Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial

Mieke van Schaik; Eline J Arends; Darius Soonawala; Ellen van Ommen; Karina de Leeuw; Maarten Limper; Pieter van Paassen; Tom W J Huizinga; René E M Toes; Cees van Kooten; Joris I Rotmans; Ton J Rabelink; Y K Onno Teng

doi:10.1186/s13063-022-06874-w

Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial

Mieke van Schaik, Eline J Arends, Darius Soonawala, Ellen van Ommen, Karina de Leeuw, Maarten Limper, Pieter van Paassen, Tom W J Huizinga, René E M Toes, Cees van Kooten, Joris I Rotmans, Ton J Rabelink, Y K Onno Teng^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.

METHODS: Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.

DISCUSSION: The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03747159 . Registered on 20 November 2018.

Original language	English
Article number	939
Number of pages	10
Journal	Trials
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s13063-022-06874-w
Publication status	Published - 12 Nov 2022

Keywords

Adult
Humans
Rituximab/adverse effects
Lupus Nephritis/chemically induced
Lupus Erythematosus, Systemic/diagnosis
Immunosuppressive Agents/adverse effects
Treatment Outcome
Prednisolone/adverse effects
Randomized Controlled Trials as Topic
Multicenter Studies as Topic
Clinical Trials, Phase III as Topic

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10.1186/s13063-022-06874-wLicence: CC BY

Cite this

van Schaik, M., Arends, E. J., Soonawala, D., van Ommen, E., de Leeuw, K., Limper, M., van Paassen, P., Huizinga, T. W. J., Toes, R. E. M., van Kooten, C., Rotmans, J. I., Rabelink, T. J., & Teng, Y. K. O. (2022). Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial. Trials, 23(1), Article 939. https://doi.org/10.1186/s13063-022-06874-w

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title = "Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial",

abstract = "BACKGROUND: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.METHODS: Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.DISCUSSION: The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.TRIAL REGISTRATION: ClinicalTrials.gov NCT03747159 . Registered on 20 November 2018.",

keywords = "Adult, Humans, Rituximab/adverse effects, Lupus Nephritis/chemically induced, Lupus Erythematosus, Systemic/diagnosis, Immunosuppressive Agents/adverse effects, Treatment Outcome, Prednisolone/adverse effects, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Clinical Trials, Phase III as Topic",

author = "{van Schaik}, Mieke and Arends, {Eline J} and Darius Soonawala and {van Ommen}, Ellen and {de Leeuw}, Karina and Maarten Limper and {van Paassen}, Pieter and Huizinga, {Tom W J} and Toes, {Ren{\'e} E M} and {van Kooten}, Cees and Rotmans, {Joris I} and Rabelink, {Ton J} and Teng, {Y K Onno}",

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = nov,

day = "12",

doi = "10.1186/s13063-022-06874-w",

language = "English",

volume = "23",

journal = "Trials",

issn = "1745-6215",

publisher = "BioMed Central Ltd",

number = "1",

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van Schaik, M, Arends, EJ, Soonawala, D, van Ommen, E, de Leeuw, K, Limper, M, van Paassen, P, Huizinga, TWJ, Toes, REM, van Kooten, C, Rotmans, JI, Rabelink, TJ & Teng, YKO 2022, 'Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial', Trials, vol. 23, no. 1, 939. https://doi.org/10.1186/s13063-022-06874-w

TY - JOUR

T1 - Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus

T2 - study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial

AU - van Schaik, Mieke

AU - Arends, Eline J

AU - Soonawala, Darius

AU - van Ommen, Ellen

AU - de Leeuw, Karina

AU - Limper, Maarten

AU - van Paassen, Pieter

AU - Huizinga, Tom W J

AU - Toes, René E M

AU - van Kooten, Cees

AU - Rotmans, Joris I

AU - Rabelink, Ton J

AU - Teng, Y K Onno

PY - 2022/11/12

Y1 - 2022/11/12

N2 - BACKGROUND: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.METHODS: Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.DISCUSSION: The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.TRIAL REGISTRATION: ClinicalTrials.gov NCT03747159 . Registered on 20 November 2018.

AB - BACKGROUND: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate.METHODS: Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections.DISCUSSION: The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE.TRIAL REGISTRATION: ClinicalTrials.gov NCT03747159 . Registered on 20 November 2018.

KW - Adult

KW - Humans

KW - Rituximab/adverse effects

KW - Lupus Nephritis/chemically induced

KW - Lupus Erythematosus, Systemic/diagnosis

KW - Immunosuppressive Agents/adverse effects

KW - Treatment Outcome

KW - Prednisolone/adverse effects

KW - Randomized Controlled Trials as Topic

KW - Multicenter Studies as Topic

KW - Clinical Trials, Phase III as Topic

U2 - 10.1186/s13063-022-06874-w

DO - 10.1186/s13063-022-06874-w

M3 - Article

C2 - 36371234

SN - 1745-6215

VL - 23

JO - Trials

JF - Trials

IS - 1

M1 - 939

ER -