Safety and Efficacy Study of Subcutaneous Belimumab and Intravenous Rituximab Co-administration in Subjects With Primary Sjogren's Syndrome
Condition: Sjogren's Syndrome
MeSH terms: Sjogren's Syndrome; Syndrome
Intervention: Belimumab; Rituximab; Placebo belimumab; Placebo rituximab
Intervention description: 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.; Rituximab will be provided as a 100 mg concentrated solution for infusion. It is a clear, colorless liquid.; The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use.; Placebo rituximab will be provided as solution for infusion. It is a clear, colorless liquid.
Intervention MeSH terms: Rituximab; Belimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 86.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Subcutaneous; Rituximab; Intravenous; Safety; Efficacy; Sjogren's syndrome; Belimumab

Summary:

      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).
    

Eligibility criteria:

        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:

               1. 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.

               2. 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.