Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03921398 |
| Other study ID # |
APHP180500 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 18, 2019 |
| Est. completion date |
August 11, 2022 |
Study information
| Verified date |
July 2023 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial 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.
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 Agency of Biomedicine).
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.
