Daikenchuto for Intestinal Dysmotility and Prevention of Postoperative Paralytic Ielus After Pancreaticoduodenectomy (JAPAN-PD)

Effect of Daikenchuto (TJ-100) on Intestinal Dysmotility and For the Prevention of Postoperative Paralytic Ileus in Patients Undergoing Pancreaticoduodenectomy: A Multicenter, Randomized, Placebo-Controlled Phase II Trial

A multicenter randomized-controlled trial of daikenchuto (TJ-100), a traditional Japanese herbal medicine (Kampo), to investigate its effect on intestinal dysmotility and for the prevention of postoperative paralytic ileus.

Study Overview

• Status: Unknown
• Conditions: Paralytic Ileus
• Intervention / Treatment: Drug: Oral/enteral TJ-100 solution; Drug: Oral/enteral placebo solution

Detailed Description

Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is used for prevention and treatment of postoperative ileus. TJ-100 extract powder (Tsumura & Co., Tokyo, Japan) is manufactured as an aqueous extract containing 2.2 % Japanese pepper, 5.6 % processed ginger, 3.3 % ginseng, and 88.9 % maltose syrup powder. A recent randomized, parallel-group, double-blind, placebo-controlled, dose-response trial demonstrated that TJ-100 accelerates colonic transit time, particularly in the ascending colon. Given its potential actions in the intestinal tract, it seems reasonable to postulate that TJ-100 may play a role in improving and preventing bowel dysmotility. This study was designed to investigate the effect of TJ-100 on intestinal dysmotility and for the prevention of postoperative paralytic ileus in patients undergoing pancreaticoduodenectomy.

The primary endpoint is the incidence of postoperative paralytic ileus. Secondary endpoints are QOL assessment by the Gastrointestinal Symptom Rating Scale (GSRS) Score (Japanese Version) and visual analogue scale, the change in ratio of abdominal circumference, the incidence of postoperative complications, the length of hospital day, and the incidence of surgical site infection. Two hundred patients are required for the study (100 patients per group).

• Study Type: Interventional
• Enrollment (Anticipated): 220
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Hiroshima, Japan
    • Hiroshima University
  • Shizuoka, Japan
    • Shizuoka Cancer Center Hospital
  • Wakayama, Japan, 641-8510
    • Wakayama Medical University
  • Aichi
    • Nagoya, Aichi, Japan
      • Nagoya University
  • Osaka
    • Suita, Osaka, Japan
      • Osaka University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with periampullary tumors (extrahepatic bile duct tumor, tumors of ampulla of Vater and duodenal tumor) and pancreatic tumors (pancreatic cancer, intraductal papillary mucinous neoplasm of the pancreas, pancreatic endocrine tumor and pancreatic neuroendocrine tumor) of the head of the pancreas who are scheduled to undergo PD.
• Age of at least 20 years old at the time of registration.
• All patients provided written informed consent before initiation of study-related procedures.

Exclusion Criteria:

• Clinically problematic cardiac disease.
• Liver cirrhosis or active hepatitis.
• Severe pulmonary disease (interstitial pneumonia, pulmonary fibrosis, pulmonary emphysema etc.).
• Chronic renal failure requiring hemodialysis.
• Other malignant disease that can influence the adverse effect.
• Patients with tumors requiring resection of colon.
• Patients who are expected to have severe intra-abdominal adhesion due to past surgical history or past peritonitis history.
• Patients who had used gastrointestinal prokinetic medication, antipsychotic medication or antidepressants.
• Patients who had used Japanese herbal (Kampo) medicines within 4 weeks before registration.
• Pregnant or lactating women.
• Any other medical condition that makes the patient unsuitable for inclusion in the study according to the opinion of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oral/enteral TJ-100 solution	Drug: Oral/enteral TJ-100 solution; Oral TJ-100 solution (5 g tid, 15 g/day) given immediately before meals or every 8 h from preoperative day 3 to postoperative day 7 for 10 consecutive days. A diluent TJ-100 solution given immediately after surgery and on postoperative day 1 via Argyle enteral feeding tube (10 Fr), which terminates in the jejunum to prevent aspiration pneumonia.; Other Names: A
Placebo Comparator: Oral/enteral placebo solution	Drug: Oral/enteral placebo solution; Oral placebo solution (5 g tid, 15 g/day) given immediately before meals or every 8 h from preoperative day 3 to postoperative day 7 for 10 consecutive days. A diluent placebo solution given immediately after surgery and on postoperative day 1 via Argyle enteral feeding tube (10 Fr), which terminates in the jejunum to prevent aspiration pneumonia.; Other Names: B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative paralytic ileus (including the duration of paralysis)	Delayed passage of first flatus for 72 hours (3.0 days) after surgery, or a postoperative condition that requires an intervention for the ileus. Every 12 hours is counted as 0.5 postoperative day and every 24 hours as 1.0 postoperative day.	72 hours
The duration until the first flatus after surgery.	The first passages of flatus will be confirmed by patients themselves and they will inform it to the medical staffs.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QOL assessment by the Gastrointestinal Symptom Rating Scale (GSRS) Score (Japanese Version)	QOL assessment by the Gastrointestinal Symptom Rating Scale (GSRS) Score (Japanese Version) on postoperative day 7.	7 days
Abdominal pain and abdominal distention scores on the Visual Analogue Scale.	Abdominal pain and abdominal distention scores on the Visual Analogue Scale on postoperative day 3.	3 days
The change ratio of abdominal circumference.	The change ratio of abdominal circumference on postoperative day 3 and operative day just after surgery	3 days
The incidence of postoperative complication.	The incidence of postoperative complication based on Dindo's classification.	14 days
The length of postoperative hospital day.	Patients were discharged only when they fulfilled the criteria as follows: a return to preoperative activities of daily living, no deep-site infections, normal laboratory data, no drains, and the possibility for oral nutrition above the basal metabolism.	30 days
The incidence of surgical site infection.	Intra-abdominal abscess was defined as intra-abdominal fluid collection with positive cultures identified by ultrasonography or computed tomography associated with persistent fever and elevations of white blood cell counts.	30 days
The long term incidence of postoperative ileus after surgery.	The follow-up investigation of the long term incidence of postoperative ileus is scheduled in two years after surgery.	2 years

Collaborators and Investigators

• Sponsor: Wakayama Medical University
• Collaborators: Epidemiological and Clinical Research Information Network
• Investigators: Principal Investigator: Hiroki Yamaue, M.D., Ph.D., Second Department of Surgery, Wakayama Medical University

Publications and helpful links

General Publications

• Maeda H, Okada KI, Fujii T, Oba MS, Kawai M, Hirono S, Kodera Y, Sho M, Akahori T, Shimizu Y, Ambo Y, Kondo N, Murakami Y, Ohuchida J, Eguchi H, Nagano H, Sakamoto J, Yamaue H. Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD. Oncol Lett. 2018 Nov;16(5):6847-6853. doi: 10.3892/ol.2018.9422. Epub 2018 Sep 7.
• Okada K, Kawai M, Hirono S, Fujii T, Kodera Y, Sho M, Nakajima Y, Satoi S, Kwon AH, Shimizu Y, Ambo Y, Kondo N, Murakami Y, Ohuchida J, Eguchi H, Nagano H, Oba MS, Morita S, Sakamoto J, Yamaue H; JAPAN-PD Investigators. Evaluation of the efficacy of daikenchuto (TJ -100) for the prevention of paralytic ileus after pancreaticoduodenectomy: A multicenter, double-blind, randomized, placebo-controlled trial. Surgery. 2016 May;159(5):1333-41. doi: 10.1016/j.surg.2015.11.019. Epub 2015 Dec 31.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Anticipated): August 1, 2016

Study Registration Dates

• First Submitted: May 16, 2012
• First Submitted That Met QC Criteria: May 29, 2012
• First Posted (Estimate): May 30, 2012

Study Record Updates

• Last Update Posted (Estimate): December 18, 2013
• Last Update Submitted That Met QC Criteria: December 17, 2013
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: pancreaticoduodenectomy; postoperative ileus; daikenchuto
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Obstruction; Ileus; Intestinal Pseudo-Obstruction; Pharmaceutical Solutions
• Other Study ID Numbers: JAPAN-PD; UMIN000007975 (Other Identifier: UMIN-CTR)