.edu
Contact: Amy Frayser (804) 828-7966 afrayser@vcu.edu
Principal Investigator: Daniel C. Grinnan, MD
Principal Investigator: Beth Rubinstein, MD
Principal Investigator: Norbert Voelkel, MD

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

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

More Information

No publications provided

Responsible Party:	Associate Director for Clinical Research, DAIT/NIAID/NIH
ClinicalTrials.gov Identifier:	NCT01086540 History of Changes
Other Study ID Numbers:	DAIT ASC01
Study First Received:	March 11, 2010
Last Updated:	December 15, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension
Autoimmune Disease
Systemic Scleroderma
Pulmonary Arterial Hypertension

Additional relevant MeSH terms:

Hypertension, Pulmonary
Hypertension
Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Connective Tissue Diseases

Skin Diseases
Pathologic Processes
Rituximab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents

ClinicalTrials.gov processed this record on February 09, 2012