Multicentre Clinical Study to Evaluate the Effect of Personalized Therapy on Patients With Immunoglobulin A Nephropathy.

NCT04662723 | Recruiting Phase 4 DMC

• 1 other identifier: 2
• Study Type: interventional
• Target: 878
• Locations: 1 country
• Sites: 2

Brief Summary

Idiopathic immunoglobulin A nephropathy (IgAN) is the most common biopsy-proven glomerulonephritis in the world. Approximately 40% of IgAN patients reach end-stage kidney disease (ESKD) 20 years after their kidney biopsy. The high prevalence of ESKD suggests the need to move from a generalized therapy for all patients to personalized therapy. Many RCTs have been conducted stratifying patients based on the laboratory findings (serum creatinine, eGFR and daily proteinuria). In contrast, data from the kidney biopsy has been used only for clinical diagnosis. Therefore, IgAN patients with active or chronic renal lesions have not been equally distributed in experimental and control arms of the randomized clinical trials (RCTs) Our clinical study of IgAN (CLIgAN) is a multicentre, prospective, controlled and open-label randomized clinical trial based on patients' stratification at the time of their kidney biopsy. The investigators will consider, first, the type of renal lesions followed by the serum creatinine values, eGFR and proteinuria. IgAN patients with active renal lesions (n=132) will be enrolled in the first RCT (ACIgAN) in which they will receive corticosteroids (pulse therapy) plus oral corticosteroids combined with RASB or RASB followed by oral corticosteroids. IgAN patients with chronic or moderate renal lesions at high or very high risk of chronic renal disease (n=294) will be enrolled in the second RCT (CHRONIgAN) in which they will receive the SGLT2 inhibitor combined with RASB compared with RASB combined with oral corticosteroids. Using this approach, the investigators hypothesize that patients could receive personalized therapy based on renal lesions to ensure that the right drug gets to the right patient at the right time. Recently, we developed a Clinical Decision Support System (CDSS) tool using artificial intelligence (artificial neural networks) to identify IgAN patients at high risk of developing ESKD. The IgAN tool (DialCheck) was validated in a retrospective cohort of IgAN patients but not in a prospective clinical study. The investigators propose to measure the power of the DiaCheck tool in patients enrolled in both RCTs to determine whether personalized therapy can slow the decline of the renal function to delay the ESKD. The CLIgAN study also includes a cutting-edge molecular study for precision therapy (PRECIgAN).

Conditions

Glomerulonephritis; Immunoglobulin A Nephropathy

Keywords

IgA nephropathy; Steroids; RAS-blockers; SGLT2-inhibitors

Outcome Measures

Primary Outcomes (12)

• -Proteinuria reduction within 6 months in IgAN patients with active renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within 6 months

  6th month

• Proteinuria reduction within 6 months in IgAN patients with active renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  12th month

• Proteinuria reduction within 6 months in IgAN patients with active renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  18th month

• Proteinuria reduction within 6 months in IgAN patients with active renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  24th month

• Proteinuria reduction within 6 months in IgAN patients with active renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  30th month

• Proteinuria reduction within 6 months in IgAN patients with active renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  36th month

• Proteinuria reduction within 6 months in IgAN patients with chronic renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  6th month

• Proteinuria reduction within 6 months in IgAN patients with chronic renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  12th month

• Proteinuria reduction within 6 months in IgAN with chronic renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  18th month

• Proteinuria reduction within 6 months in IgAN patients with chronic renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  24th month

• Proteinuria reduction within 6 months in IgAN with chronic renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  30th month

• Proteinuria reduction within 6 months in IgAN with chronic renal lesions

  Reduction of proteinuria will be calculated as difference betweeen arms within every 6 months

  36th month

Secondary Outcomes (56)

• eGFR slope change in IgAN patients with active renal lesions

  6th month

• eGFR slope change in IgAN patients with active renal lesions

  12th month

• eGFR slope change in IgAN patients with active renal lesions

  18th month

• eGFR slope change in IgAN patients with active renal lesions

  24th month

• eGFR slope change in IgAN patients with active renal lesions

  30th month

Study Arms (4)

Corticosteroids combined with RASBs

EXPERIMENTAL

Patients assigned to the corticosteroid group will receive (pulse) methylprednisolone succinate 500-1000 mg/day for 3 consecutive days followed by oral prednisolone (0.5 mg/kg/bw) on alternate days until the end of month. This treatment will be repeated for three consecutive months. In addition, patients will receive RASBs that will be titrated to their maximum anti-proteinuric effect. The dose of methylprednisolone succinate will be individualized (15 mg/kg) based on the ideal body weight. In overweight and obese IgAN patients the ideal body weight will be considered. The drug will be administered in a single daily dose intravenously for 30-60 min. To avoid obesity and diabetes corticosteroids will be administered only in the morning.

Drug: Corticosteroid; Drug: Renin-angiotensin sytem blockers

RASBs

ACTIVE COMPARATOR

Patients will receive RASBs for 3 months, titrated to their maximum anti-proteinuric effectf followed by oral corticosteroids.

Drug: Renin-angiotensin sytem blockers

SGLT2i combined with Ramipril

EXPERIMENTAL

IgAN patients with chronic renal lesions (T1,2) or moderate renal lesions (M0,1; S0,1; T0; E0; C0) at high or very high CKD risk (proteinuria\> 0.5 g/day and GFR \>30ml/min/1.73 m2) will receive SGLT2i combined with RASBs.

Drug: Renin-angiotensin sytem blockers; Drug: Sodium-glucose cotransporter 2 inhibitor

Ramipril combined with corticosteroids

ACTIVE COMPARATOR

IgAN patients with chronic renal lesions (T1,2) or moderate renal lesions (M0,1; S0,1; T0; E0; C0) at high or very high CKD risk (proteinuria\> 0.5 g/day and GFR \>30ml/min/1.73 m2) will receive RASBs for 3 months followed by oral corticosteroids.

Drug: Corticosteroid; Drug: Renin-angiotensin sytem blockers

Interventions

Corticosteroid DRUG

To reduce the progression of renal damage in IgAN Patients

Also known as: Methylprednisolone succinate, prednisolone

Corticosteroids combined with RASBs; Ramipril combined with corticosteroids

Renin-angiotensin sytem blockers DRUG

To reduce the progression of renal damage in IgAN Patients

Also known as: Ramipril, lisinopril, losartan

Corticosteroids combined with RASBs; RASBs; Ramipril combined with corticosteroids; SGLT2i combined with Ramipril

Sodium-glucose cotransporter 2 inhibitor DRUG

To reduce the progression of renal damage in IgAN Patients

Also known as: dapagliflozin, canagliflozin, empagliflozin

SGLT2i combined with Ramipril

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Only adult patients (age 18-70 years) with biopsy-proven idiopathic IgAN.
• IgAN patients with active or chronic or moderate renal lesions

You may not qualify if:

• Patients with idiopathic IgAN and nephrotic syndrome (minimal change disease at kidney biopsy)
• IgAN patients with hematuria and acute renal failure
• IgAN patients with rapidly progressive glomerulonephritis (extracapillary lesions in more than 50% of glomeruli)
• Patients with secondary IgAN (lupus nephritis, Schoenlein-Henoch purpura, liver cirrhosis)
• Any prior immunosuppressive therapy
• Superimposed IgAN in kidney transplant
• Severe liver diseases
• Infections
• Malignancies
• Pregnancy
• Patients with myocardial infarction or cerebrovascular stroke in the previous 6 months
• Uncontrolled diabetes
• Aseptic necrosis of any bone
• Other conditions that can be exacerbated by corticosteroids
• Previous adverse side effects to RASBs

Sponsors & Collaborators

• Fondazione Schena: lead
• University of Bari: collaborator

Study Sites (2)

francesco paolo Schena

Bari, BA, 70124, Italy

RECRUITING

francesco paolo Schena

Bari, BA, 70124, Italy

RECRUITING

Related Publications (23)

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• Koyama A, Igarashi M, Kobayashi M. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases. Am J Kidney Dis. 1997 Apr;29(4):526-32. doi: 10.1016/s0272-6386(97)90333-4.

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• Chapter 10: Immunoglobulin A nephropathy. Kidney Int Suppl (2011). 2012 Jun;2(2):209-217. doi: 10.1038/kisup.2012.23. No abstract available.

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• Schena FP, Anelli VW, Trotta J, Di Noia T, Manno C, Tripepi G, D'Arrigo G, Chesnaye NC, Russo ML, Stangou M, Papagianni A, Zoccali C, Tesar V, Coppo R; members of the VALIGA study. Development and testing of an artificial intelligence tool for predicting end-stage kidney disease in patients with immunoglobulin A nephropathy. Kidney Int. 2021 May;99(5):1179-1188. doi: 10.1016/j.kint.2020.07.046. Epub 2020 Sep 2.

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• Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, Cattran DC, Coppo R, D'Agati V, D'Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009 Sep;76(5):546-56. doi: 10.1038/ki.2009.168. Epub 2009 Jul 1.

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• Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009 Sep;76(5):534-45. doi: 10.1038/ki.2009.243. Epub 2009 Jul 1.

  PMID: 19571791 BACKGROUND

• Kang SH, Choi SR, Park HS, Lee JY, Sun IO, Hwang HS, Chung BH, Park CW, Yang CW, Kim YS, Choi YJ, Choi BS. The Oxford classification as a predictor of prognosis in patients with IgA nephropathy. Nephrol Dial Transplant. 2012 Jan;27(1):252-8. doi: 10.1093/ndt/gfr295. Epub 2011 May 23.

  PMID: 21606384 BACKGROUND

• 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.

  PMID: 26630142 BACKGROUND

• 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.

  PMID: 28763548 BACKGROUND

• Shen XH, Liang SS, Chen HM, Le WB, Jiang S, Zeng CH, Zhou ML, Zhang HT, Liu ZH. Reversal of active glomerular lesions after immunosuppressive therapy in patients with IgA nephropathy: a repeat-biopsy based observation. J Nephrol. 2015 Aug;28(4):441-9. doi: 10.1007/s40620-014-0165-x. Epub 2015 Jan 14.

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• Shi SF, Wang SX, Jiang L, Lv JC, Liu LJ, Chen YQ, Zhu SN, Liu G, Zou WZ, Zhang H, Wang HY. Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification. Clin J Am Soc Nephrol. 2011 Sep;6(9):2175-84. doi: 10.2215/CJN.11521210. Epub 2011 Aug 18.

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MeSH Terms

Conditions

Glomerulonephritis; Glomerulonephritis, IGA

Interventions

Adrenal Cortex Hormones; Methylprednisolone Hemisuccinate; Prednisolone; Ramipril; Lisinopril; Losartan; Sodium-Glucose Transporter 2 Inhibitors; dapagliflozin; Canagliflozin; empagliflozin

Condition Hierarchy (Ancestors)

Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Methylprednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Tetrazoles; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs; Thiophenes; Sulfur Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Francesco P Schena

  Fondazione Schena

  STUDY CHAIR

• francesco P Schena

  Fondazione Schena

  STUDY DIRECTOR

Central Study Contacts

Francesco P Schena

CONTACT

3336771291; paolo.schena@uniba.it

francesco P Schena

CONTACT

3336771291; fp.schena@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: President and scientif director

Model Details: After the enrolment the eligible biopsy-proven IgAN patients will be randomized, separately, in each trial in a 1 to 1 ratio via a web-based program generating random numbers. The allocation will be not blinded to the group of assignment.

Study Record Dates

• First Submitted: November 27, 2020
• First Posted: December 10, 2020
• Study Start: May 1, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 31, 2028
• Last Updated: April 2, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Six years
• Access Criteria: Publications or reports

Locations

IT (2)