Experiments
Study Protocol

Efficacy and safety of tamsulosin in medical expulsive therapy for ureteric stones with renal colic in outpatient adults: a multicentre, prospective, randomised, double-blind, placebo controlled clinical trial.

The Urolithiasis Group of Chinese Urological Association

 

Background
Urolithiasis is an ancient disease which affects up to 20% of populations throughout the world . Ureteric stones account for approximately 20% of urolithiasis cases. Ureteric stones with renal colic is a very common condition in daily urological outpatient. Therefore, Medical expulsive therapy(MET)for ureteric stones has gained widespread attention in the last years.  α1-Adrenoceptor subtypes has been identified as α1- (α1a, αa1b and α1d) by functional, radioligand-binding and molecular biological techniques in urinary tract. Among these subtypes , α1a, which is distributed  in the bladder neck, and α1d, which is predominant in the distal ureter, generally regulate smooth muscle tone. Tamsulosin is a methoxybenzenesulphonamide derivative and an α-adrenoceptor antagonist that has higher affinity for α1A/α1D adrenoceptors.As α1-adrenoceptor is likely maintaining ureteral tonus and resistance to stop ureteral calculus from being expelled, blocking α1a and α1d with tamsulosin might account for the impressive expulsion rate of ureteral stones. Therefore, it has been suggested that blockade of α-adrenoceptors will result in decreased ureteral peristaltic activity with a consequent loss of intraureteric pressure and an increase in fluid transport ability.So the efficacies of alpha-adrenoreceptor antagonists have been tested during MET in numerous clinical trials, and most results have suggested that patients with ureteric stones seem to benefit from MET.  In most of aforementioned randomized studies suggested that tamsulosin in MET augments stone expulsion rates, reduces the time to stone expulsion, and lowers analgesia requirements for ureteric stones, however, some pitfalls in study design affect the strength of these results and conclusions were noted, such as small sample size, single-center trial, and no placebo-controls . For these reasons, it was important that a multicenter, randomized, double blind, placebo-controlled study are needed to strengthen the evidence regarding MET with tamsulosin.

 

Methods/Design
 A prospective, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of  tamsulosin 0.4 mg once daily which was designed by the urolithiasis group of Chinese Urological Association. In 30 outpatients of medical centers , a total of 1440 ureteric stones patients aged 18 to 60 with renal colic randomly assign in a 1:1 ratio to receive tamsulosin or placebo. Each center observe 48 patients.
The surveillance period was 28 days. The primary endpoint was the overall stone expulsion rate. The secondary endpoints included the stone expulsion time, rate of pain relief therapy, mean analgesic consumption for recurrent renal colic, and incidence of side effects.The analysis will be based on all participants as randomized (intention to treat). Trial registration:  ChiCTR-TRC-11001339

Inclusion criteria: 18-60 years of age; emergency admission for renal colic; largest dimension of the single ureteral stone is 4-6 mm in size; and diagnosed with plain abdominal radiography, urinary ultrasonography, non-contrast computed tomography (CT);capable of giving written informed consent, which includes compliance with the requirements of the trial.

Exclusion criteria: patients with fevers, urinary tract infections, severe hydronephrosis, acute or chronic renal insufficiency (estimated glomerular filtration rate < 60 ml/min per 1.73 m2), urethrostenosis, ureter strictures, gastric ulcers, diabetes mellitus, hypotension, pregnancy, lactation, and current use of alpha--adrenoreceptor antagonists, calcium channel blockers, or corticosteroids. Patients were excluded if they had a history of ipsilateral ureteral surgery, spontaneous stone expulsion, or known or suspected allergy to one of the study medications.

The participants randomly assign in a 1:1 ratio to receive tamsulosin or placebo for a maximum of 28 days according to a randomization list. Each patient of tamsulosin group will receive 0.4 mg of tamsulosin orally once daily; and Each patient in placebo group will receive a placebo orally once daily. All participants will be encouraged to maintain a water intake of 2L daily. Additionally, the patients will be allowed to use pain relief therapy with a 50-mg diclofenac suppository as needed. Participants will be advised to filter their urine and be asked to stop taking their medication if they pass their stones during the course of treatment. After participants began to take the study medication, they will be given diary cards listing possible reactions to the medicine and be asked to fill out a form to record any reactions they had. Participants will be requested to visit their local outpatient for a non-contrast abdominal CT weekly and follow up 4 weeks. During the follow-up visits, patients will be asked whether or not they experience aute episodes of renal colic, and if so, the number of colic episodes, the side effects of the drugs, if present, will be recorded, and notes will be taken if the stones pass spontaneously. Overall diclofenac consumption and frequency of pain relief medications will be also recorded.

Non-contrast abdominal CT will be performed to assess the stone location at the end of the study. For patients with a stone-free ureter on the final abdominal CT, but stone expulsion will be ignorant, the date of the last positive stone status will be recorded. Absence of stone expulsion after 4 weeks will be considered failed therapy. In these cases, continued watchful waiting, URSL, or ESWL will be performed.
Discontinuation of study medication and intervention before the end of the study due to uncontrollable pain, adverse events, urinary tract infections, acute renal failure, or the patient’s desire for stone removal will be also considered failed therapy. These patients will be included in the final analysis on an intention-to-treat basis. Patients who experienced stone expulsion before taking the first medication, who withdraw  their consent, or who lost to follow-up will be excluded from the analysis.

 

Study Outcomes
The primary endpoint is the overall stone expulsion rate. The secondary endpoints are the stone expulsion time, rate of pain relief therapy, means analgesic consumption for recurrent renal colic, and incidence of side effects.
Statistical analysis
Randomization (double-blinded) will be performed using a stratified permuted randomization algorithm. Stratification factors include age, gender, and stone size. All randomly assigned patients will be included in the efficacy and safety analysis. Sample data will be Inserted in an opposite database and analyzed using SPSS 18.0. A complete deScriptive analysis of all available variables will be performed. A significance level of 0.05 was chosen for all tests.

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