The Efficacy and Safety of Dapagliflozin in the Treatment of Hereditary Kidney Disease With Proteinuria in Children

Официальное название

The Efficacy and Safety of Dapagliflozin in the Treatment of Hereditary Kidney Disease With Proteinuria in Children: a Prospective, Randomized Crossover Trial

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат Dapagliflozin+Standard Treatment for 12 weeks,washout period for 4 weeks，then Standard Treatment alone for12 weeks
  ①Dapagliflozin+Standard Treatment for 12 weeks. Dapagliflozin therapy (Farxiga®, 10 mg tablets) is administered orally once daily,with dose adjustment based on body weight: 5 mg/day for participants ≤30 kg; 5 mg/day initially (first week), then increased to 10 mg/day for participants \>30 kg Standard Treatment:standard renin-angiotensin-aldosterone system inhibitor (RAASi) therapy(The dosage will be maintained at the pre-enrollment level throughout the entire treatment period, with no adjustment
• Препарат Standard Treatment alone for 12 weeks ,washout period for 4 weeks ,then Dapagliflozin+Standard Treatment for 12 weeks
  ①Standard Treatment for 12 weeks Standard Treatment:Standard renin-angiotensin-aldosterone system inhibitor (RAASi) therapy alone for 12 weeks.(The dosage will be maintained at the pre-enrollment level throughout the entire treatment period, with no adjustments made during therapy.) ②Washout period for 4 weeks Participants should maintenance RAASi therapy while discontinuing dapagliflozin. ③Dapagliflozin+Standard Treatment for 12 weeks Dapagliflozin therapy (Farxiga®, 10 mg tablets) is adminis

Первичные конечные точки

• Changes in 24-hour urinary protein excretion from baseline to week 12 [Срок оценки: From baseline to week 12]

Вторичные конечные точки (6)

• Changes in urinary protein to creatinine ratio (UPCR) levels from baseline to week 12 [Срок оценки: From baseline to week 12]
• Changes in urinary albumin to creatinine ratio (UACR) levels from baseline to week 12 [Срок оценки: From baseline to week 12]
• Changes in serum albumin levels from baseline to week 12 [Срок оценки: From baseline to week 12]
• Changes in estimated glomerular filtration rate from baseline to week 12 [Срок оценки: From baseline to week 12]
• Changes in blood pressure from baseline to week 12 [Срок оценки: From baseline to week 12]
• Changes in weight from baseline to week 12 [Срок оценки: From baseline to week 12]

Критерии участия

Критерии включения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Children's Hospital of Fudan University — Шанхай

Публикации

• 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. PMID 37528029
• 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. PMID 38738698
• 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. PMID 38671190
• 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. PMID 30149957
• 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. PMID 30524708
• 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 J PMID 32559474
• 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 ab PMID 34560136
• 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. PMID 32855502

Идентификаторы

NCT: NCT06890143 · DAPA-PedHKD

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗