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In August 2015, the Swiss National Science Foundation launched the first call to fund Investigator Initiated Clinical Trials (IICT). One of these first round funded IICTs is the NOSTONE trial, which is supported by the CTU Bern.

The NOSTONE clinical trial is a multicenter, randomized, placebo-controlled, double-blind, parallel-group trial with the purpose to assess the efficacy of standard and low dose of a thiazide in the recurrence prevention of calcium-containing kidney stones.

Study background

Nephrolithiasis is a global health care problem with a current lifetime risk of 13 % in men and 7 % in women. Without a specific treatment, 5- and 20-year recurrence rates are ca. 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 recurrent stone disease is an attractive approach.
About 80 % 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 recurrent calcareous stone formation has been tested in several RCTs. With the exception of two trials, thiazides significantly reduced stone recurrence, on average by 50 %. Most of these trials are from the 1980ies and 90ies and the cumulative number of patients studied is remarkably low for this disease (n ≈ 300). A recent systematic review of published RCTs of thiazides in the prevention of stone recurrence identified major methodological issues in all trials. Problems encountered include: lack of double-blinding, no intention-to-treat analysis, unclear allocation concealment, lack of adverse event and drop out reporting, and unknown baseline risk of disease severity. Furthermore, very high doses of thiazides were employed in these trials, up to 100 mg daily. At such high doses, side effects occur in 30 – 40 % of patients and include electrolyte disturbances, hypocitraturia, gout, impaired glucose tolerance, skin rashes and decreased libido. Nowadays, thiazides are widely used in the treatment of recurrent nephrolithiasis and arterial hypertension, but at significantly lower doses. However, in the case of recurrent nephrolithiasis this practice is not supported by randomized evidence and consequently, we do not know whether the currently employed low dose thiazide regimens are effective in reducing the risk for stone recurrence.


Evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known.


We plan to conduct a 3 year prospective, multicentric, double-blind, placebo-controlled trial to assess the effectiveness of standard and low dose treatment in the prevention of calcium containing kidney stones.

Study methodology

416 patients will be recruited from 8 cantonal hospitals, 5 university hospitals and directly from the Swiss Kidney Stone Cohort (SKSC). SKSC was recently initiated as a prospective cohort of patients with recurrent kidney stones as part of the NCCR Kidney.
We will include adult, treatment-naïve patients with recurrent (2 or more stone episodes in the last 10 years) calcium containing kidney stones (containing 50% or more of calcium oxalate, calcium phosphate or a mixture of both). Patients with secondary causes of calcareous nephrolithiasis and pregnant women will be excluded from the study. Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg or placebo. All patients will receive state-of-the art dietary counseling according to current guidelines.
The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome and reduction in calciuria, oxaluria and urinary pH.


Inclusion criteria

  1. Informed Consent as documented by signature
  2. Age 18 years or older
  3. Recurrent kidney stone disease (≥ 2 stone events within the last 10 years prior to randomization)
  4. Any past kidney stone containing 50% or more of calcium oxalate, calcium phosphate or a mixture of both

Exclusion criteria

  1. Pharmacologic prevention for stone recurrence less than 3 months prior to randomization
  2. Patients with secondary causes of recurrent calcareous nephrolithiasis including:
    • Severe eating disorders (anorexia or bulimia)
    • Chronic inflammatory bowel disease, bariatric surgery, intestinal surgery with malabsorbtion or chronic diarrheal status
    • Sarcoidosis
    • Primary hyperparathyroidism
    • Complete distal tubular acidosis
    • Active malignancy
  3. 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
    • Denusomab
    • Teriparatide
    • Glucocorticoids
  4. Obstructive uropathy, if not treated successfully
  5. Urinary tract infection, if not treated successfully
  6. Chronic kidney disease (defined as CKD-EPI eGFR < 30 mL/min per 1,73 m2 body surface area for more than 3 months)
  7. Patients with a kidney transplant
  8. > 3 gout arthritis episodes within one year prior to randomisation or gout arthritis requiring uric acid lowering therapy
  9. Cystinuria at screening
  10. Hypokalemia (blood potassium level < 3 mmol/L) at screening
  11. Hyponatremia (blood sodium level < 125 mmol/L) at screening
  12. 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 postmenonpausal for less than 12 months)]
  13. Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial
  14. Inability to understand and follow the protocol
  15. Known allergy to the study drug


For more detailed information please visit clinicaltrials.gov or Kofam.