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 the 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 function test abnormality, or imaging studies will be eligible for 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 agreed to participate in the trial, the patients will be registered as 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 are 20 years or older
- They are diagnosed as acute cholangitis by treating gastroenterologists.
- 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.
- Patients did not provide written informed consent.
- Biliary duct obstruction was not removed.
- Treating physicians or the investigators judged that inclusion in the study was inappropriate.
The presence of bacteraemia is not an exclusion criterion.
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 the 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 centrally at the study centre (Division of Infectious Diseases Therapeutics, Kobe University Graduate School of Medicine). We will use an electronic data capture system to conduct randomization and data collection.
The antibiotics given to the study participants should be commercially available and approved for use in Japan. They will be used at the marketed accepted dosage as in each package insert. The initial antibiotics will be selected at the discretion of either the treating physician or the 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 that are suspected or occurred in 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 the 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) maintenance of body temperature under 37.8oC for more than 48 hours; (2) systolic blood pressure above 90 mmHg; (3) heart rate below 100/minute; (4) respiratory rate i below 24/minute; and oxygen saturation at room air above 90%. In the LCT group, intravenous antibiotics will be given for the duration of usual care, at least for 7 days, at the discretion of both the treating gastroenterologists and the consultant infectious diseases doctors, provided that there are no biliary duct obstructions remaining, as in the inclusion/exclusion criteria. In the 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, occur and either the treating physicians or the consultant infectious diseases doctors can drop the case from the intervention. They will still be included to the analysis on an 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 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 a 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.
Clinical outcomes are confirmed by the investigators either by calling the patients using telephone or at an outpatient clinic visit, or by checking the clinical chart if the patients were still hospitalized.
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 the 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 a specific data and safety monitoring board but the steering committee will perform an interim analysis to ensure 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 with the numbers of patients registered. The data management team will also report mortality and occurrence of serious adverse events immediately to the committee.