Sequential Belimumab and T-cell Based Therapy in SLE

Sequential Belimumab Followed by T-cell Based Therapy in the Treatment of Systemic Lupus Erythematosus (SUBTLE) - a Preliminary Proof-of-concept Mechanistic Study

Systemic lupus erythematosus (SLE) is a disease in which the immune system (the bodily system that fights infection) attacks the body's own cells and tissues, causing inflammation and organ damage if not promptly and appropriately managed. Autoantibodies (specific proteins produced by the immune system which participate in attacking self tissues and organs) are the hallmarks of SLE which are produced by a specific type of white blood cells called B cells. Belimumab (Benlysta®) is a monoclonal antibody against the B cells by blocking the action of BLyS, a protein that prolongs the longevity and enhances the functions of B cells and is found to be elevated in patients with SLE, was approved by the FDA to treat patients with SLE. This study aims to study the effects of Belimumab on T cells, another specific type of white blood cells which also play a crucial role in SLE, in patients with SLE. In this trial, 80 adult patients with SLE will be recruited, 40 of them will be assigned to receive intravenous (IV) Belimumab with standard of care therapy (SOC), and 40 to receive SOC only. After 48 weeks of exposure to Belimumab + SOC and SOC alone, the phenotype and functions of T cells will be studied and compared.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus
• Intervention / Treatment: Drug: Belimumab Injection [Benlysta]

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anselm Mak; Phone Number: +6567722598; Email: mdcam@nsu.edu.sg
• Study Contact Backup: Name: Nien Yee Kow; Phone Number: +6566015194; Email: mdckown@nus.edu.sg

Study Locations

• Singapore
  • SIngapore, Singapore
    • Recruiting
    • National University Hospital
    • Contact: Anselm Mak; Phone Number: +6567722598; Email: mdcam@nus.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 21
2. Able to understand the details of the trial and willing to give written informed consent and comply with the requirements of the study protocol.
3. Patients who fulfill the classification criteria (SLICC 2012 or ACR 1997) for SLE and have active disease (SELENA-SLEDAI ≥ 6).
4. Patients whose sera are positive for ANA (titre ≥ 1:80) or anti-dsDNA (>100U/L based on NUH standard laboratory cut-off).
5. Patients who are on stable dose of prednisolone (0-40mg/day) and/or non-steroidal anti-inflammatory, antimalarial or immunosuppressive drugs for at least 30 days before first study dose.
6. Females of child-bearing potential and non-sterilized males with female partners of child-bearing potential may participate this trial only if they use a reliable means of contraception.
7. Females of child-bearing potential must have a negative serum pregnancy test within three weeks prior to baseline.

Exclusion Criteria:

1. They have severe active nephritis and/or active CNS lupus and/or other autoimmune diseases e.g. RA, mixed connective tissue disease, scleroderma, dermatomyositis and polymyositis.
2. They are pregnant.
3. They have had previous treatment with any B-cell and T-cell targeted biologic therapy, intravenous (IV) cyclophosphamide within 6 months of enrolment, intravenous immunoglobulins or prednisolone (>100mg/day) within 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belimumab + SOC; Patients will be administered Belimumab, 10mg/kg, intravenously (IV) (together with SOC) in 1 hour on days 0, 14, and 28, and then every 28 days (4 weeks) until week 48.	Drug: Belimumab Injection [Benlysta]; Belimumab, IV infusion, 10mg/kg on days 0, 14, 28 then every 28 days until week 48.
No Intervention: SOC only; Patients will receive SOC based on the discretion of attending physicians in accordance with the clinical disease manifestations of SLE and NUH practice of the treatment of SLE.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing the ratio of Treg/Teff in Belimumab + SOC arm with SOC-only arm	The enumeration of T-cell subsets by multi-color flow cytometry including Th1 (CD4+Tbet+), Th2 (CD4+GATA3+), Th17 (CD4+RoRgamat+) and Treg (CD4+CD25+FoxP3+) cells, as well as CD19+CD20+ B cells after staining with respective fluorescent-conjugated antibodies.	Baseline, week 4, week 12, week 24, week 36, week 48 and week 60
Identifying and comparing the TCR sequence of the variable regions (CDR1, CDR2 and CDR3) and their RNA expression profile before and after 48 weeks of Belimumab therapy	TCR sequencing and RNA expression with the use of the state-of-the-art 10x Genomic nano-droplet technology.	up to week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the numeric difference in other T cell subsets (Th1, Th2 and Th17) between the 2 arms	The enumeration of T-cell subsets by multi-color flow cytometry.	Baseline, week 4, week 12, week 24, week 36, week 48 and week 60
To compare the potential improvement of cognitive function between the 2 arms	The use of the computerized Automated Neuropsychological Assessment Matrix (ANAM) which serves as an initial screening tool to pick up subtle cognitive dysfunction in healthy populations and serial assessments to track the progress of cognitive dysfunction in SLE patients over time.	Baseline and week 52

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Anselm Mak, National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2021
• Primary Completion (Estimated): May 20, 2025
• Study Completion (Estimated): May 20, 2025

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: June 24, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Belimumab
• Other Study ID Numbers: 10743-SUBTLE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No