Effect of Immunosuppression in IgA Nephropathy
Primary Purpose
Biopsy-proven IgA Nephropathy
Status
Unknown status
Phase
Phase 4
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Immunosuppressive treatment
intensive supportive care
Sponsored by
About this trial
This is an interventional treatment trial for Biopsy-proven IgA Nephropathy focused on measuring IgA nephropathy, immunosuppression
Eligibility Criteria
Inclusion Criteria:
- Biopsy-proven IgA nephropathy within 5 years of enrollment
- Persistent proteinuria of UPCR ≥ 1.0 g/g creatinine during 12-week supportive care including RAS blockers
- baseline eGFR ≥ 30 ml/min/1.73 m2 assessed by CKD-EPI equation
Exclusion Criteria:
- Nephrotic syndrome, atypical IgA nephropathy
- Crescents ≥ 25%
- Overt pulmonary tuberculosis
- Malignancy within 5 years of enrollment
- Pregnancy or breast feeding
- Active hepatitis, chronic hepatitis, liver cirrhosis, HIV
- Kidney transplant
- Current use of immunosuppressive treatment or prior use of immunosuppressive drugs within 1 year of enrollment
- Uncontrolled hypertension (> 160/100 mmHg)
- Aged < 19 years
- Secondary IgA nephropathy such as lupus nephritis, chronic liver disease, or Henoch-Schlein purpura
- Involvement of other clinical trials within 3 months of enrollment
Sites / Locations
- Severance Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Immunosuppression
Intensive supportive care
Arm Description
corticosteroids or cyclophosphamide added on corticosteroids
intensive supportive care with RAS blockers, blood pressure control, and protein restriction diet
Outcomes
Primary Outcome Measures
progression of disease
a composite of a ≥ 30% decline in eGFR from the baseline or the onset of ESRD
progression of disease
a composite of a ≥ 30% decline in eGFR from the baseline or the onset of ESRD
Secondary Outcome Measures
Changes in urinary protein excretion and hematuria
Changes in urinary protein excretion and hematuria
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03468972
Brief Title
Effect of Immunosuppression in IgA Nephropathy
Official Title
Effect of Immunosuppression in IgA Nephropathy
Study Type
Interventional
2. Study Status
Record Verification Date
February 2019
Overall Recruitment Status
Unknown status
Study Start Date
March 2019 (Anticipated)
Primary Completion Date
May 2023 (Anticipated)
Study Completion Date
May 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yonsei University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, leading to end stage renal disease (ESRD) in up to 30 to 40% of patients with in a few decades after diagnosis. Several therapeutic options have been used in clinical practice. However, no treatments can completely stop the progression of IgAN. Given the pathogenic mechanism of IgAN, many researchers have tried to treat patients with IgAN using immunosuppression such as corticosteroids. To date, there have been conflicting results on the effects of immunosuppression in IgAN. Earlier studies from Italian groups showed that corticosteroid treatment significantly attenuated kidney function decline and decreased the development of ESRD. Since then, the beneficial effects of corticosteroids have generally been accepted for treatment of IgAN particularly in patients with high degree of proteinuria > 1.0 g/day despite maximal conservative care during 3 to 6 months. However, a recent interventional study by German group, known as the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial, showed that immunosuppressive treatment in addition to intensive supportive care did not significantly improve renal outcome and resulted in more treatment-related side effects. Moreover, the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study, another randomized controlled study from China, was early terminated because of safety concern related to corticosteroids. Interestingly, the primary composite outcome occurred significantly less in the methylprednisolone group as compared to the placebo group despite more serious adverse events in the former group. With this background in mind, we designed a multicenter prospective randomized controlled open-label trial; a step-wise therapeutic approach with corticosteroids or add-on cyclophosphamide therapy in IgAN patients with persistent proteinuria who have preserved eGFR of ≥ 30 ml/min/1.73 m2. A total of 19 hospitals will participate in this study. During 12 weeks before the enrollment, all patients will receive maximal supportive care including the use of RAS blockers, blood pressure control with a target of <130/80 mmHg, and protein restriction diet. If proteinuria does not decrease < 1.0 g/g creatinine, patients will be randomly assigned to continue supportive care, or to receive corticosteroids. At 3 months after randomization, patients in the corticosteroid arm who have persistent proteinuria of ≥ 1.0 g/g creatinine, or fast decline in eGFR ≥ 15% from the baseline value, will additionally receive cyclosphosphamide during the following 3 months. Patients who have substantial decreased amount of proteinuria < 1.0 g/g creatinine at 3 months will continue protocol-based corticosteroids during the same period. At 6 months after randomization, patients who receive add-on cyclophosphamide will switch to azathioprine as a maintenance therapy and those who receive corticosteroids alone will discontinue the treatment and will be followed up during 24 months thereafter. At least 87 subjects (a total of 174) would be required for each group to detect 13.5% difference in response rates between the two groups based on previous studies if type I error rate is 5% and type II error is 20% given 20% of drop-out rate during the study period. The primary endpoint is the development of a ≥ 30% decline in eGFR from the baseline or the onset of ESRD. This study will unveil conflicting results on the effects of immunosuppressive treatment in IgAN patients at high risk of progression.
Detailed Description
The investigators will conduct a multicenter prospective randomized controlled open-label trial; a step-wise therapeutic approach in IgAN patients with persistent proteinuria who have preserved eGFR of ≥ 30 ml/min/1.73 m2. During 3-6 months before the enrollment, all patients will receive maximal supportive care including the use of RAS blockers, blood pressure control with a target of <130/80 mmHg, and protein restriction diet. If proteinuria does not decrease < 1.0 g/g creatinine, patients will be randomly assigned to continue supportive care, or to receive corticosteroids. At 3 months after randomization, patients in the corticosteroid arm who have persistent proteinuria of ≥ 1.0 g/g creatinine, or fast decline in eGFR ≥ 15% from the baseline value, will additionally receive cyclosphosphamide during the following 3 months. Patients who have substantial decreased amount of proteinuria < 1.0 g/g creatinine at 3 months will continue protocol-based corticosteroids during the same period. At 6 months after randomization, patients who receive add-on cyclophosphamide will switch to azathioprine as a maintenance therapy and those who receive corticosteroids alone will discontinue the treatment and will be followed up during 24 months thereafter. At least 87 subjects (a total of 174) would be required for each group to detect 13.5% difference in response rates between the two groups based on previous studies if type I error rate is 5% and type II error is 20% given 20% of drop-out rate during the study period.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Biopsy-proven IgA Nephropathy
Keywords
IgA nephropathy, immunosuppression
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
174 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Immunosuppression
Arm Type
Experimental
Arm Description
corticosteroids or cyclophosphamide added on corticosteroids
Arm Title
Intensive supportive care
Arm Type
Active Comparator
Arm Description
intensive supportive care with RAS blockers, blood pressure control, and protein restriction diet
Intervention Type
Drug
Intervention Name(s)
Immunosuppressive treatment
Intervention Description
At 3 months after randomization, patients in the corticosteroid arm who have persistent proteinuria of ≥ 1.0 g/g creatinine, or fast decline in eGFR ≥ 15% from the baseline value, will additionally receive cyclosphosphamide during the following 3 months. Patients who have substantial decreased amount of proteinuria < 1.0 g/g creatinine at 3 months will continue protocol-based corticosteroids during the same period. At 6 months after randomization, patients who receive add-on cyclophosphamide will switch to azathioprine as a maintenance therapy and those who receive corticosteroids alone will discontinue the treatment and will be followed up during 24 months thereafter. Assessment of outcome will be done at 6 months and at 36 months.
Intervention Type
Other
Intervention Name(s)
intensive supportive care
Intervention Description
During 3-6 months before the enrollment, all patients will receive maximal supportive care including the use of RAS blockers, blood pressure control with a target of <130/80 mmHg, and protein restriction diet. If proteinuria does not decrease < 1.0 g/g creatinine, patients will be randomly assigned to continue supportive care, or to receive corticosteroids.
Primary Outcome Measure Information:
Title
progression of disease
Description
a composite of a ≥ 30% decline in eGFR from the baseline or the onset of ESRD
Time Frame
6 months
Title
progression of disease
Description
a composite of a ≥ 30% decline in eGFR from the baseline or the onset of ESRD
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Changes in urinary protein excretion and hematuria
Time Frame
6 months
Title
Changes in urinary protein excretion and hematuria
Time Frame
36 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
19 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Biopsy-proven IgA nephropathy within 5 years of enrollment
Persistent proteinuria of UPCR ≥ 1.0 g/g creatinine during 12-week supportive care including RAS blockers
baseline eGFR ≥ 30 ml/min/1.73 m2 assessed by CKD-EPI equation
Exclusion Criteria:
Nephrotic syndrome, atypical IgA nephropathy
Crescents ≥ 25%
Overt pulmonary tuberculosis
Malignancy within 5 years of enrollment
Pregnancy or breast feeding
Active hepatitis, chronic hepatitis, liver cirrhosis, HIV
Kidney transplant
Current use of immunosuppressive treatment or prior use of immunosuppressive drugs within 1 year of enrollment
Uncontrolled hypertension (> 160/100 mmHg)
Aged < 19 years
Secondary IgA nephropathy such as lupus nephritis, chronic liver disease, or Henoch-Schlein purpura
Involvement of other clinical trials within 3 months of enrollment
Facility Information:
Facility Name
Severance Hospital
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Seung Hyeok Han, MD, Ph.D
Phone
82-2-2228-1984
Email
hansh@yuhs.ac
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
19628647
Citation
Manno C, Torres DD, Rossini M, Pesce F, Schena FP. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant. 2009 Dec;24(12):3694-701. doi: 10.1093/ndt/gfp356. Epub 2009 Jul 23. Erratum In: Nephrol Dial Transplant. 2010 Apr;25(4):1363-4.
Results Reference
result
PubMed Identifier
26630142
Citation
Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, Panzer U, Peters H, Benck U, Mertens PR, Kuhlmann U, Witzke O, Gross O, Vielhauer V, Mann JF, Hilgers RD, Floege J; STOP-IgAN Investigators. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015 Dec 3;373(23):2225-36. doi: 10.1056/NEJMoa1415463.
Results Reference
result
PubMed Identifier
28763548
Citation
Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, Monaghan H, Zhao M, Barbour S, Reich H, Cattran D, Glassock R, Levin A, Wheeler D, Woodward M, Billot L, Chan TM, Liu ZH, Johnson DW, Cass A, Feehally J, Floege J, Remuzzi G, Wu Y, Agarwal R, Wang HY, Perkovic V; TESTING Study Group. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017 Aug 1;318(5):432-442. doi: 10.1001/jama.2017.9362.
Results Reference
result
PubMed Identifier
18930568
Citation
Lv J, Zhang H, Chen Y, Li G, Jiang L, Singh AK, Wang H. Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis. 2009 Jan;53(1):26-32. doi: 10.1053/j.ajkd.2008.07.029. Epub 2008 Oct 19.
Results Reference
result
PubMed Identifier
10093981
Citation
Pozzi C, Bolasco PG, Fogazzi GB, Andrulli S, Altieri P, Ponticelli C, Locatelli F. Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet. 1999 Mar 13;353(9156):883-7. doi: 10.1016/s0140-6736(98)03563-6.
Results Reference
result
PubMed Identifier
25677392
Citation
Tesar V, Troyanov S, Bellur S, Verhave JC, Cook HT, Feehally J, Roberts IS, Cattran D, Coppo R; VALIGA study of the ERA-EDTA Immunonephrology Working Group. Corticosteroids in IgA Nephropathy: A Retrospective Analysis from the VALIGA Study. J Am Soc Nephrol. 2015 Sep;26(9):2248-58. doi: 10.1681/ASN.2014070697. Epub 2015 Feb 12.
Results Reference
result
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Effect of Immunosuppression in IgA Nephropathy
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