Last updated: 07/17/2024 17:14:09
Safety and efficacy study of subcutaneous belimumab and intravenous rituximab co-administration in subjects with primary Sjogren’s syndrome
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: 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
Trial description: 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).
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
Number of participants with SAEs
Timeframe: Up to Week 68
Number of participants with AESIs
Timeframe: Up to Week 68
Secondary outcomes:
The European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) score over time
Timeframe: Up to Week 68
Stimulated salivary flow over time
Timeframe: Up to Week 68
Oral dryness numeric response scale over time
Timeframe: Up to Week 68
B cell quantification within salivary gland biopsy at Week 24
Timeframe: Week 24
Interventions:
Drug: Belimumab
Drug: Rituximab
Drug: Placebo belimumab
Drug: Placebo rituximab
Enrollment:
86
Observational study model:
Not applicable
Primary completion date:
2020-23-06
Time perspective:
Not applicable
Clinical publications:
Xavier Mariette, Francesca Barone, Chiara Baldini, Hendrika Bootsma, Kenneth L Clark, Salvatore De Vita, David H Gardner, Robert B Henderson, Michael Herdman, Karoline Lerang, Prafull Mistry, Raj Punwaney, Raphaele Seror, John Stone, Paul LA van Daele, Andre van Maurik, Nicolas Wisniacki, David A Roth, Paul Peter Tak. A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome. JCI Insight. 2022;7(23): e163030
DOI: 10.1172/jci.insight.163030
PMID: 36477362
Medical condition
Sjogren's Syndrome
Product
belimumab, rituximab
Collaborators
Not applicable
Study date(s)
February 2016 to June 2020
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- 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.
- 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.
Inclusion and exclusion 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
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.
Trial location(s)
Location
GSK Investigational Site
Buenos Aires, Buenos Aires, Argentina, C1111AL
Status
Study Complete
Location
GSK Investigational Site
L'Hospitalet de Llobregat, Spain, 08907
Status
Study Complete
Location
GSK Investigational Site
London, London, United Kingdom, E1 4DG
Status
Study Complete
Location
GSK Investigational Site
Mainz, Rheinland-Pfalz, Germany, 55131
Status
Study Complete
Location
GSK Investigational Site
Newcastle-upon-Tyne, United Kingdom, NE1 4LP
Status
Study Complete
Location
GSK Investigational Site
Swindon, Wiltshire, United Kingdom, SN3 6BB
Status
Study Complete
Location
GSK Investigational Site
Trois-Rivieres, Québec, Canada, G8Z 1Y2
Status
Study Complete
Location
GSK Investigational Site
Tuebingen, Baden-Wuerttemberg, Germany, 72076
Status
Study Complete
Location
GSK Investigational Site
Udine, Friuli-Venezia-Giulia, Italy, 33100
Status
Study Complete
Study documents
Study report synopsis
Available language(s): English
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2020-23-06
Actual study completion date
2020-23-06
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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