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

NCT02631538 | Completed Phase 2 Results DMC

• 2 other identifiers: 2018422015-000400-26
• Study Type: interventional
• Target: 86
• Locations: 10 countries
• Sites: 36

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).

Conditions

Sjogren's Syndrome

Keywords

Subcutaneous; Rituximab; Intravenous; Safety; Efficacy; Sjogren's syndrome; Belimumab

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• 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

• 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

• 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

• Absolute Values for B-cells (Cluster of Differentiation 20 [CD20]) Within Salivary Gland Biopsy at Week 24

  At Week 24

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Subjects will receive belimumab placebo weekly subcutaneous injections to Week 52 and rituximab placebo infusions at Weeks 8 and 10.

Drug: Placebo belimumab; Drug: Placebo rituximab

Belimumab monotherapy

EXPERIMENTAL

Subjects will receive 200 mg weekly subcutaneous injections of belimumab to Week 52 and placebo rituximab infusions at Weeks 8 and 10.

Drug: Belimumab; Drug: Placebo rituximab

Belimumab and Rituximab co-administration therapy

EXPERIMENTAL

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; Drug: Rituximab; Drug: Placebo belimumab

Rituximab monotherapy

ACTIVE COMPARATOR

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; Drug: Placebo belimumab

Interventions

Belimumab DRUG

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.

Belimumab and Rituximab co-administration therapy; Belimumab monotherapy

Rituximab DRUG

Rituximab will be provided as a 100 mg concentrated solution for infusion. It is a clear, colorless liquid.

Belimumab and Rituximab co-administration therapy; Rituximab monotherapy

Placebo belimumab DRUG

The placebo control will be provided as a sterile liquid product in a prefilled syringe. Each syringe will be of a single use.

Belimumab and Rituximab co-administration therapy; Placebo; Rituximab monotherapy

Placebo rituximab DRUG

Placebo rituximab will be provided as solution for infusion. It is a clear, colorless liquid.

Belimumab monotherapy; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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%).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (36)

GSK Investigational Site

Buenos Aires, C1111AL, Argentina

Location

GSK Investigational Site

Córdoba, 5000, Argentina

Location

GSK Investigational Site

Toronto, Ontario, M5T 2S8, Canada

Location

GSK Investigational Site

Trois-Rivières, Quebec, G8Z 1Y2, Canada

Location

GSK Investigational Site

Bordeaux, 33000, France

Location

GSK Investigational Site

Le Kremlin-Bicêtre, 94275, France

Location

GSK Investigational Site

Lille, 59037, France

Location

GSK Investigational Site

Paris, 75012, France

Location

GSK Investigational Site

Paris, 75013, France

Location

GSK Investigational Site

Paris, 75014, France

Location

GSK Investigational Site

Paris, 75475, France

Location

GSK Investigational Site

Paris, 75651, France

Location

GSK Investigational Site

Strasbourg, 67098, France

Location

GSK Investigational Site

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

GSK Investigational Site

Mainz, Rhineland-Palatinate, 55131, Germany

Location

GSK Investigational Site

Bad Abbach, 93077, Germany

Location

GSK Investigational Site

Berlin, 10117, Germany

Location

GSK Investigational Site

Hamburg, 22763, Germany

Location

GSK Investigational Site

Udine, Friuli Venezia Giulia, 33100, Italy

Location

GSK Investigational Site

Pisa, Tuscany, 56126, Italy

Location

GSK Investigational Site

Perugia, Umbria, 06122, Italy

Location

GSK Investigational Site

Brescia, 25123, Italy

Location

GSK Investigational Site

Padua, 35128, Italy

Location

GSK Investigational Site

Amsterdam, 1081 HZ, Netherlands

Location

GSK Investigational Site

Rotterdam, 3015 CE, Netherlands

Location

GSK Investigational Site

Oslo, 0372, Norway

Location

GSK Investigational Site

Barcelona, 08034, Spain

Location

GSK Investigational Site

L'Hospitalet de Llobregat, 08907, Spain

Location

GSK Investigational Site

Madrid, 28041, Spain

Location

GSK Investigational Site

Madrid, 28050, Spain

Location

GSK Investigational Site

Malmo, SE-205 02, Sweden

Location

GSK Investigational Site

Stockholm, SE-141 86, Sweden

Location

GSK Investigational Site

Swindon, Wiltshire, SN3 6BB, United Kingdom

Location

GSK Investigational Site

Edgbaston, B15 2GW, United Kingdom

Location

GSK Investigational Site

London, E1 4DG, United Kingdom

Location

GSK Investigational Site

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Related Publications (2)

• Mariette X, Barone F, Baldini C, Bootsma H, Clark KL, De Vita S, Gardner DH, Henderson RB, Herdman M, Lerang K, Mistry P, Punwaney R, Seror R, Stone J, van Daele P, van Maurik A, Wisniacki N, Roth DA, Tak PP. A randomized, phase II study of sequential belimumab and rituximab in primary Sjogren's syndrome. JCI Insight. 2022 Dec 8;7(23):e163030. doi: 10.1172/jci.insight.163030.

  PMID: 36477362 DERIVED

• Raymond K, Maher S, Saucier CD, O'Connor M, Yarlas A, Kosinski M, Chen WH, Gairy K. Validation of the PROFAD-SSI-SF in Patients with Primary Sjogren's Syndrome with Organ Involvement: Results of Qualitative Interviews and Psychometric Analyses. Rheumatol Ther. 2023 Feb;10(1):95-115. doi: 10.1007/s40744-022-00493-2. Epub 2022 Oct 13.

  PMID: 36227531 DERIVED

MeSH Terms

Conditions

Sjogren's Syndrome

Interventions

belimumab; Rituximab

Condition Hierarchy (Ancestors)

Arthritis, Rheumatoid; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Xerostomia; Salivary Gland Diseases; Mouth Diseases; Stomatognathic Diseases; Dry Eye Syndromes; Lacrimal Apparatus Diseases; Eye Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2015
• First Posted: December 16, 2015
• Study Start: February 17, 2016
• Primary Completion: June 23, 2020
• Study Completion: June 23, 2020
• Last Updated: June 9, 2021
• Results First Posted: June 9, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

AR (2); CA (2); FR (9); SE (2); GB (4); DE (5); ES (4); NO (1); NL (2); IT (5)