Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05358652 |
| Other study ID # |
ISS 13844 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 15, 2021 |
| Est. completion date |
January 15, 2023 |
Study information
| Verified date |
April 2022 |
| Source |
Fundacin Biomedica Galicia Sur |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Lupus nephritis (LN) may affect approximately half of patients with Systemic Lupus
Erythematosus (SLE). LN is a major cause of morbidity and the most important predictor of
mortality in patients with SLE. Some 5-20% of patients with LN may develop end-stage renal
disease within 10 years of follow-up from the time of diagnosis. Other studies have described
progression to end-stage renal disease in 10-30% of patients with LN.
The European League Against Rheumatism, the European Renal Association and the European
Dialysis and Transplant Association have recently updated their recommendations for the
management of LN. These recommend the use of intravenous (IV) methylprednisolone boluses
followed by lower doses of oral glucocorticoids (GC) and place mycophenolate mofetil (MMF)
and the European regimen of cyclophosphamide (CYC) as the immunosuppressive drugs of first
choice, with the IV CYC regimen for certain more aggressive cases. They also consider the use
of "multitarget therapy" based on the combination of tacrolimus (TAC) and MMF and GC in
patients with proteinuria in the nephrotic range who have not responded to the first line of
treatment. For refractory active renal disease, they recommend as an alternative the use of
rituximab (RTX) 1000 mg IV repeated after 15 days.
Belimumab has been shown to be significantly more effective than placebo in the treatment of
patients with active LN. This finding will lead to positioning belimumab in the therapeutic
algorithm for LN.
However, in clinical practice these immunosuppressive drugs are not always effective in the
treatment of LN, and even one in 3 patients with an initial favorable response may experience
renal recurrence.
The choice of the appropriate treatment for LN and its early initiation are key to improve
the prognosis of these patients and to avoid progression to chronic renal failure.
The identification of biomarkers capable of predicting the response (or lack thereof) to one
or another therapy at the time of LN diagnosis would allow to implement precision medicine,
thus constituting a revolution in the treatment of patients with LN. Allows more targeted
treatments with greater specificity to be established.
The objective of this project is to analyze histopathological biomarkers in the renal biopsy
to predict the renal response to the different drugs used in the treatment of LN. This would
contribute to a more specific and cost-effective therapeutic strategy.
Description:
Sample size For this proof-of-concept study, our objective is to analyze around 60 renal
biopsy samples (expandable according to the results obtained).
Methods:
The following general variables will be collected:
- demographic data: age, sex, ethnicity.
- clinical data on SLE:
- diagnosis and chronological data: time of SLE diagnosis, time of LN diagnosis, time form
SLE diagnosis to LN.
- 1997 ACR SLE classification criteria,
- activity: involvement of different organs and systems by SELENA-SLEDAI at the time of LN
diagnosis and at the time of the last evaluation of the patient (or death, if
applicable).
- damage: by item and by domain according to the Systemic Lupus International
Collaborating Clinics Damage Index (SDI) at the time of LN diagnosis and at the time of
the last evaluation of the patient (or death, if applicable).
- comorbidity: arterial hypertension, diabetes, dyslipemia, smoking habit, severe
infections, neoplasms, etc. at the time of LN diagnosis and at the time of the last
evaluation of the patient (or death, if applicable).
- laboratory data at the time of LN diagnosis and at the time of the last evaluation of
the patient (or death, if applicable):
- blood (general tests): acute phase reactants (erythrocyte sedimentation rate and
C-reactive protein), full blood count, creatinin, glomerular filtration rate, blood urea
nitrogen, liver function tests, lipid profile.
- blood (serological tests): complement (C3 and C4), levels of anti-dsDNA antibodies,
antiphospholipid antibodies: anticardiolipin (Ig M and Ig G), anti-beta2GP-1 (Ig M and
Ig G), lupus anticoagulant.
- urine: hematuria, piuria, proteinuria, casts.
- histopathological markers of renal biopsy:
- histological class according to the 2003 ISN/RPS classification.
- National Institutes of Health (NIH) activity index: score (maximum 24) and by item
(endocapillary hypercellularity, neutrophils/karyiorrhexis, hyaline deposits/wire loops,
fibrinoid necrosis, cellular o fibrocellular crescents, interstitial inflammation).
- National Institutes of Health (NIH) chronicity index: score (maximum 12) and by item
(global glomerulosclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis).
- markers related to B lymphocytes which may include but is not limited to: CD19, CD20 and
CD138.
- markers related to BLyS (B lymphocyte stimulator) and its functional consequences which
may include but is not limited to expression of BLyS and its receptors: BAFF-R, BCMA and
TACI.
- markers related to other cell lineages which may include but is not limited to: CD3 for
T cells and CD68 for macrophages.
- markers whose determination in urine has proved useful in the diagnosis and follow-up of
LN which may include but is not limited to the proinflammatory cytokine Monocyte
Chemoattractant Protein-1 (MCP-1) and the Neutrophil Gelatinase Associated Lipocalin
(NGAL).
- SLE therapeutical data (including duration of the treatment):
- treatments for SLE prior to the diagnosis of LN: antimalarials, glucocorticoids (maximum
dose), immunosuppressants: azathioprine (AZA), mophetil mycophenolate (MMF),
cyclophosphamide (CYC); biological therapies: belimumab, rituximab.
- treatment of LN: glucocorticoids (maximum dose), immunosuppressants: AZA, MMF, CYC;
biological therapies: belimumab, rituximab.
- therapeutical data of comorbidities (including duration of the treatment):
antihypertensive agents, oral antidiabetics, insulin, hypolipidemic drugs.
- Evolution/prognosis of SLE: accumulated damage by using SDI (by item and by domain),
comorbidities accrual, severe infections, organ failure, death.
Variables will be collected to establish different patterns of response to treatment and
evolution of LN:
1. complete renal response, defined according to EULAR/ERA-EDTA recommendations (13):
proteinuria <0.5 g/24 hours and (near) normal estimated GFR.
2. partial renal response, defined according to EULAR/ERA-EDTA recommendations: ≥50%
proteinuria reduction to subnephrotic levels and (near) normal eGFR
3. no response: all the other cases.
4. proteinuria levels at 12 months of treatment,
5. renal relapse as defined as reproducible increase in uPCR to >1 g if the baseline value
was <0.2 g, to >2 g if the baseline value was between 0.2 g and 1 g, or more than twice
the value at baseline if the baseline value was >1 g AND/OR reproducible decrease in GFR
of >20%, accompanied by proteinuria (>1 g), and/or RBC and/or WBC cellular casts (yes/no
and number of flares), e) time to first flare, f) chronic renal failure,
6. end-stage renal disease requiring dialysis and/or renal transplantation. Data collection
will be based on the clinical history of the patients included in the study.
Confidentiality will be respected in accordance with RD 1720/2007 and the Data Protection
Laws. Approval will be requested from the Galician Clinical Research Ethics Committee (CEIC)
as well as from the CEIC of each center, if necessary.
EXPERIMENTAL STRATEGY AND RATIONALE In this project we will use renal biopsies from patients
with LN. These samples, preserved in 10% formaldehyde and embedded in paraffin blocks by the
corresponding Anatomic Pathology Services, correspond to patients with LN who underwent renal
biopsy in the centers participating in the project.
BLyS (B lymphocyte stimulator) plays a key role in the pathophysiology of LN. Therefore, in
this study we will focus on markers related to BLyS and its functional consequences. On the
one hand, we will analyze among others the expression levels of BLyS and its receptors
(BAFF-R, BCMA and TACI), since the expression levels of BLyS and its receptors are elevated
in serum and renal biopsies of patients with LN and are associated with disease progression
and severity.
On the other hand, because BLyS induces B cell survival, we will analyze the expression
levels of different B cell markers such as CD19 and CD20 among others. Finally, we will
analyze the plasma cell marker CD138, since plasma cell infiltration is associated with
increased severity of lupus nephritis. We will analyze the expression levels of markers of
other cell lineages such as CD3 for T cells and CD68 for macrophages.
We will also analyze at least 2 biomarkers whose urinary levels in patients with LN have been
associated with a worse prognosis of LN: the chemokine MCP-1 (monocyte chemoattractant
protein-1) and the enzyme NGAL (neutrophil gelatinase-associated lipocalin).
The expression of these markers will be initially determined by immunohistochemical staining
of renal biopsies, which are preserved in formaldehyde. The samples will be stained and
analyzed mainly in the Anatomic Pathology Service of the "Complejo Hospitalario Universitario
de Vigo" and in the laboratories of the "Instituto de Investigación Sanitaria Galicia Sur"
(IISGS), although the different participating centers will participate in this work to the
extent possible and cost-effective for the project. Different methods of quantification will
be used in function of the stains of the different markers.
STATISTICAL ANALYSIS In the descriptive study, numerical variables will be expressed as mean
± standard deviation (SD) or median and interquartile range (IQR), depending on whether the
distribution is normal or not, respectively. We will establish 2 groups of patients,
according to the response to treatment and the clinical evolution of the patient with LN
(i.e., complete remission yes/no). To establish differences between patients in these 2
groups, we will use the χ2 test for categorical variables or Fisher's exact test when the
expected frequencies are small, the t-Student test for normal continuous variables, and the
Mann-Whitney U test for variables with non-normal distribution.
Different methods to analyze and/or mitigate the missing data problem will be used.
The percentage of positive cells and staining intensity will be correlated with the different
patterns of response to treatment and evolution of LN.
Univariate and multivariate linear logistic regression analyses will be performed to explore
the relationships between the different variables studied (clinical, histopathological,
therapeutic...) and the presence of the different renal outcomes (dependent variable). Values
of p <0.05 will be considered significant.
We will carry out other different statistical methods according to the results that we
observe from our initial analysis.
Statistical analyses will be performed by the Statistical Specialist of the IRIDIS Group.
TIMELINES Development of the definitive protocol: month 1. Submission and Approval by Ethics
Committee: months 1-3. Renal samples identification and preparation: months 4-5. Informed
consent signatures: months 4-6. Shipment of renal samples: months 4-6. Anatomo-pathological
and laboratory studies: months 7-12. Review of clinical charts: months 7-12. Monitoring of
the database: months 13-15. Statistical analysis: month 16. Elaboration of the final report:
month 17-18.
RESEARCH TEAM Principal Investigator: Dr. José Mª Pego Reigosa, Rheumatology Specialist,
Complexo Hospitalario Universitario de Vigo. IRIDIS-VIGO Group (Investigation in Rheumatology
and Immune-Mediated Diseases), Instituto de Investigación Sanitaria Galicia Sur (IISGS).
Researchers in the coordinating center: Dr. Irene Altabás González (Rheumatologist, Complexo
Hospitalario Universitario de Vigo, IRIDIS-VIGO Group), Dr. Noemí Martínez López de Castro
(Hospital Pharmacist, Complexo Hospitalario Universitario de Vigo, IRIDIS-VIGO Group), Dr.
Carmen Fachal Bermúdez (Nephropathologist, Complexo Hospitalario Universitario de Vigo) and
Dr. Samuel García Pérez (Molecular Biologist, Senior Researcher, IRIDIS-VIGO Group).
Collaborating centers (Rheumatology, Nephrology, Pathological Anantomy Services): Hospital 12
de octubre (Madrid, Spain), Hospital Araba (Vitoria, Spain), Hospital Germans Trias i Pujol
(Barcelona, Spain), Hospital del Mar (Barcelona, Spain) and Hospital Dr. Negrín (Gran
Canaria, Spain).
