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Trial registered on ANZCTR


Registration number
ACTRN12618000601235
Ethics application status
Approved
Date submitted
18/10/2017
Date registered
18/04/2018
Date last updated
18/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Elucidating pathways of progression of chronic kidney disease in FSGS.
Scientific title
Pathogenic molecular/cellular responses leading to chronic kidney disease in primary Focal and Segmental Glomerulosclerosis (FSGS) in Indians
Secondary ID [1] 293130 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
GRACE: FSGS-I (Glomerular Research And Clinical Experiments: Focal and Segmental Glomerulosclerosis in Indians)
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Focal Segmental Glomerulosclerosis 305093 0
Chronic kidney disease 305094 0
Glomerulonephritis 305095 0
Condition category
Condition code
Renal and Urogenital 304406 304406 0 0
Kidney disease
Inflammatory and Immune System 304407 304407 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The exposure to be studied is primary focal segmental glomerulosclerosis (FSGS). At baseline, the demography, clinical features, investigations, renal biopsy and treatment details will be recorded in case report forms. The follow-up will be at least twice a year for 24 months. At follow-up the relevant clinical features, investigations and treatment details will be recorded in the case report forms. The duration of follow up for participants in the study is 24 months from the time of recruitment.
Intervention code [1] 299378 0
Early Detection / Screening
Comparator / control treatment
Disease control group will be adult patients diagnosed to have glomerulonephritis other than FSGS by renal biopsy. At baseline, the demography, clinical features, investigations, renal biopsy and treatment details will be recorded in case report forms. Healthy controls will be participants who have no known illnesses. There is no follow-up for the control arm.
Control group
Active

Outcomes
Primary outcome [1] 303642 0
The lymphocyte subsets (CD4+, CD8+, natural killer cells) will be enumerated in peripheral blood and renal tissue collected at baseline using flow-cytometry techniques. It is a composite outcome. This is an exploratory outcome.
Timepoint [1] 303642 0
Baseline
Primary outcome [2] 304832 0
The localisation and activation state of the lymphocyte subsets in the renal tissue at baseline using flow-cytometry techniques. It is a composite outcome.
Timepoint [2] 304832 0
Baseline
Primary outcome [3] 304833 0
Cytokine profile of the lymphocyte subsets involved in hypoxia and fibrosis pathway in the renal tissue at baseline using enzyme linked immuno-sorbent assay and immuno-histochemistry staining. This is an exploratory outcome.
Timepoint [3] 304833 0
Baseline
Secondary outcome [1] 339743 0
Establish the source of urinary exosomes in FSGS with RT-PCR, PCR, LC-MS techniques at baseline.
Timepoint [1] 339743 0
Baseline
Secondary outcome [2] 339744 0
Establish the molecular cargo of urinary exosomes in FSGS with RT-PCR, PCR, LC-MS techniques at baseline.
Timepoint [2] 339744 0
Baseline
Secondary outcome [3] 339745 0
Establish clinical features of kidney disease as determined using demography, medical records and baseline investigations.
Timepoint [3] 339745 0
Baseline
Secondary outcome [4] 344442 0
Clinical response as assessed by 24 hour urine protein and CKD-EPI eGFR (derived from serum creatinine) and classified as complete response, partial response, no response, progressive CKD stages, end stage kidney disease.
Complete response is defined as 24 hour urine protein less than or equal to 300mg per day and CKD-EPI eGFR greater than or equal to 60ml/min/1.73m2.
Partial response is defined as 50% education in proteinuria from baseline and 24 hour urine protein less than or equal to 3.5 g/day along stable CKD-EPI eGFR not more than 25% of the baseline values.
No response is defined as persistent or increasing proteinuria with stable stable CKD-EPI eGFR not more than 25% of the baseline values.
Progressive CKD stages is when the renal function worsens with or without proteinuria.
End stage kidney disease is defined as CKD-EPI eGFR less than or equal to 15ml/min/1.73m2 with or without the need for renal replacement therapy.
Timepoint [4] 344442 0
24 months
Secondary outcome [5] 344444 0
Describe toxicities and side effects of treatment. This will be assessed through medical records, hospital records, patient-reported, etc. The side effects that may occur are infections, steroid induced diabetes, Cushing's etc.
Timepoint [5] 344444 0
24 months

Eligibility
Key inclusion criteria
Inclusion criteria for the FSGS study group
i. Adult patients (age greater than or equal to 18 years)
ii. Diagnosed as primary FSGS by renal biopsy
iii. Immunosuppressive treatment naïve for at least one month prior to renal biopsy
iv. Baseline estimated GFR (glomerular filtration rate) between 15-60ml/min/1.73m2
v. Willingness to be included in the study
Inclusion criteria for the Disease control group
i. Adult patients (age greater than or equal to 18 years)
ii. Diagnosed as primary glomerulonephritis other than FSGS by renal biopsy
iii. Immunosuppressive treatment naïve for at least one month prior to renal biopsy
iv. Baseline estimated GFR (glomerular filtration rate) between 15-60ml/min/1.73m2
v. Willingness to be included in the study
Inclusion criteria for the Healthy control group
i. Adults (age greater than or equal to 18 years)
ii. No known illnesses
iii. Willingness to be included in the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for the FSGS study group
i. Secondary FSGS
ii. Glomerular filtration rate (GFR) as estimated by the CKD-EPI equation
<15ml/min/1.73m2 or >60ml/min/1.73m2
iii. Patients with systemic diseases that can affect the kidneys like diabetes, systemic lupus erythematosus, presence of HIV, HbsAg, HCV infections, malignancies etc.
iv. Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study.
Exclusion criteria for Disease control group
i. Secondary glomerulonephritis
ii. Glomerular filtration rate (GFR) as estimated by the CKD-EPI equation
<15ml/min/1.73m2 or >60ml/min/1.73m2
iii. Patients with systemic diseases that can affect the kidneys like diabetes, systemic lupus erythematosus, presence of HIV, HbsAg, HCV infections, malignancies etc.
iv. Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study.
Exclusion criteria for Healthy control group
i. Age greater than or equal to 18 years
ii. Any known systemic illnesses

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample size- Since this is an exploratory study, there is no formal sample size calculation. It is a pilot study that will give us important pathogenetic information for planning further large cohort studies. We will be recruiting 50 biopsy proven FSGS subjects with 20 disease and 20 healthy controls. Twenty healthy people will serve as controls for standardization of test results. Twenty disease controls (non-FSGS primary glomerulonephritis) will be recruited as controls for changes in biomarkers due to renal impairment and proteinuria.

Statistical Analysis- Categorical baseline characteristics (e.g. sex, race, co-morbid illnesses, etc) will be expressed with the number and percent of subjects in each treatment group. Quantitative characteristics (e.g., age and weight) will be summarized by mean and standard deviation or median [inter quartile range], depending on data distribution. The number and percent of subjects will be provided for each reason for premature discontinuation. Differences in proportions will be evaluated by chi square or Fisher’s exact tests. Comparisons between groups will be performed using Student's t-test or the Mann-Whitney U test depending on the data distribution. Correlation between treatment and clinical response will be done with tests as described above. The risk factors for progressive disease will be evaluated using a Cox proportional hazard model with a stepwise backward elimination method.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2018
Actual
Date of last participant enrolment
Anticipated
14/03/2019
Actual
Date of last data collection
Anticipated
28/02/2021
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment outside Australia
Country [1] 9284 0
India
State/province [1] 9284 0
Tamil Nadu

Funding & Sponsors
Funding source category [1] 297756 0
Hospital
Name [1] 297756 0
Royal Brisbane and Women’s Hospital (RBWH) Research Grant
Country [1] 297756 0
Australia
Funding source category [2] 297768 0
Government body
Name [2] 297768 0
National Health and Medical Research Council (NHMRC) Project Grant
Country [2] 297768 0
Australia
Funding source category [3] 297769 0
Hospital
Name [3] 297769 0
Department of Nephrology CKD Research Fund
Country [3] 297769 0
India
Primary sponsor type
Hospital
Name
Christian Medical College
Address
Department of Nephrology,
Christian Medical College,
Vellore-632004, Tamil Nadu
Country
India
Secondary sponsor category [1] 296793 0
Hospital
Name [1] 296793 0
Royal Brisbane and Women’s Hospital (RBWH)
Address [1] 296793 0
Bowen Bridge Road and Butterfield St, Herston Queensland 4029
Country [1] 296793 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298819 0
The Institutional Review Board (Silver, Research and Ethics Committee) of the Christian Medical College
Ethics committee address [1] 298819 0
Christian Medical College,
Vellore-632004,
Tamil Nadu,
India
Ethics committee country [1] 298819 0
India
Date submitted for ethics approval [1] 298819 0
19/04/2017
Approval date [1] 298819 0
12/09/2017
Ethics approval number [1] 298819 0
IRB min. 10650 [Other]
Ethics committee name [2] 298830 0
Royal Brisbane and Women’s Hospital (RBWH) Human Research Ethics Committee
Ethics committee address [2] 298830 0
RBWH, Level 7 Block 7, Butterfield St, Herston Queensland 4029
Ethics committee country [2] 298830 0
Australia
Date submitted for ethics approval [2] 298830 0
31/05/2017
Approval date [2] 298830 0
07/06/2017
Ethics approval number [2] 298830 0
Ref No. 2002/011

Summary
Brief summary
Background: An understanding of the molecular pathways driving persistent renal inflammation is essential to decipher the pathogenesis of various forms of kidney diseases and to develop novel and more-efficient targeted therapeutics to prevent end stage kidney disease. Cell and molecular pathways will be tested for utility as a non-invasive precision diagnostic that is adjunct to traditional histopathology. Regulatory and switch points in the pathogenesis will be tested as targets for more specific therapeutic immunosuppression.
Aim: We aim to define the lymphocyte subsets, explore novel hypoxia-inducible pathways and characterize proximal tubular epithelial cell (PTEC) derived urinary exosomes and their contribution to tubulointerstitial inflammation/fibrosis and thus, progression of FSGS.
Methods: Clinical information, blood, urine and renal tissue will be collected in 50 consecutive patients who are clinically suspected to have FSGS. The samples will be processed in those whose histological diagnosis is in keeping with the clinical suspicion of FSGS. Patients with glomerulonephritis other than FSGS will be treated as disease controls and we will also recruit 20 healthy controls. The source of biosamples in these experiments will be the blood, urine and renal tissue collected from patients at the time of kidney biopsy performed for clinical indications.
Results: We hope to describe patient, demography and clinical variables and map these to histopathology, steroid responsiveness and disease/ patient outcomes. The study will enumerate the localisation, activation state and cytokine profile of the lymphocyte subsets in the peripheral blood and renal tissue. We will describe the molecular profiling of pathways for hypoxia response, mitochondrial activity, apoptosis/necrosis and tissue remodelling/fibrosis in renal tissue and urine and establish both the source (location of renal injury) and molecular cargo of urinary exosomes in FSGS.
Conclusions: The results of these experiments will define novel pathogenic pathways in FSGS about inflammation, hypoxia and fibrosis. These can in turn help us in developing novel therapeutic targets for treatment of FSGS.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78330 0
Prof Suceena Alexander
Address 78330 0
Department of Nephrology,
Christian Medical College,
Vellore- 632004,
Tamil Nadu,
India.
Country 78330 0
India
Phone 78330 0
+91-416-2282053
Fax 78330 0
+91-416-2282035
Email 78330 0
[email protected]
Contact person for public queries
Name 78331 0
Suceena Alexander
Address 78331 0
Department of Nephrology,
Christian Medical College,
Vellore- 632004,
Tamil Nadu,
India.
Country 78331 0
India
Phone 78331 0
+91-416-2282053
Fax 78331 0
+91-416-2282035
Email 78331 0
[email protected]
Contact person for scientific queries
Name 78332 0
Helen Healy
Address 78332 0
Director, Kidney Health Service
Head, Conjoint Kidney Research Laboratory
Metro North Hospital and Health Service
Level 9, Ned Hanlon Building
RBWH
Butterfield St, Herston Queensland 4029
Country 78332 0
Australia
Phone 78332 0
+61 7 3646 1682
Fax 78332 0
Email 78332 0
[email protected]

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What supporting documents are/will be available?

Current supporting documents:


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23566Study protocol  [email protected]

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