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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 : Recruiting
First Posted : February 20, 2017
Last Update Posted : February 16, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

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.


Condition or disease Intervention/treatment Phase
Nephrolithiasis Drug: Placebo oral capsule Drug: 12.5 mg hydrochlorothiazide Drug: 25.0 mg hydrochlorothiazide Drug: 50.0 mg hydrochlorothiazide Phase 3

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 416 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Prevention
Official Title: Randomized Double-blind Placebo-controlled Trial Assessing the Efficacy of Standard and Low Dose Hydrochlorothiazide Treatment in the Prevention of Recurrent Nephrolithiasis
Actual Study Start Date : March 9, 2017
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Stones

Arm Intervention/treatment
Placebo Comparator: Placebo
Once daily for 3 years
Drug: Placebo oral capsule
Once daily for 3 years

Experimental: 12.5 mg hydrochlorothiazide
Once daily for 3 years
Drug: 12.5 mg hydrochlorothiazide
Once daily for 3 years

Experimental: 25.0 mg hydrochlorothiazide
Once daily for 3 years
Drug: 25.0 mg hydrochlorothiazide
Once daily for 3 years

Experimental: 50.0 mg hydrochlorothiazide
Once daily for 3 years
Drug: 50.0 mg hydrochlorothiazide
Once daily for 3 years




Primary Outcome Measures :
  1. Number of stone recurrences [ Time Frame: After 3 years ]
    Composite of symptomatic or radiological recurrences


Secondary Outcome Measures :
  1. Number of symptomatic stone recurrences [ Time Frame: After 3 years ]
  2. Number of radiologic stone recurrences [ Time Frame: After 3 years ]
    Measured by low-dose CT



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03057431


Contacts
Contact: Daniel Fuster, Prof MD +41 (0)31 632 31 44 daniel.fuster@insel.ch
Contact: Luca Tamò, PhD +41 (0)31 631 30 87 luca.tamo@ctu.unibe.ch

Locations
Switzerland
Kantonsspital Aarau Recruiting
Aarau, Switzerland, 5001
Contact: Florian Buchkremer, MD       florian.buchkremer@ksa.ch   
University Hospital Basel Recruiting
Basel, Switzerland, 4031
Contact: Michael Mayr, MD       michael.mayr@usb.ch   
Ospedale Regionale di Bellinzona e Valli (San Giovanni) Recruiting
Bellinzona, Switzerland, 6500
Contact: Luca Gabutti, Prof MD       luca.gabutti@eoc.ch   
Bern University Hospital (Inselspital) Recruiting
Bern, Switzerland, 3010
Contact: Daniel Fuster, Prof MD       daniel.fuster@insel.ch   
Kantonsspital Graubünden Recruiting
Chur, Switzerland, 7000
Contact: Reto Venzin, MD       Reto.Venzin@ksgr.ch   
Hôpitaux universitaires de Genève (HUG) Recruiting
Geneve, Switzerland, 1205
Contact: Thomas Ernandez, MD       thomas.ernandez@hcuge.ch   
Centre hospitalier universitaire vaudois (CHUV) Recruiting
Lausanne, Switzerland, 1011
Contact: Olivier Bonny, Prof MD-PhD       olivier.bonny@unil.ch   
Ospedale Regionale di Lugano (Civico) Recruiting
Lugano, Switzerland, 6900
Contact: Carlo Schönholzer, MD       carlo.schoenholzer@eoc.ch   
Luzerner Kantonsspital Recruiting
Luzern, Switzerland, 6000
Contact: Urs Odermatt, MD       urs.odermatt@luks.ch   
Hôpital de Sion Recruiting
Sion, Switzerland, 1951
Contact: Daniel Teta, Prof MD-PhD       daniel.teta@hopitalvs.ch   
Kantonsspital St. Gallen Recruiting
St.Gallen, Switzerland, 9007
Contact: Irene Koneth, MD       irene.koneth@kssg.ch   
University Hospital Zürich Recruiting
Zurich, Switzerland, 8091
Contact: Alexander Ritter, MD       alexander.ritter@usz.ch   
Sponsors and Collaborators
University Hospital Inselspital, Berne
Investigators
Principal Investigator: Daniel Fuster, Prof MD Division of Nephrology and Hypertension, Bern University Hospital, Bern, Switzerland

Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT03057431     History of Changes
Other Study ID Numbers: 2016-01475
First Posted: February 20, 2017    Key Record Dates
Last Update Posted: February 16, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital Inselspital, Berne:
kidney stones
hydrochlorothiazide

Additional relevant MeSH terms:
Nephrolithiasis
Kidney Calculi
Kidney Diseases
Urologic Diseases
Urolithiasis
Urinary Calculi
Calculi
Pathological Conditions, Anatomical
Hydrochlorothiazide
Antihypertensive Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action