NCT03057431

Hydrochlorothiazide for Kidney Stone Recurrence Prevention

Randomized Double-blind Placebo-controlled Trial Assessing the Efficacy of Standard and Low Dose Hydrochlorothiazide Treatment in the Prevention of Recurrent Nephrolithiasis

• Status: Completed
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 416 (actual)
• Sponsor: Insel Gruppe AG, University Hospital Bern · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Nephrolithiasis

Interventions

Type	Name	Description
DRUG	Placebo oral capsule	Once daily for 3 years
DRUG	12.5 mg hydrochlorothiazide	Once daily for 3 years
DRUG	25.0 mg hydrochlorothiazide	Once daily for 3 years
DRUG	50.0 mg hydrochlorothiazide	Once daily for 3 years

Timeline

• Start date: 2017-03-09
• Primary completion: 2021-12-03
• Completion: 2022-04-30
• First posted: 2017-02-20
• Last updated: 2024-02-01
• Results posted: 2024-02-01

Locations

12 sites across 1 country: Switzerland