A Randomized, Double-Blind, Placebo-Controlled Study of Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis

Institutional Review Board, Hospital for Special Surgery

The safety of our participants is our top priority. The trial/study is approved and periodically reviewed by the Institutional Review Board (IRB), which includes doctors, administrators, ethicists, and members of the general public. The safety of clinical trials is reviewed by the U.S. Food and Drug Administration.

Before enrolling in a clinical trial or research study, the investigator will explain the purpose of the trial/study, its expected benefits, any possible risks or side effects, and what your role will be. If you want to join the trial/study, you must sign informed consent documents. You can leave a trial/study at any time without penalty.

For further information, see Understanding Clinical Trials/Research Studies.

Principal Investigator

Robert F. Spiera, MD

Co-Investigators

Lindsay S. Lally, MD 
Jessica K Gordon, MD 
Kimberly Showalter Lakin, MD, MS
David R. Fernandez, MD, PhD
Liza Morales
Mia Diaz
Ryan Heise

Summary

The main purpose of this randomized controlled clinical trial is to learn about the safety of the experimental treatment of SSc with the combination of rituximab, belimumab and background MMF. This study may or may not be able to show whether this is an effective treatment for SSc. Patient's overall participation will be over a period of 16 months.

We expect to enroll 30 patients for this study. Enrollment periods will be 2 years.

There will be a 3-month follow up visit. This visit is built into the study and will consist of the following. 

• Review of medical history, including a detailed medication review 
• Physical exam with height, weight and vital signs
• Modified Rodnan Skin Score, tender joint count
• Collection of patient questionnaires (SF-36, SHAQ-DI, PROMIS-29, SSPRO, CSSRS, UCLA SCTC GIT 2.0)
• Patient & Physician Global Assessments
• Laboratory tests including CBC, CMP, LFT, Serum IgG and urine pregnancy test in WOCBP

Inclusion/Exclusion Criteria

Inclusion Criteria

1. Age greater than or equal to eighteen years and less than or equal to 80.
2. Classification of systemic sclerosis (SSc), as defined using the 2013 American College of Rheumatology/European Union League Against Rheumatism classification of SSc.
3. Diagnosis of dcSSc, as defined by LeRoy and Medsger.
4. Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud’s symptom.
5. A modified Rodnan Skin Score (mRSS) of  ≥ 14

Exclusion Criteria

1. Inability to render informed consent in accordance with institutional guidelines.
2. Disease duration of greater than 3 years.
3. Patients with mixed connective tissue disease or “overlap” unless the dominant features of the illness are diffuse systemic sclerosis.
4. Limited scleroderma.
5. Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin.
6. The use of other anti-fibrotic agents including colchicine, D-penicillamine, or tyrosine kinase inhibitors (nilotinib, imatinib, dasatinib) in the month prior to enrollment.
7. Use in the prior month of corticosteroids at doses exceeding the equivalent of prednisone 10 mg daily.  Use of corticosteroid at < 10 mg of prednisone can continue during the course of the study.
8. Concurrent serious medical condition which in the opinion of the investigator makes the patient inappropriate for this study such as uncontrollable CHF, arrhythmia, severe pulmonary or systemic hypertension, severe GI involvement, hepatic impairment, serum creatinine of greater than 2.0, active infection, severe diabetes, unstable atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular disease.
9. A positive pregnancy test at entry into this study.  Men and women with reproductive potential will be required to use effective means of contraception through the course of the study, such as (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) double-barrier methods (such as a condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository)(3) an intrauterine device (IUD) or intrauterine system (IUS) (4) estrogenic vaginal ring (5) percutaneous contraceptive patches, or (6) implants of levonorgestrel or etonogestrel. Approved hormonal contraceptives (such as birth control pills, patches, implants or injections) may interact with and reduce the effectiveness of MMF so women receiving MMF who are using oral contraceptives for birth control should employ an additional method (e.g. barrier method). Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use.
10. Women not willing to use effective birth control for the duration of the study
11. Breastfeeding. 
12. Participation in another clinical research study involving the evaluation of another investigational drug within ninety days of entry into this study.
13. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted or requiring supplemental oxygen and forced vital capacity (FVC) of less than 45% of predicted.
14. Grade 3 hypogammaglobulinemia
15. Have a significant IgG deficiency (IgG level < 400 mg/dL)
16. Have an IgA deficiency (IgA level < 10 mg/dL)
17. Have a historically positive HIV test or test positive at screening for HIV
18. Neutrophils <1.5X10E9/L
19. Hepatitis status:
    • Serologic evidence of current or past Hepatitis B (HB) infection based on the results of testing for HBsAg and HBcAb as follows:
      • Patients positive for HBsAg or HBcAb are excluded
    • Positive test for Hepatitis C antibody
20. Known active bacterial, viral, fungal, mycobacterial, or other infection or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening
21. Infection history:
    • Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria)
    • Hospitalization for treatment of infection within 60 days of Day 0.
    • Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of Day 0
22. Suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes zoster and atypical mycobacteria)
23. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
24. Prior use of Belimumab, Rituximab, or other B-Cell depleting therapies ever
25. The use of other biologics including TNF inhibitors, abatacept, or tocilizumab within the washout period mandated in the table below for each particular drug:

Drug	Washout Period
Tocilizumab	1 month for patients on 2mg/kg or 4 mg/kg. 2 months for patients on 8mg/kg.
Cyclophosphamide (oral or IV)	3 months
Abatacept	2.5 months
TNF Inhibitors	Etanercept – 1 mo Infliximab – 2 mo Adalimumab – 2.5 mo
Any biologic investigational agent (e.g., abetimus sodium, anti CD40L antibody, BG9588/ IDEC 131)	365 days prior to belimumab
Any non-biologic investigational agent	30 days prior to belimumab

 

26. Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator’s judgment, pose a significant suicide risk.
27. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0.
28. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
29. Live vaccines within 30 days prior to baseline
30. Have a history of malignant neoplasm within the last 5 years with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years
31. Have a history of a primary immunodeficiency
32. Have any other clinically significant abnormal laboratory value in the opinion of the investigator
33. Have any intercurrent significant medical or psychiatric illness that the investigator considers would make the candidate unsuitable for the study

Contact Information

Liza Morales, Clinical Research Coordinator
Moralesl@hss.edu
212-774-2048