Background
Author, Year | Treatment, Dose | Allocation Concealment | Blinding | Intention-to-treat Analysis | Withdrawals described | Selection for Hypercalciuria | Follow-Up (Years) | Treated/ Placebo, n/N | Events/Total, n/N Thiazide | Events/Total, n/N Placebo | RR c | Recurrence Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Brocks, 1981 [29] | Bendroflumethiazide, 2.5 mg TID a | Unclear | Double-blind | No | No | No | 1.6 | 33/29 | 5/33 | 5/29 | NS | Composite |
Scholz, 1982 [31] | HCTZ, 25 mg BID b | Unclear | Double-blind | No | No | No | 1 | 25/26 | 6/25 | 6/26 | NS | Symptomatic |
Laerum, 1984 [23] | HCTZ, 25 mg BID | Unclear | Double-blind | Yes | Yes | No | 3 | 23/25 | 5/23 | 12/25 | 0.45 | Composite |
Wilson, 1984 [26] | HCTZ, 100 mg daily | Unclear | Open-label | No | No | No | 2.8 | 23/21 | 0.15 stones/year | 0.32 stones/year | 0.48 | Symptomatic |
Robertson, 1985 [27] | Bendroflumethazide, 2.5 mg TID | Unclear | Open-label | No | No | No | 3–5 | 13/9 | 0.22 stones/year | 0.58 stones/year | 0.38 | Symptomatic |
Mortensen, 1986 [24] | Bendroflumethazide, 2.5 mg | Unclear | Double-blind | No | No | No | 2 | 12/10 | 0/12 | 4/10 | – | Composite |
Ettinger, 1988 [22] | Chlorthalidone, 25 m /50 mg | Adequate | Double-blind | No | Yes | No | 3 | 19/23/31 (25 mg /50 mg/placebo) | 6/42 | 14/31 | 0.32 | Composite |
Ohkawa, 1992 [25] | Trichlormethiazide, 4 mg | Unclear | Open-label | No | No | Yes | 2.14–2.21 | 82/93 | 24/82 | 57/93 | 0.42 | Composite |
Borghi, 1993 [21] | Indapamide, 2.5 mg daily | Unclear | Open-label | No | Yes | Yes | 3 | 25/25 | 3/25 | 9/25 | 0.33 | Composite |
Ahlstrand, 1996 [30] | HCTZ, 25 mg BID | Unclear | Open-label | Yes | Yes | Yes | 3.6–4.3 | 17/22 | 9/17 | 19/22 | 0.61 | Composite |
Fernandez-Rodriguez, 2006 [28] | HCTZ, 50 mg daily | Unclear | None stated | Yes | No withdrawals | No | 3 | 50/50 | 16/50 | 28/50 | 0.57 | Composite |
Methods / design
Study objectives
Overall objective
Primary objective
Secondary objectives
Safety objectives
Study outcomes
Primary outcome
Secondary outcomes
Safety outcomes
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Hypokalemia, defined as blood potassium level < 3 mmol/L.
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Hyponatremia, defined as blood sodium level < 125 mmol/L.
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Hypomagnesemia, defined as blood magnesium level < 0.5 mmol/L.
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Gouty arthritis if recurrence > 3 times per year or requiring uric acid lowering therapy.
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Newly developed overt diabetes mellitus (defined as fasting glucose level ≥ 7 mmol/L or random Glucose ≥11 mmol/L or hemoglobin A1c ≥ 6.5%).
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Allergic reaction of skin if considered by the local investigator to be potentially related to the study medication.
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Heart rate, systolic and diastolic blood pressure at the right arm in sitting position after at least 5 min rest will be recorded at all study visits.
Study design
Study sites
Study population
Eligibility criteria
Inclusion criteria | |
Individuals fulfilling all of the following inclusion criteria are eligible for study participation: | |
- 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 | |
Exclusion criteria | |
The presence of any one of the following exclusion criteria will lead to exclusion of the individual: | |
- 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 malabsorbtion or chronic diarrhea | |
- 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 | |
- 1,25 -OH Vitamin D (calcitriol) | |
- Calcium supplementation | |
- Bisphosphonates | |
- Denusomab | |
- 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) | |
- 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 | |
- 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 |
Criteria for withdrawal / discontinuation of participants
Discontinuation of study investigational medicinal product | |
Study IMP must be permanently discontinued if any of the following occurs: | |
- If any exclusion criterion applies during the trial, except the incompatible medications. The IMP will be discontinued only if the patient took the medications listed in the exclusion criteria for more than 4 months | |
- If the responsible study investigator feels that treatment with the study regimen is harmful to the participant’s well-being | |
- If patient is non-compliant with the study intervention as judged by the investigator and/or the sponsor | |
- Pregnancy in a study participant | |
- Hypokalemia (blood potassium level < 3 mmol/L) not responsive to supplementation therapy | |
- Profound hyponatremia (blood sodium level < 125 mmol/L) recurring after temporary suspension of IMP | |
- CKD-EPI eGFR < 30 mL/min per 1,73 m2 body surface area for more than 3 months | |
- Gouty arthritis recurring > 3 times per year or requiring uric acid lowering therapy | |
- Allergic reaction of skin as judged by the investigator | |
- > 3 recurrences of symptomatic stone events during the trial | |
Discontinuation of study | |
Study participants must be withdrawn from the study if the following occurs: | |
- At the participants own request | |
- If, in the investigator’s opinion, continuation of the study would be harmful to the subject’s wellbeing |