Background

Acute uncomplicated lower urinary tract infection (UTI) is one of the most common bacterial infections. Patients usually present with dysuria, urinary urgency, urinary frequency, and suprapubic pain/tenderness [1]. In the United States, there are > 7 million outpatients with UTIs and about 1 million inpatients each year [2]. Approximately 150 million people are diagnosed with UTI each year worldwide [3]. UTI, which can cause shock and death, ranks third among all diseases that die from infection [4]. Gram-negative bacteria, especially Enterobacteriaceae, is the common cause of both community-acquired and hospital-acquired UTIs [3, 5]. Many Chinese medicines that have a heat-clearing and detoxicating function have been proven to have the bacteriostasis on pathogenic microorganisms, which can inhibit or destroy the formation of toxic substances [6, 7]. In the antibacterial test against mice, it was found that San** tablets (SJT) have strong bacteriostasis activity [8].

SJT have the effects of clearing heat, detoxicating, eliminating dampness, and treating stranguria [31]. 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. SAS 9.1.3 statistical software PROC PLAN procedure statements will be used, the seed number given, and randomized grou** 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 trial, the investigator will be able to obtain the randomized number and drug number of each patient from the designated central randomized platform.

Interventions

All researchers are clinical doctors and receive standardized training for the diagnostic interview before the start of the trial. LT are licensed for UTI with proven curative effect and safety [32]. Therefore, levofloxacin had been selected as the active control medicine. Participants in the experimental group will receive SJT plus LT placebo orally four times a day for seven days. Participants in control group 1 will take LT plus SJT placebo four times a day for seven days. Participants in control group 2 will take SJT and LT four times a day for the first five days and SJT plus LT placebo four times a day for the last two days. Patient visits are required after seven days of 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. The LT placebo is made of 56% microcrystalline cellulose, 42% starch, 1.5% silicon dioxide, and 0.5% talcum powder. The SJT and LT placebos are similar to the SJT and LT in size, color, shape, taste, smell, and packaging. SJT and its placebo and the LT placebo are produced by Guilin San** Pharmaceutical Co., Ltd. and can be preserved for two years. LT is provided by First Sankyo Pharmaceutical (Bei**g) Co., Ltd. at a dosage of 100 mg and can be preserved for two years. The recommended dosage of LT 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.

Table 1 Administration methods in the experimental and control groups

Follow-up

All included patients will be re-evaluated after seven days of 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 Fig. 2.

Fig. 2
figure 2

Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) figure

Outcome measures

Effective rate

The effective rate will be evaluated from three dimensions: symptoms; urine leukocytes; 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; mild: total score ≤ 8, moderate: total score 9–15, severe: total score ≥ 16), if the severity of the disease decreases from severe to moderate, or from moderate to mild, the symptoms are improved; symptoms score sheet of TCM (SSST; cure: total score = 0, effective: total score 0–6, invalid: total score ≥ 6); overactive bladder symptom score (OABSS; if the urgent urination score > 2 and total score > 3, OAB will be diagnosed; mild: total score ≤ 5, moderate: total score 6–11, severe: total score ≥ 12). The CSESUSI will use a scoring method to record the changes of symptoms and signs before and after treatment, such as shivering, fever, dysuria, urinal pain, urinary urgency, urinary frequency, lower abdomen distending pain, lumbago, and percussion tenderness over kidney region. The SSST uses a scoring method to record the changes of symptoms, tongue, and pulse in TCM before and after treatment. The 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 seven days of treatment, it indicates that the patient is cured. If these symptoms partially disappeared after seven days of treatment, it indicates that the treatment is effective but not cured. If there was no obvious remission and the symptoms of infection persisted after seven days of treatment, it indicates that the treatment is invalid.

Secondary outcome measure

  1. (i)

    The urine leukocytes of 252 participants will be assessed. If the value of urine leukocytes is returned to normal after seven days of treatment, it indicates the patient is cured. If the value of urine leukocytes is reduced but not returned to normal after seven days of treatment, it indicates that the treatment is effective. If the value of urine leukocytes is still higher than the normal value after seven days, it indicates the treatment is invalid.

  2. (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 seven days of 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

  1. (i)

    Criteria of cure: the evaluation of clinical symptoms reached the level of cure after seven days of treatment; the value of urine leukocytes returned to the normal value; the original infected bacteria was cleared after seven days of treatment. All three criteria must be met.

  2. (ii)

    Criteria of effective treatment: the clinical symptoms were alleviated but did not reach the level of cure after seven days of treatment; the value of urine leukocytes was reduced but not returned to normal after seven days of treatment. Either of these criteria must be met.

  3. (iii)

    Criteria of invalid treatment: the clinical symptoms were not alleviated after seven days of treatment; the value of urine leukocytes was still higher than normal after seven days of treatment; the original infected bacteria were still cultured from the original infection position after seven days of treatment. All three criteria must be met.

Recurrence rate

Patients who were cured will attend the second follow-up after 28 days to assess the recurrence rate. Recurrence criteria must include item (i) and either (ii) or (iii) at the same time, or item (i) alone.

Primary outcome measure

  1. (i)

    The recurrence rate of cured participants will be assessed by the symptoms of acute uncomplicated lower UTI. The assessment tools of renewed symptoms will also use the three participant self-rating scales (see Additional file 2): CSESUSI; SSST; and OABSS. If the symptoms of cured patients reappeared in the fourth week after the end of medication, it indicates the participant has relapsed.

Secondary outcome measures

  1. (ii)

    The recurrence rate of cured participants will be assessed by urine leukocytes. If the urine leukocyte value of cured patients increased again in the fourth week after the end of medication, it indicates the participant has relapsed.

  2. (iii)

    The recurrence rate of cured participants will be assessed by bacteriological examination. If the urine culture of cured patients indicated that the original urinary tract pathogen is positive again in the fourth week after the end of medication, it indicates the participant has relapsed.

Safety assessments

Safety measurements included laboratory indices and AEs. All patients will undergo the following laboratory examination before enrollment and at the end of the clinical trial. Changes in 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); and (iii) ECG. The occurrence of any AEs in trial participants, such as subjective discomfort of patients and abnormal laboratory results, will be recorded in the CRF during the whole trial process. We will withdraw patients who have severe AEs, as it will be unsafe for them to continue the trial. Meanwhile, we will give them relevant medical care and follow them up until the reaction has terminated.

Informed consent

Before enrolling patients in the trial, the investigating doctor will 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 control

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; AEs; drug preservation and storage; written informed consent; participant compliance; and laboratory examination data. In particular, the authenticity and accuracy of the CRF, program implementation, and determination of AEs will be strictly inspected.

Data management

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

Data analysis will be performed by professional statisticians using SPSS 22.0. Three datasets will be conducted: intention-to-treat; per-protocol set; and safety dataset. The intention-to-treat refers to the patients who have been randomized; 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 trial; per-protocol set analysis will be conducted for curative effect. The safety dataset refers to the randomized cases that have taken a tested drug at least once with safety evaluation data after treatment. We use mean ± standard deviation (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 Ethics Committee of **Yuan Hospital, China Academy of Chinese Medical Sciences (identifier 2018XLA03l-3); Ethics Committee of Longhua Hospital Shanghai University of Traditional Chinese Medicine (identifier 2018LCSY034); the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (identifier BF2018–083-01); the Ethics Committee of Hubei Hospital of Traditional Chinese Medicine (identifier SL2018-C19–01); the Ethics Committee of the Affiliated hospital of Chengdu University of Traditional Chinese Medicine (identifier 2018KL-053); and the Ethics Committee of 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 SJT 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.

Discussion

This study was designed to evaluate the efficacy, safety, and recurrence rate of SJT for the patients with acute uncomplicated lower UTI. A total of 252 patients were divided into three groups in a randomized, double-blind, double-dummy, parallel control, multicenter clinical trial. To our knowledge, this is the first study protocol to evaluate the recurrence rate and the effects of reducing or substituting antibiotics of SJT for the treatment of acute uncomplicated lower UTI. The first aim of this trial is to determine whether SJT can reduce the use of antibiotics (control group 2 versus control group 1, non-inferiority test); the second aim is to determine whether SJT can substitute the use of antibiotics (experimental group versus control group 1, non-inferiority test). The recurrence rate will be assessed at 28-day follow-up after being cured to determine whether SJT can reduce the recurrence rate. To facilitate high validity and reliability, a strict quality control and high-quality methodology is indispensable. We describe in detail the method of randomization, allocation concealment, blinding, interventions, recruitment, and data collection. The results from this trial may provide evidence on the effectiveness, safety, recurrence rate, and reduce or substitute antibiotics of SJT.

Strengths and limitations of this study

  • This is a well-designed study to assess the efficacy, safety, and recurrence rate of SJT for acute uncomplicated lower UTI in adults.

  • The results from this randomized, double-blind, double-dummy, parallel control of positive drug, multicenter clinical trial will provide new evidence of the efficacy and recurrence rate of SJT for acute uncomplicated lower UTT.

  • This study will provide evidence of SJT for reducing or substituting the use of antibiotics for acute uncomplicated lower UTI, which can guide rational application of antibiotics.

  • This trial will be implemented in six hospitals in Chinese patients; this can strengthen its generalizability.

  • One limitation is the results of participant symptoms evaluate scales might have subjective factors.

  • Another limitation is the participant symptoms evaluate scales, which might exaggerate the severity of the symptoms of acute uncomplicated lower UTI.

Trial status

This trial was registered in the Clinical Trials USA registry (registration no. NCT03658291) on 4 September 2018. Recruitment will begin in January 2019 and it is anticipated that enrollment will be completed in December 2019.