Sjogren's Syndrome
Conditions
Keywords
Subcutaneous, Rituximab, Intravenous, Safety, Efficacy, Sjogren's syndrome, Belimumab
Brief 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).
Interventions
DRUGPlacebo belimumab
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.
DRUGBelimumab
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.
DRUGRituximab
Rituximab will be provided as a 100 mg concentrated solution for infusion. It is a clear, colorless liquid.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Up to Week 68 | 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. |
| Number of Participants With Adverse Event of Special Interests (AESIs) | Up to Week 68 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68 | 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. |
| Stimulated Salivary Flow Rate Over Time | Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68 | 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). |
| Oral Dryness Numeric Response Scale (NRS) Over Time | Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68 | 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). |
| Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24 | At Week 24 | Minor salivary gland biopsies were taken for histological analysis to quantify CD20 B Cells. |
Countries
Argentina, Canada, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
This study was conducted in 10 countries across 31 centers. Participants were randomized to receive one of the four treatments; Placebo, Belimumab + Rituximab Co-administration therapy, Belimumab Monotherapy or Rituximab Monotherapy.
Pre-assignment details
A total of 162 participants were screened of which 76 were screen failures. A total of 86 participants were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received belimumab matching placebo weekly subcutaneous injections up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment General Follow-Up (GFU) period. | 13 |
| Belimumab + Rituximab Co-administration Therapy Participants received belimumab 200 milligrams (mg) weekly subcutaneous injections for 24 weeks followed by belimumab matching placebo injections weekly up to Week 52; along with rituximab 1000 mg intravenous infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period. | 24 |
| Belimumab Monotherapy Participants received 200 mg weekly subcutaneous injections of belimumab up to Week 52 and rituximab matching placebo infusions at Weeks 8 and 10 in the treatment period. Participants then entered in a 16-week no-treatment GFU period. | 24 |
| Rituximab Monotherapy Participants received 1000 mg intravenous rituximab infusions at Weeks 8 and 10 and weekly subcutaneous injections of belimumab matching placebo up to Week 52 in the treatment period. Participants then entered in a 16-week no-treatment GFU period. | 25 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| General Follow-up (GFU) (Up to Week 68) | Lost to Follow-up | 1 | 0 | 0 | 1 |
| Treatment Period (Up to Week 52) | Adverse Event | 1 | 5 | 2 | 2 |
| Treatment Period (Up to Week 52) | Lack of Efficacy | 1 | 1 | 0 | 0 |
| Treatment Period (Up to Week 52) | Physician Decision | 1 | 0 | 0 | 1 |
| Treatment Period (Up to Week 52) | Reached stopping criteria | 0 | 0 | 1 | 0 |
| Treatment Period (Up to Week 52) | Withdrawal by Subject | 1 | 1 | 2 | 5 |
Baseline characteristics
| Characteristic | Placebo | Total | Rituximab Monotherapy | Belimumab Monotherapy | Belimumab + Rituximab Co-administration Therapy |
|---|---|---|---|---|---|
| Age, Continuous | 52.7 Years STANDARD_DEVIATION 12.67 | 51.1 Years STANDARD_DEVIATION 13.06 | 55.2 Years STANDARD_DEVIATION 15.07 | 52.0 Years STANDARD_DEVIATION 11.49 | 45.1 Years STANDARD_DEVIATION 10.93 |
| Race/Ethnicity, Customized African American/African Heritage | 1 Participants | 6 Participants | 1 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized African American/African Heritage and Asian Heritage | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 0 Participants | 5 Participants | 0 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage | 12 Participants | 69 Participants | 21 Participants | 18 Participants | 18 Participants |
| Sex: Female, Male Female | 13 Participants | 80 Participants | 23 Participants | 22 Participants | 22 Participants |
| Sex: Female, Male Male | 0 Participants | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 1 / 24 | 0 / 24 | 0 / 25 |
| other Total, other adverse events | 12 / 13 | 24 / 24 | 23 / 24 | 17 / 25 |
| serious Total, serious adverse events | 0 / 13 | 3 / 24 | 2 / 24 | 4 / 25 |
Outcome results
Primary
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.
Time frame: Up to Week 68
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | Cardiac Disorders | 0 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | Severe Skin Reactions | 0 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | PML | 0 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | Depression/Suicide/Self-injury | 0 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | All Infections of Special Interest | 2 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | PASR | 4 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | PRES | 0 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | Deaths | 0 Participants |
| Placebo | Number of Participants With Adverse Event of Special Interests (AESIs) | Malignant Neoplasms | 0 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Deaths | 1 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Cardiac Disorders | 1 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Severe Skin Reactions | 0 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PASR | 2 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Malignant Neoplasms | 0 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | All Infections of Special Interest | 1 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PML | 0 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PRES | 0 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Depression/Suicide/Self-injury | 3 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Deaths | 0 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Malignant Neoplasms | 0 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PASR | 3 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | All Infections of Special Interest | 3 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Depression/Suicide/Self-injury | 5 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Severe Skin Reactions | 0 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Cardiac Disorders | 0 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PRES | 0 Participants |
| Belimumab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PML | 0 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Cardiac Disorders | 1 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Depression/Suicide/Self-injury | 1 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | All Infections of Special Interest | 2 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PML | 0 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PRES | 0 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | PASR | 5 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Severe Skin Reactions | 0 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Deaths | 0 Participants |
| Rituximab Monotherapy | Number of Participants With Adverse Event of Special Interests (AESIs) | Malignant Neoplasms | 1 Participants |
Primary
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.
Time frame: Up to Week 68
Population: Safety Population comprised of all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any SAE | 0 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any non-SAE | 12 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any non-SAE | 24 Participants |
| Belimumab + Rituximab Co-administration Therapy | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any SAE | 3 Participants |
| Belimumab Monotherapy | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any SAE | 2 Participants |
| Belimumab Monotherapy | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any non-SAE | 23 Participants |
| Rituximab Monotherapy | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any SAE | 4 Participants |
| Rituximab Monotherapy | Number of Participants With Serious Adverse Events (SAE) and Non-serious AEs (Non-SAE) | Any non-SAE | 17 Participants |
Secondary
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.
Time frame: At Week 24
Population: Completer Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24 | 380.21719 Cells per millimeter square | Standard Deviation 569.908102 |
| Belimumab + Rituximab Co-administration Therapy | Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24 | 8.65550 Cells per millimeter square | Standard Deviation 20.199794 |
| Belimumab Monotherapy | Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24 | 396.86058 Cells per millimeter square | Standard Deviation 781.245844 |
| Rituximab Monotherapy | Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24 | 650.76069 Cells per millimeter square | Standard Deviation 1311.360352 |
Secondary
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.
Time frame: Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68
Population: Completer Population comprised of participants who completed the 52 Week treatment visits and general follow up phase of the study including the visit at Week 68. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 52;n=8, 17, 19 ,16 | -2.87 Scores on a scale | Standard Error 1.294 |
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 24; n=8, 17, 19 ,16 | -2.87 Scores on a scale | Standard Error 1.324 |
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 68;n=8, 17, 19 ,16 | -1.75 Scores on a scale | Standard Error 1.4 |
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 36; n=8, 17, 19 ,16 | -3.12 Scores on a scale | Standard Error 1.52 |
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 12; n=8, 17, 19 ,15 | -2.00 Scores on a scale | Standard Error 1.449 |
| Belimumab + Rituximab Co-administration Therapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 36; n=8, 17, 19 ,16 | -4.09 Scores on a scale | Standard Error 1.045 |
| Belimumab + Rituximab Co-administration Therapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 52;n=8, 17, 19 ,16 | -5.67 Scores on a scale | Standard Error 0.89 |
| Belimumab + Rituximab Co-administration Therapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 68;n=8, 17, 19 ,16 | -5.73 Scores on a scale | Standard Error 0.962 |
| Belimumab + Rituximab Co-administration Therapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 24; n=8, 17, 19 ,16 | -5.32 Scores on a scale | Standard Error 0.911 |
| Belimumab + Rituximab Co-administration Therapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 12; n=8, 17, 19 ,15 | -4.85 Scores on a scale | Standard Error 0.996 |
| Belimumab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 36; n=8, 17, 19 ,16 | -4.23 Scores on a scale | Standard Error 0.995 |
| Belimumab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 12; n=8, 17, 19 ,15 | -3.87 Scores on a scale | Standard Error 0.949 |
| Belimumab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 24; n=8, 17, 19 ,16 | -3.87 Scores on a scale | Standard Error 0.869 |
| Belimumab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 52;n=8, 17, 19 ,16 | -4.76 Scores on a scale | Standard Error 0.85 |
| Belimumab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 68;n=8, 17, 19 ,16 | -3.87 Scores on a scale | Standard Error 0.918 |
| Rituximab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 52;n=8, 17, 19 ,16 | -4.32 Scores on a scale | Standard Error 0.919 |
| Rituximab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 24; n=8, 17, 19 ,16 | -5.25 Scores on a scale | Standard Error 0.94 |
| Rituximab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 12; n=8, 17, 19 ,15 | -4.22 Scores on a scale | Standard Error 1.048 |
| Rituximab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 36; n=8, 17, 19 ,16 | -4.94 Scores on a scale | Standard Error 1.079 |
| Rituximab Monotherapy | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Scores Over Time | Week 68;n=8, 17, 19 ,16 | -4.38 Scores on a scale | Standard Error 0.994 |
95% CI: [-7.39, -0.58]
95% CI: [-4.54, 0.81]
95% CI: [-4.12, 1.41]
95% CI: [-5.47, 1.23]
95% CI: [-6.38, 0.67]
95% CI: [-3.75, 1.78]
95% CI: [-3.52, 2.26]
95% CI: [-5.34, 1.6]
95% CI: [-2.5, 3.2]
95% CI: [-5.67, 0.77]
95% CI: [-3.99, 1.08]
95% CI: [-2.68, 2.55]
95% CI: [-4.17, 2.18]
95% CI: [-1.2, 3.97]
95% CI: [-4.66, 2.73]
95% CI: [-2.76, 3.05]
95% CI: [-2.15, 3.86]
95% CI: [-4.76, 2.53]
95% CI: [-2.25, 3.66]
95% CI: [-5.95, 0.34]
95% CI: [-3.39, 1.56]
95% CI: [-3.91, 1.2]
95% CI: [-4.99, 1.21]
95% CI: [-2.97, 2.08]
95% CI: [-2.21, 3.24]
Secondary
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).
Time frame: Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68
Population: Completer Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Oral Dryness Numeric Response Scale (NRS) Over Time | Baseline (Screening); n= 8, 17, 19, 16 | 7.6 Scores on a scale | Standard Deviation 1.51 |
| Placebo | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 12; n=8, 17, 19, 16 | 6.1 Scores on a scale | Standard Deviation 2.59 |
| Placebo | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 24; n=8, 17, 19, 15 | 5.8 Scores on a scale | Standard Deviation 2.38 |
| Placebo | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 36; n=8, 17, 19, 16 | 5.8 Scores on a scale | Standard Deviation 2.76 |
| Placebo | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 52; n=8, 17, 19, 16 | 5.6 Scores on a scale | Standard Deviation 2.13 |
| Placebo | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 68; n=8, 17, 19, 16 | 6.6 Scores on a scale | Standard Deviation 2.26 |
| Belimumab + Rituximab Co-administration Therapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 68; n=8, 17, 19, 16 | 6.1 Scores on a scale | Standard Deviation 2.63 |
| Belimumab + Rituximab Co-administration Therapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 36; n=8, 17, 19, 16 | 5.9 Scores on a scale | Standard Deviation 2.26 |
| Belimumab + Rituximab Co-administration Therapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Baseline (Screening); n= 8, 17, 19, 16 | 7.4 Scores on a scale | Standard Deviation 1.46 |
| Belimumab + Rituximab Co-administration Therapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 24; n=8, 17, 19, 15 | 5.3 Scores on a scale | Standard Deviation 1.83 |
| Belimumab + Rituximab Co-administration Therapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 12; n=8, 17, 19, 16 | 5.7 Scores on a scale | Standard Deviation 1.96 |
| Belimumab + Rituximab Co-administration Therapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 52; n=8, 17, 19, 16 | 5.7 Scores on a scale | Standard Deviation 1.92 |
| Belimumab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 12; n=8, 17, 19, 16 | 6.9 Scores on a scale | Standard Deviation 2.32 |
| Belimumab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 24; n=8, 17, 19, 15 | 6.8 Scores on a scale | Standard Deviation 2.51 |
| Belimumab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 36; n=8, 17, 19, 16 | 6.6 Scores on a scale | Standard Deviation 2.19 |
| Belimumab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 68; n=8, 17, 19, 16 | 6.9 Scores on a scale | Standard Deviation 2.34 |
| Belimumab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 52; n=8, 17, 19, 16 | 7.0 Scores on a scale | Standard Deviation 2.4 |
| Belimumab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Baseline (Screening); n= 8, 17, 19, 16 | 7.2 Scores on a scale | Standard Deviation 2.14 |
| Rituximab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 52; n=8, 17, 19, 16 | 6.3 Scores on a scale | Standard Deviation 2.32 |
| Rituximab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 68; n=8, 17, 19, 16 | 6.1 Scores on a scale | Standard Deviation 2.62 |
| Rituximab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 12; n=8, 17, 19, 16 | 5.1 Scores on a scale | Standard Deviation 2.77 |
| Rituximab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 36; n=8, 17, 19, 16 | 6.2 Scores on a scale | Standard Deviation 2.51 |
| Rituximab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Baseline (Screening); n= 8, 17, 19, 16 | 7.3 Scores on a scale | Standard Deviation 1.91 |
| Rituximab Monotherapy | Oral Dryness Numeric Response Scale (NRS) Over Time | Week 24; n=8, 17, 19, 15 | 5.6 Scores on a scale | Standard Deviation 2.72 |
Secondary
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).
Time frame: Baseline (Screening [within 35 days prior to Day 0]), Week 12, Week 24, Week 36, Week 52 and Week 68
Population: Completer Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Stimulated Salivary Flow Rate Over Time | Baseline (Screening); n=8, 17, 19 ,16 | 0.470 Milliliter per minute | Standard Deviation 0.247 |
| Placebo | Stimulated Salivary Flow Rate Over Time | Week 12; n=8, 17, 19 ,16 | 0.486 Milliliter per minute | Standard Deviation 0.2045 |
| Placebo | Stimulated Salivary Flow Rate Over Time | Week 24; n=8, 17, 19 ,16 | 0.554 Milliliter per minute | Standard Deviation 0.3054 |
| Placebo | Stimulated Salivary Flow Rate Over Time | Week 36; n=8, 17, 19 ,15 | 0.404 Milliliter per minute | Standard Deviation 0.2497 |
| Placebo | Stimulated Salivary Flow Rate Over Time | Week 52; n=8, 17, 19 ,16 | 0.531 Milliliter per minute | Standard Deviation 0.3782 |
| Placebo | Stimulated Salivary Flow Rate Over Time | Week 68; n=8, 17, 19 ,15 | 0.361 Milliliter per minute | Standard Deviation 0.1628 |
| Belimumab + Rituximab Co-administration Therapy | Stimulated Salivary Flow Rate Over Time | Week 68; n=8, 17, 19 ,15 | 0.879 Milliliter per minute | Standard Deviation 0.8167 |
| Belimumab + Rituximab Co-administration Therapy | Stimulated Salivary Flow Rate Over Time | Week 36; n=8, 17, 19 ,15 | 1.039 Milliliter per minute | Standard Deviation 1.1027 |
| Belimumab + Rituximab Co-administration Therapy | Stimulated Salivary Flow Rate Over Time | Baseline (Screening); n=8, 17, 19 ,16 | 0.714 Milliliter per minute | Standard Deviation 0.6294 |
| Belimumab + Rituximab Co-administration Therapy | Stimulated Salivary Flow Rate Over Time | Week 24; n=8, 17, 19 ,16 | 0.784 Milliliter per minute | Standard Deviation 0.79 |
| Belimumab + Rituximab Co-administration Therapy | Stimulated Salivary Flow Rate Over Time | Week 12; n=8, 17, 19 ,16 | 0.754 Milliliter per minute | Standard Deviation 0.8342 |
| Belimumab + Rituximab Co-administration Therapy | Stimulated Salivary Flow Rate Over Time | Week 52; n=8, 17, 19 ,16 | 0.999 Milliliter per minute | Standard Deviation 1.1457 |
| Belimumab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 12; n=8, 17, 19 ,16 | 0.493 Milliliter per minute | Standard Deviation 0.3733 |
| Belimumab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 24; n=8, 17, 19 ,16 | 0.454 Milliliter per minute | Standard Deviation 0.4105 |
| Belimumab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 36; n=8, 17, 19 ,15 | 0.506 Milliliter per minute | Standard Deviation 0.4261 |
| Belimumab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 68; n=8, 17, 19 ,15 | 0.517 Milliliter per minute | Standard Deviation 0.4499 |
| Belimumab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 52; n=8, 17, 19 ,16 | 0.582 Milliliter per minute | Standard Deviation 0.6084 |
| Belimumab Monotherapy | Stimulated Salivary Flow Rate Over Time | Baseline (Screening); n=8, 17, 19 ,16 | 0.425 Milliliter per minute | Standard Deviation 0.3292 |
| Rituximab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 52; n=8, 17, 19 ,16 | 0.693 Milliliter per minute | Standard Deviation 0.7813 |
| Rituximab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 68; n=8, 17, 19 ,15 | 0.733 Milliliter per minute | Standard Deviation 0.785 |
| Rituximab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 12; n=8, 17, 19 ,16 | 0.581 Milliliter per minute | Standard Deviation 0.5265 |
| Rituximab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 36; n=8, 17, 19 ,15 | 0.689 Milliliter per minute | Standard Deviation 0.5907 |
| Rituximab Monotherapy | Stimulated Salivary Flow Rate Over Time | Baseline (Screening); n=8, 17, 19 ,16 | 0.618 Milliliter per minute | Standard Deviation 0.6211 |
| Rituximab Monotherapy | Stimulated Salivary Flow Rate Over Time | Week 24; n=8, 17, 19 ,16 | 0.724 Milliliter per minute | Standard Deviation 0.8901 |