Belimumab Treatment Holiday and Treatment Re-start Study in Lupus Patients

An Open-label, Non-randomized, 52-Week Study to Evaluate Treatment Holidays and Rebound Phenomenon After Treatment With Belimumab 10 mg/kg in Systemic Lupus Erythematosus Subjects

This study will assess the effect of a 24-week withdrawal followed by a 28-week reintroduction of belimumab 10 mg/kg plus standard of care medications in subjects with stable low systemic lupus erythematosus (SLE) disease activity. Rebound phenomenon will be assessed for subjects who have permanently withdrawn from further belimumab treatment.

Study Overview

• Status: Completed
• Conditions: Systemic Lupus Erythematosus
• Intervention / Treatment: Drug: Belimumab

Detailed Description

This study will assess the effect of a 24-week withdrawal of belimumab followed by a 28-week reintroduction of belimumab 10 mg/kg plus standard of care medications on immunogenicity, markers of biological activity, efficacy, and safety in subjects with stable low systemic lupus erythematosus (SLE) disease activity. Additionally, this study will assess rebound phenomenon in subjects with any disease level of SLE who have permanently withdrawn from further belimumab treatment

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100044
    • GSK Investigational Site
  • Beijing, China, 100032
    • GSK Investigational Site
  • Anhui
    • Hefei, Anhui, China, 230001
      • GSK Investigational Site
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • GSK Investigational Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • GSK Investigational Site
• Japan
  • Chiba, Japan, 275-8580
    • GSK Investigational Site
  • Ehime, Japan, 791-0295
    • GSK Investigational Site
  • Hokkaido, Japan, 060-8604
    • GSK Investigational Site
  • Miyagi, Japan, 980-8574
    • GSK Investigational Site
  • Nagasaki, Japan, 857-1195
    • GSK Investigational Site
  • Tokyo, Japan, 162-8655
    • GSK Investigational Site
  • Tokyo, Japan, 104-8560
    • GSK Investigational Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 700-721
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 110-744
    • GSK Investigational Site
  • Seoul, Korea, Republic of
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 133-792
    • GSK Investigational Site
  • Suwon, Kyonggi-do, Korea, Republic of, 443-721
    • GSK Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90048
      • GSK Investigational Site
  • New York
    • Manhasset, New York, United States, 11030
      • GSK Investigational Site
  • Texas
    • Dallas, Texas, United States, 75246
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Received a minimun of 6 months therapy with with belimumab 10 mg/kg in their current SLE belimumab continuation study.
• Be 18 years of age at the Day 0 visit.
• Non-prenant, non-lactating females willing to comply with specific birth control requirements as set forth in the protocol.
• Able to provide written informed consent to participate.
• Subjects who wish to enroll in the control group and the group taking a 6 month belimumab treatment holiday will need a SELENA SLEDAI score of 3 or less after the minimum of 6 months belimumab therapy, as well as having C3 and C4 complement levels at or above the lower limit of the central laboratory reference range, and are on a stable SLE treatment regimen during the 30 day screening period prior to Day 0.
• Subjects who wish to enroll in the long-term discontinuation group have voluntarily withdrawn from their continuation studies.

Exclusion Criteria:

• Subjects who have developed clinical evidence of significant, unstable or uncontrolled, acute or chronic diseases not due to SLE, or experienced an adverse event (AE) in their belimumab continuation study that could, in the opinion of the principle investigator, put the subject at undue risk.
• Subjects who have developed any other medical diseases, laboratory abnormalities, or conditions that, in the opinion of the principle investigator, makes the subject unsuitable for the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Holiday Group; Subjects in the Treatment Holiday Group will undergo a 6 month belimumab treatment holiday while remaining on standard of care SLE therapy, then re-start belimumab therapy for 6 months while receiving standard of care SLE therapy.	Drug: Belimumab; Monthly intravenous infusions dosed as 10 mg/kg body weight
Active Comparator: Control Group; Subjects in the Control Group will continue to receive monthly belimumab therapy, in addition to standard of care SLE therapy for 52 weeks.	Drug: Belimumab; Monthly intravenous infusions dosed as 10 mg/kg body weight
No Intervention: Long-Term Discontinuation Group; Subjects in the Long-Term Discontinuation Group have elected to discontinue further belimumab therapy and will remain on standard of care SLE therapy as directed by the investigator, and agree to return for monthly visits for 52 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Time to First SLE Flare Index (SFI)	SFI Flare was defined as a mild/moderate or severe flare according to the modified Safety of Estrogen in Lupus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA SLEDAI) SLE Flare Index (modified excluded severe flares from the SELENA SLEDAI flare assessment that were triggered only by an increase in SELENA SLEDAI score to >12).Time to first SFI flare is defined as the number of days from Day 0 visit date to the date the participant has a flare (event date - Day 0 visit date + 1) in the 52 Week/Holiday phase; (event date - treatment re-start date + 1) in the Re-start Holiday phase. Day 0 visit date is defined as Day 0 from present study. Median time to first SFI flare is reported; estimated using the product-limit method.	Up to 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of SLE Index Flare Per Subject Year	Rate per subject year of SFI flare was calculated as total number of flares divided by total subject years in interval. The total subject years for each participant was calculated as (Week 52/ Exit visit date minus Day 0 visit date + 1) for Long-term discontinuation and treatment control groups. For treatment holiday phase group the subject-years for each participant was calculated as (Week 24/Treatment Re-start/Exit visit date minus Day 0 Visit date + 1)/365.25. For re-start treatment holiday phase group the subject-years for each participant was calculated as (Week 52/Exit visit date minus Week 24/Treatment Re-start date + 1)/365.25. Day 0 visit date is defined as Day 0 from present study.	Up to 52 weeks
Median Time to First Severe SFI Flare	The SLE Flare Index categorizes SLE flare as "mild or moderate" or "severe" based on a positive assessment for at least 1 of 5 variables as follows: Change in SELENA SLEDAI score from the most recent assessment to current; Change in signs or symptoms of disease activity; Change in prednisone dosage; Use of new medications for disease activity or hospitalization; Change in Physician's Global Assessment (PGA) score; Hospitalization for SLE activity is an additional category included only for a severe flare. Time to first severe flare is defined as (event date-Day 0 visit date) + 1 for Long-term discontinuation, treatment control groups and holiday phase group. For holiday phase group data censored at last flare assessment by treatment re-start date. Time to first severe flare is defined as (event date-treatment re-start date) + 1 for Re-start treatment holiday group. Median time to first severe SFI flare is reported; estimated using the product-limit method.	Up to 52 weeks
Number of Participants With Evidence of Rebound	Rebound is defined as SELENA SLEDAI score during the first 24 weeks that exceeds the Baseline SELENA SLEDAI score in the participant's respective original parent study. Baseline is defined as the Day 0 visit from the parent study. SELENA SLEDAI assessments consist of 24 individual weighted items in which signs and symptoms, laboratory tests, and physician's assessment for each of 9 organ systems are given a weighted score and summed if present (marked 'Yes') at the time of the visit or in the preceding 10 days. The maximum theoretical score is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease (marked 'No'). Any time during the first 24 weeks of this study has been reported.	Up to 24 weeks
Number of Participants With Confirmed True Positive Belimumab Anti-drug Antibodies (ADA)	Immunogenicity assay results were categorized as negative or positive. A persistent positive result was defined as a positive post-Day 0 visit immunogenic response that occurred for at least 2 consecutive assessments or a single result at the final assessment. A transient positive result was defined as a single post-Day 0 visit positive immunogenic response that did not occur at the final assessment. Any time post-Day 0 visit data are reported (or post-Week 24 for Treatment Holiday - Restart phase). Day 0 visit date is defined as Day 0 from present study.	Up to 52 weeks
Percentage Change From Baseline in Immunoglobulin	Serum samples were collected at indicated time-points for analysis of immunoglobulins: Immunoglobulin G (IgG), Immunoglobulin A (IgA), and Immunoglobulin M (IgM). Baseline is defined as the Day 0 visit from parent studies. Percentage change from Baseline is equal to 100* (value at specified visit minus Baseline value) divided by Baseline value.	Baseline (Day 0 from parent studies); Day 0 and 8, 16, 24, 32, 40, 48 and 52 weeks
Percentage Change From Baseline in Autoantibody:Anti-double Stranded Deoxyribonucleic Acid (dsDNA)	Blood samples were collected at indicated time-points for analysis of autoantibodies like dsDNA. Baseline is defined as the Day 0 visit from parent studies. Percentage change from Baseline is equal to 100* (Value at specified visit minus Baseline value) divided by Baseline value.	Baseline (Day 0 from parent studies); Day 0 and 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 weeks
Percentage Change From Baseline in Autoantibody: Antinuclear Antibody (ANA)	Blood samples were collected at indicated time-points for analysis of autoantibodies like ANA. Only participants who had an ANA value measured in INDEX at the parent studies Baseline were included in this analysis. Baseline is defined as the Day 0 visit from parent studies. Percentage change from Baseline is equal to 100* (Value at specified visit minus Baseline value) divided by Baseline value.	Baseline (Day 0 from parent studies); Day 0 and 24 and 52 weeks
Percentage Change From Baseline in Complement Levels	Blood samples were collected at indicated time-points for analysis of complement levels like complement 3 (C3) and complement 4 (C4). Baseline is defined as the Day 0 visit from parent studies. Percentage change from Baseline is equal to 100* (Value at specified visit minus Baseline value) divided by Baseline value.	Baseline (Day 0 from parent studies); Day 0 and 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 weeks
Percentage Change From Baseline in B Cell Subsets	Blood samples were collected at indicated time-points for analysis of Activated B cells subsets like Activated CD19+CD20+CD69+, cluster of differentiation 20+ (CD20+), Memory CD19+CD20+CD27+, Naive CD19+CD20+CD27-, Plasma CD19+CD20-CD138+, Plasmacytoid CD19+CD20+CD138+, and SLE Subset CD19+CD38b+CD27b+Lymph. Baseline is defined as the Day 0 visit from parent studies. Percentage change from Baseline is equal to 100* (Value at specified visit minus Baseline value) divided by Baseline value.	Baseline (Day 0 from parent studies); Day 0 and 8, 16, 24, 32, 40 and 52 weeks
Percentage Change From 24 Week in B Cell Subsets: Treatment Holiday Group (Re-start Phase)	Blood samples were collected at indicated time-points for analysis of Activated B cells subsets like Activated CD19+CD20+CD69+, CD20+, Memory CD19+CD20+CD27+, Naive CD19+CD20+CD27-, Plasma CD19+CD20-CD138+, Plasmacytoid CD19+CD20+CD138+, and SLE Subset CD19+CD38b+CD27b+Lymph. Percentage change from Week 24 of present study was calculated as 100*(value at specified visit - Week 24 value) divided by week 24 value. The data below is only reported for the Treatment Holiday Group (Re-start phase). Participants in this group restarted belimumab therapy one day after Week 24, hence the Baseline for this outcome measure was Week 24 visit. No other groups were measured for this outcome.	Week 24, 32, 40 and 52 weeks
SELENA SLEDAI Scores Change From Baseline	SELENA SLEDAI assessments consist of 24 individual weighted items in which signs and symptoms, laboratory tests, and physician's assessment for each of 9 organ systems are given a weighted score and summed if present (marked 'Yes') at the time of the visit or in the preceding 10 days. The maximum theoretical score is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease (marked 'No'). Data are reported at the specified time-points from Day 0 (of present study) up to Week 52. Baseline is defined as the Day 0 from parent studies. Change from Baseline is equal to (Value at specified visit minus Baseline value).	Baseline (Day 0 from parent studies); Day 0 and 4, 8, 12, 16, 20, 24, 28, 32,36, 40, 44, 48 and 52 weeks
Number of Days of Daily Prednisone Dose >=7.5 mg/Day and/or Increased by 25 Percent From Day 0 of This Study	All corticosteroids are converted to a prednisone equivalent average daily dose (mg/day). The average daily dose at Day 0 was used to assess the relative change in daily dose on a given day. The average daily dose at Day 0 was calculated as sum of the daily dose across all days from the Screening visit date up to and including Day 0 visit date divided by the number of days in the time period. Data reported are the median number of days on which the specified criteria was met for Day 0 to Week 24, Week 24 to Week 52, Day 0 to Week 52. For treatment holiday group, Day 0 to Week 24 corresponds to holiday phase, Week 24 to Week 52 corresponds to treatment Re-start phase.	Day 0 to Week 24; Week 24 to Week 52; Day 0 to Week 52
Number of Days of Daily Prednisone Dose <=7.5 mg/Day and/or Decreased by 25 Percent From Day 0 of This Study	All corticosteroids are converted to a prednisone equivalent average daily dose (mg/day). The average daily dose at Day 0 was used to assess the relative change in daily dose on a given day. The average daily dose at Day 0 was calculated as sum of the daily dose across all days from the Screening visit date up to and including Day 0 visit date divided by the number of days in the time period. Data reported are the median number of days on which the specified criteria was met for Day 0 to Week 24, Week 24 to Week 52, Day 0 to Week 52. For treatment holiday group, Day 0 to Week 24 corresponds to holiday phase, Week 24 to Week 52 corresponds to treatment Re-start phase.	Day 0 to Week 24; Week 24 to Week 52; Day 0 to Week 52

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Bae SC, Bass DL, Chu M, Curtis P, Dimelow R, Harvey L, Ji B, Kurrasch R, Muzaffar S, Punwaney R, Roth DA, Song YW, Xie W, Zhang F. The effect of 24-week belimumab treatment withdrawal followed by treatment restart in patients with SLE: an open-label, non-randomised 52-week study. Arthritis Res Ther. 2022 Feb 16;24(1):46. doi: 10.1186/s13075-022-02723-y.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2014
• Primary Completion (Actual): December 14, 2018
• Study Completion (Actual): December 14, 2018

Study Registration Dates

• First Submitted: April 17, 2014
• First Submitted That Met QC Criteria: April 17, 2014
• First Posted (Estimate): April 21, 2014

Study Record Updates

• Last Update Posted (Actual): January 31, 2020
• Last Update Submitted That Met QC Criteria: January 21, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: immunogenicity; Systemic Lupus Erythematosus; belimumab; rebound; PGA; Lymphostat-B; treatment holiday; SELENA SLEDAI
• 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: 116027