Transcriptional and Immine Parameters of Response to Belinumab

• ClinicalTrials.gov Identifier: NCT04570306
• Recruitment Status: Unknown
• First Posted: September 30, 2020
• Last Update Posted: December 7, 2020
• Sponsor: Biomedical Research Foundation, Academy of Athens
• Information provided by (Responsible Party): DIMITRIOS BOUMPAS, Biomedical Research Foundation, Academy of Athens

Tracking Information

• First Submitted Date: June 19, 2020
• First Posted Date: September 30, 2020
• Last Update Posted Date: December 7, 2020
• Estimated Study Start Date: December 31, 2020
• Estimated Primary Completion Date: December 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 25, 2020)

Changes in blood transcriptome in relation to clinical response induced by belimumab [ Time Frame: 1, 3 and 6 months ]

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 25, 2020)

• Changes in blood transcriptome in relation to low disease activity induced by belimumab [ Time Frame: 3 and 6 months ]
  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 low disease activity in SLE (according to the Low Disease Activity State definition)
• Changes in blood transcriptome in relation to remission induced by belimumab [ Time Frame: 6 months ]
  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 remission in SLE (according to the Definition of Remission [DORIS] in SLE)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Transcriptional and Immine Parameters of Response to Belinumab
• Official Title: Whole Blood Transcriptional and Mass Cytometry Immune Profiling in Systemic Lupus Erythematosus (SLE) Patients to Discern the Salutary Effects of Belimumab on Halting Disease Progression and Flares Without Compromising Host Fitness
• 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.

Detailed Description

B-cell activating factor (BAFF) excess causes lupus disease by exerting costimulatory effects on the B-cell compartment but also on a variety of non-B-cell subsets such as T-helper cells and monocytes/dendritic cells. The 2019 updated European League Against Rheumatism (EULAR) recommendations for SLE recommend usage of belimumab (anti-BAFF mAb) in persistently active or flaring disease based upon evidence for efficacy, reduction of flares and organ damage accrual without increasing the risk of infections. Still, belimumab is usually reserved for established, refractory cases. It is conceivable that earlier usage may halt the progression of the disease, especially prevent flares and dysfunction in major organs. The investigators have completed a combined genetic and transcriptomic analysis in the peripheral blood of SLE patients and have characterized distinct gene signatures for disease activity/flare and severity. Using machine learning techniques, the investigators can predict SLE patients likely to develop major organ involvement. In vitro and gene profiling studies in purified lupus monocytes indicate that these cells exist - under the effect of type I interferon - in a "high alert" autoreactive and metabolic state (reminiscent of 'trained immunity'), which may contribute to risk of flares, tissue injury but also major comorbidities seen in SLE, particularly accelerated atherosclerosis and infections. Based upon the clinical experience accumulated thus far, it is likely that belimumab may neutralize these molecular signatures for flares and disease progression without interfering with host defense immune pathways.

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 identified activity/flare, severity and major organ disease 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 of the deconvoluted RNA-seq and mass cytometry data 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, while supporting the early use of the drug.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

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

• 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 physician global assessment (PhGA) ≥1.5. Both flaring (acute exacerbation) and persistent disease activity will be considered.
• Condition: Systemic Lupus Erythematosus

Intervention

Drug: Belimumab

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.

Study Groups/Cohorts

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.

Intervention: Drug: Belimumab

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: September 25, 2020): 80
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2023
• Estimated Primary Completion Date: December 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: SLE patients:

• 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 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.

Exclusion Criteria:

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04570306
• Other Study ID Numbers: DB11
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: DIMITRIOS BOUMPAS, Biomedical Research Foundation, Academy of Athens
• Original Responsible Party: Same as current
• Current Study Sponsor: Biomedical Research Foundation, Academy of Athens
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Dimitrios T Boumpas, MD; Biomedical Research Foundation, Academy of Athens

• PRS Account: Biomedical Research Foundation, Academy of Athens
• Verification Date: December 2020