Transcriptional and Immune Parameters of Response to Belimumab

NCT04570306 | Completed FDA Drug

• 1 other identifier: DB11
• Study Type: observational
• Target: 85
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators propose to perform RNA-sequencing of the whole blood initially, in a cohort of 80 SLE patients who will receive belimumab as part of standard clinical practice, in order to assess intra-patient longitudinal (baseline, 1, 3 and 6 months) transcriptome changes and examine whether treatment can ameliorate the activity/flare, severity and major organ disease gene signatures. The investigators will also obtain preliminary information on molecular signatures predicting clinical responses and the impact of belimumab on gene signatures of host defense against viral and bacterial (including mycobacterial) pathogens. Using modules of cell type-specific genes and co-expression gene networks, The investigators will deconvolute our data to define pertinent molecular alterations in specific immune cell types. Results will be validated and functionally characterized by single-cell mass cytometry (performed at the aforementioned time points), which enables investigation of the cell identity (including subsets of B-cells and myeloid cells of particular relevance to the disease) and activation status at protein level (e.g. phosphorylation) through next-generation, high-dimensional flow cytometry. Through a focused analysis followed by targeted gene expression and function studies in purified monocytes, the investigators will determine whether belimumab can restore "SLE-primed" monocytes thus, alleviating their inflammatory and pro-atherogenic phenotype and enhancing their bactericidal activity. Collectively, these studies will provide novel mechanistic insights on the beneficial efficacy/toxicity ratio of belimumab therapy in SLE.

Conditions

Systemic Lupus Erythematosus

Keywords

transcriptome; trained immunity; host-pathogen defense

Outcome Measures

Primary Outcomes (1)

• Changes in blood transcriptome in relation to clinical response induced by belimumab

  To evaluate changes in SLE blood transcriptome that are induced by treatment with belimumab with emphasis on the reversibility of previously-defined gene signatures for disease activity/flare, severity/progression and major organ involvement. Results will be correlated with validated patient outcomes such as clinical response (defined according to SLE Responder Index-4).

  1, 3 and 6 months

Secondary Outcomes (2)

• Changes in blood transcriptome in relation to low disease activity induced by belimumab

  3 and 6 months

• Changes in blood transcriptome in relation to remission induced by belimumab

  6 months

Study Arms (1)

Belimumab-treated SLE patients

SLE patients with active disease who will be started on add-on treatment with belimumab on top of standard of care.

Drug: Belimumab

Interventions

Belimumab DRUG

The study will involve 80 adult patients diagnosed with SLE who will be started on belimumab (standard approved dose of i.v. 10 mg/kg or subcutaneous 200 mg/week) due to active disease. The intention to start belimumab will be made by the treating Rheumatologist(s), in accordance to the current standard of care, and on the basis of shared physician-patient decision making.

Belimumab-treated SLE patients

Eligibility Criteria

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

Study Population

The study will involve 80 adult patients diagnosed with SLE (according to the SLICC 2012 and/or EULAR/ACR 2019 classification criteria) who will be started on belimumab (standard approved dose of i.v. 10 mg/kg or subcutaneous 200 mg/week) due to active disease. The intention to start belimumab will be made by the treating Rheumatologist(s), in accordance to the current standard of care, and on the basis of shared physician-patient decision making. Active SLE is defined as the combination of clinical (i.e., excluding serology) SLEDAI-2K ≥6 and/or physician global assessment (PhGA) ≥1.5. Both flaring (acute exacerbation) and persistent disease activity will be considered.

You may qualify if:

• who meet the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and/or European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 classification criteria;
• have active disease defined as the combination of clinical (i.e., excluding serology) SLEDAI-2000 ≥6 and/or physician global assessment (PhGA) ≥1.5. Both flaring (acute exacerbation) and persistent disease activity will be considered;
• are started belimumab (standard approved dose of i.v. 10 mg/kg or subcutaneous 200 mg/week) due to active disease. The intention to start belimumab will be made by the treating Rheumatologist(s), in accordance to the current standard of care, and on the basis of shared physician-patient decision making.

You may not qualify if:

• age \<18 years
• co-existing rheumatic or other autoimmune disease
• pregnancy
• active infection
• history of malignant disorder

Sponsors & Collaborators

• Biomedical Research Foundation, Academy of Athens: lead
• Attikon Hospital: collaborator
• University Hospital of Heraklion: collaborator
• GlaxoSmithKline: collaborator

Study Sites (1)

BRFAA

Athens, 11527, Greece

Location

Related Publications (8)

• Steri M, Orru V, Idda ML, Pitzalis M, Pala M, Zara I, Sidore C, Faa V, Floris M, Deiana M, Asunis I, Porcu E, Mulas A, Piras MG, Lobina M, Lai S, Marongiu M, Serra V, Marongiu M, Sole G, Busonero F, Maschio A, Cusano R, Cuccuru G, Deidda F, Poddie F, Farina G, Dei M, Virdis F, Olla S, Satta MA, Pani M, Delitala A, Cocco E, Frau J, Coghe G, Lorefice L, Fenu G, Ferrigno P, Ban M, Barizzone N, Leone M, Guerini FR, Piga M, Firinu D, Kockum I, Lima Bomfim I, Olsson T, Alfredsson L, Suarez A, Carreira PE, Castillo-Palma MJ, Marcus JH, Congia M, Angius A, Melis M, Gonzalez A, Alarcon Riquelme ME, da Silva BM, Marchini M, Danieli MG, Del Giacco S, Mathieu A, Pani A, Montgomery SB, Rosati G, Hillert J, Sawcer S, D'Alfonso S, Todd JA, Novembre J, Abecasis GR, Whalen MB, Marrosu MG, Meloni A, Sanna S, Gorospe M, Schlessinger D, Fiorillo E, Zoledziewska M, Cucca F. Overexpression of the Cytokine BAFF and Autoimmunity Risk. N Engl J Med. 2017 Apr 27;376(17):1615-1626. doi: 10.1056/NEJMoa1610528.

  PMID: 28445677 BACKGROUND

• Kang S, Fedoriw Y, Brenneman EK, Truong YK, Kikly K, Vilen BJ. BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis. J Immunol. 2017 Apr 1;198(7):2602-2611. doi: 10.4049/jimmunol.1600281. Epub 2017 Feb 24.

  PMID: 28235864 BACKGROUND

• Urowitz MB, Ohsfeldt RL, Wielage RC, Kelton KA, Asukai Y, Ramachandran S. Organ damage in patients treated with belimumab versus standard of care: a propensity score-matched comparative analysis. Ann Rheum Dis. 2019 Mar;78(3):372-379. doi: 10.1136/annrheumdis-2018-214043. Epub 2019 Jan 4.

  PMID: 30610066 BACKGROUND

• Panousis NI, Bertsias GK, Ongen H, Gergianaki I, Tektonidou MG, Trachana M, Romano-Palumbo L, Bielser D, Howald C, Pamfil C, Fanouriakis A, Kosmara D, Repa A, Sidiropoulos P, Dermitzakis ET, Boumpas DT. Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity. Ann Rheum Dis. 2019 Aug;78(8):1079-1089. doi: 10.1136/annrheumdis-2018-214379. Epub 2019 Jun 5.

  PMID: 31167757 BACKGROUND

• Novakovic B, Habibi E, Wang SY, Arts RJW, Davar R, Megchelenbrink W, Kim B, Kuznetsova T, Kox M, Zwaag J, Matarese F, van Heeringen SJ, Janssen-Megens EM, Sharifi N, Wang C, Keramati F, Schoonenberg V, Flicek P, Clarke L, Pickkers P, Heath S, Gut I, Netea MG, Martens JHA, Logie C, Stunnenberg HG. beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell. 2016 Nov 17;167(5):1354-1368.e14. doi: 10.1016/j.cell.2016.09.034.

  PMID: 27863248 BACKGROUND

• van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, Zhong ZJ, Freimuth W. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012 Aug;71(8):1343-9. doi: 10.1136/annrheumdis-2011-200937. Epub 2012 Feb 15.

  PMID: 22337213 BACKGROUND

• Goh C, Knight JC. Enhanced understanding of the host-pathogen interaction in sepsis: new opportunities for omic approaches. Lancet Respir Med. 2017 Mar;5(3):212-223. doi: 10.1016/S2213-2600(17)30045-0.

  PMID: 28266329 BACKGROUND

• Monaco G, Lee B, Xu W, Mustafah S, Hwang YY, Carre C, Burdin N, Visan L, Ceccarelli M, Poidinger M, Zippelius A, Pedro de Magalhaes J, Larbi A. RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types. Cell Rep. 2019 Feb 5;26(6):1627-1640.e7. doi: 10.1016/j.celrep.2019.01.041.

  PMID: 30726743 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood RNA tubes, ethylenediaminetetraacetic acid (EDTA) tubes for genomic DNA extraction

MeSH Terms

Conditions

Lupus Erythematosus, Systemic

Interventions

belimumab

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Dimitrios T Boumpas, MD

  Biomedical Research Foundation, Academy of Athens

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chairman Department of Medicine, Medical School, National and Kapodestrian University of Athens

Study Record Dates

• First Submitted: June 19, 2020
• First Posted: September 30, 2020
• Study Start: December 16, 2020
• Primary Completion: December 16, 2023
• Study Completion: December 16, 2023
• Last Updated: June 11, 2024

Record last verified: 2024-06

Locations

GR (1)