Clinical trial NCT06890143: The Efficacy and Safety of Dapagliflozin in the Treatment of Hereditary Kidney Disease With Proteinuria in Children
Official title: The Efficacy and Safety of Dapagliflozin in the Treatment of Hereditary Kidney Disease With Proteinuria in Children: a Prospective, Randomized Crossover Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Pediatric Hereditary Kidney Diseases
Keywords: hereditary kidney diseases
proteinuria
dapagliflozin
children
Lead sponsor: Children's Hospital of Fudan University
Sponsor class: OTHER
Collaborators: name: Guangzhou Women and Children's Medical Center
name: Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
name: Shandong Provincial Hospital
name: The First Affiliated Hospital of Henan University of Traditional Chinese Medicine
name: Wuhan Children's Hospital
name: Xuzhou Children Hospital
name: First Affiliated Hospital, Sun Yat-Sen University
name: Kunming Children's Hospital
name: The Children's Hospital of Zhejiang University School of Medicine
name: Children's Hospital of Nanjing Medical University
name: Zhengzhou Children's Hospital, China
name: Xiamen Women's and Children's Hospital
name: Guiyang Maternity and Child Health Care Hospital
name: Maternal and Child Health Care Hospital of Hainan Province
name: Children's Hospital of The Capital Institute of Pediatrics
name: Second Affiliated Hospital of Wenzhou Medical University
name: Xian Children's Hospital
name: The Second Hospital of Hebei Medical University
name: Wuxi Women's & Children's Hospital
name: First People's Hospital of Urumqi
First posted: 2025-03-21
Enrollment: 44
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study is a multicenter, randomized controlled crossover trial aimed to evaluate the efficacy and safety of dapagliflozin in the treatment of hereditary kidney disease with proteinuria in children

Detailed description: Chronic kidney disease (CKD) poses a significant public health threat to children, with hereditary kidney diseases exhibiting limited therapeutic efficacy in reducing proteinuria. Global studies have demonstrated that dapagliflozin significantly reduces proteinuria in adults with CKD; however, its role in pediatric hereditary kidney diseases lacks strong evidence .This study aims to investigate the efficacy and safety of dapagliflozin in children with proteinuric hereditary kidney diseases.

This is a multicenter, open-label, block-randomized, crossover clinical trial with 1:1 allocation. A total of 44 participants will be enrolled to compare the efficacy and safety of dapagliflozin combined with standard renin-angiotensin-aldosterone system inhibitor (RAASi) therapy versus RAASi therapy alone.

The primary endpoint is the change in 24-hour urinary protein levels from baseline to 12 weeks of treatment. Secondary endpoints include: urinary protein-to-creatinine ratio (UPCR), urinary albumin-to-creatinine ratio (UACR), serum albumin levels, estimated glomerular filtration rate (eGFR), blood pressure changes, and body weight changes.

Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of hereditary kidney disease (identification of pathogenic genes through molecular genetic testing; for Alport syndrome, molecular diagnosis is not necessarily required if diagnosed based on clinical and pathological findings; for those with a clear family history and a high clinical suspicion of hereditary kidney disease).
* 24 - hour urinary protein level \> 0.2 g or urinary protein to creatinine ratio (UPCR) \> 0.2 mg/mg.
* Calculate the estimated glomerular filtration rate (eGFR) using the Schwartz formula (36.5 \* height in cm / serum creatinine in μmol/L), with eGFR ≥ 60 ml/min/1.73 m².
* Stable use of the basic treatment drug RAASi (including ACEI/ARB) for more than 4 weeks, and no dosage adjustment during the treatment period.
* Willingness to sign the informed consent form.

Exclusion Criteria:Exclusion applies if any of the following criteria are met:

* Treatment with hormones/immunosuppressive agents within the previous 4 weeks.
* Treatment with SGLT2 inhibitors within the previous 4 weeks.
* Comorbid diabetes.
* Uncontrolled urinary tract infection.
* Evidence of urinary tract obstruction such as dysuria.
* Blood pressure below the 5th percentile for the same gender, age, and height.
* Organ transplantation.
* Tumor.
* Presence of any of the following definite evidence of liver disease: ALT/AST reaching 2 times the normal value, hepatic encephalopathy, esophageal varices, or portal shunt surgery.
* Comorbid medical conditions that may affect drug absorption, distribution, metabolism, and excretion, including but not limited to any of the following: active inflammatory bowel disease within the past 6 months, history of major gastrointestinal surgery (such as gastrectomy, gastroenterostomy, intestinal resection), gastrointestinal ulcer, gastrointestinal or rectal bleeding within the past 6 months, pancreatic injury or pancreatitis within the past 6 months.
* Subjects at risk of dehydration or volume depletion, which may affect drug efficacy or safety.
* Participation in other drug trials within the previous 4 weeks.
* Blood loss exceeding 400 ml within the previous 8 weeks.
* Poor past medication compliance or unwillingness to complete the trial.
* Any other medical conditions that may place the patient at a higher risk due to participation in this study.

Primary outcomes:
measure: Changes in 24-hour urinary protein excretion from baseline to week 12
timeFrame: From baseline to week 12
Secondary outcomes:
measure: Changes in urinary protein to creatinine ratio (UPCR) levels from baseline to week 12
timeFrame: From baseline to week 12
measure: Changes in urinary albumin to creatinine ratio (UACR) levels from baseline to week 12
timeFrame: From baseline to week 12
measure: Changes in serum albumin levels from baseline to week 12
timeFrame: From baseline to week 12
measure: Changes in estimated glomerular filtration rate from baseline to week 12
timeFrame: From baseline to week 12
measure: Changes in blood pressure from baseline to week 12
timeFrame: From baseline to week 12
measure: Changes in weight from baseline to week 12
timeFrame: From baseline to week 12
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Children's Hospital of Fudan University
state: Shanghai
Study officials:
affiliation: Children's Hospital of Fudan University
name: YIHUI ZHAI
role: STUDY_DIRECTOR
References:
citation: Chinese Preventive Medicine Association for Kidney Disease. [Guidelines for the early evaluation and management of chronic kidney disease in China]. Zhonghua Nei Ke Za Zhi. 2023 Aug 1;62(8):902-930. doi: 10.3760/cma.j.cn112138-20221013-00755. Chinese.
citation: The Expert Group of Chinese Expert Consensus on the Clinical Application of Sodium-glucose Cotransporter 2 Inhibitors in Patients with Chronic Kidney Disease. Chinese expert consensus on the clinical application of sodium-glucose cotransporter 2 inhibitors in patients with chronic kidney disease. Chin Med J (Engl). 2024 Jun 5;137(11):1264-1266. doi: 10.1097/CM9.0000000000003145. Epub 2024 May 13. No abstract available.
citation: O'Hara DV, Lam CSP, McMurray JJV, Yi TW, Hocking S, Dawson J, Raichand S, Januszewski AS, Jardine MJ. Applications of SGLT2 inhibitors beyond glycaemic control. Nat Rev Nephrol. 2024 Aug;20(8):513-529. doi: 10.1038/s41581-024-00836-y. Epub 2024 Apr 26.
citation: Koppe L, Fouque D. The Role for Protein Restriction in Addition to Renin-Angiotensin-Aldosterone System Inhibitors in the Management of CKD. Am J Kidney Dis. 2019 Feb;73(2):248-257. doi: 10.1053/j.ajkd.2018.06.016. Epub 2018 Aug 24.
citation: Herrington WG, Preiss D, Haynes R, von Eynatten M, Staplin N, Hauske SJ, George JT, Green JB, Landray MJ, Baigent C, Wanner C. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J. 2018 Dec;11(6):749-761. doi: 10.1093/ckj/sfy090. Epub 2018 Oct 25.
citation: Cherney DZI, Dekkers CCJ, Barbour SJ, Cattran D, Abdul Gafor AH, Greasley PJ, Laverman GD, Lim SK, Di Tanna GL, Reich HN, Vervloet MG, Wong MG, Gansevoort RT, Heerspink HJL; DIAMOND investigators. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol. 2020 Jul;8(7):582-593. doi: 10.1016/S2213-8587(20)30162-5.
citation: Heerspink HJL, Cherney D, Postmus D, Stefansson BV, Chertow GM, Dwyer JP, Greene T, Kosiborod M, Langkilde AM, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Toto RD, Wheeler DC; DAPA-CKD Trial Committees and Investigators. A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function. Kidney Int. 2022 Jan;101(1):174-184. doi: 10.1016/j.kint.2021.09.005. Epub 2021 Sep 22.
citation: Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020 Oct;16(10):556-577. doi: 10.1038/s41574-020-0392-2. Epub 2020 Aug 27.
citation: Ravani P, Rossi R, Bonanni A, Quinn RR, Sica F, Bodria M, Pasini A, Montini G, Edefonti A, Belingheri M, De Giovanni D, Barbano G, Degl'Innocenti L, Scolari F, Murer L, Reiser J, Fornoni A, Ghiggeri GM. Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial. J Am Soc Nephrol. 2015 Sep;26(9):2259-66. doi: 10.1681/ASN.2014080799. Epub 2015 Jan 15.
citation: Heerspink HJL, Jongs N, Chertow GM, Langkilde AM, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Greene T; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):743-754. doi: 10.1016/S2213-8587(21)00242-4. Epub 2021 Oct 4.
citation: Waijer SW, Vart P, Cherney DZI, Chertow GM, Jongs N, Langkilde AM, Mann JFE, Mosenzon O, McMurray JJV, Rossing P, Correa-Rotter R, Stefansson BV, Toto RD, Wheeler DC, Heerspink HJL. Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial. Diabetologia. 2022 Jul;65(7):1085-1097. doi: 10.1007/s00125-022-05694-6. Epub 2022 Apr 21.
citation: Jongs N, Greene T, Chertow GM, McMurray JJV, Langkilde AM, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):755-766. doi: 10.1016/S2213-8587(21)00243-6. Epub 2021 Oct 4.
citation: HEERSPINK H J L, STEFáNSSON B V, CORREA-ROTTER R, et al. Dapagliflozin in Patients with Chronic Kidney Disease
citation: Heerspink HJL, Stefansson BV, Chertow GM, Correa-Rotter R, Greene T, Hou FF, Lindberg M, McMurray J, Rossing P, Toto R, Langkilde AM, Wheeler DC; DAPA-CKD Investigators. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020 Feb 1;35(2):274-282. doi: 10.1093/ndt/gfz290.
citation: Rajasekeran H, Reich HN, Hladunewich MA, Cattran D, Lovshin JA, Lytvyn Y, Bjornstad P, Lai V, Tse J, Cham L, Majumder S, Bowskill BB, Kabir MG, Advani SL, Gibson IW, Sood MM, Advani A, Cherney DZI. Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study. Am J Physiol Renal Physiol. 2018 Mar 1;314(3):F412-F422. doi: 10.1152/ajprenal.00445.2017. Epub 2017 Nov 15.
citation: Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, Barrett TD, Weidner-Wells M, Deng H, Matthews DR, Neal B. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018 Sep;6(9):691-704. doi: 10.1016/S2213-8587(18)30141-4. Epub 2018 Jun 21.
citation: Kadowaki T, Nangaku M, Hantel S, Okamura T, von Eynatten M, Wanner C, Koitka-Weber A. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME(R) trial. J Diabetes Investig. 2019 May;10(3):760-770. doi: 10.1111/jdi.12971. Epub 2019 Jan 7.
citation: Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, Bull S, Cannon CP, Charytan DM, de Zeeuw D, Edwards R, Greene T, Heerspink HJL, Levin A, Pollock C, Wheeler DC, Xie J, Zhang H, Zinman B, Desai M, Perkovic V; CREDENCE study investigators. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol. 2017 Dec 13;46(6):462-472. doi: 10.1159/000484633. Online ahead of print.
citation: Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects. J Am Soc Nephrol. 2017 Jan;28(1):368-375. doi: 10.1681/ASN.2016030278. Epub 2016 Aug 18.
citation: Tirucherai GS, LaCreta F, Ismat FA, Tang W, Boulton DW. Pharmacokinetics and pharmacodynamics of dapagliflozin in children and adolescents with type 2 diabetes mellitus. Diabetes Obes Metab. 2016 Jul;18(7):678-84. doi: 10.1111/dom.12638.
citation: Dekkers CCJ, Gansevoort RT, Heerspink HJL. New Diabetes Therapies and Diabetic Kidney Disease Progression: the Role of SGLT-2 Inhibitors. Curr Diab Rep. 2018 Mar 27;18(5):27. doi: 10.1007/s11892-018-0992-6.
citation: Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017 Feb;60(2):215-225. doi: 10.1007/s00125-016-4157-3. Epub 2016 Nov 22.
citation: Petrovic D, Stojimirovic B. Proteinuria as a risk factor for the progression of chronic renal disease. Vojnosanit Pregl. 2008 Jul;65(7):552-8. doi: 10.2298/vsp0807552p. No abstract available.
citation: Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcantoni C, de Jong PE, de Zeeuw D, Shahinfar S, Ruggenenti P, Remuzzi G, Levey AS; AIPRD Study Group. Angiotensin-Converting Enzymne Inhibition and Progression of Renal Disease. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease. Kidney Int. 2001 Sep;60(3):1131-40. doi: 10.1046/j.1523-1755.2001.0600031131.x.
citation: Leung AK, Wong AH, Barg SS. Proteinuria in Children: Evaluation and Differential Diagnosis. Am Fam Physician. 2017 Feb 15;95(4):248-254.
citation: Sumida K, Molnar MZ, Potukuchi PK, George K, Thomas F, Lu JL, Yamagata K, Kalantar-Zadeh K, Kovesdy CP. Changes in Albuminuria and Subsequent Risk of Incident Kidney Disease. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):1941-1949. doi: 10.2215/CJN.02720317. Epub 2017 Sep 11.
citation: Romagnani P, Remuzzi G, Glassock R, Levin A, Jager KJ, Tonelli M, Massy Z, Wanner C, Anders HJ. Chronic kidney disease. Nat Rev Dis Primers. 2017 Nov 23;3:17088. doi: 10.1038/nrdp.2017.88.
citation: Yang CW, Harris DCH, Luyckx VA, Nangaku M, Hou FF, Garcia Garcia G, Abu-Aisha H, Niang A, Sola L, Bunnag S, Eiam-Ong S, Tungsanga K, Richards M, Richards N, Goh BL, Dreyer G, Evans R, Mzingajira H, Twahir A, McCulloch MI, Ahn C, Osafo C, Hsu HH, Barnieh L, Donner JA, Tonelli M. Global case studies for chronic kidney disease/end-stage kidney disease care. Kidney Int Suppl (2011). 2020 Mar;10(1):e24-e48. doi: 10.1016/j.kisu.2019.11.010. Epub 2020 Feb 19.
citation: Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, Chen M, He Q, Liao Y, Yu X, Chen N, Zhang JE, Hu Z, Liu F, Hong D, Ma L, Liu H, Zhou X, Chen J, Pan L, Chen W, Wang W, Li X, Wang H. Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet. 2012 Mar 3;379(9818):815-22. doi: 10.1016/S0140-6736(12)60033-6.