We will conduct a multi-centre, open-label, randomized, non-inferiority trial to compare SCT with conventional LCT in treating patients with acute cholangitis. The final trial report will follow the Consolidated Standards of Reporting Trials (CONSORT) statement and its extension to non-inferiority trials . This study was registered at University Hospital Medical Information Network under registry number UMIN000028382. The study protocol was written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 1).
The study will be conducted at four tertiary referral hospitals in Japan (Table 1).
Patients with acute cholangitis diagnosed by gastroenterologists based on findings such as fever, abdominal pain, liver test abnormality, or imaging studies will be eligible for the trial entry. If the infectious diseases doctors were allowed to participate in the care of the patients, and if the treating physicians and the patients accept to participate in the trial, the patients will be registered as the potential study participants. The study participants will be enrolled in this trial if they meet all of the inclusion criteria and none of the exclusion criteria. Patients will be included if they (1) are 20 years or older; (2) are diagnosed as acute cholangitis by treating gastroenterologists; (3) biliary duct obstruction was removed via procedures such as endoscopic retrograde cholangiopancreatography (ERCP), or there is no evidence of biliary duct obstruction by tests such as imaging studies to begin with. Presence of bacteraemia is not an exclusion criterion.
Patients will be excluded if (1) they did not provide written informed consent; (2) biliary duct obstruction was not removed, or (3) treating physicians or the investigators judged that inclusion of to the study inappropriate.
Ethics and informed consent
The clinical trial will be carried out according to the principles of the Declaration of Helsinki and Ethical Guidelines for Medical and Health Involving Human Subjects published by the Ministry of Health, Labour and Welfare of Japan and the Japanese Ministry of Education, Culture, Sports, Science and Technology. The study protocol was approved by the ethics committees of participating hospitals. Written informed consent will be obtained from all patients or their representatives.
Randomization and allocation concealment
Patients are randomly allocated to each treatment arm at a 1:1 ratio before or within 24 hours after initiating antimicrobial therapy. Randomization will be performed using a stochastic minimization procedure at the study centre. We will use electronic data capture system to conduct randomization and data collection.
Antibiotics given to the study participants should be commercially available and approved to use in Japan. They will be used as marketed accepted dosage as in each package insert. Initial antibiotics will be selected as discretion of either treating physician or consultant infectious diseases doctor. Selected antibiotics can be changed to other antibiotics during the treatment based on culture/susceptibility tests results, or potential adverse reactions suspected/occurred to the patient. Dose adjustments based on patients’ renal function or others are performed as judged appropriate and necessary by the consultant infectious diseases doctors.
In SCT group, intravenous antibiotics will be continued at least for five days, and can be discontinued if all of the following criteria were fulfilled: (1) there was maintenance of body temperature under 37.8oC for more than 48 hours; (2) systolic blood pressure became above 90 mmHg; (3) heart rate is below 100/minute; (4) respiratory rate is below 24/minute; and oxygen saturation at room air is above 90%. In LCT group, intravenous antibiotics will be given for the duration of usual care, at least for 7 days, as discretion of both treating gastroenterologists and consultant infectious diseases doctors, provided that there are no biliary duct obstructions remaining, as in inclusion/exclusion criteria. In SCT group, positive blood culture results will not alter the duration of the treatment unless other complications which necessitate prolongation of the treatment, such as abscess or infective endocarditis, and either treating physicians or consultant infectious diseases doctors can drop the case from the intervention. They will still be included to the analysis as intention to treat (ITT) basis, but will be excluded from the per-protocol analysis.
Assessment and follow-up
Clinical assessment is performed at baseline and daily throughout the study treatment, at the end of therapy (EOT) and at discharge from the hospital or 30 days after the onset (end of study, EOS).
The primary outcome is clinical cure at 30 days after their onset (EOS). Clinical cure is defined as disappearance of all clinical symptoms which were present upon the diagnosis,
The secondary outcomes are clinical improvement after 30 days, mortality at day 30 after the diagnosis, or in-hospital mortality, occurrence of adverse effects, and occurrence of recurrence or complications of acute cholangitis. Clinical improvement is defined as decrease but not disappearance of clinical symptoms which were present upon the diagnosis.
The primary efficacy analysis will assess the non-inferiority of the clinical cure rate of SCT compared with LCT. The margin of non-inferiority is set at 10% on the statistically acceptable tolerance and clinical acceptable margin. This margin has been used as accepted in the field of infectious diseases [12,13]. Therefore, the non-inferiority of SCT is concluded if the upper limit of the one-sided 97.5% confidence interval (CI) for the difference in clinical response (standard-SCT) is less than 10%. To achieve the power of 80% with α level of 2.5%, assuming as stated in the previous retrospective study with the clinical cure rate of 95% with standard therapy with the same cure rate in SCT , with a non-inferiority margin of –10%, 75 patients are required in each group.
We will analyse data using both intention-to-treat and per-protocol analysis. The per-protocol analysis population will consist of all randomized patients who are not lost to follow-up and have no major protocol deviations. We will attest the non-inferiority of the primary outcome on the basis of the normal theory test for binomial proportions. We will conduct the primary analysis without adjustment of potential confounders.
Secondary outcomes will also be analysed under non-inferiority assumption, as appropriate. Pre-defined subgroup analyses for the primary and secondary outcomes include; (1) presence or absence of septic shock at diagnosis, (2) presence or absence of bacteraemia, (3) initial antibiotics covering or not covering causative organisms, (4) Gram positive organisms causing cholangitis, and (5) qSOFA score.
All P-values are one-sided, and P<0.025 is considered statistically significant. All statistical analyses will be performed using STATA version 15.0 (StataCorp, College Station, TX, USA), and R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).
The trial will be managed by Division of Infectious Diseases, Kobe University Hospital, Kobe, Japan. The data centre is located at the same place, and the data managers will centrally monitor the data during the study period. A steering committee was involved in protocol development and will oversee study progress (Table 2). We will not have specific data and safety monitoring board but will perform an interim analysis by the steering committee to make sure the safety and efficacy of the trial therapy and will monitor the integrity and validity of the data collected and the conduct of the clinical trial. The data management team will report to the steering committee monthly the numbers of registration. The data management team will also report mortality and occurrence of serious adverse events immediately to the committee.