Targeting the Pathophysiology of Sickle Cell-Related Kidney Disease Using the SGLT2 Inhibitors, Empagliflozin

Обзор

Sickle cell anemia (SCA) is an inherited red blood disorder. The kidneys are among the most commonly affected organ systems in SCA. The Food and Drug Administration (FDA) has approved empagliflozin as a treatment to reduce the decline of kidney function in those with kidney disease. The proposed research study aims to determine whether empagliflozin can prevent the progression of kidney dysfunction in patients with sickle cell anemia (SCA) who are at high risk of developing advanced chronic kidney disease (CKD).

Вмешательства

• Препарат Empagliflozin (oral)
  10 mg

Первичные конечные точки

• Efficacy of empagliflozin - urine biomarker: Adenosine [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Efficacy of empagliflozin - urine biomarker: Nephrin [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Efficacy of empagliflozin - urine biomarker: Kidney injury molecule-1 [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Efficacy of empagliflozin R2* Cortical Oxygenation on kidney fMRI [Срок оценки: From enrollment to the end of treatment at 48 weeks]

Вторичные конечные точки (7)

• Effects of empagliflozin on UACR [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Effects of empagliflozin on 24-hour urine protein [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Effects of empagliflozin on measures of eGFR [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Effects of empagliflozin on serum biomarker: suPAR [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Effects of empagliflozin on serum biomarker: Et-1 [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Effects of empagliflozin on serum biomarker: VCAM-1 [Срок оценки: From enrollment to the end of treatment at 48 weeks]
• Effects of empagliflozin on serum biomarker: sFLTI-1 [Срок оценки: From enrollment to the end of treatment at 48 weeks]

Критерии участия

Критерии включения

• Documentation of SCA genotype (HbSS or HbSβ0-thalassemia)
• Albuminuria defined by a UACR of 100 - 2,000 mg/g creatinine at the screening
• Hemoglobin (Hb) ≥ 5.5 g/dL during screening
• For participants taking Endari, the dose of Endari must be stable for at least one month prior to signing the ICF and with no anticipated need for dose adjustments during the study
• For participants on crizanlizumab or chronic red blood cell transfusions, the therapy must have started at least 3 months prior to consent
• For participants taking an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), the dose must be stable for at least 3 months prior to signing the ICF and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator
• Participants must demonstrate regular compliance with clinic visits and outpatient management
• Participants, if female and of childbearing potential, will use highly effective methods of contraception from study start to 30 days after the last dose of the study drug
• Participant has provided documented informed consent or assent

Критерии исключения

• Concurrent diagnosis of diabetes mellitus
• Female who is breast feeding, pregnant, or unwilling to use birth control as described in the protocol
• Prior hypersensitivity or intolerance to a sodium-glucose cotransporter-2 inhibitor (SGLT2i)
• Active or open leg ankle ulcer
• Chronic urinary tract infection
• Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior to signing consent
• Hepatic dysfunction characterized by alanine aminotransferase (ALT) >5× ULN
• Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed
• Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive
• Moderate to severe CKD (defined by an eGFR < 30 mL/min/1.73m2, on chronic dialysis, or having received a kidney transplantation)
• History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy)
• History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:

• Unstable angina pectoris or myocardial infarction or elective coronary intervention
• Uncontrolled clinically significant arrhythmias
• Any condition affecting drug absorption, such as major surgery involving the stomach (e.g. bariatric surgery) or small intestine (prior cholecystectomy is acceptable)
• Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of agent, whichever is longer, or is currently participating in another trial of an investigational agent or medical device)
• Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent
• Contraindication to MRI (certain pacemakers, electronic implants, shrapnel in the eyes, or certain intracranial aneurysm clips)

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of Illinois Chicago, Sickle Cell Center — Chicago

Публикации

• Srivastava A, Cai X, Lee J, Li W, Larive B, Kendrick C, Gassman JJ, Middleton JP, Carr J, Raphael KL, Cheung AK, Raj DS, Chonchol MB, Fried LF, Block GA, Sprague SM, Wolf M, Ix JH, Prasad PV, Isakova T. Kidney Functional Magnetic Resonance Imaging and Change in eGFR in Individuals with CKD. Clin J Am Soc Nephrol. 2020 Jun 8;15(6):776-783. doi: 10.2215/CJN.13201019. Epub 2020 Apr 28. PMID 32345747
• Prasad PV, Li LP, Thacker JM, Li W, Hack B, Kohn O, Sprague SM. Cortical Perfusion and Tubular Function as Evaluated by Magnetic Resonance Imaging Correlates with Annual Loss in Renal Function in Moderate Chronic Kidney Disease. Am J Nephrol. 2019;49(2):114-124. doi: 10.1159/000496161. Epub 2019 Jan 22. PMID 30669143
• Prasad PV, Li W, Raj DS, Carr J, Carr M, Thacker J, Li LP, Wang C, Sprague SM, Ix JH, Chonchol M, Block G, Cheung AK, Raphael K, Gassman J, Wolf M, Fried LF, Isakova T; CKD Optimal Management with BInders and NicotinamidE (COMBINE) study group. Multicenter Study Evaluating Intrarenal Oxygenation and Fibrosis Using Magnetic Resonance Imaging in Individuals With Advanced CKD. Kidney Int Rep. 2018 Ju PMID 30450473
• Wang J, Silaghi P, Guo C, Harro D, Eitzman DT. Inhibition of sodium-glucose cotransporter-2 improves anaemia in mice and humans with sickle cell disease, and reduces infarct size in a murine stroke model. J Cell Mol Med. 2024 Sep;28(17):e70091. doi: 10.1111/jcmm.70091. PMID 39267208
• Tian Q, Guo K, Deng J, Zhong Y, Yang L. Effects of SGLT2 inhibitors on haematocrit and haemoglobin levels and the associated cardiorenal benefits in T2DM patients: A meta-analysis. J Cell Mol Med. 2022 Jan;26(2):540-547. doi: 10.1111/jcmm.17115. Epub 2021 Dec 8. PMID 34878225
• von Eynatten M, Baumann M, Heemann U, Zdunek D, Hess G, Nawroth PP, Bierhaus A, Humpert PM. Urinary L-FABP and anaemia: distinct roles of urinary markers in type 2 diabetes. Eur J Clin Invest. 2010 Feb;40(2):95-102. doi: 10.1111/j.1365-2362.2009.02220.x. Epub 2009 Nov 11. PMID 19912308
• Johannes T, Mik EG, Nohe B, Unertl KE, Ince C. Acute decrease in renal microvascular PO2 during acute normovolemic hemodilution. Am J Physiol Renal Physiol. 2007 Feb;292(2):F796-803. doi: 10.1152/ajprenal.00206.2006. Epub 2006 Oct 31. PMID 17077389
• Grune T, Sommerburg O, Siems WG. Oxidative stress in anemia. Clin Nephrol. 2000 Feb;53(1 Suppl):S18-22. PMID 10746801

Идентификаторы

NCT: NCT07175051 · 2025-0637

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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