Randomized Double-blind Placebo-controlled Trial Assessing the Efficacy of Standard and Low Dose Hydrochlorothiazide Treatment in the Prevention of Recurrent Nephrolithiasis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 416
- 试验地点
- 12
- 主要终点
- Number of Participants With Stone Recurrences
研究概览
简要总结
The investigators plan to assess the efficacy of standard and low dose HCTZ treatment in the recurrence prevention of calcium-containing kidney stones. More specifically, the investigators aim to assess the dose-response relationship for three different dosages of HCTZ.
Study intervention: HCTZ 12.5 mg, 25 mg or 50 mg once daily per os for 24 or 36 months. In addition, all patients in HCTZ treatment arms will receive state-of-the-art non-pharmacologic recommendations for stone prevention according to current guidelines.
Control intervention: Placebo once daily per os for 24 to 36 months. In addition, all patients in the placebo arm will receive state-of-the-art non-pharmacologic recommendations for stone prevention according to current guidelines.
详细描述
Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Without specific treatment, 5- and 20-year recurrence rates are 40% and 75%, respectively. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach.
About 80-90% of stones are composed of calcium oxalate with various admixtures of calcium phosphate. Increased excretion of calcium in the urine, hypercalciuria, is the most common metabolic abnormality encountered in patients with recurrent nephrolithiasis. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. The effect of thiazides to reduce the risk of stone recurrence has been attributed to their ability to decrease urinary calcium excretion. However, other factors, such as reduction of urinary pH and urinary oxalate excretion, probably contribute to this effect. Efficacy of thiazides on recurrence prevention of calcareous nephrolithiasis was tested in 11 randomized controlled trials (RCTs). With the exception of two trials, thiazides significantly reduced stone recurrence. Most of these trials are from the 1980's and 90's and the cumulative number of patients studied is remarkably low for such a prevalent disease. Our systematic review of these RCTs revealed major methodological deficiencies in all trials, including: lack of double-blinding and intention-to-treat analysis, unclear allocation concealment, lack of adverse event and drop out reporting and unknown baseline risk of disease severity. Furthermore, high doses of thiazides were employed in all trials, in the case of the best studied thiazide, hydrochlorothiazide (HCTZ), up to 100 mg daily. At such high doses, side effects occur frequently. Nowadays, thiazides are widely used in the treatment of recurrent nephrolithiasis and arterial hypertension, but at significantly lower doses. In the case of recurrent nephrolithiasis, however, this practice is not supported by randomized evidence and consequently, the investigators do not know whether the currently employed low dose thiazide regimens are effective in reducing the risk for stone recurrence.
Thus, evidence for benefits and harms of thiazide diuretics in the prevention of calcium-containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known.
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
- Double (Participant, Care Provider)
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
- •Informed Consent as documented by signature
- •Age 18 years or older
- •Recurrent kidney stone disease (≥ 2 stone events within the last 10 years prior to randomization)
- •Any past kidney stone containing 50% or more of calcium oxalate, calcium phosphate or a mixture of both
排除标准
- •Pharmacologic prevention for stone recurrence less than 3 months prior to randomization
- •Patients with secondary causes of recurrent calcareous nephrolithiasis including:
- •Severe eating disorders (anorexia or bulimia)
- •Chronic inflammatory bowel disease, bariatric surgery, intestinal surgery with malabsorption or chronic diarrheal status
- •Sarcoidosis
- •Primary hyperparathyroidism
- •Complete distal tubular acidosis
- •Active malignancy
- •Patients with the following medications:
- •Thiazide or loop diuretics
- •Carbonic anhydrase inhibitors (including topiramate)
- •Xanthine oxidase inhibitors (febuxostat or allopurinol)
- •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
- •Urinary tract infection, if not treated successfully
- •Chronic kidney disease (defined as CKD-EPI eGFR < 30 mL/min per 1,73 m2 body surface area for more than 3 months)
- •Patients with a kidney transplant
- •> 3 gout arthritis episodes within one year prior to randomisation or gout arthritis requiring uric acid lowering therapy
- •Cystinuria at screening
- •Hypokalemia (blood potassium level < 3 mmol/L) at screening
- •Hyponatremia (blood sodium level < 125 mmol/L) at screening
- •Pregnant and lactating women [pregnancy test to be performed for women of child-bearing potential (defined as women who are not surgically sterilized/ hysterectomized, and/ or who are postmenopausal for less than 12 months)]
- •Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial
- •Inability to understand and follow the protocol
- •Known allergy to the study drug
研究组 & 干预措施
Placebo
Once daily for 3 years
干预措施: Placebo oral capsule (Drug)
12.5 mg hydrochlorothiazide
Once daily for 3 years
干预措施: 12.5 mg hydrochlorothiazide (Drug)
25.0 mg hydrochlorothiazide
Once daily for 3 years
干预措施: 25.0 mg hydrochlorothiazide (Drug)
50.0 mg hydrochlorothiazide
Once daily for 3 years
干预措施: 50.0 mg hydrochlorothiazide (Drug)
结局指标
主要结局
Number of Participants With Stone Recurrences
时间窗: After 3 years
Composite of symptomatic or radiological recurrences, defined as either a symptomatic kidney stone passage or radiological kidney stone recurrence on CT. Symptomatic recurrence was defined as the visible passage of a stone with or without accompanying typical symptoms (such as flank or loin pain and hematuria) or as the presence of a symptomatic or asymptomatic stone that was determined to require surgical removal. If a patient had symptoms during the trial that were suggestive of a possible stone passage but no visible stone had been observed, local investigators evaluated the symptoms of the patient and judged whether a stone passage had occurred. Radiological recurrence was defined as a new stone formed or enlargement of a preexisting stone.
次要结局
- Number of Symptomatic Stone Recurrences(After 3 years)
- Number of Radiologic Stone Recurrences.(After 3 years)