Randomized, Double-blind, Placebo-controlled Crossover Trial Assessing the Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Primary outcome component 1 - calcium oxalate supersaturation in urine (empagliflozin treatment)
研究概览
简要总结
The aim of this study is to test the effect of a new drug on the composition of the urine in kidney stone patients. This new drug (Jardiance®, substance: empagliflozin) is currently approved in Switzerland for the treatment of patients with diabetes. Data from previous studies with and without diabetes suggest that it may have a beneficial effect on the composition of the urine and thereby reduce the risk of developing kidney stones.
详细描述
Kidney stones - a global epidemic associated with obesity and diabetes
Kidney stones are a worldwide healthcare problem with a current lifetime risk of ~18.8 % in men and ~9.4 % in women in Western civilizations. Recurrence rates are high, up to 40 % and 75 % at 5 and 10 years, respectively. Hospitalizations, surgery and lost work time associated with kidney stones cause enormous healthcare-related expenditures. Although kidney stone disease is traditionally considered an isolated renal disorder, there is overwhelming evidence that it is in fact a systemic disease. Arterial hypertension, obesity, diabetes mellitus, gouty diathesis, dyslipidemia, cardiovascular disease, chronic kidney disease and low bone mass are much more prevalent in kidney stone formers than in non-stone formers. It is currently unknown if stone disease is a cause of this co-morbidity per se or if it is a consequence of the same underlying conditions that lead to these disorders and kidney stones. Clearly, however, these co-morbidities contribute significantly to stone-related morbidity and mortality.
The strong, positive and independent association of Body Mass Index (BMI) with kidney stone disease is well established. The magnitude of the increased risk is larger in women than in men. In addition to BMI, significant weight gain is also associated with a greater risk of developing symptomatic kidney stone disease in the future. In recent decades, the prevalence of both kidney stone disease and obesity increased significantly, irrespective of age, sex and race. In large cross-sectional analyses, the prevalence of both symptomatic and asymptomatic kidney stones increased proportionally with the number of metabolic syndrome features present. Both calcium and uric acid stones are associated with obesity, but the ratio of calcium stones to uric acid stones is lower in obese compared to non-obese stone formers, suggesting a disproportionate increase of uric acid stone disease in obesity. Absolute urinary excretion rates of stone formation promoters (calcium, phosphate, oxalate and uric acid) as well as urinary supersaturation ratios for calcium oxalate and uric acid are increased in obese individuals. In addition, there is a well documented negative association of BMI with urinary pH in both stone formers and non-stone formers, and low urinary pH is the main driver of uric acid stone formation. The latter may be explained by insulin resistance which affects the generation of renal ammonium by direct and indirect mechanisms. In contrast to urinary pH, urinary calcium excretion (the main driver for calcium stone formation) is not independently associated with BMI but rather due to other factors known to affect urinary calcium excretion (e.g. secondary to increased sodium and animal protein intake).
Supersaturation - driver of kidney stone formation
Supersaturation, the presence of a material in solution at a concentration above its own solubility, is the driving force for crystallization and therefore kidney stone formation. Relevant supersaturations for kidney stones disease in humans include calcium oxalate, brushite (calcium phosphate) and uric acid. At a supersaturation <1, crystals dissolve, at a supersaturation >1, crystals form. Urinary supersaturations calculated from ambulatory 24 h urine collections accurately reflect the long-term average supersaturation values in the urine and are highly correlated with the kidney stone composition encountered in the individual kidney stone former. Treatments that reduced stone events in Randomized Controlled Trials (RCTs) are highly correlated with reductions in urinary supersaturations. A recent analysis of a large 5-year kidney stone RCT revealed that as early as 1 week after randomization, every 10 % reduction of urinary calcium oxalate supersaturation from baseline was associated with an 8 % reduction in the risk of stone recurrence during follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Empagliflozin and placebo will be provided in identically looking bottles. Besides the consecutive number, packs and pack content will look identical. Therefore, all trial personnel that is involved in recruitment and care of patients, trial assessment, monitoring and analyses will be blinded to the assigned trial arm.
入排标准
- 年龄范围
- 18 Years 至 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent as documented by signature
- •Age between 18 and 74 years old
- •One or more kidney stone event(s) in the past
- •Any past kidney stone containing ≥ 80 % of calcium or ≥ 80 % of uric acid
- •HbA1c < 6.5 %
排除标准
- •Patients with secondary causes of recurrent nephrolithiasis:
- •Severe eating disorders (anorexia or bulimia)
- •Chronic bowel disease, past intestinal or bariatric surgery
- •Sarcoidosis
- •Primary hyperparathyroidism
- •Complete distal tubular acidosis
- •Patients with the following medications:
- •Anti-diabetic treatment (insulin and non-insulin agents)
- •Patients not able or not willing to stop the following medication during the period of participation in the trial (including a time window of 4 weeks wash out prior to randomization):
- •Diuretics (thiazide and loop diuretics)
- •Carbonic anhydrase inhibitors (including topiramate)
- •Xanthine oxidase inhibitors
- •Alkali, including potassium citrate or sodium bicarbonate
- •Treatment with 1,25-OH Vitamin D (calcitriol)
- •Calcium supplementation
- •Bisphosphonates, Denosumab, Teriparatide
- •Glucocorticoids
- •Obstructive uropathy, if not treated successfully
- •Genito-urinary infection, if not treated successfully
- •Chronic kidney disease (defined as CKD-EPI eGFR < 60 mL/min per 1.73 m2 body surface area)
- •Kidney transplant
- •Pregnant and lactating women [urine pregnancy test to be performed for women of childbearing potential (defined as women who are not surgically sterilized/ hysterectomized, and/ or who are postmenopausal for less than 12 months)] or women of childbearing potential that refuse to use an effective contraceptive method (birth control pill or IUD).
- •Inability to understand and follow the protocol
- •Known allergy to the study drug
- •Participation in another interventional clinical trial within 4 weeks prior to baseline and during the current trial
研究组 & 干预措施
Empagliflozin + Placebo
1 capsule containing 25 mg empagliflozin per day for 14 days, followed by a 14-42 days wash-out phase and a second treatment phase with 1 capsule containing placebo for 14 days.
干预措施: Empagliflozin 25 MG (Drug)
Empagliflozin + Placebo
1 capsule containing 25 mg empagliflozin per day for 14 days, followed by a 14-42 days wash-out phase and a second treatment phase with 1 capsule containing placebo for 14 days.
干预措施: Placebo (Other)
Placebo + Empagliflozin
1 capsule containing placebo per day for 14 days, followed by a 14-42 days wash-out phase and a second treatment phase with 1 capsule containing 25 mg empagliflozin for 14 days.
干预措施: Empagliflozin 25 MG (Drug)
Placebo + Empagliflozin
1 capsule containing placebo per day for 14 days, followed by a 14-42 days wash-out phase and a second treatment phase with 1 capsule containing 25 mg empagliflozin for 14 days.
干预措施: Placebo (Other)
结局指标
主要结局
Primary outcome component 1 - calcium oxalate supersaturation in urine (empagliflozin treatment)
时间窗: Oxalate supersaturation will be determined at baseline and after 14 days treatment with empagliflozin
The primary endpoint is composed of three primary outcomes that will be assessed separately. 1) change in calcium oxalate supersaturation after empagliflozin treatment Calcium oxalate supersaturation will be calculated by the Equil-2 program from the oxalate concentration in urine.
Primary outcome component 1 - calcium oxalate supersaturation in urine (placebo treatment)
时间窗: Oxalate supersaturation will be determined at baseline and after 14 days treatment with placebo
The primary endpoint is composed of three primary outcomes that will be assessed separately. 1) change in calcium oxalate supersaturation after placebo treatment as a comparator for empagliflozin treatment Calcium oxalate supersaturation will be calculated by the Equil-2 program from the oxalate concentration in urine.
Primary outcome component 2 - calcium phosphate supersaturation in urine (empagliflozin treatment)
时间窗: Calcium phosphate supersaturation will be determined at baseline and after 14 days treatment with empagliflozin
The primary endpoint is composed of three primary outcomes that will be assessed separately. 2) change in calcium phosphate supersaturation after empagliflozin treatment Calcium phosphate supersaturation will be calculated by the Equil-2 program from the calcium phosphate concentration in urine.
Primary outcome component 2 - calcium phosphate supersaturation in urine (placebo treatment)
时间窗: Calcium phosphate supersaturation will be determined at baseline and after 14 days treatment with placebo
The primary endpoint is composed of three primary outcomes that will be assessed separately. 2) change in calcium phosphate supersaturation after placebo treatment as a comparator for empagliflozin treatment Calcium phosphate supersaturation will be calculated by the Equil-2 program from the calcium phosphate concentration in urine.
Primary outcome component 3 - uric acid supersaturation in urine (empagliflozin treatment)
时间窗: Uric acid supersaturation will be determined at baseline and after 14 days treatment with empagliflozin
The primary endpoint is composed of three primary outcomes that will be assessed separately. 3) change in uric acid supersaturation after empagliflozin treatment Uric acid supersaturation will be calculated by the Equil-2 program from the uric acid concentration in urine.
Primary outcome component 3 - uric acid supersaturation in urine (placebo treatment)
时间窗: Uric acid supersaturation will be determined at baseline and after 14 days treatment with placebo
The primary endpoint is composed of three primary outcomes that will be assessed separately. 3) change in uric acid supersaturation after placebo treatment as a comparator for empagliflozin treatment Uric acid supersaturation will be calculated by the Equil-2 program from the uric acid concentration in urine.
次要结局
- Blood chloride level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood phosphate level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood magnesium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood LDL cholesterol level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood uric acid level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood triglycerides level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood ionized calcium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Venous bicarbonate level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood total cholesterol level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood HDL cholesterol level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood osmolality change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood creatinine level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Venous pCO2 change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Venous pH change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood albumin level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood alcaline phosphatase activity change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood sodium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood total calcium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood potassium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood glucose level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood urea level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood haemoglobin A1c level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine calcium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine phosphate level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine magnesium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine urea level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine osmolality level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine citrate level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine sulfate level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood 1,25-OH vitamine D level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood 25-OH vitamine D level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood FGF23 level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood parathormone level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Blood TSH activity change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine sodium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine potassium level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine chloride level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine oxalate level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine uric acid level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine pCO2 change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine glucose level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine ammonia level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine creatinine level change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Urine pH change from baseline(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Calculated outcomes 1: estimated glomerular filtration rate (eGFR) (Blood)(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Calculated outcomes 2: titratable acid (urine)(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)
- Calculated outcomes 3: bicarbonate (urine)(Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline.)