Study Protocol

Efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones: a multicentre, prospective, randomised, double-blind, placebo controlled clinical trial.

General Information

Registration Number: ChiCTR-TRC-11001339

Registration Status: Prospective registration

Source(s) of funding:Astellas Pharma (China) Co., Ltd.

Study design:Randomized parallel controlled trial

Study type:Interventional study

Target disease:distal ureteral stones

Objectives of Study:To evaluate efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones

Primary sponsor:The Urolithiasis Group of Chinese Urological Association

Study leader:Zhangqun Ye




3.Selection of Patients

4.Trial interventions

5.Identification and enrollment of potential participants

6.Randomization and allocation

7.Treatment Methods and Medication Schedule

8.Treatment Compliance

9.Original and Concomitant Conditions

10.Effective and safety evaluation

11.Opening emergency letters and unblinded processing

12.Data management

13.Statistical analysis

14.Quality control of clinical trials

15.Data storage

1. Background

Urolithiasis is an ancient disease which affects up to 20% of populations throughout the world. ureteral stones account for approximately 20% of urolithiasis cases. ureteral stones with renal colic is a very common condition in daily urological outpatient. Therefore, Medical expulsive therapy (MET) for ureteral stones has gained widespread attention in the last years. MET refers to the administration of drugs (such as tamsulosin, an alpha(α)-adrenoceptor antagonist) to relax the smooth muscle of the ureter and inhibit peristaltic activity through blockade of α1-adrenoceptors. α1-adrenoceptor subtypes has been identified as α1- (α1a, α1b 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 α-1d, 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-adrenoceptor subtypes. 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 intraureteral pressure and an increase in fluid transport ability. So the efficacies of α-adrenoreceptor antagonists have been tested during MET in numerous clinical trials, and most results have suggested that patients with ureteral 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 ureteral 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, this multicenter randomized double blind trial which compared tamsulosin to placebo is needed to strengthen the evidence regarding MET with tamsulosin for distal ureteral stones .

2. Methods/design

A prospective, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of tamsulosin 0.4 mg once daily which was designed by the urologists of urolithiasis group of Chinese Urological Association, and researchers of Astellas Pharma (the study sponsor and manufacturer of the placebo). In 30 outpatient department of medical centers, a total of 3450 ureteral stone patients aged 18 to 60 with renal colic will take part in the trial. Each center will observe 115 patients. Pain relief therapy is the application of nonsteroidal anti-inflammatory analgesic diclofenac sodium suppository.

3. Selection of Patients 3.1. Inclusion criteria:
• Adults between 18-60 years of age (inclusive).

• Emergency admission for renal colic.

• Presence of unilateral presentation with single ureteral stone confirmed by plain abdominal radiography, urinary ultrasonography, non-contrast computed tomography (CT) of the kidney, ureter and bladder

• A stone in the distal ureter with largest dimension of 4-7 mm in size

• Subjects must be capable of giving written informed consent, which includes compliance with the requirements of the trial.

3.2. Exclusion criteria:

• Patients with fevers, urinary tract infection, severe hydronephrosis

• Women who have a known or suspected pregnancy(confirmed by a pregnancy test) or are breastfeeding
• Patients with chronic kidney disease renal insufficiency (estimated glomerular filtration rate < 60 ml/min per 1.73 m2)

• Patients with abnormal renal tract anatomy (such as a solitary kidney, a duplex urinary system, horseshoe kidney or urethrostenosis)

• Patients currently using of alpha adrenoreceptor antagonists, calcium channel blockers, or corticosteroids

• Patients with known or suspected contraindication or allergy to one of the study medications

• Patients with urethrostenosis, ureter strictures, gastric ulcers, diabetes mellitus, hypotension(systolic blood pressure<100mmHg)

• Patients with a history of ipsilateral ureteral surgery or spontaneous stone expulsion

4. Trial interventions

① Tamsulosin, 0.4 mg of tamsulosin orally once daily up to a maximum of 28 days.

② Placebo, 2 capsules of placebo orally once daily up to a maximum of 28 days.

5. Identification and enrollment of potential participants

The total study period includes a two week screening period, a four week surveillance period, and a one week follow-up period. As standard practice, urologists will screen patients with renal colic and hematuria for emergency admission for suspected distal ureteral stone. All potential patients identified will be recorded. Following adequate pain relief therapy and diagnosis of ureteral stones by plain abdominal radiography(kidney-ureters-bladder), urinary ultrasonography, or non-contrast computed tomography (CT) of kidney-ureters-bladder, qualified patients (according to the inclusion and exclusion criteria) will be provided with a patient information leaflet. The information leaflet will be given to each potential participant to explain the benefits and known risks of this trial. It shall specifically explain that the trial will investigate the effect of tamsulosin against placebo and explain the likelihood of participants receiving trial treatments. A member of the local research team will identify whether the patient is interested in the trial and will ensure that any questions the patients have are answered appropriately. Signed informed consent forms will be obtained from the participants in all centers, by an individual who is appropriately trained. On providing consent, the patient will be randomized to one of the two treatment groups. For patients not included in the study, the reasons for non-inclusion (for example, they were ineligible or refuse to take part in) will be recorded to inform the CONSORT diagram.

6. Randomization and allocation

Qualified patients who have signed the informed consent will be randomly assigned by algorithm to receive tamsulosin or placebo in a 1:1 ratio for a maximum of four weeks
of the surveillance period. The randomization algorithm was created in the SAS software simulation by a statistician from statistician department of Tongji Medical College. The preparatory work of trial medication kit coding and emergency letters will be completed by personnel not involved with the trial, and the participant kits containing encapsulated trial medication will have a random number generated by the algorithm. Upon randomization, the participant will be allocated a unique participant study number and assigned a coded participant kit to ensure that the participant, investigator, and trial personnel remain blind to treatment.

All trial medication will be accompanied with emergency letters with the corresponding number; these letters will be kept with the main researcher in each center. Urologists will distribute each drug kit according to the order of each visiting patient and the number of coded participant kits; drugs shall not be chosen and the drug number should be remain unchanged during the entire experiment. Participants will receive their trial drug kit with same code throughout the trial. The researchers will distribute drugs according to the flow chart of the study requirements and timely fill out the registration form of drug release. The analysis will be based on all participants having had a randomized treatment. Trial registration: ChiCTR-TRC-11001339

7. Treatment Methods and Medication Schedule

Each patient of tamsulosin group will receive 0.4 mg of tamsulosin orally once daily, and each patient in placebo group will receive 2 capsules of placebo orally once daily after breakfast in morning. 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 begin 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 after the four week surveillance period. During the follow-up visits, patients will be asked whether or not they experienced acute episodes of renal colic, and if so, the number of colic episodes, and the side effects of the drugs, if present. This data 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.

8. Treatment Compliance

As the number of remaining doses must be counted for each participant as part of the compliance evaluation, the pill bottle for each participant must be returned to the researchers. If the compliance evaluation shows that less than 80% or greater than 120% of the medication was consumed, that participant will be noted as having poor compliance. The termination of the study because of poor compliance will be recorded in CRF.

9. Original and Concomitant Conditions

All conditions with which patient is affected within three months will be recorded. A condition with a manifestation before the trial will be considered as a concomitant condition. The first occurring condition in the study, or the exacerbation of concomitant diseases during the study, will be recorded as adverse events in the case report form.

10. Effective and safety evaluation 10.1. Effective evaluation

Stone expulsion: 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 the date of stone expulsion is unknown, the date of the last positive stone status will be recorded. Participants will be advised to filter their urine with unified filter net. The primary observation sought is the overall stone expulsion rate. The secondary observations sought include the stone expulsion time, rate of pain relief therapy, average analgesic consumption for recurrent renal colic, and incidence of side effects.

10.2. Safety evaluation

10.2.1. Evaluation of adverse events
The evaluation of clinical safety will be completed with spontaneous adverse event reports of patients and the direct observations of the clinical. In addition, patients will be asked about adverse events at each follow-up.

Safety evaluation in laboratory

The blood samples will be collected at the first and participant outpatient visits. Laboratory evaluation index:

.The aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine (Cr), prothrombin time

.The hemoglobin, red blood cells, white blood cells and platelets

.The urine routine examination

.The ECG examination

Laboratory evaluation will be carried out in each center; any abnormal values of clinical significance will be reported to the clinician. If an abnormal value occurs at different stages after medication consumption has begun, the adverse events will be recorded in the table to determine the relationship with the test of drug.

10.2.2. Adverse Events

The definition: From the time between the patient's signed informed consent and enrollment in the trial to the last follow-up visit, any adverse medical events, regardless of whether there is a causal relationship with the trial medication, will be noted.
Adverse events include the following:

• Suspected adverse drug reactions.

• All conditions related to drug overdose, drug abuse, drug withdrawn, or allergic or toxic reaction.

• Apparently unrelated conditions, including exacerbation of previously existing conditions.

• Injury or accident. Note: if a medical condition (such as dizziness) and an accident (such as a fall) happen in same time, these should be reported as two different adverse events. Consequences from any accidents should be record in the notes (for example "hip fracture caused by fall").
• Abnormal physiological examination or physical examination findings that may result in a need for clinical treatment or further research (as different from repeated experiments to verify this trial's results).

• Abnormal results from laboratory examination that may result in a need for clinical treatment or further research (as different from repeated experiments to verify this trial's results). If these abnormalities are related other reported events (e.g., jaundice patients with elevated liver enzymes), the multiple events should be described in the clinical incident reporting notes, not as an adverse event alone.

10.2.3. The common adverse drug events

The side effects of tamsulosin are rare. Occasionally patients complained of abnormal ejaculation, rhinitis, dizziness, fatigue, postural hypotension and other discomfort.

10.2.4. Obtaining information on adverse events

The doctors should report the overall adverse events to researchers with concise medical terms from clinician directly observed or participant's self reporting. In addition, doctors are required to ask about adverse events at the beginning of each patient visit. At the first visit, the doctor should ask, "Before you begin to take the trial medication, are there any health problems?" After the treatment has begun, the doctor should ask, "Since the last visit, have there been any health problems?"

10.2.5. The adverse event recording

During the trial, adverse event should truthfully be filled in the record. Adverse events will be recorded the time of occurrence, with special note of their severity, duration, measures taken and prognosis. Adverse events should be recorded in the specified CRF adverse events table.
The criterion of serious degree of adverse reaction : when adverse events are filled in the CRF table, the researchers will use mild, moderate and severe to describe the intensity of adverse events. To ensure a unified standard, the grading of event intensity are as follows:

• Mild: does not affect normal function of the subject.

• Moderate: to a certain extent, affect normal function of the subject.

• Severe: significantly affected normal function of the subject.
The distinction between severity and intensity of adverse event should be noted. Severe is used to describe the strength, not necessarily a Severe Adverse Event (SAE). For example, the headache may be severe in strength, but not included in the SAE, unless it complies with the following SAE standards:

10.2.6. The judgment standard of the relationship between adverse events and drug trials

The following five levels of classification evaluation standards should be used by researchers to assess the possible correlation between adverse events and drug research:

• The reaction is certainly related: the reaction occurs within a reasonable amount of time after use of the drug, the reaction is consistent with the known reactions of the drug; the patient shows improvement after discontinuation of the drug, and repeated administration of the drug prompt reemergence of the reaction.

• The reaction may be related: the reaction occurs within a reasonable amount of time after use of the drug, the reaction is consistent with the known or suspected reactions of the drug, but the patient's clinical status or other treatments may also produce the reaction.

• The reaction may not be related: the reaction does not seem to occur within a reasonable amount of time after use of the drug, the reaction is not consistent with the known or suspected reactions of the drug, and the patient's clinical status or other treatments may produce the reaction.

• The reaction is not related: the reaction does not occur within a reasonable amount of time after use of the drug, the reaction is not consistent with the known or suspected reactions of the drug, and the patient's clinical status or other treatments may have the reaction, disease state improvement or stop the elimination reaction to other treatments, the repeated use of other treatment reaction.

• The reaction cannot be evaluated: the reaction occurred with no clear relation to the order of time after administration, types and the drug was similar to other known, while using the drugs may also cause the same reaction.

10.2.7. Serious adverse event

Definition of serious adverse event, adverse events consistent with the following one or more standard classified as serious adverse events (SAE):
. Death

. Immediate Risk of Death

. Hospitalization

. Permanent or serious disability

. Birth Defects

A medical event in which there is no cause of death, the risk of life, or hospitalization medical event, but appropriate medical judgment would require the patient undergo drug or surgical treatment to avoid death, risk of death, or hospitalization, should also be considered a SAE.

10.2.8. Record and report serious adverse events

In the case of serious adverse events in clinical trials, a report must be made immediately and sent to the unit and main research units. At the same time, researchers must fill out the serious adverse reaction table, with a record of serious adverse events in time, severity, duration, measures and prognosis.

11. Opening emergency letters and unblinded processing

In the event of a patient emergency and an immediate need identify the trial medicine, the research unit can use the number issued with each drug to find the corresponding emergency letter stating the drug being consumed by the patient. At the same time, immediately notify CRA treatment results. Researchers should complete the case report form with a detailed record of the unblinding reason, including the date and signature. In general, the researchers may not easily unblind. If the patient is unblinded, then the patient trial will be aborted, and processed as a lost case.

12. Data management

The case report form will be filled out and returned by the researchers; each Selected case must have a completed case report form. The completion of the case report form by the CRA review will be done by the second joint transfer data administrator.
Data entry and modification of data entry and management is the responsibility of the specified data management unit. The data administrator will use a data management software input program for data entry management. In order to ensure the accuracy of the data, double entry and proofreading will be performed by two independent data administrators.

If there are case report form questions, the data administrator will produce a question and answer sheet (DRQ), and issue queries to researchers through the CRA. Researchers should answer as soon as possible and return data modification, confirmation and entry according to the researcher's answer to the data administrator. When necessary, data can be reissued by DRQ.

Data will be locked by researcher. The main sponsor, the data administrator, and statistical analysis personnel will blindly audit data and determine the statistical population. If there is confirmation that the the database is correct, statistical analysis on database will be locked afterward.

13. Statistical analysis

13.1. Estimation of sample size

Tamsulosin versus placebo between-group comparisons were evaluated. The sample size required to conduct this study was estimated by well-trained statisticians at the Tongji medical college and Huazhong University of Science and Technology. Our null hypothesis was an absence of an effect of tamsulosin, compared to placebo, on stone expulsion, and a higher stone expulsion rate for the tamsulosin than placebo group (86% versus 80%, respectively). At a power of 95% and a significant type I error rate of 0.01, a sample size ≥3100 was required, with 1550 patients per group (tamsulosin and placebo), for chi-squared analysis. Considering a drop-out rate of 10%, 3450 patients were enrolled in the trial.

13.2. Statistical analysis of data definition

13.2.1. Treatment of (Intent-to-treat, ITT) population

The ITT population refers to all those in the randomized, double-blind trial who use at least one drug treatment. The curative effect evaluation of the corresponding patients will constitute the study population with ITT. The ITT percentage of the relevant part of the efficacy of the missing data will be used prior to the last observation data transfer (LOCF) method to supplement.
According to the guidelines provided for the completion of double-blind medication, deviate no important program, completed all the evaluation content of patients constitute the study population data sets to determine the PP, will be blind review after the completion of the test time. The PP population will meet the following criteria:

• Meeting the test protocol specified criteria of inclusion / exclusion;

• Completion of all planned visits;

• No use of any products that may affect drug efficacy evaluation or treatment during the trial;

• Good Compliance (80%-120%).

13.2.2. Control population

All randomized groupings, as long as taking a drug research and carried out at least once a safety assessment of patients, the study constitutes a crowd safety. The safety population is the main population of the study of safety evaluation.

13.3. Statistical Analysis

Statistical analysis will use the Stata statistical analysis software for calculation. All statistical tests will use a bilateral test, P value is less than or equal to 0.05 will be deemed to have statistical significance. The measurement data of different treatment group visits will be analyzed for standard deviations. Differences within groups before and after treatment will be compared with a paired t test. Changes in the two groups before and after treatment will be analyzed by t test and Wilcoxon rank sum test. Different treatment group visits will be counted by frequency (percentage or proportion) for statistical deScription. Changes in the two groups before and after treatment will be analyzed by χ2 test or non parametric test. An analysis comparing the total loss rate and drop-out rate due to adverse events of the two groups will be performed by χ2 test. The t test or χ2 test will be performed to compare the demographic data and other basic value indicators and verify that the two groups were balanced. The rate by which stones disappear or / and decreased the event will be compared with the CMH χ2 method of center correction. A covariance analysis method will be used to consider the pain score changes as compared with the baseline. A χ2 test will be used to compare the incidence rate of adverse events for the two groups, and a list of adverse events that happened in the test will be generated;
the relationship between the results of laboratory tests before and after the experiment of normal / abnormal changes and abnormal and the test of drug.

14.Quality control of clinical trials

In the course of this study, a quality control officer will be appointed by the sponsor

of the CRA for on-site monitoring of regular hospital visits, ensuring that all protocols of the research program are strictly adhered to and verifying that the research data has been filled in correctly. To participate in the study, personnel must go through the consisted training to ensure consistent recording and judgment standard. The whole process of clinical trials shall be double-blind. The researchers should fill in the table according to requirements of case report truthfully, carefully, and in detail, to ensure that the case report form is true and reliable. The abnormality judging standards for laboratory examination shall be used, with normal reference range units. All observations from the clinical trial should be verified, to ensure the reliability of data and to ensure that the conclusions of clinical trials are justified by in the original data source. In the clinical trials and the data processing method of data management stage has a corresponding requirement to be verified. While drop-out losses may occur, staff should take active measures control the drop-out rate to stay below 20%. Informed consent will be obtained from patients with ethical requirements and the clinical trials must follow the declaration of Helsinki (edition of 2000) and Chinese relevant codes, clinical trial regulations. This trial is subject to the Tongji Hospital leader of this experimental research unit affiliated with the Tongji Medical College of Huazhong University of Science and Technology Ethics Committee approving the trial before implementation . The doctor has the responsibility to provide to each of the patients Selected for this study (or to their designated representative) a written document with a complete and comprehensive introduction to the purpose, the procedures, and the possible risks of the study. Patients are to be informed that they have the right to withdraw from the study at any time. The top must give each patient a written patient informed consent (with appendix form is included in the scheme). The doctor has the responsibility to obtain informed consent from each patient before entering them into the study, and that approval will be stored.
15.Data storage

In order to guarantee the supervision and evaluation of the sponsor, researchers

should agree to all research data preservation, including confirmation of all participating subjects (can effectively check the records in different such as CRF and hospital original records), all the original signature of the patients informed consent, CRF, drug distribution with record, etc.