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

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ClinicalTrials.gov Identifier: NCT03057431
Recruitment Status : Active, not recruiting
First Posted : February 20, 2017
Last Update Posted : November 20, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

Tracking Information
First Submitted Date  ICMJE February 15, 2017
First Posted Date  ICMJE February 20, 2017
Last Update Posted Date November 20, 2019
Actual Study Start Date  ICMJE March 9, 2017
Estimated Primary Completion Date August 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 15, 2017)
Number of stone recurrences [ Time Frame: After 3 years ]
Composite of symptomatic or radiological recurrences
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 15, 2017)
  • Number of symptomatic stone recurrences [ Time Frame: After 3 years ]
  • Number of radiologic stone recurrences [ Time Frame: After 3 years ]
    Measured by low-dose CT
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Double-blind Placebo-controlled Trial Assessing the Efficacy of Standard and Low Dose Hydrochlorothiazide Treatment in the Prevention of Recurrent Nephrolithiasis
Official Title  ICMJE Randomized Double-blind Placebo-controlled Trial Assessing the Efficacy of Standard and Low Dose Hydrochlorothiazide Treatment in the Prevention of Recurrent Nephrolithiasis
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Prevention
Condition  ICMJE Nephrolithiasis
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Once daily for 3 years
    Intervention: Drug: Placebo oral capsule
  • Experimental: 12.5 mg hydrochlorothiazide
    Once daily for 3 years
    Intervention: Drug: 12.5 mg hydrochlorothiazide
  • Experimental: 25.0 mg hydrochlorothiazide
    Once daily for 3 years
    Intervention: Drug: 25.0 mg hydrochlorothiazide
  • Experimental: 50.0 mg hydrochlorothiazide
    Once daily for 3 years
    Intervention: Drug: 50.0 mg hydrochlorothiazide
Publications * Dhayat NA, Faller N, Bonny O, Mohebbi N, Ritter A, Pellegrini L, Bedino G, Schönholzer C, Venzin RM, Hüsler C, Koneth I, Del Giorno R, Gabutti L, Amico P, Mayr M, Odermatt U, Buchkremer F, Ernandez T, Stoermann-Chopard C, Teta D, Rintelen F, Roumet M, Irincheeva I, Trelle S, Tamò L, Roth B, Vogt B, Fuster DG. Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial. BMC Nephrol. 2018 Dec 10;19(1):349. doi: 10.1186/s12882-018-1144-6.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 15, 2017)
416
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 31, 2021
Estimated Primary Completion Date August 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 malabsorption 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
    • Denosumab
    • 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 postmenopausal 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03057431
Other Study ID Numbers  ICMJE 2016-01475
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Hospital Inselspital, Berne
Study Sponsor  ICMJE University Hospital Inselspital, Berne
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Daniel Fuster, Prof MD Division of Nephrology and Hypertension, Bern University Hospital, Bern, Switzerland
PRS Account University Hospital Inselspital, Berne
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP