Objective and design
This is a randomized, double blind, double dummy, parallel control of positive drug, multicentre clinical study. The study will be conducted in the XiYuan Hospital, China Academy of Chinese Medical Sciences; the Longhua Hospital Shanghai University of Traditional Chinese Medicine; the Guangdong Provincial Hospital of Traditional Chinese Medicine; the Hubei Hospital of Traditional Chinese Medicine; the Affiliated hospital of Chengdu University of Traditional Chinese Medicine; the Yunnan Provincial Hospital of Traditional Chinese Medicine. Ethical clearance for the trial was obtained from ethics committee of the six hospitals. Patients with acute uncomplicated lower UTI undergo a standardized baseline evaluation before treatment comprising detailed history taking, physical examination and laboratory testing. All included patients are randomly divided into three groups: experimental group, control group 1 and control group 2. The experimental group receives SJT plus levofloxacin tablets (LT) placebo; the control group 1 receives LT plus SJT placebo; and the control group 2 receives SJT plus LT on the first 5 days, SJT plus LT placebo on the last 2 days. The efficacy and safety of the Sanjin tablets will be assessed after 7 days’ treatment; the recurrence rate will be assessed at 28 days’ follow-up after cured. The trial is conducted in accordance with the World Medical Association Declaration of Helsinki and Good Clinical Practice of Pharmaceutical Products[17, 18]. After a full explanation by the clinicians, written informed consent will be obtained from the included subjects before intervention[19, 20]. Strict data management and quality control will be conducted in this trial[21, 22]. This trial was registered in the Clinical Trials USA registry (registration No. NCT03658291) on 4 September 2018 and will be carried out from January 2019 to December 2019. The study design is shown in figure 1. The protocol follows the recommendations of the SPIRIT initiative [see Additional file 1] , and the trial results will be reported according to the latest version of the CONSORT statement .
Patient and public involvement
Patients were not involved in the research question, design, conduct, outcome measures and data analysis of the study. Only medically trained clinicians carry out the patient recruitment and management in the study. The clinicians will describe the purpose, burden of the intervention, procedure and potential risks of this trial to the participants themselves or their designated representative before the recruitment. We will disseminate the results of this study to participants through patients organizations and open lectures.
The effective rate will be taken as the main outcome measure of the clinical trial. According to a previous study, it showed that the effective rate of Sanjin tablets was 77.14% in the treatment of simple bacterial lower urinary tract infection. On the basis of a 0.9 power to detect a significant difference (α=0.01, two-sided), 76 participants will be required for each group. 228 participants will be required for the three groups in a 1:1:1 ratio. Considering a 20% drop-out rate, we plan to include 252 patients in the whole trial.
Participants and recruitment
Diagnostic criteria of western medicine and TCM
The western medicine diagnostic criteria of acute uncomplicated lower UTI will refer to the Guidelines for the diagnosis and treatment of urological diseases in China (2014 ed). The TCM diagnostic criteria of acute uncomplicated lower UTI will refer to the Clinic terminology of traditional Chinese medical diagnosis and treatment-syndromes, Internal Medicine of TCM[27, 28, 29]. According to the characteristics and functions of Sanjin tablets, it is proposed to select the syndrome of dampness-heat in the lower jiao as the syndrome of TCM in this trial.
Inclusion criteria are as follows: (i) >18 and <50 years old; (ii) meet the western diagnostic criteria of acute uncomplicated lower UTI, the disease duration does not exceed 72 hours; (iii) bacterial culture result will be sensitive to levofloxacin (bacterial culture and clinical treatment will be conducted at the same time); (iv) the syndrome differentiation of TCM is syndrome of dampness-heat in the lower jiao; (v) did not receive antibiotic treatment within 48 hours before being selected; (vi) do not pregnant or lactating; (vii) sign the written informed consent form for the clinical trial.
Exclusion criteria are as follows: (i) allergic to the test drug or quinolones; (ii) there was a history of bacterial culture that was not sensitive to levofloxacin; (iii) diagnosed as complicated UTI; (iv) patients with urinary calculi or obstruction, urinary tuberculosis, renal papillary necrosis, perinephric abscess or neurogenic bladder; (v) combined with vaginitis symptoms, genital ulcers or gonorrhea; (vi) combined with severe cardiopulmonary disease, liver and kidney disease, advanced tumor and other serious or progressive disease; (vii) have a neurological or mental illness and can not cooperate; (viii) use other antibacterial drugs in combination; (ix) pregnant, lactational women or recent birth planners; (x) taking part in another clinical trial within 3 months before being selected.
Patients will leave the trial when one of the following criteria is met: (i) wrongly included; (ii) are poorly compliant or pregnant; (iii) no medication or any records of follow-up; (iv) occurrence of allergic reactions or serious adverse events; (v) participants have other complications or special physiological changes during the trial; (vi) patients have been treated with other medicines during the trial; (vii) not alleviated or the symptoms are aggravated. Participants may withdraw from the study at anytime for any reason.
Randomization and allocation concealment
The randomization will be used for patients’ allocation. The randomization will be performed by an independent statistician. The random numbers are divided into three groups sequentially: experimental group, control group 1 and control group 2. Using SAS 9.1.3 statistical software PROC PLAN procedure statements, given the seed number, and randomized grouping tables will be generated for the 252 patients receiving treatment. On-site drug blinding will be carried out, and emergency unblinding procedures will be created. Blinded materials will be kept by a full-time investigator who will not participate in any part of the trial. During the course of the trial, the investigator will be able to obtain the randomized number and drug number of each patient from the designated central randomized platform.
This is a double-blind (with patients and clinicians blinded) and double-dummy study. A two-stage blind design was used. The first stage was group A, group B, group C, and the second stage was randomly assigned to experimental group, control group 1 and control group 2 according to SAS software, without correspondence to group A, group B, group C. Treatment assignments will not be revealed until the whole process is complete. If patients have severe adverse events, clinicians will log on to the central platform to unblind the patients as an emergency and provide relevant treatment. Once the blinding is broken, the patient with this number will be withdrawn from the trial, and the clinicians will record the reasons in the CRF. To achieve blinding, all three groups will use the same kind of packaging to encase the drug or placebo. Size, colour, shape, taste, smell and packaging of the placebo are made identical to that of the corresponding medicine by adding artificial pigment.
All researchers are clinical doctors and receive standardized training for the diagnostic interview before the start of the trial. Levofloxacin tablets are licensed for UTI with proven curative effect and safety. Therefore, levofloxacin have been selected as the active control medicine. Participants in the experimental group will receive SJT plus LT placebo orally four times a day for 7 days. Participants in the control group 1 will take LT plus SJT placebo four times a day for 7 days. Participants in the control group 2 are about to receive SJT and LT four times a day for the first 5 days, SJT plus LT placebo four times a day for the last 2 days. Patients’ visits are required after 7 days’ treatment. This is a placebo-controlled study; all participants receive the same number of pills with varying proportions of active drug and placebo to ensure that patients and clinicians are not aware of the allocated treatment aim. The SJT placebo is composed of 55% microcrystalline cellulose, 41% starch, 2% caramel, 1.5% silicon dioxide and 0.5% talcum powder. LT placebo is made of 56% microcrystalline cellulose, 42% starch, 1.5% silicon dioxide and 0.5% talcum powder. The SJT placebo and LT placebo are similar to the Sanjin tablets and levofloxacin tablets in size, colour, shape, taste, smell and packaging, respectively. SJT and its placebo and LT placebo are produced by Guilin Sanjin Pharmaceutical Co., Ltd and can be preserved for 2 years. Levofloxacin tablets is provided by First Sankyo Pharmaceutical (Beijing) Co., Ltd at a dosage of 100 mg and can be preserved for 2 years. The recommended dosage of Levofloxacin tablets is 2-3 times a day, one pill at a time; hence, in order to meet the requirements of the blinding, the administration method of this medicine has been designed as described in Table 1.
All included patients will be re-evaluated after 7 days’ treatment follow-ups as an outpatient to assess the efficacy and safety. The patients who were cured will receive the second follow-up after 28 days to assess the recurrence rate. Patients whose symptoms worsened will receive a supply of relevant medicine and a written withdrawal schedule. Assessment of study endpoints and duration of follow-up is shown in figure 2.
The effective rate will be evaluated from three dimensions: symptoms, urine leukocyte and bacteriological examination.
Primary Outcome Measure
The symptoms of acute uncomplicated lower UTI will be assessed. The assessment tools for symptoms of acute uncomplicated lower UTI are three participant self-rating scales [see Additional file 2]: criteria sheet for evaluating the severity of urinary system infection (CSESUSI); symptoms score sheet of TCM (SSST); OABSS. The CSESUSI will use scoring method to record the changes of symptoms and signs before and after treatment; focus on the record of shiver, fever, dysuria, urinal pain, urinary urgency, urinary frequency, lower abdomen distending pain, lumbago and percussion tenderness over kidney region. The SSST use scoring method to record the changes of symptoms, tongue and pulse in TCM before and after treatment. The Overactive Bladder Symptom Score (OABSS) has been found to be reliable and valid and highly responsive to treatment related fluctuations in overactive bladder symptoms. Repeating the test after an acceptable treatment interval is an effective way to assess the efficacy of a particular drug regimen on OAB symptoms[33, 34]. If the symptoms disappeared after 7 days’ treatment, it indicates that the subject is cured. If these symptoms partially disappeared after 7 days’ treatment, it indicates that the treatment is effective but not cured. If there was no obvious remission and the symptoms of infection persisted after 7 days’ treatment, it indicates that the treatment is invalid.
Secondary Outcome Measure
(i) The urine leukocyte of 252 participants will be assessed. If the value of urine leukocyte returned to the normal value after 7 days’ treatment, it indicates the subject is cured. If the value of urine leukocyte reduced but not returned to the normal value after 7 days’ treatment, it indicates that the treatment is effective. If the value of urine leukocyte was still higher than normal value after 7 days, it indicates invalid treatment.
(ii) The bacteriological examination of 252 participants will be assessed. If the original infected part of the specimen did not regenerate the original infected pathogen after 7 days’ treatment, it indicates the original bacteria is cleared. If the original pathogen was still cultured in the culture of the specimen from the original infection position, it indicates the original bacteria is not cleared.
Criteria of comprehensive efficacy
(i) Criteria of cured：the evaluation of clinical symptoms reached the level of cure after 7 days’ treatment; the value of urine leukocyte returned to the normal value; the original infected bacteria was cleared after 7 days’ treatment. The above three must be included at the same time.
(ii) Criteria of effective treatment：the clinical symptoms were alleviated but not reached the level of cure after 7 days’ treatment; the value of urine leukocyte reduced but not returned to the normal value after 7 days’ treatment. Anyone of both is regarded as effective.
(iii) Criteria of invalid treatment：the clinical symptoms were not alleviated after 7 days’ treatment; the value of urine leukocyte was still higher than normal value after 7 days’ treatment; the original infected bacteria was still cultured from the original infection position after 7 days’ treatment. The above three must be included at the same time.
Patients who were cured will receive the second follow-up after 28 days to assess the recurrence rate. Recurrence criteria: has “(i)”, and has one of “(ii)”or“(iii)” at the same time.
Primary Outcome Measure
(i) The recurrence rate of cured subjects will be assessed by the symptoms of acute uncomplicated lower UTI. The assessment tools of recrudescent symptoms will also use the three participant self-rating scales [see Additional file 2]: criteria sheet for evaluating the severity of urinary system infection (CSESUSI); symptoms score sheet of TCM (SSST); OABSS. If the symptoms of cured subjects reappeared in the fourth week after the end of medication, it indicates the subject has relapsed.
Secondary Outcome Measure
(ii) The recurrence rate of cured subjects will be assessed by urine leukocyte. If the urine leukocyte value of cured subjects rose again in the fourth week after the end of medication, it indicates the subject has relapsed.
(iii) The recurrence rate of cured subjects will be assessed by bacteriological examination. If the urine culture of cured subjects indicated that the original urinary tract pathogen is positive again in the fourth week after the end of medication, it indicates the subject has relapsed.
Safety measurements included laboratory indices and adverse events. All patients will undergo the following laboratory examination before enrollment and at the end of the clinical trial. Changes in the laboratory indices before and after the clinical trial will be compared to conducting a safety analysis. Laboratory indices are: (i) routine blood and urine testing; (ii) liver function (AST、ALT、TBIL、DBIL、γ-GT、ALP) and kidney function (Scr、BUN); (iii) ECG. The occurrence of any adverse events in trial participants, such as subjective discomfort of patients and abnormal laboratory results, will be recorded in the case report forms (CRF) during the whole trial process. We will withdraw patients who have severe adverse events, as it is unsafe for them to continue the trial. Meanwhile, we will give them relevant medical care and follow them up until the reaction has terminated.
Before enrolling patients in the trial, the investigating doctor will be completely and comprehensively describe the purpose, procedure, and potential risks of this trial in writing to the patient themselves or their designated representative. Patients will be informed that they have the right to withdraw from the trial at any time. Each patient must provide written informed consent before participating in this study; this consent will be kept in the study file.
Quality assessment will be conducted in the following aspects in this trial: the progress of the trial, the qualifications of the investigators, the mastery of the program, the authenticity, accuracy and completeness of the CRF, archival preservation, program implementation, adverse events, drug preservation and storage, written informed consent, subjects compliance, and laboratory examination data. In particular, the authenticity and accuracy of the CRF, program implementation, and determination of adverse events will be strictly inspected.
The patients in this trial will be recruited patients. Therefore, the original data will include the CRF, patient log card, original laboratory examination, and written informed consent. The inspector will regularly visit all centers to conduct a data quality inspection. The authenticity and accuracy of data will be checked by original laboratory comparison, telephone follow-up with patients, and examination of the integrity, timeliness, and normalization of data. The paper form of the data will be collected after approval inspection. The researcher who is responsible for data entry will build an EpiData-based database with double-recorded data entry by two people, and consistency testing will be carried out to ensure the accuracy of data.
Data analysis will be performed by professional statisticians using SPSS 22.0. Three data sets will be conducted: intention-to-treat, per-protocol set, and safety data set. The intention-to-treat refers to patients who have received treatment at least once and one follow-up visit; an intentional analysis will be conducted for curative effect. The per-protocol set refers to all cases that do not violate the protocol and complete the programme; per-protocol set analysis will be conducted for curative effect. The safety data set refers to the randomized cases that take a tested drug at least once with safety evaluation data after treatment. We use mean±SD for continuous variables and percentages for categorical variables. In measured indices, the independent t-test will be used for hypothesis testing of the normal variables, while the Wilcoxon rank sum test will be used for hypothesis testing of the skewed variables. The χ2 test will be used for hypothesis testing of the counted indices. The statistical analyses will use the two sided hypothesis test. P ≤ 0.05 will be set as the significant level.
Ethics and dissemination
The protocol has been approved by the Ethic Committee of the XiYuan Hospital, China Academy of Chinese Medical Sciences (identifier 2018XLA03l-3); Ethics Committee of the Longhua Hospital Shanghai University of Traditional Chinese Medicine (identifier 2018LCSY034); Ethics Committee of the Guangdong Provincial Hospital of Traditional Chinese Medicine (identifier BF2018-083-01); Ethics Committee of the Hubei Hospital of Traditional Chinese Medicine (identifier SL2018-C19-01); Ethics Committee of the Affiliated hospital of Chengdu University of Traditional Chinese Medicine (identifier 2018KL-053); Ethics Committee of the Yunnan Provincial Hospital of Traditional Chinese Medicine (identifier 2018LLZ-014-NO.01). The protocol has been registered in the Clinical Trials USA registry (registration No. NCT03658291) on 4 September 2018 [see Additional file 3]. The trial will help to demonstrate if Sanjin tablets is effective and safe for patients with acute uncomplicated lower UTI. We will publish the results of this study in peer-reviewed journals to ensure widespread dissemination.