Safety and Efficacy Study of Subcutaneous Belimumab and Intravenous Rituximab Co-administration in Subjects With Primary Sjogren's Syndrome

Study Overview
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Brief Summary
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This study is a multi-national, multi-center, double-blind (sponsor open), randomized, placebo-controlled trial in subjects with active primary Sjögren's syndrome designed to understand the safety and tolerability profile of belimumab/ rituximab co-administration and of belimumab monotherapy; and to evaluate whether either co-administration therapy or belimumab monotherapy has a substantive effect on disease activity. This study will consist screening period, double blind treatment period, a general follow-up period and individualized follow-up period. Approximately 70 subjects will be recruited into the study initially. At Day 0, subjects will be randomized 1:2:2:2 to one of the four treatment arms placebo arm, belimumab monotherapy arm, co-administration therapy arm and rituximab monotherapy arm. Once a sufficient number of subjects have completed the Week 24, interim analyses and sample size re-estimation will be conducted. The total number of subjects randomized may increase following sample size re-estimation up to a maximum of 120 recruited into the study. Subjects in all arms will receive investigational product (IP) until Week 52 (completion of the treatment phase). All subjects will enter a 16-week general follow-up period after the Week 52 visit or after discontinuation if a subject discontinues IP and withdraws from the treatment phase visits prior to Week 52. After completing the general follow-up period, subjects with cluster of differentiation (CD)19+ B-cell levels below the lower limit of normal (or less than 90 percent [%] of baseline, if baseline value was below lower limit of normal [LLN]) will enter an individualized safety follow-up phase and return to the clinic for visits every 12 weeks with monthly calls between visits to evaluate subjects for any serious adverse events (SAEs) related to IP or study participation, fatal SAEs, and designated adverse event of special interests (AESIs) (i.e., infections, malignancies, or depression, suicide/self-injury), and to check concomitant medications. The total duration of participation of a subject in this study will be approximately up to a maximum of 2 years (i.e., up to Week 104).

Official Title
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A Randomized, Double Blind (Sponsor Open), Comparative, Multicenter Study to Evaluate the Safety and Efficacy of Subcutaneous Belimumab (GSK1550188) and Intravenous Rituximab Co-administration in Subjects With Primary Sjögren's Syndrome

Conditions
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Sjogren's Syndrome

Intervention / Treatment
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* Drug: Belimumab
* Drug: Rituximab
* Drug: Placebo belimumab
* Drug: Placebo rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >=18 years, at the time of signing the informed consent. Documented Primary Sjögren's Syndrome by American European Consensus Group criteria including: either anti-Sjogren's-syndrome-related antigen A (SS-A) or anti-Sjogren's-syndrome-related antigen B (SS-B) positive. Baseline unstimulated salivary flow >0.0 mL/min or evidence of glandular reserve function (stimulated baseline salivary flow >0.05 mL/min). Symptomatic oral dryness (>=5/10 on subject completed numeric response scale). Systemically active disease, ESSDAI >=5 points. Male and female subjects; females of child bearing potential are eligible if using effective contraception: Female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotropin [hCG] test), not lactating, and at least one of the following conditions applies: Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study; otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to follow one of the options in the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication up to Week 68 after Day 0. Ability to understand and comply with the protocol-required procedures and provision of informed consent. Exclusion Criteria: Diagnosis of secondary Sjögren's syndrome. Active life-threatening or organ-threatening complications of Sjogren's-syndrome (SS) disease at the time of screening based on treating physician evaluation including but not restricted to (1) vasculitis with renal, digestive, cardiac, pulmonary or central nervous system (CNS) involvement characterized as severe, (2) active CNS or peripheral nervous system (PNS) involvement requiring high dose steroids, (3) severe renal involvement defined by objective measures, (4) lymphoma. History of major organ transplant (including hematopoietic stem cell transplant). History of malignancy within past 5 years (with the exception of adequately treated: [1] cervical carcinoma Stage 1B or less, [2] non-invasive basal cell and squamous cell skin carcinoma). History of infection requiring long term systemic therapy including: (1) history of positive human immunodeficiency virus (HIV) serology, (2) positive serology for Hepatitis C virus (HCV), (3) positive serology for Hepatitis B (HB), defined as: HB surface antigen positive (HBsAg+) OR HB core antibody positive (HBcAb+). Previous serious opportunistic or atypical infections or hospitalization for treatment of infection within 364 days of Day 0 or use of parenteral (intravenous [IV] or intramuscular [IM]) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within 364 days of prior to Day 0. Patients in a severely immunocompromised state. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies. History of significant medical illness (or planned surgical procedure) which in the opinion of the investigator would interfere with the study procedures and / or assessments - including but not limited to immunoglobulin G4 (IgG4) disease or prior head or neck irradiation. Severe heart failure (New York Heart Association, Class IV) or other severe, uncontrolled cardiac disease. Tuberculosis (TB), defined as: prior history of TB infection; suspicion of TB infection or current TB infection At risk of suicide, as indicated by a lifetime history of attempted suicide or significant suicidal ideation over the 6 months prior to the screening visit; or, if in the Investigator's judgment, the subject is at risk for a suicide attempt. Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML) - not otherwise explained - or confirmed PML. Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or showing an average corrected QT using Bazett's formula (QTcB) or corrected QT using Fridericia's formula (QTcF) interval >=450 milliseconds (msec) (>=480 msec for subjects with a Bundle Branch Block) over 3 consecutive ECGs. Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Use of systemic immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), mizoribine, calcineurin inhibitors [e.g., tacrolimus, cyclosporine], sirolimus, 6-mercaptopurine, or thalidomide within 60 days prior to Day 0. Have received cyclophosphamide within 180 days prior to Day 0. Have received anti- B lymphocyte stimulator (BLyS), anti-CD 20, anti-CD22 or anti-CD52 or any other B-cell depleting agent within 364 days prior to Day 0. Have received abatacept or any biologic agent within 180 day prior to Day 0 (with exception of denosumab). Have received intravenous immunoglobulin (IVIG) or plasmapheresis within 90 days prior to Day 0. Have received oral steroid >10 milligram (mg) prednisone equivalent/day within 30 days prior to Day 0 or oral steroid >20 mg prednisone equivalent / day for a minimum of two consecutive weeks within 60 days prior to Day 0. Have received parenteral steroid within 60 days prior to Day 0. Have received a live vaccine within 30 days of Day 0. Current participation in any other interventional trial. Planned blood donation during the treatment and follow up periods of the study. Subjects who are unable or unwilling to administer, or to have a caregiver administer subcutaneous injections. Drug or alcohol abuse or dependence. History of hypersensitivity to belimumab and/or rituximab or known to have titers of human anti-mouse antibody or human anti-chimeric antibody or history of hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. Have an IgA deficiency (IgA level <10 milligram per deciliter [mg/dL]). Any of the following screening laboratory values: White blood cells (WBC) <2 x 10^9/L; Neutrophils <1.5 x 10^9/Liter (L); Circulating IgG or IgM levels <lower limit of normal (according to central laboratory range); Aspartate aminotransferase (AST) >2.0 times the upper limit of normal; Alkaline phosphatase (ALP) >1.5 times the upper limit of normal; Bilirubin >1.5 times the upper limit of normal; CD4 count <400 cells per cubic millimetre (cells/mm^3); CD8 count <150 cells/mm^3; CD19+ B-lymphocyte counts <0.1 x 10^9/L.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will receive belimumab placebo weekly subcutaneous injections to Week 52 and rituximab placebo infusions at Weeks 8 and 10. | Drug: Placebo belimumab<br>* The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use.<br>Drug: Placebo rituximab<br>* Placebo rituximab will be provided as solution for infusion. It is a clear, colorless liquid.<br>|
| Experimental: Belimumab monotherapy<br>Subjects will receive 200 mg weekly subcutaneous injections of belimumab to Week 52 and placebo rituximab infusions at Weeks 8 and 10. | Drug: Belimumab<br>* Belimumab will be provided as a 200 mg sterile, liquid product in a prefilled syringe. Each syringe contains 1.0 mL of 200 mg/mL belimumab. Each syringe will be a single use.<br>Drug: Placebo rituximab<br>* Placebo rituximab will be provided as solution for infusion. It is a clear, colorless liquid.<br>|
| Experimental: Belimumab and Rituximab co-administration therapy<br>Subjects will receive belimumab 200 mg SC weekly for 24 weeks followed by weekly placebo belimumab injections to Week 52 with rituximab 1000 mg intravenously at Weeks 8 and 10. | Drug: Belimumab<br>* Belimumab will be provided as a 200 mg sterile, liquid product in a prefilled syringe. Each syringe contains 1.0 mL of 200 mg/mL belimumab. Each syringe will be a single use.<br>Drug: Rituximab<br>* Rituximab will be provided as a 100 mg concentrated solution for infusion. It is a clear, colorless liquid.<br>Drug: Placebo belimumab<br>* The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use.<br>|
| Active Comparator: Rituximab monotherapy<br>Subjects will receive 1000 mg IV rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of placebo belimumab to Week 52. | Drug: Rituximab<br>* Rituximab will be provided as a 100 mg concentrated solution for infusion. It is a clear, colorless liquid.<br>Drug: Placebo belimumab<br>* The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations based on medical or scientific judgment and is associated with liver injury and impaired liver function. Data for number of participants with SAE and non-SAE has been summarized. | Up to Week 68 | 
| Number of Participants With Adverse Event of Special Interests (AESIs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AESIs were Malignant Neoplasms, Post-Administration Systemic Reactions (PASR), All Infections of Special Interest (opportunistic infections, herpes zoster, tuberculosis and sepsis), Depression/suicide/self-injury, Deaths and study specific AESI which includes: severe skin reaction per GlaxoSmithKline (GSK) Adjudication, cardiac disorders, Posterior Reversible Encephalopathy Syndrome (PRES) and Progressive multifocal leukoencephalopathy (PML). Data for number of participants with AESI has been summarized. | Up to Week 68 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | The ESSDAI is a physician assessed disease activity index developed by EULAR consortium consisting of twelve different clinically relevant organ specific domains; cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathy and biological. Each domain has 3 or 4 possible activity levels (i.e., no, low, moderate, high [if available]) using a 4-point scale, ranging from 0 (No activity) to 3 (High activity). Higher score indicates high disease activity. Each domain is assigned a weight between 1 and 6. The Total ESSDAI Scores are obtained by multiplying the level of activity (domain score) by the domain weights, ranges between 0 (no activity) and 123 (highest activity). Higher score indicates more disease activity. Baseline value is the screening visit value (within 35 days prior to Day 0). Change from Baseline was defined as the post-dose visit value minus Baseline value. | Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68 | 
| Stimulated Salivary Flow Rate Over Time | Participants were instructed to chew a piece of paraffin wax for a period of 5 minutes and saliva was collected. The volume of saliva (milliliter) was divided by the duration of the test (minutes) to calculate the stimulated salivary flow rate (milliliter per minute). Baseline value is the screening visit value (within 35 days prior to Day 0). | Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68 | 
| Oral Dryness Numeric Response Scale (NRS) Over Time | Oral dryness was reported by participants on a numeric response scale, ranging from 0 (no dryness) to 10 (maximal dryness), higher score indicates worst imaginable dryness. Baseline value is the screening visit value (within 35 days prior to Day 0). | Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68 | 
| Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24 | Minor salivary gland biopsies were taken for histological analysis to quantify CD20 B Cells. | At Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Subcutaneous, Rituximab, Intravenous, Efficacy, Sjogren's syndrome, Belimumab