Ignite Creation Date:
2024-05-06 @ 5:35 PM
Last Modification Date:
2024-10-26 @ 2:31 PM
Study NCT ID:
NCT05358652
Status:
UNKNOWN
Last Update Posted:
2022-05-03
First Post:
2022-04-28
Brief Title:
Precision Medicine in LN A Multicenter Proof-of-concept Study for Histopathological Biomarkers Analysis in Renal Biopsy
Sponsor:
Fundacin Biomedica Galicia Sur
Organization:
Fundacin Biomedica Galicia Sur
Study Overview
Official Title:
Precision Medicine in Lups Nephritis A Multicenter Proof-of-concept Study for Histopathological Biomarkers Analysis in Renal Biopsy
Status:
UNKNOWN
Status Verified Date:
2022-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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
Detailed 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 ISNRPS classification
National Institutes of Health NIH activity index score maximum 24 and by item endocapillary hypercellularity neutrophilskaryiorrhexis hyaline depositswire 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
Evolutionprognosis 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 EULARERA-EDTA recommendations 13 proteinuria 05 g24 hours and near normal estimated GFR
2 partial renal response defined according to EULARERA-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 02 g to 2 g if the baseline value was between 02 g and 1 g or more than twice the value at baseline if the baseline value was 1 g ANDOR reproducible decrease in GFR of 20 accompanied by proteinuria 1 g andor RBC andor WBC cellular casts yesno and number of flares e time to first flare f chronic renal failure
6 end-stage renal disease requiring dialysis andor 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 17202007 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 ie complete remission yesno To establish differences between patients in these 2 groups we will use the χ2 test for categorical variables or Fishers 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 andor 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 005 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
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 ISNRPS classification
National Institutes of Health NIH activity index score maximum 24 and by item endocapillary hypercellularity neutrophilskaryiorrhexis hyaline depositswire 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
Evolutionprognosis 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 EULARERA-EDTA recommendations 13 proteinuria 05 g24 hours and near normal estimated GFR
2 partial renal response defined according to EULARERA-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 02 g to 2 g if the baseline value was between 02 g and 1 g or more than twice the value at baseline if the baseline value was 1 g ANDOR reproducible decrease in GFR of 20 accompanied by proteinuria 1 g andor RBC andor WBC cellular casts yesno and number of flares e time to first flare f chronic renal failure
6 end-stage renal disease requiring dialysis andor 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 17202007 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 ie complete remission yesno To establish differences between patients in these 2 groups we will use the χ2 test for categorical variables or Fishers 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 andor 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 005 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None