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

NCT01086540 | Completed Phase 2 Results DMC

• 1 other identifier: DAIT ASC01
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 17

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.

Conditions

Systemic Sclerosis-Associated PAH

Keywords

Pulmonary Arterial Hypertension (PAH); Autoimmune Disease; Systemic Scleroderma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (18)

• Change From Baseline in Pulmonary Vascular Resistance Measured by Right Heart Catheterization at Week 24

  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

  Baseline (Pre Treatment Initiation) to Week 24 and Week 48

• Time to Clinical Worsening

  Baseline (Pre Treatment Initiation) to Week 48

• Time to the Change or Addition of New Pulmonary Arterial Hypertension (PAH) Therapeutic Medications

  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

  Baseline (Pre Treatment Initiation) to Week 24 and Week 48

Study Arms (2)

Rituximab+PAH SOC

EXPERIMENTAL

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; Diagnostic Test: CMRI; Drug: prednisone; Drug: methylprednisolone; Drug: diphenhydramine; Drug: acetaminophen

Placebo + PAH SOC

PLACEBO COMPARATOR

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; Diagnostic Test: CMRI; Drug: prednisone; Drug: methylprednisolone; Drug: diphenhydramine; Drug: acetaminophen

Interventions

Rituximab BIOLOGICAL

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.

Also known as: Rituxan®

Rituximab+PAH SOC

Placebo OTHER

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.

Also known as: Placebo for rituximab

Placebo + PAH SOC

CMRI DIAGNOSTIC_TEST

Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.

Also known as: cardiac MRI, cardiac Magnetic Resonance Imaging

Placebo + PAH SOC; Rituximab+PAH SOC

prednisone DRUG

Prednisone dose of 40 mg (or equivalent) by mouth administered the night before and the morning of each study drug infusion.

Also known as: prednisone tablets, Rayos®

Placebo + PAH SOC; Rituximab+PAH SOC

methylprednisolone DRUG

Methylprednisolone (or equivalent corticosteroid) administered intravenously 30 minutes prior to each study drug infusion.

Also known as: corticosteroid

Placebo + PAH SOC; Rituximab+PAH SOC

diphenhydramine DRUG

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.

Also known as: Benadryl®

Placebo + PAH SOC; Rituximab+PAH SOC

acetaminophen DRUG

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.

Also known as: Tylenol®

Placebo + PAH SOC; Rituximab+PAH SOC

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Autoimmunity Centers of Excellence: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (17)

Stanford Health Care

Stanford, California, 94305, United States

Location

University of Colorado Health Sciences Center

Aurora, Colorado, 80045, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins University, Pulmonary and Critical Care Medicine

Baltimore, Maryland, 21205, United States

Location

Boston University Medical Center

Boston, Massachusetts, 02118, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota Health Clinics and Surgery Center

Minneapolis, Minnesota, 55455, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

University of North Carolina at Chapel Hill: UNC Hospitals

Chapel Hill, North Carolina, 27514, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15261, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Southwestern Medical Center-William P. Clements University Hospital

Dallas, Texas, 75390, United States

Location

University of Texas: Memorial Herman Hospital

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (5)

• 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.

  PMID: 33651671 RESULT

• 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.

  PMID: 33856964 RESULT

• 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.

  PMID: 34107236 RESULT

• 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.

  PMID: 34107229 RESULT

• 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.

  PMID: 28963118 DERIVED

Related Links

• The National Institute of Allergy and Infectious Diseases (NIAID)
• The Division of Allergy, Immunology, and Transplantation (DAIT)

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Autoimmune Diseases; Scleroderma, Systemic

Interventions

Rituximab; Prednisone; Methylprednisolone; Adrenal Cortex Hormones; Diphenhydramine; Acetaminophen

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Immune System Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Prednisolone; Pregnadienetriols; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Ethylamines; Amines; Organic Chemicals; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Acetanilides; Anilides; Amides; Aniline Compounds

Limitations and Caveats

Study was powered at 50% (60 participants, 30 per arm) to detect a treatment group difference of 33 meters in the six minute walk test. Enrollment ended early with 57 participants randomized instead of the planned 60.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Mark Nicolls, M.D.

  Stanford University

  STUDY CHAIR

• David B. Badesch, M.D.

  University of Colorado Health Sciences Center (Aurora, CO)

  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: Division of Rheumatology and Clinical Immunology

  STUDY CHAIR

• Aryeh Fischer, MD

  National Jewish Health: University of Colorado School of Medicine

  STUDY CHAIR

• Roham Zamanian, MD

  Stanford University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 11, 2010
• First Posted: March 15, 2010
• Study Start: June 24, 2011
• Primary Completion: June 5, 2018
• Study Completion: December 15, 2019
• Last Updated: February 21, 2023
• Results First Posted: August 21, 2020

Record last verified: 2023-01

Locations

US (17)