Objective

Postoperative early oral or enteral intake is a crucial element of the ERAS protocol. The DKB 14 Study is a multicentre randomised, double-blind, placebo-controlled trial that aims to determine the enhancement effect of TJ-100 on oral and enteral caloric intake and its ability to prevent postoperative paralytic ileus in patients after LDLT and DDLT.

Resources

A research grant from Tsumura & Co, Tokyo, Japan.

End points

The following primary end points will be evaluated at postoperative day (POD) 7:

• Total oral or enteral caloric intake;

• Abdominal distension determined using numeric rating scales (NRS);

• Abdominal pain determined using NRS.

The following secondary end points will be evaluated:

• Chronological changes in total oral or enteral caloric intake at POD 3, 5, 7, 10 and 14;

• Chronological changes in NRS at POD 5, 7, 10 and 14;

• Elapsed time from extubation until the first postoperative defaecation;

• Quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese V.1.2) at POD 7 and 14;

• Liver function determined by measuring total protein, albumin, total bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, choline esterase at POD 3, 5, 7, 10 and 14;

• Liver regeneration rates determined by CT and calculated as postoperative liver volume/graft liver weight at the time of LT between POD 14 and 21 and graft volume for all patients except those who underwent whole LT;

• The incidence of bacteraemia until POD 14 and bacterial strain;

• Trough levels of immunosuppressants at POD 3, 5, 7, 10 and 14;

• The incidence of acute cellular rejection until POD 14;

• Discharge or not within 2 months after LT;

• Flow speed and volume of the portal vein at POD 3, 5, 7, 10 and 14;

• Ascites volume (mL/day) from abdominal drain at POD 3, 5, 7, 10 and 14.

Eligibility criteria

Exclusion

• Uncontrollable active infection other than liver

• Uncontrollable malignant diseases other than hepatocellular carcinoma

• Clinically problematic dysfunction of other organs

• Likely to have severe intra-abdominal adhesion due to a history of surgeries or past history of mechanical ileus

• Medication with antipsychotic, antidepressant or gastrointestinal prokinetic drugs

• Patients who take other Kampo medicines

• Women who are pregnant or lactating

• Any other medical condition that would render a patient unsuitable for inclusion according to the opinion of the investigator (at each institution).

Registration

An eligibility report form will be delivered to the registration centre at the Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital. Eligible patients will be centrally randomised to either Arm A (TJ-100) or Arm B (placebo) in accordance with the minimisation method for assigning patients to Arm A or Arm B according to the type of LT (LDLT or DDLT), body weight (<60 or ≥60 kg), age (<50 or ≥50 years) and the institution as variables before LT. Information regarding required follow-up evaluations will then be sent from the registration centre at the Institute for Advancement of Clinical and Translational Science.

The randomisation list will not be known in advance by the investigators. The statistical analysis and preparation of tables and graphs for the report of the study by the statistician of the study will be blinded to the extent possible. The unblinding may take place only after all data have been entered into the database of the study, all requests have been closed and the database has been frozen by the Data Manager of the study.

Treatment methods

Prohibited or permitted drugs

Prohibited drugs: drugs that are known to promote bowel movement are prohibited during the protocol treatment: erythromycin, acetylcholine chloride, itopride hydrochloride, mosapride citrate, aclatonium napadisilate, neostigmine methylsulfate, pantethine, panthenol, prostaglandin F2α, prosultiamine, fursultiamine, trimebutine maleate, amidotrizoate sodium meglumine.

Permitted drugs: metoclopramide or domperidone to treat postoperative nausea/vomiting, and immunosuppressants including tacrolimus, cyclosporine, steroid, azathioprine, mizoribin and mycophenolate mofetil.

Criteria for discontinuing the protocol treatment

Grade 3 postoperative diarrhoea or other clinical adverse effects (CTCAE V.4.0 criteria).

Data collection

Prospective data about all patients including medical history, physical findings, laboratory findings, perioperative clinical information and complications will be collected.

Study design and statistical analysis

The primary end points will be statistically evaluated at POD 7 (total oral or enteral caloric intake, abdominal distension and abdominal pain determined using NRS).

The multiplicity issue (inflation of type I error) due to the analysis of three end points will be addressed using the fixed-sequence testing method. The order of the tests will be fixed, which controls the familywise error rate. The testing procedure will start from a hypothesis about the total oral and enteral caloric intake, and will be followed by the NRS for abdominal distension and the NRS for abdominal symptoms in that order. Each test will proceed only if all previously tested hypotheses have been rejected. Each hypothesis will be tested at the 5% significance level. The sample size was calculated on the basis of our previous finding that the mean value of the total oral and enteral caloric intake at POD 7 without the administration of TJ-100 is about 1000 kcal/day (SD=850) (unpublished data). We speculated that patients administered with TJ-100 would have an intake of 500 kcal/day more than those who were not administered with TJ-100. Thus, assuming that the two arms have the same SD, the sample size was calculated on the basis of a t test with a two-sided significance level of 5% and a power of 80%, which resulted in a requirement of 47 patients per group. Taking about 15% exclusion from analysis into account, the number of patients to be accrued was set at 55 per treatment arm (110 in total). If the sample for analyses is 47 per group and the two-sided significance level is 5%, and if the probability of an event in which the value of the NRS in Arm A is larger than that in Arm B is about 0.62, then the Wilcoxon rank-sum test would have an approximate power of 80% for each NRS test of abdominal distension and abdominal symptoms. The first primary end point, the total oral and enteral caloric intake at POD 7, will be compared between the two treatment groups using the t test. The second and the third primary end points, the values of NRS on abdominal distension and abdominal pain, will be compared between the two treatment groups using the Wilcoxon rank-sum test. When the total oral and caloric enteral intake data at POD 7 for 50 patients are collected, we will conduct an interim analysis to confirm the distribution of total oral and enteral caloric intake at POD 7 under double-blind conditions. If the distribution obviously deviates from the normal distribution, then the Wilcoxon rank-sum test will be used for the primary analysis of the total oral and enteral caloric intake at POD 7.

Participating institutions

Fourteen leading Japanese institutions that perform LT will participate in this trial.

Registration of the protocol

The protocol was approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. Written informed consent will be obtained from all patients before enrolment and randomisation by investigators. The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.

Study status

This study is currently collecting data and there has not been any publication concerning the analysis of the data collected to date.