Effect of Sodium-Glucose Cotransporter 2 Inhibition on Urinary Biomarkers of Kidney Injury After Platinum-Based Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Urinary KIM-1/Creatinine (uKIM-1/Cr) expression at 72 hours
研究概览
简要总结
Patients with cancer who receive platinum-based chemotherapy are at increased risk of kidney injury caused by these drugs. This form of toxicity can lead to treatment delays, dose reductions, or permanent discontinuation of chemotherapy, all of which can negatively impact cancer outcomes and increase patient morbidity. Despite the clinical significance, there are currently no effective strategies to prevent platinum-induced kidney damage. Existing preventive measures-such as hydration, mannitol use, and magnesium supplementation-are limited and not always effective.
This clinical trial investigates whether a type of medication known as a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor, specifically dapagliflozin, can protect the kidneys from damage during platinum-based chemotherapy in patients with solid tumors. Researchers believe that blocking SGLT2 in the kidney may reduce toxicity in the proximal tubules-the area most affected by platinum drugs.
The primary goal of this study is to compare the levels of a specific urinary biomarker of kidney injury (called KIM-1) 72 hours after chemotherapy, between patients who receive dapagliflozin and those who receive a placebo. Lower levels of this biomarker may indicate that dapagliflozin is helping protect the kidneys.
Secondary goals include comparing additional urinary biomarkers of kidney damage and function-such as EGF (epidermal growth factor), N-acetyl-β-D-glucosaminidase (uNAG), albumin (AlbU), and β2-microglobulin (uβ2-m)-at 72 hours and 7 days after chemotherapy. The study will also assess:
The percentage of patients who develop acute kidney injury, Changes in estimated glomerular filtration rate (a measure of kidney function), Electrolyte abnormalities (sodium, magnesium, phosphorus), And any adverse events associated with dapagliflozin use. As exploratory objectives, the trial will also evaluate cancer treatment response between groups (using RECIST 1.1 criteria) and the overall safety and tolerability of dapagliflozin compared to placebo.
This is a randomized, double-blind, placebo-controlled clinical trial, meaning that participants will be randomly assigned to receive either dapagliflozin or a placebo, and neither the patients nor the study team will know who receives which treatment until the study ends.
The central hypothesis is that dapagliflozin will reduce urinary biomarkers of kidney injury by at least 50% compared to placebo, offering a potential protective strategy against platinum-induced nephrotoxicity without interfering with cancer treatment.
详细描述
Platinum-based chemotherapy agents such as cisplatin and carboplatin are widely used in the treatment of various solid tumors due to their efficacy. However, their clinical utility is frequently limited by nephrotoxicity, predominantly targeting the proximal tubular epithelium. This can lead to acute kidney injury (AKI), electrolyte imbalances (notably hypomagnesemia, hyponatremia, and hypophosphatemia), and progression to chronic kidney disease (CKD). Current preventive strategies are largely supportive and include aggressive hydration, mannitol-induced diuresis, and magnesium supplementation, none of which offer specific cellular protection.
Recent evidence suggests that inhibitors of the sodium-glucose cotransporter type 2 (SGLT2 inhibitors or iSGLT2s), such as dapagliflozin, may confer renal protective effects beyond their original indication for type 2 diabetes mellitus. Mechanistically, SGLT2 inhibition reduces proximal tubular reabsorption of sodium and glucose, leading to improved tubular oxygenation and reduced inflammatory and oxidative stress signaling. This has been associated with reduced progression of CKD and favorable modulation of tubular injury markers in both diabetic and non-diabetic populations.
The present study, DAPA-ARMOR, is a randomized, double-blind, placebo-controlled clinical trial designed to assess the nephroprotective effects of dapagliflozin in adult patients with solid tumors undergoing platinum-based chemotherapy. The hypothesis is that short-term prophylactic administration of dapagliflozin can reduce proximal tubular injury, as evidenced by changes in urinary biomarkers.
The primary endpoint is the difference in urinary levels of Kidney Injury Molecule-1 (KIM-1) 72 hours after platinum administration, between the intervention (dapagliflozin) and control (placebo) arms.
Secondary endpoints include changes in additional urinary biomarkers associated with tubular injury and repair:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent form
- •Diagnosis of a solid tumor requiring a platinum-based chemotherapy regimen (cisplatin or carboplatin)
- •Expected survival > 4 months
- •ECOG performance status 0-2
排除标准
- •History of nephrectomy
- •History of kidney transplant
- •Concurrent use of known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, cyclophosphamide, ifosfamide, methotrexate)
- •Type 1 diabetes mellitus
- •Poorly controlled type 2 diabetes (HbA1c > 8% or fasting glucose > 200 mg/dL in the past month)
- •Active glomerulopathy
- •Prior use of SGLT2 inhibitors or current indication for their use
- •eGFR < 20 ml/min/1.73 m²
- •Active urinary tract infection
- •Unresolved obstructive uropathy
- •Participation in another clinical trial
- •History of recurrent genitourinary infections
研究组 & 干预措施
Dapagliflozin
This arm aims to evaluate the potential nephroprotective effect of SGLT2 inhibition using urinary biomarkers of tubular injury.
干预措施: Dapagliflozin 10 MG Oral Tablet (Drug)
Placebo
This group serves as a control to evaluate the efficacy and safety of dapagliflozin in preventing platinum-induced nephrotoxicity.
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Urinary KIM-1/Creatinine (uKIM-1/Cr) expression at 72 hours
时间窗: 72 hours (Day 3) after platinum administration
Measurement of urinary KIM-1 normalized to creatinine (uKIM-1/Cr \[pg/mg\]) to evaluate renal tubular injury at 72 hours after platinum-based chemotherapy, comparing dapagliflozin vs. placebo.
次要结局
- Urinary Epidermal Growth Factor levels adjusted by creatinine (EGF/Cr)(Baseline to Day 3 and Day 7)
- Urinary N-acetyl-β-D-glucosaminidase levels adjusted by creatinine (uNAG/Cr)(Baseline to Day 3 and Day 7)
- Urinary Albumin levels adjusted by creatinine (AlbU/Cr)(Baseline to Day 3 and Day 7)
- Urinary Kidney Injury Molecule-1 levels adjusted by creatinine (KIM-1/Cr)(Baseline to day 7 after platinum administration)
- Urinary β2-microglobulin levels adjusted by creatinine (uβ2-m/Cr)(Baseline to Day 3 and Day 7)
- Incidence of Acute Kidney Injury (AKI) at 72 hours and Day 7(Baseline to Day 3 and Day 7)
- Safety and tolerability of dapagliflozin in patients with solid tumors receiving platinum-based chemotherapy(From first dose of study drug through 4 weeks of follow-up)
- Estimated Glomerular Filtration Rate (eGFR) at 72 hours and Day 7(72 hours (Day 3), 168 hours (Day 7) after platinum administration)