Sanjin tablets for acute uncomplicated lower urinary tract infection (syndrome of dampness-heat in the lower jiao): protocol for randomized, double-blind, double-dummy, parallel control of positive drug, multicenter clinical trial

This is a randomized, double-blind, double-dummy, parallel control of positive drug, multicentre clinical study. The study will be conducted at: 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; and 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 will 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; control group 1 receives LT plus SJT placebo; and control group 2 receives SJT plus LT on the first five days, SJT plus LT placebo on the last two days. After seven days of treatment, the efficacy and safety of three groups will be evaluated. The first aim 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 the 28-day follow-up after being cured to determine whether SJT can reduce the recurrence rate. 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 participants 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 Fig. 1. The protocol follows the recommendations of the SPIRIT initiative (see Additional file 1) [23] and the trial results will be reported according to the latest version of the CONSORT statement [24].

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 SJT was 77.14% in the treatment of simple bacterial lower urinary tract infection [25]. 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.

This is a double-blind (patients and clinicians are blinded) and double-dummy study [30]. A two-stage blind design was used. The first stage was group A, group B, and group C; the second stage was randomization to the experimental group, control group 1, and control group 2 according to SAS software, without correspondence to group A, group B, and group C. Treatment assignments will not be revealed until the whole process is complete. If patients have severe AEs, 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 case report form (CRF). To achieve blinding, all three groups will use the same kind of packaging to encase the drug or placebo. Size, color, 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. 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 Sanjin Pharmaceutical Co., Ltd. and can be preserved for two years. LT is provided by First Sankyo Pharmaceutical (Beijing) 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.

The effective rate will be evaluated from three dimensions: symptoms; urine leukocytes; and bacteriological examination.

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.

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.

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 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.

The protocol has been approved by: the Ethics Committee of XiYuan 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.