Identifying New Therapeutic Targets for Lupus Treatment (ELUDIAL)

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ClinicalTrials.gov Identifier: NCT03921398

Recruitment Status : Recruiting

First Posted : April 19, 2019

Last Update Posted : June 18, 2021

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Sponsor:

Collaborator:

Institut National de la Santé Et de la Recherche Médicale, France

Information provided by (Responsible Party):

Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

Lupus is an autoimmune disease affecting mainly young women (9/1). Lupus nephritis (LN) occurs in 30% of the cases of lupus and is associated with end stage renal disease (ESRD) in 17 to 25% of cases after 10 years. Overall, nearly 7% of lupus patients will develop ESRD due to LN. Historically, 5-year survival after LN was lower than 20%. Nowadays, 45% of patients suffer from multiple relapses that are associated with an intermediate risk of ESRD. When ESRD occurs, lupus activity decreases progressively to reach a stable extinct state. At this stage it is possible to stop all medications to control lupus, without any flare of lupus activity. Lupus extinction following ESRD corresponds to a state of complete remission. Obtaining such a result before ESRD would avoid damages to several organs and side effects of immunosuppressive therapy. Understanding the mechanisms responsible for lupus extinction following ESRD is an innovative approach to decipher lupus pathophysiology. The objective of the study is to identify the mechanisms responsible for lupus extinction and to propose new therapeutic options based on these new mechanisms. Mechanisms responsible for lupus extinction are unknown. Lupus extinction depends on the duration of ESRD. Accumulation of several toxins that kidneys would normally eliminate in the urine is a hallmark of ESRD. Such toxins are called "uremic toxins" since they accumulate during "uremia" (ESRD). They affect biological systems such as fertility and immunity that are both closely related to lupus pathophysiology. The investigators hypothesize that studying LN extinction after ESRD will provide novel therapeutic targets to extinct lupus before ESRD. To this end, they will investigate several non-exclusive hypotheses based on previous findings of our consortium, or issued from clinical observations: the sexual dysfunction hypothesis and the ESRD-associated immune cells dysfunction hypothesis. In parallel, they will conduct an open screening of new mechanisms underlying the lupus extinction through the characterization of the differential gene expression profile associated with lupus extinction in patients undergoing dialysis.

Condition or disease
Lupus Nephritis

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Detailed Description:

Lupus is an autoimmune disease affecting mainly young women (9/1). Lupus nephritis (LN) occurs in 30% of patients and is associated with end stage renal disease (ESRD) in 17 to 25% of cases after 10 years. Overall, nearly 7% of lupus patients will develop ESRD due to LN. Historically, the 5-year survival after LN was below 20%. Nowadays, 45% of patients suffer from multiple relapses that are associated with an intermediate risk of ESRD. When ESRD occurs, lupus activity decreases progressively to reach a stable extinct state. At this stage it is possible to stop all medications to control lupus, without any flare of lupus activity. Lupus extinction following ESRD corresponds to a state of complete remission. Obtaining such a result before ESRD would prevent the damages of active lupus to several organs and side effects of immunosuppressive therapy. Understanding the mechanisms responsible for lupus extinction following ESRD is an innovative approach to decipher lupus pathophysiology.

The objective of this study is to identify the mechanisms responsible for lupus extinction in ESRD (candidate pathways) and to propose new therapeutic options targeting those candidates.

There is an important need for treatment innovation for systemic lupus and LN. A large number of biotherapies have been developed recently based on the known pathophysiology of the disease. Despite important efforts made by the medical community, many research groups, and pharmaceutical companies, randomized clinical trials (RCT) failed to validate innovative treatment strategies for several decades. This project proposes the identification of new treatment solutions through explorations in a field free of previous investigation in that aim.

A detailed knowledge of lupus extinction is required to understand its pathophysiology. This study will detail the timeframe of, and the factors associated with lupus extinction after ESRD. Moreover, previous investigations had been conducted separately in different projects and mainly provided descriptive results. Then a global and integrative strategy of research will be built in an attempt to embrace the subject as broadly as possible and maximize the opportunities to obtain successful outcome. The project will investigate specific hypotheses that were developed from the investigators' experience and based on the expertise of the consortium, both in lupus and immune dysfunction and in ESRD and uremic toxins. The addition of a "without a priori" approach by a systematic screening of gene expression associated with lupus extinction in haemodialysis will allow the investigators to propose a large panel of potential candidates to investigate further. Altogether, identifying the causes responsible for lupus extinction following ESRD is an innovative approach to discover new therapeutic targets. The investigators hypothesize that mimicking LN extinction due to ESRD provides a unique opportunity to propose new strategies to treat active lupus and LN before ESRD. The mechanisms responsible for lupus extinction are unknown. Lupus extinction depends on the duration of ESRD. Accumulation of several toxins that kidneys would normally eliminate in the urine is a hallmark of ESRD. Such toxins are called "uremic toxins" since they accumulate during "uremia" (ESRD). They affect biological systems such as fertility and immunity that are both closely related to lupus pathophysiology.

The investigators hypothesize that studying lupus extinction after ESRD will provide novel therapeutic targets to extinct lupus before ESRD. To this end, they propose to investigate several non-exclusive hypotheses based on previous findings: the sexual dysfunction hypothesis and the ESRD-associated immune cells dysfunction hypothesis. In parallel, they will conduct an open screening of new mechanisms underlying the lupus extinction through the characterization of the differential gene expression profile associated with lupus extinction in patients on chronic haemodialysis, comparing gene expression of dialysis patients with extinct lupus versus patients with still active lupus at the time of the study.

They first propose a comparison of active and extinct lupus in patients with ESRD. Lupus patients on chronic haemodialysis in Ile-de-France (n=75) will be recruited for the biological and clinical comparison between patients with persistent lupus activity to those with extinct lupus. These dialysis patients have been identified from the national REIN registry, which prospectively collects data for all incident patients undergoing renal replacement therapy (dialysis or kidney transplantation). A specific authorization was obtained from the Scientific Board of the REIN Registry at Agence de la Biomédecine). Additionally, patients with active lupus prior to treatment and no ESRD will serve as a "positive control" group (n=45) for markers of cellular activation and blood transcriptomic profile during lupus nephritis.

Study Design

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Study Type :	Observational [Patient Registry]
Estimated Enrollment :	140 participants
Observational Model:	Case-Crossover
Time Perspective:	Cross-Sectional
Target Follow-Up Duration:	1 Day
Official Title:	Identifying New Therapeutic Targets for Lupus Treatment
Actual Study Start Date :	June 18, 2019
Estimated Primary Completion Date :	June 1, 2022
Estimated Study Completion Date :	June 1, 2022

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Lupus Nephritis Glomerulonephritis

U.S. FDA Resources

Groups and Cohorts

Group/Cohort
Patients with ESRD Patients with history of biopsy-proven lupus nephritis (all classes of lupus nephritis)
Patients with active lupus prior to treatment and no ESRD Patients with biopsy-proven ACTIVE lupus nephritis
Healthy individuals Healthy individuals

Outcome Measures

Primary Outcome Measures :

Nombre of patients treated by sequential haemodialysis with lupus extinction [ Time Frame: Inclusion ]
non-renal SELENA SLEDAI score < 4 and absence

Biospecimen Retention: Samples With DNA

Blood and saliva samples Feces samples

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Lupus patients on chronic haemodialysis in Ile-de-France (n=75) will be recruited for biological and clinical comparison between patients with persistent lupus activity to those with extinct lupus. These dialysis patients have been identified from the national REIN registry, which prospectively collects data for all incident patients undergoing renal replacement therapy (dialysis or kidney transplantation).

Additionally, patients with active lupus prior to treatment and no ESRD will serve as a "positive control" group (n=45) for markers of cellular activation and blood transcriptomic profile during lupus nephritis.

Healthy controls are required to establish reference values for assays specifically developed for the ELUDIAL study.

Criteria

INCLUSION CRITERIA

For the group of 75 patients on hemodialysis

Age ≥ 18 years,
History of biopsy-proven lupus nephritis (all classes of lupus nephritis)

For the group of 45 patients with active lupus, not on hemodialysis

Age ≥ 18 years,
Biopsy-proven ACTIVE lupus nephritis

For the group of 20 healthy individuals

• Age ≥ 18 years

EXCLUSION CRITERIA

For the group of 75 patients on hemodialysis

No written informed consent
Past-history of kidney transplantation
Active infection
Active allergy (such as hay fever)
Pregnant or breastfeeding women
Non-affiliation to a social security regime
Protected adults (individuals under guardianship by court order)

For the group of 45 patients with active lupus, not on hemodialysis

No written informed consent
Immunosuppressive therapy (except corticosteroids)
Corticosteroids pulse before renal biopsy
Pregnant or breastfeeding women
Non-affiliation to a social security regime
Protected adults (individuals under guardianship by court order)

For the group of 20 healthy individuals

No written informed consent
Immunosuppressive therapy (including corticosteroids)
History of autoimmune disease
Pregnant or breastfeeding women
Non-affiliation to a social security regime
Protected adults (individuals under guardianship by court order)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03921398

Contacts

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Contact: Eric DAUGAS, MD PhD	33140257101	eric.daugas@aphp.fr
Contact: François GAILLARD, MD PhD	33140257101	gaillard.f@protonmail.com

Locations

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France
Hôpital Bichat	Recruiting
Paris, France, 75018
Contact: Eric DAUGAS, MD PhD

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Institut National de la Santé Et de la Recherche Médicale, France

Investigators

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Principal Investigator:	Eric DAUGAS, MD PhD	Assistance Publique - Hôpitaux de Paris

More Information

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Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT03921398
Other Study ID Numbers:	APHP180500
First Posted:	April 19, 2019 Key Record Dates
Last Update Posted:	June 18, 2021
Last Verified:	June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Assistance Publique - Hôpitaux de Paris:


Lupus nephritis haemodialysis

Additional relevant MeSH terms:

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Nephritis Lupus Nephritis Kidney Diseases Urologic Diseases Glomerulonephritis	Lupus Erythematosus, Systemic Connective Tissue Diseases Autoimmune Diseases Immune System Diseases

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