Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome (BELISS)

A Phase 2, Proof of Concept, 52-Week Open Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS (BAFF) Antibody, in Subjects With Primary Sjögren's Syndrome

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by an increase in BAFF (BLyS) levels and a resulting B cell hyperactivity. B cells are involved in the pathogenesis of SS in both systemic and glandular features, and B cell downregulation may lead to a decrease of disease activity. Moreover, pathogenesis of SS is closed to that of Systemic lupus erythematosus, where Belimumab has been proven to be effective.

Study Overview

• Status: Completed
• Conditions: Sjögren's Syndrome
• Intervention / Treatment: Drug: Belimumab

Detailed Description

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by an increase in BAFF (BLyS) levels and a resulting B cell hyperactivity. B cells are involved in the pathogenesis of SS in both systemic and glandular features, and B cell downregulation may lead to a decrease of disease activity. Moreover, pathogenesis of SS is closed to that of Systemic lupus erythematosus, where Belimumab has been proven to be effective.

This phase II open-label study has 2 mains objectives:

• To evaluate the proof of concept of efficacy of belimumab in subjects with SS
• To evaluate the safety and tolerability of belimumab in subjects with SS Belimumab will be administered (10mg/kg on D0 D14 D28 and every 28 days for 24 weeks, with extension to 48 weeks if responders) to all patients

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Le Kremlin Bicêtre, France, 94275
    • Assistance Publique - Hôpitaux de Paris : BICETRE Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have a diagnosis of primary SS according to the updated American European Consensus Group Criteria. In addition, patients must be always positive for anti-SSA or anti-SSB antibodies
• Have the presence, at screening, of Systemic involvement (polysynovitis, skin, renal, lung, CNS involvement, peripheral neuropathy, vasculitis, autoimmune cytopenia, defined in Annex 1) or persistent (up to 2 months) parotid, submandibular or lachrymal gland swelling of more than 2 cm OR

Objective sicca (positive oral and/or ocular tests reported in the American European Consensus Group Criteria) with at least one among the following biological features of serum B lymphocyte activation :

increased IgG levels increased free light chain levels of immunoglobulins (according to central laboratory ranges) increased serum beta2-microglobulin levels decreased C4 levels (C4 levels inferior to central laboratory ranges) monoclonal gammapathy cryoglobulinemia OR

• SS of more recent onset, i.e., less than 5 years of duration of symptoms, associated with:

  • oral or ocular dryness
  • fatigue
  • musculoskeletal pain (i.e, 3 criteria for response as reported at page (ix-x), characterized by VAS score more than 50/100 in all the 3 fields.

Exclusion Criteria:

1. Any BLyS-targeted (BLyS-receptor fusion protein [BR3], TACI Fc, or belimumab) at any time.

2. Any of the following within 364 days of Day 0:

   • B-cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab]
   • A biologic investigational agent other than B cell targeted therapy (eg, abetimus sodium, anti CD40L antibody [BG9588/ IDEC 131]).

4- Intravenous or oral cyclophosphamide within 180 days of Day 0.

5- Any of the following within 90 days of Day 0:

• Anti-TNF therapy
• Interleukin-1 receptor antagonist
• Abatacept
• Interleukin-6 receptor antagonist
• Intravenous immunoglobulin
• Prednisone > 100 mg/day

• Plasmapheresis.

  9- Very severe SS disease.

  10- Major organ or hematopoietic stem cell/marrow transplant.

  11- Unstable or uncontrolled acute or chronic diseases not due to SS

  13- History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.

  14- Required management of acute or chronic infections, as follows:

• Currently on any suppressive therapy for a chronic infection
• Hospitalization for treatment of infection within 60 days of Day 0.

• Use of parenteral (IV or IM) antibiotics

  16- Historically or at screening positive test for HIV antibody, hepatitis C virus antibodies, or, hepatitis B surface antigen (HbsAg) (with or without positive serum HBV DNA), or antiHBcAg positivity (without anti-HbsAg positivity).

  17- Grade 3 or greater laboratory abnormality based on the protocol toxicity scale except for the following that are allowed:

• Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.
• Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to creatinine ratio allowed). (mentioned earlier in Exclusion #8)
• Stable Grade 3 neutropenia or stable Grade 3 white blood cell count.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: Belilumab	Drug: Belimumab; Belimumab will be administered at 10 mg/kg at Days 0, 14, 28 and then every 28 days until week 24 for all patients and week 48 for those considered responders at week 28.; Other Names: Benlysta; HGS1006, LymphoStat-B™,; Human Monoclonal Anti-BLyS (BAFF) Antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
response rate	A response is defined as the fulfilment of any 2 of the 5 following response criteria(values are compared to that of baseline [Day0]): ≥ 30% reduction of the patient's dryness VAS; ≥ 30% reduction of the patient's fatigue VAS; ≥ 30% reduction of the patient's musculoskeletal pain VAS; ≥ 30% reduction of the physician's systemic activity VAS; ≥ 25% reduction of serum levels of any of the following B cell activation biomarkers (free light chains of immunoglobulin, beta2-microglobulin, monoclonal component, cryoglobulinemia, IgG) or ≥ 25% C4 increase	week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety and tolerability of belimumab	Evaluate the safety and tolerability of belimumab in subjects with SS	52 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Human Genome Sciences Inc.
• Investigators: Principal Investigator: Xavier Mariette, PhD, Rheumatology Department of BICETRE Hospital

Publications and helpful links

General Publications

• Bowman SJ, Fisher BA. Stratifying primary Sjogren's syndrome: killers in the balance? Arthritis Res Ther. 2015 Dec 7;17:351. doi: 10.1186/s13075-015-0878-9.
• Seror R, Nocturne G, Lazure T, Hendel-Chavez H, Desmoulins F, Belkhir R, Ravaud P, Benbijja M, Poirier-Colame V, Taoufik Y, Mariette X. Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjogren's syndrome: results of the BELISS study. Arthritis Res Ther. 2015 Sep 4;17(1):241. doi: 10.1186/s13075-015-0750-y.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: July 9, 2010
• First Submitted That Met QC Criteria: July 9, 2010
• First Posted (Estimate): July 12, 2010

Study Record Updates

• Last Update Posted (Estimate): July 3, 2012
• Last Update Submitted That Met QC Criteria: July 1, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Sjögren's syndrome; Belimumab; Sjögren disease
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Eye Diseases; Disease; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Stomatognathic Diseases; Mouth Diseases; Lacrimal Apparatus Diseases; Arthritis, Rheumatoid; Xerostomia; Salivary Gland Diseases; Dry Eye Syndromes; Syndrome; Sjogren's Syndrome; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Belimumab
• Other Study ID Numbers: P090208