Clinical trial NCT04742907
Conditions: Enhanced Recovery After Surgery
Sponsor: Tsumura USA
Start date: 2021-07-29; Completion date: 2024-05-01
Enrollment: 402 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, randomized, double-blinded, placebo-controlled study will evaluate the effect of TU-100 on resolution of postoperative ileus (POI) in subjects undergoing open or laparoscopic bowel resection (BR).

Detailed description:
Subjects will be screened up to 28 days before their planned surgery and will be randomized 1:1:1 (TU-100 15 g/day: TU-100 7.5 g/day: placebo) on postoperative Day 1 before the first dose of study medication. After randomization, subjects will receive a total daily dose of TU-100 15g, TU-100 7.5 g, or matching placebo (3 times per day (TID)) until hospital discharge or ≤ 10 days (whichever is earlier). All subjects will be treated with study medication as adjunct to an enhanced recovery (ERAS) pathway for gastrointestinal (GI) recovery.

Arms: arm 1: Subjects will receive a total daily dose of TU-100 5 g TID until hospital discharge or ≤ 10 days (whichever is earlier). arm 2: Subjects will receive a total daily dose of TU-100 2.5 g TID until hospital discharge or ≤ 10 days (whichever is earlier). arm 3: Subjects will receive placebo TID until hospital discharge or ≤ 10 days (whichever is earlier).
Interventions: intervention 1: TU-100 intervention 2: Placebo
Intervention descriptions: intervention 1: Treatment with investigational product intervention 2: Treatment with placebo product

Protocol documents:
Prot_SAP_000.pdf: 




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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the 
Safety and Efficacy of TU-100 as an Adjunct to an Enhanced Recovery after 
Surgery (ERAS) Protocol in Subjects Undergoing Bowel Resection 
Protocol Number: 
TU100P2T4 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement 
• 
I, the undersigned, have reviewed this protocol, including appendices, and I will conduct the 
study as described in compliance with this protocol (and amendments), GCP, and relevant 
International Council for Harmonisation (ICH) guidelines. 
• 
I am thoroughly familiar with the appropriate use of the study drug, as described in this protocol 
and any other information provided by Tsumura USA, Inc. including, but not limited to, the 
current investigator’s brochure. 
• 
Once the protocol has been approved by the independent ethics committee (IEC)/institutional 
review board (IRB), I will not modify this protocol without obtaining prior approval of Tsumura 
USA, Inc. and of the IEC/IRB. I will submit the protocol amendments and/or any informed 
consent form modifications to Tsumura USA, Inc. and the IEC/IRB, and approval will be 
obtained before any amendments are implemented. 
• 
I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Tsumura USA, Inc. study drug and of their delegated study-related duties and 
functions as described in the protocol. 
• 
I ensure that source documents and trial records that include all pertinent observations on each of 
the site’s trial subjects will be attributable, legible, contemporaneous, original, accurate, and 
complete. 
• 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. No subject names will be disclosed. All 
subjects will be identified by assigned numbers on all case report forms, laboratory samples, or 
source documents forwarded to the Sponsor. Clinical information may be reviewed by the 
Sponsor or its agents or regulatory agencies. Agreement must be obtained from the subject before 
disclosure of subject information to a third party. 
• 
Information developed in this clinical study may be disclosed by Tsumura USA, Inc. to other 
clinical investigators, regulatory agencies, or other health authority or government agencies as 
required. 
<Name> 
<Title> 
Investigator Signature 
 
 
Date (DD-Mmm-YYYY) 
 
Institution 


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2 
SYNOPSIS 
Title of Study: 
Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Safety and Efficacy 
of TU-100 as an Adjunct to an Enhanced Recovery after Surgery (ERAS) Protocol in Subjects 
Undergoing Bowel Resection 
Protocol Number: 
TU100P2T4 
Investigators/Study 
Sites: 
Up to approximately 55 study sites in the United States 
Phase of 
Development: 
Phase 2 
Objectives: 
The primary objective of this study is to compare the effect of TU-100 with placebo, in 
conjunction with an enhanced recovery pathway for gastrointestinal (GI) recovery, on resolution of 
postoperative ileus (POI) following bowel resection (BR) as assessed by recovery of upper and 
lower GI motility. 
Secondary objectives: 
• 
Evaluate the effect of TU-100 compared with placebo on measures of early GI recovery 
related outcomes including hospital length of stay (see secondary endpoint list) 
• 
Evaluate the safety and tolerability of TU100 compared with placebo after daily in-hospital 
dosing (up to 10 days) 
• 
Evaluate TU-100 compared with placebo with regards to the incidence and severity of 
hepatobiliary adverse events (AEs) 
Exploratory objective: 
• 
Explore the potential effects of TU-100 on other early postoperative surgical outcomes 
related to its mechanism of action (see exploratory endpoint list) 
Study Endpoints: 
Primary endpoint: 
The primary efficacy endpoint is the time to achieve recovery of GI motility as measured by a 
composite endpoint representing upper (time to first toleration of clear liquids) AND lower (time to 
first bowel movement [BM] OR absence of distention AND presence of bowel sounds AND flatus) 
GI recovery. This endpoint is referred to as gastrointestinal recovery (GIR). 
GIR = Time to first toleration of clear liquids (i.e., time at which the subject transitions from clear 
liquids to the next diet stage; [full liquids or solids]) 
 
AND 
(Time to first BM) OR (absence of distension + presence of bowel sounds + flatus) 
Secondary efficacy endpoints: 
• 
Time to GI-2 recovery (i.e., time to first toleration of solids AND time to first BM) 
• 
Time to ready for discharge (based solely on GI recovery) 
• 
Time to discharge order written 
• 
Length of hospital stay (based on calendar day of discharge order written) 
• 
Proportion of GIR responders 
o 
GIR by day 
• 
POI-related morbidity (primary POI only) 
o 
POI that required readmission within 7 days of discharge, or 
o 
Need for postoperative nasal gastric tube (NGT) insertion to manage symptoms 
of POI (i.e., vomiting/retching, abdominal distension) per protocol guidelines 
• 
Time to first toleration of clear liquids, i.e., time at which the subject transitions from 
clear liquids to the next diet stage; (full liquids or solids) 
• 
Time to first BM 
• 
Time to absence of distension and presence of bowel sounds and flatus (i.e., time to 
when all 3 conditions have been achieved) 
• 
Time to toleration of solids (i.e., able to eat a meal that requires chewing without a 
vomiting episode by the time the next consecutive meal is offered) 
o 
Note, if the first solid meal is consumed on the day of hospitalization (i.e., the 
day of surgery), the time to toleration of solids is as stated (e.g., the time to eat 
solids without a vomiting episode by the time the next consecutive meal is 
offered). Further, if the first solid meal is consumed on the day of discharge, 
the time to toleration of solids criteria is met if there is no vomiting prior to 
discharge. In all cases, the actual time that should be recorded on the electronic 


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case report form is the time the meal was consumed by the subject, not the 
cutoff time for vomiting prior to next consecutive meal or discharge. 
Safety endpoints: 
• 
Incidence of AEs 
• 
Clinical laboratory tests (hematology and serum chemistry, especially liver function tests 
[LFTs]) 
o 
Close observation if early signals of possible drug induced liver injury (DILI) 
are detected and confirmed 
▪ 
Repeating aminotransferases (aspartate aminotransferase [AST], 
alanine aminotransferase [ALT]), and total bilirubin tests 3 times 
weekly (the initial retest will occur within 48 hours) until stable or 
discontinuation of study drug; frequency of retesting can decrease to 
once a week or less if abnormalities stabilize or the study drug has 
been discontinued and the subject is asymptomatic. 
▪ 
Obtaining more detailed history of symptoms and prior or concurrent 
diseases 
▪ 
Obtaining a history of concomitant drug use (including 
nonprescription medications and herbal and dietary supplement 
preparations), alcohol use, recreational drug use, and special diets if 
not already captured in medical history 
▪ 
Ruling out active hepatitis virus types A, B, C, D, and E; 
autoimmune or alcoholic hepatitis; nonalcoholic steatohepatitis 
(NASH); hypoxic/ischemic hepatopathy; and biliary tract disease 
▪ 
Obtaining a history of exposure to environmental chemical agents 
▪ 
Consideration of GI or hepatology consultations 
• 
Incidence of independently assessed hepatobiliary AEs 
• 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) 
• 
12-lead electrocardiogram (ECG) test results 
Exploratory endpoints: 
• 
Subject-reported (eDiary) occurrence of nausea, vomiting and/or retching, and 
abdominal bloating per day 
• 
Subject-reported (eDiary) number of episodes of vomiting and/or retching per day 
• 
Subject-reported (eDiary) bothersomeness of nausea and abdominal bloating by day 
• 
Incidence and severity of nausea, vomiting and/or retching, abdominal bloating based on 
spontaneous AE reporting from safety database 
• 
Postoperative antiemetic rescue 
• 
Postoperative complications 
▪ 
Prolonged POI: 
• 
Minimal incision BR (laparoscopic or robotically-assisted 
or hand-assisted): Unresolved POI by postoperative Day 3 
• 
Laparotomy (open) BR: unresolved POI by postoperative 
Day 5 
NOTE: POI = primary POI (i.e., POI that is not secondary to surgical 
complication, such as anastomotic leak, abscess formation, or sepsis 
etc.) 
▪ 
Recurrent POI (prolongs hospital stay or results in readmission - 
based on investigator assessment) 
▪ 
Surgical site infection 
▪ 
Anastomotic leak 
▪ 
Early postoperative mechanical small bowel obstruction (EPSBO) 


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• 
Confirmed by the presence of a transition point between 
dilated and decompressed bowel demonstrated on 
abdominal imaging 
o 
Time to discontinue intravenous (IV) fluids 
o 
Time to transition to oral analgesics 
o 
Hospital readmission (within 7 days and within 30 days of discharge) 
Study Design: 
This multicenter, randomized, double-blinded, placebo-controlled study will evaluate the effect of 
TU-100 on resolution of POI in subjects undergoing open or minimally invasive BR. Straight, 
hand-assisted, and robotically-assisted laparoscopic approaches are allowed. Subjects undergoing 
major abdominal resective intestinal surgeries (BRs; e.g., small BR, large BR, rectal resections 
[low anterior resection], total colectomy with ileo-rectal anastomosis) will be eligible for 
enrollment. 
Subjects will be screened up to 28 days before their planned surgery and will be randomized 1:1:1 
(TU-100 15 g/day: TU-100 7.5 g/day: placebo) on postoperative Day 1 before the first dose of 
study medication. Subjects will be stratified based on surgical approach (open versus 
laparoscopic). After randomization, subjects will receive a total daily dose of TU-100 15g, TU-100 
7.5 g, or matching placebo (TID) until hospital discharge or   10 days (whichever is earlier). All 
subjects will be treated with study medication as adjunct to an enhanced recovery (i.e., ERAS) 
pathway for GI recovery, the components of which are standardized, to the extent possible, by the 
protocol (standard of care). 
There will be 2 independent committees with additional safety oversight. Each will have a formal 
charter and their specific roles will be discussed within the protocol. 
• 
Data and safety and monitoring board (DSMB; clinical trial safety oversight) 
• 
Clinical endpoint adjudication committee (CEAC; for assessment of hepatobiliary AEs) 
The overall study design is shown below: 
 
• 
Abbreviations: R = Randomized; S = Surgery. 
• 
a 
Treatment will be for a maximum of 10 days while subjects are 
hospitalized. If a subject is discharged before postoperative Day 10, study 
medication will be discontinued upon hospital discharge. 
Selection of Subjects: 
Main Inclusion Criteria: Eligible subjects are males or females ≥ 18 years of age with an American 
Society of Anesthesiologist Physical Status Score of 1 to 3 who are scheduled for an elective BR. 
The BR may be open or laparoscopic (straight, hand-assisted, or robotically assisted) and may 
include small BR, large BR, total colectomy with ileo-rectal anastomosis, or rectal resection. The 
anticipated hospital stay is ≥ 4 days with at least 3 overnight stays. 
• 
Please follow your local testing guidelines for SARS-CoV-2. If testing is mandatory at 
your institution, a positive result would be exclusionary 
• 
Subjects with prior history of COVID-19 must be confirmed recovered per CDC criteria 
and have a SARS-CoV-2 negative test result 
• 
If a subject contracts COVID-19 during the interval between screening and pre-surgery 
Day -1, he or she may be rescreened once recovered, assuming the subject meets all 
other inclusion/exclusion criteria and per investigator clinical judgement 
Main Exclusion Criteria: Subjects are not eligible if they are scheduled for a type of surgery not 


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listed in the inclusion criteria, if a surgery is required for an ongoing GI infection, bowel obstruction, 
or perforated bowel, or if the subject requires a ventral hernia repair through component separation 
techniques or placement of mesh. Subjects requiring any additional resections beyond the intestine 
(e.g., hepatectomy, distal pancreatectomy, pancreaticoduodenectomy, gastric resection, uterine 
resection) or concomitant surgeries (with the exception of biopsies) are not eligible as are subjects 
requiring resection of the rectum (resection of a portion of the rectum is permitted as part of a low 
anterior resection). Subjects requiring the formation of a stoma (ileostomy or colostomy) or stoma 
reversals with anastomosis, or who have a functional colostomy or ileostomy are not eligible. 
Subjects who use an enteral feeding device (including, but not limited to, nasogastric tube, 
nasoduodenal tube, or gastric tube) within 30 days of surgery are also not eligible. Subjects who 
have an ongoing history of short bowel syndrome, chronic constipation (≤3 spontaneous BMs/week), 
chronic diarrhea (3 or more loose stools per day that last for at least 4 weeks), complete bowel 
obstruction, or a history of GI dysmotility are not eligible. 
Planned Sample Size: 
The study is expected to enroll approximately 402 eligible subjects (with expected loss to 
follow-up or censorship of primary endpoint) with a 1:1:1 randomization ratio over a post-surgery 
period (up to 10 days). 
Based on historical evidence, it is assumed that a small proportion of subjects will be lost to 
follow-up or will have events censored due to required analytical methods. To account for this 
anticipated loss in contribution of events to the primary endpoint, an additional 36 subjects 
(approximately 10% of 366) will be enrolled to achieve a final sample size of 402 subjects (134 per 
group). 
Investigational 
Therapy: 
TU-100, an herbal product manufactured by Tsumura & Co (Tsumura; Tokyo, Japan), is a granular 
formulation of daikenchuto. TU-100 will be provided in sachets of 2.5 gr. Subjects will receive 
TU-100 TID by mouth (in a solution with water) from Day 1 (the day after surgery) through 
Day 10 or hospital discharge (whichever occurs earlier).  
Reference Therapy: 
Placebo will be similar in appearance to TU-100 and will be provided in sachets of 2.5 gr. Subjects 
will receive placebo by mouth (in a solution with water) from Day 1 (the day after surgery) 
through Day 10 or hospital discharge (whichever occurs earlier). 
Treatment Duration: 
Each subject will receive study drug or matching placebo starting on Day 1 through Day 10 or 
hospital discharge (whichever occurs earlier). All dosing will be in the hospital (no outpatient 
dosing).  
Efficacy: 
The primary efficacy variable will be time to Gastrointestinal Recovery (TGIR), which will be the 
time to recovery of both upper (time to first toleration of liquids), and lower (first BM OR absence 
of distention AND bowel sounds AND flatus) GIR. 
Secondary efficacy assessments: 
• 
Time to GI-2 recovery (i.e., time to first toleration of solids AND time to first BM) 
• 
Time to ready for discharge (based solely on GI recovery) 
• 
Time to discharge order written 
• 
Length of hospital stay (based on calendar day of discharge order written) 
• 
Proportion of GIR responders (GIR by day) 
• 
POI-related morbidity (primary POI only) defined as 1) POI that required readmission 
within 7 days of discharge or 2) Need for postoperative NGT insertion to manage 
symptoms 
• 
Time to first toleration of clear liquids 
• 
Time to first BM 
• 
Time to absence of distention and presence of bowel sounds and flatus (all 3 achieved) 
• 
Time to toleration of solids 
Exploratory assessments: 
• 
Subject-reported (eDiary) occurrence of nausea, vomiting and/or retching, and abdominal 
bloating per day 
• 
Subject-reported (eDiary) number of episodes of vomiting/retching per day 
• 
Subject-reported (eDiary) bothersomeness of nausea and abdominal bloating by day 
• 
Incidence and severity of nausea, vomiting/retching, abdominal bloating based on 
spontaneous AE reporting from safety database 
• 
Postoperative antiemetic rescue 
• 
Postoperative complications, including prolonged or recurrent POI, infection at site, 
anastomotic leak, or bowel obstruction 
• 
Time to discontinue IV fluids 
• 
Time to transition to oral analgesics 
• 
Hospital readmission (within 7 days and within 30 days of discharge) 


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Safety: 
Safety measures include the following 
• 
Incidence of AEs 
• 
Clinical laboratory tests (hematology, serum chemistry including liver transaminases, and 
LFTs, and close observation for possible DILI) 
• 
Incidence of independently assessed hepatobiliary AEs 
• 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and body 
temperature) 
• 
12-lead ECG test results 
Pharmacokinetics: 
Sparse sampling will be conducted to evaluate the pharmacokinetics (PK) of TU-100 constituents 
(e.g., HAS, HBS). 
Statistical Methods 
and Planned 
Analyses: 
Populations: 
Safety analysis set: All randomized subjects who receive at least 1 dose of study medication. The 
Safety Analysis Set will be used primarily for the analysis of safety data. Subjects will be classified 
based upon the treatment received. 
Full analysis set (FAS): All randomized subjects who receive at least 1 dose of study medication, 
who underwent an elective BR surgery as specified in the protocol, and who provided at least 1 
post-surgery assessment of the primary endpoint (GIR) during the treatment period. The FAS will 
be used primarily for the analysis of efficacy data. Participants will be analyzed according to the 
treatment group to which they are randomized. 
Per-protocol analysis (PP) set: A subset of the FAS who: 
• 
Had a protocol-specified surgery 
• 
Did not take prohibited medications during the treatment period that could affect the 
primary endpoint 
• 
Had otherwise complied with the protocol without any other major protocol deviation (any 
exceptions for inclusion/exclusion criteria granted by the Sponsor/medical monitor will 
not be considered protocol violations) 
PK analysis set: All subjects who have PK data available for at least 1 dose of TU-100. 
The primary efficacy variable is time to TGIR, a composite endpoint defined as the following: 
TGIR = maximum (time to first toleration of liquids; time to first BM OR [absence of distention 
AND bowel sounds AND flatus]) 
Time to an event is defined as the elapsed time, in hours, from the end of surgery to the time of the 
first event, to be calculated as: 
Time to event (hours) = (time of the event − time of end of surgery) 
The primary analysis of TGIR will be based on the Cox proportional hazard model (Cox PH) that 
includes the main effects for treatment and surgical approach (open versus laparoscopic). The 
estimates of time to event for the quartiles (25%, 50%, 75%), hazard ratios and their corresponding 
one-sided 95% confidence intervals (CIs), the Wald Chi-square one-sided P values from the Cox 
analysis will be summarized. The ties in the data will be handled by the Breslow method. 
A secondary analysis will be applied for TGIR using the Cox PH model including main effects for 
treatment, surgical approach (open versus laparoscopic), and covariates such as surgical type, 
gender, age (years), post-operation opioid consumption (mg morphine equivalents), thoracic 
epidural use, and surgery duration (hours). Backward method will be used to select statistically 
significant covariates (P <0.1). Adjusted P value and hazard ratio (HR) will be provided after the 
final model is selected. 
In addition, TGIR will be assessed for TU-100 versus placebo at each dose level using a stratified 
log-rank with the one stratum used for randomization: surgical approach (open versus 
laparoscopic). The Kaplan-Meier estimate of the median TGIR and the corresponding 1-sided 95% 
CIs calculated using the Greenwood’s formula will be presented. Plot of the Kaplan-Meier estimate 
of the survival distribution function over time will be presented. The restricted mean survival time 
(RMST) at time t* using the Kaplan-Meier estimate of the survival function will also be provided, 
where t* is the minimum of the largest observed time (event or censored) in each of the 2 groups. 
Furthermore, the difference in RMST, as well as the ratio of RMST between 2 groups will be 
evaluated. Similar analyses will be applied for other time to event efficacy endpoints.  
A secondary efficacy variable, time to ready for discharge (based solely on the treating medical 
team’s determination of GI recovery), which is defined as the time to the assessment date of “ready 
for hospital discharge.” Length of stay is based on the time to the calendar day of discharge order 
written from the calendar day of surgery. 
Treatment effect on other numeric variables will be analyzed using an analysis of variance 
(ANOVA) if normally distributed, or the Wilcoxon rank sum test otherwise. Treatment effect on 
categorical variables will be analyzed using the stratified Miettinen and Nurminen (M&N) method 
(stratified by surgical approach), or the logistic regression model if appropriate. 










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3.1 
List of In-text Tables 
Table 1. Schedule of Assessments ........................................................................................44 
Table 2. Laboratory Assessments..........................................................................................64 
Table 3. Classification of Adverse Events by Intensity ........................................................66 
Table 4. Classification of Adverse Events by Relationship to Study Drug ..........................66 
 
 
 


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3.2 
List of In-text Figures 
Figure 1. Study Design ...........................................................................................................28 
Figure 2. Packaging of TU-100 ..............................................................................................39 
 


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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BM 
bowel movement 
BMI 
body mass index 
BR 
bowel resection 
CEAC 
clinical endpoint adjudication committee 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cox PH 
Cox proportional hazard model 
CSR 
clinical study report 
DILI 
drug induced liver injury 
DSMB 
data and safety and monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
EPSBO 
early postoperative mechanical small bowel obstruction 
ERAS 
enhanced recovery after surgery 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GI 
gastrointestinal 
GIR 
gastrointestinal recovery 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability Accountability Act 
HIV 
human immunodeficiency virus 
HR 
Hazard ratio 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 


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Abbreviation 
Definition 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web response system 
LFT 
liver function test 
LOS 
length of stay 
MedDRA 
Medical Dictionary for Regulatory Activities 
NASH 
nonalcoholic steatohepatitis 
NGT 
nasal gastric tube 
NPO 
nothing by mouth 
NSAID 
nonsteroidal anti-inflammatory drug 
PI 
principal investigator 
PK 
pharmacokinetic 
POI 
postoperative ileus 
PONV 
postoperative nausea and vomiting 
PP 
Per-protocol 
QTc 
corrected QT interval 
QTcF 
QT interval with Fridericia correction 
RMST 
restricted mean survival time 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reactions 
TAP 
transverse abdominis plane [block] 
TEAE 
treatment-emergent adverse event 
TGIR 
time to gastrointestinal recovery 
TID 
3 times per day (i.e., 6 hours ± 1 hour apart) 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 
 












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Benefits 
TU-100 has been evaluated across multiple patient populations and conditions within the US 
development program. Primary efficacy endpoints in completed US Phase 2 surgery studies were 
not met; however, these studies were small and uncontrolled (Study TU100P2T1) and not 
prospectively designed to evaluate the effect of TU-100 compared with placebo on GI 
recovery/POI (Studies TU100P2T1 and TU100P2T3). Thus, within this context, the question 
regarding potential benefit remains unanswered. 
 
Nevertheless, there were signals that TU-100 may have improved GI recovery after colorectal 
resection including lower antiemetic use for nausea and numerically lower LOS compared with 
placebo in the Phase 2 trial of subjects undergoing laparoscopic colectomy (TU100P2T3). 
Moreover, in Japanese investigator-initiated trials, daikenchuto, used with varying dosing 
paradigms, was associated with accelerated time to first bowel movement (BM) in some patients 
undergoing open large BR, hepatectomy, and gastrectomy, particularly for those thought to have 
POI (Katsuno 2015, Kono 2019, Shimada 2015, Yoshikawa 2015). However, due to differences 
in SOC and dosing regimens used in Japan compared with the US, these data must be interpreted 
within that context. 
 
Thus, this adequate and well-controlled Phase 2 study is designed specifically to directly evaluate 
the effect of TU-100 compared with placebo on GI recovery and other related key early in-hospital 
outcomes (e.g., postoperative GI-related complications, hospital LOS) following major abdominal 
surgery. 
 
Details regarding known or anticipated benefits and risks, as well as reasonably anticipated AEs 
for TU-100 may be found in the IB. 
 
5.4 
Study Rationale 
Nonclinical studies performed to date have demonstrated daikenchuto’s ability to improve 
intestinal motility, improve intestinal blood flow, and prevent the incidence of adhesions and 
anastomotic leaks after colorectal surgery in animal models. It is thought that TU-100 would 
have the potential to have similar benefits in humans to prevent POI after colorectal surgery. 
 
In completed US Phase 2 surgery studies, although primary efficacy endpoints were not 
achieved, neither study was prospectively designed to evaluate the effect of TU-100 compared 
with placebo on GI recovery/POI. However, there were signals that TU-100 may have impacted 
GI recovery after colorectal resection including lower antiemetic use for nausea and numerically 
lower LOS compared with placebo in the Phase 2 trial of subjects undergoing laparoscopic 
colectomy. Moreover, in investigator-initiated Phase 3 trials in large BR, hepatectomy, and 
gastrectomy conducted in Japan, time to first BM was accelerated in some subjects, particularly 
those thought to have POI (Katsuno 2015, Kono 2019, Shimada 2015, Yoshikawa 2015). 
 
In clinical trials, TU-100 has been shown to be well tolerated. The most common AEs have been 
GI-related. In order to systematically evaluate the potential risk for DILI, based on post-
marketing surveillance in Japan suggesting the potential for risk of liver injury, close oversight 
of safety will be implemented. 
 


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This adequate and well-controlled Phase 2 study is designed specifically to directly evaluate the 
effect of TU-100 on GI recovery and other related key early in-hospital outcomes (e.g., 
postoperative GI-related complications, hospital LOS) following BR. 








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7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This multicenter, randomized, double-blinded, placebo-controlled study will evaluate the effect 
of TU-100 on resolution of POI in subjects undergoing open or minimally invasive BR. Straight, 
hand-assisted, and robotically-assisted laparoscopic approaches are allowed. Subjects undergoing 
major abdominal resective intestinal surgeries (BRs; e.g., small BR, large BR, rectal resections 
[low anterior resection], total colectomy with ileo-rectal anastomosis) will be eligible for 
enrollment.  
 
Subjects will be screened up to 28 days before their planned surgery and will be randomized 
1:1:1 (TU-100 15 g/day: TU-100 7.5 g/day: placebo) on postoperative Day 1 before the first dose 
of study medication. Subjects will be stratified based on surgical approach (open versus 
laparoscopic). After randomization, subjects will receive a total daily dose of TU-100 15 g, 
TU-100 7.5 g, or matching placebo TID until hospital discharge or   10 days (whichever is 
earlier). All subjects will be treated with study medication as adjunct to an enhanced recovery 
(i.e., ERAS) pathway for GI recovery, the components of which are standardized, to the extent 
possible, by the protocol (SOC) (See Section 7.2). 
 
Efforts will be made to obtain 134 subjects in each of the 3 treatment groups for a total of 
402 subjects. 
 
There will be 2 independent committees with additional safety oversight. Each will have a 
formal charter and their specific roles will be discussed within this protocol. 
 
• Data and safety monitoring board (DSMB; clinical trial safety oversight) 
• Clinical endpoint adjudication committee (CEAC; for assessment of hepatobiliary AEs) 
This study follows the FDA guidance on the conduct of clinical trials and statistical considerations 
for clinical trials during the COVID-19 pandemic as necessary. 
 
Figure 1 presents the study design. 
 


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Figure 1. 
Study Design 
 
• 
Abbreviations: R = Randomized; S = Surgery. 
• 
a 
Treatment will be for a maximum of 10 days while subjects are hospitalized. If a subject is 
discharged before postoperative Day 10, study medication will be discontinued upon hospital discharge. 
 
7.2 
Discussion of Study Design 
The clinical development program is designed to explore the benefit of TU-100 given after BR 
surgery to prevent the occurrence of POI and as adjunct to ERAS. Previous studies with TU-100 
showed that it was generally well tolerated. In completed Phase 2 studies in the US, while 
primary efficacy endpoints were not achieved, it should be noted that these studies were not 
designed to evaluate the effect of TU-100 compared with placebo on GI recovery or POI; 
therefore, the question regarding potential benefit after BR remains unanswered. However, there 
were signals that TU-100 had an impact on GI recovery after colorectal resection, including less 
need for nausea medication and a lower number of adverse symptoms. 
 
The in-hospital observation period is up to 10 days after GI surgery. TU-100 is administered in 
addition to the routine standard of ERAS care (see Section 10.2.1) and provides a multimodal 
approach in order to enhance recovery after surgery. Treatment with TU-100 should begin 
immediately after randomization to provide its effect on GI recovery and ERAS. Hospitalization 
of subjects provides a controlled setting to assure compliance with study drug administration and 
allows accurate monitoring of efficacy and safety measures by study staff. 
 
The following provides a rationale for the duration of in-hospital dosing: 
• The most favorable benefit-risk profile for TU-100 was expected to occur within the 
period of highest risk for delayed GI recovery and associated complications, i.e., during 
the subject’s hospital stay. 
• Based on TU-100’s mechanism of action and the clinical presentation of POI, it is 
anticipated that the optimal dosing duration is beginning the day after surgery and 


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continuing through the early postoperative period, during which GI motility should be 
resuming. 
• Discontinuing TU-100 at discharge is appropriate as surgical patients are routinely not 
discharged before achieving GI recovery milestones. Continuing dosing after discharge 
would offer no further substantive benefit to the subject and cause unnecessary drug 
exposure. 
• In-hospital dosing allows for close oversight of subjects for both safety and efficacy. 
7.3 
End of Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed all study periods, including Discharge Follow-up Visit on the 30 days (+15 days) after 
discharge as indicated in the Schedule of Assessments (Table 1). 
 
The end of the study will be the last subject’s last visit or the last subject’s scheduled 
visit/assessment as indicated in the Schedule of Assessments (Table 1). 
 


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8 
SELECTION OF STUDY POPULATION 
Section 7.1 provides information regarding number of subjects planned to be randomized. All 
subjects must pass the screening eligibility before and after surgery. All subjects must pass the 
randomization eligibility criteria before randomization on Day 1 in order to be randomized. The 
screening eligibility criteria are outlined in Section 8.1 and Section 8.2. Randomization 
eligibility criteria are included in Section 8.4. 
 
8.1 
Inclusion Criteria 
To be considered eligible to participate in this study, a subject must meet all the inclusion criteria 
listed below: 
1. 
Male or female ≥ 18 years of age 
2. 
Women of childbearing potential (WOCBP) or men whose sexual partners are WOCBP; 
must be able and willing to use at least 1 highly effective method of contraception during 
the study and for 30 days after the last dose of study drug. A female subject is considered 
to be a WOCBP following menarche and until she is in a postmenopausal state for 
12 months or otherwise permanently sterile (for which acceptable methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy). Highly effective 
methods of contraception include intrauterine contraceptive device; intrauterine 
hormone-releasing system; combined hormonal or progestogen-only contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal); bilateral tubal 
ligation or occlusion; vasectomy; condom in combination with contraceptive cream, jelly, 
or foam; or abstinence. Male subjects must agree to not donate sperm during the study 
period after drug is given until the 30-day follow-up. 
3. 
American Society of Anesthesiologists Physical Status Score of 1 to 3 
4. 
Scheduled for an elective BR as listed below via open or laparoscopic (straight, 
hand-assisted, robotically assisted) approach 
a) Small BR 
b) Large BR (partial colectomy) 
c) Total colectomy with ileo-rectal anastomosis 
d) Rectal resection (low anterior resection) 
5. 
Based on investigator assessment, subject’s hospital stays anticipated to be ≥ 4 calendar 
days (i.e., at least 3 overnight stays). It is anticipated that the subject will not be 
discharged until they have achieved upper and lower GI recovery per the protocol 
definition. 
6. 
Eastern Cooperative Oncology Group performance status of 0 or 1 
7. 
Ability to understand the study procedures, have agreed to participate in the study 
program, and have voluntarily provided informed consent 


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8.2 
Exclusion Criteria 
To be considered eligible to participate in this study, a subject must not meet any of the 
exclusion criteria listed below: 
1. 
Scheduled for a BR that is not listed in this protocol (Inclusion Criterion #4) 
2. 
Requires emergency surgery or surgery in the presence of ongoing GI infection, bowel 
obstruction, or perforated bowel 
3. 
Requires ventral hernia repair through component separation techniques or placement of 
mesh 
4. 
Requires any additional resections beyond the intestine (e.g., hepatectomy, distal 
pancreatectomy, pancreaticoduodenectomy, gastric resection, uterine resection), or 
concomitant surgeries (with the exception of biopsies) 
5. 
Requires resection of the rectum (Note: Resection of a portion of the rectum is permitted 
as part of a low anterior resection) 
6. 
Requires the formation of a stoma (ileostomy or colostomy) or stoma reversals with 
anastomosis  
7. 
History of previous surgeries, illness, or behavior that in the opinion of the investigator 
might confound the study results or pose additional risk in administering the study 
procedures 
8. 
Have a functional colostomy or ileostomy 
9. 
Ongoing history of short bowel syndrome, chronic constipation (3 spontaneous BMs per 
week), chronic diarrhea (3 or more loose stools per day that last for at least 4 weeks), and 
history of GI dysmotility or use of enteral feeding device (including, but not limited to, 
nasogastric tube, nasoduodenal tube, or gastric tube) within 30 days of surgical procedure 
preoperatively 
10. 
Complete bowel obstruction 
11. 
Received radiation therapy to the abdomen or pelvis within 2 months of scheduled 
surgery 
12. 
Received chemotherapy within 1 month of scheduled surgery 
13. 
Chemotherapy or radiation-induced bowel dysfunction 
14. 
Diagnosed with advanced or metastatic colon cancer (Stage IV by tumor, node, and 
metastasis classification) 
15. 
Hepatic impairment (defined as Child-Pugh A, B, or C) 
16. 
Active hepatitis 
17. 
Decompensated cirrhosis, i.e., history of hepatic encephalopathy, ascites, and variceal 
bleeding 
18. 
Abnormal coagulation parameters (e.g., international normalized ratio [INR] > 1.5 × the 
ULN) and not on Coumadin 
19. 
Abnormal liver tests 


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a) ALT or AST > ULN  
b) Alkaline phosphatase (ALP) > ULN  
c) Total bilirubin or direct bilirubin > ULN  
Note: Subjects with an elevated indirect bilirubin (< 2 × ULN) and who meet all other 
liver test criteria (ALT, AST, ALP, and direct bilirubin) are eligible for participation in 
the study (e.g., patients with known Gilbert’s disease) 
 
20. 
Positive COVID-19 test result within 72 hours prior to surgery 
21. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
(including known human immunodeficiency virus [HIV]), diabetes, symptomatic 
congestive heart failure and ejection fraction < 35%, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
protocol requirements 
22. 
Chronic pain syndrome unrelated to the planned surgery requiring consistent 
management with analgesics and/or other non-pharmacologic modalities 
23. 
Myocardial infarction within 3 months 
24. 
Moderate to severe renal impairment (i.e., estimated glomerular filtration rate [eGFR 
< 60 mL/min/1.73m2] or estimated creatinine clearance < 60 mL/min) 
25. 
Corrected QT interval (QTc) > 500 msec 
26. 
Diabetic gastroparesis 
27. 
Compromised immune system, either from treatment with corticosteroids or other 
immunosuppressive agent within 2 weeks of surgery or from immunosuppressive disease 
(e.g., known HIV) 
28. 
Immunosuppressive therapy 
Note: Subjects with inflammatory bowel disease who are receiving immunosuppressive 
therapy, including biologics or corticosteroids, are allowed to continue their therapy. 
Perioperative use of immunomodulators (e.g., azathioprine, methotrexate) in these 
patients is also permitted 
 
29. 
Pregnant (identified by a positive serum pregnancy test) or lactating, or are not 
postmenopausal (no menses for at least 1 year) and are of childbearing potential and not 
using an accepted method of birth control (i.e., surgical sterilization, intrauterine 
contraceptive device, oral contraceptive, diaphragm, or condom in combination with 
contraceptive cream, jelly, or foam or abstinence) 
30. 
Participated in another investigational drug/biologic or medical device study within 
30 days of surgery or will be enrolled in another investigational drug or medical device 
study, or any study in which active subject participation is required outside routine 
hospital data collection during the course of the study 
31. 
Illicit drug use or alcohol abuse based on medical history, or currently engaged in illicit 
drug use or alcohol abuse. Alcohol abuse is defined as 5 or more drinks in one sitting or 
15 or more drinks in a week for men and 4 or more drinks in one sitting or 8 or more 




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1. Underwent an eligible surgery (Inclusion Criterion #4) 
2. NGT tube has been removed, if inserted intraoperatively 
3. Is able to receive oral medications 
Additionally, in order to be randomized, a subject MUST NOT have achieved both upper and 
lower GI components that comprise the primary efficacy endpoint before Day 1 
Randomization, as listed below: 
 
Upper GI 
4. Transitioned from clear liquids to full liquids and/or solid food  
Lower GI 
5. Had first BM  
OR  
Achieved all 3 events below:  
a) Absence of abdominal distension; AND  
b) Experienced first flatus after surgery; AND  
c) Presence of bowel sounds after surgery  
8.5 
Study Treatment Discontinuation, Study Withdrawal, and Termination of Subjects 
• If a subject discontinues study treatment or is withdrawn/terminated from the study for any 
reason, the study site must immediately notify the medical monitor. The date the subject is 
withdrawn from the study and/or study medication and the primary reason for 
discontinuation, regardless of if the subject withdrawn/terminated from the entire study or 
only from study medication, must be clearly documented on the electronic case report form 
(eCRF).  
• 
If a subject discontinues study medication, he or she should be encouraged to continue in the 
study, and efficacy and safety procedures should be conducted as described in this protocol. 
These patients should continue with subsequent study visits and assessments as specified in 
the protocol including follow-up visits. Study treatment discontinuation does not imply 
withdrawal/termination from the study. 
• 
If a subject is withdrawn or terminated from the study before completing the 
protocol-specified duration of treatment, safety assessments listed under Study 
Withdrawal/Termination visit in the Schedule of Assessments (Table 1) are to be completed 
at the time of withdrawal/termination (including all protocol-required laboratory tests). The 
patient will be followed for the duration of the follow-up period as specified in the protocol 
Section 10.2.4. 
• 
Note that if a subject withdraws consent for further participation in the study, no further 
study assessments are to be performed unless the subject agrees to Study 
Withdrawal/Termination assessments. 
In the event that a subject is withdrawn/terminated prematurely from the study because of a 
TEAE or serious TEAE, the TEAE or serious TEAE will be followed up until it resolves (returns 




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• ALT > 3-fold ULN in subjects with normal baseline levels or 2-fold increases above 
baseline in subjects with abnormal levels prior to drug exposure 
Close observation includes:  
• Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly (the initial retest 
will occur within 48 hours). Frequency of retesting can decrease to once a week or less if 
abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
• Obtaining a more detailed history of symptoms and prior or concurrent diseases  
• Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets  
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract disease  
• Obtaining a history of exposure to environmental chemical agents  
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin)  
• Considering gastroenterology or hepatology consultations 
Note that if additional testing is conducted, this information should be recorded in the eCRF. 
 
Note: for any subject in whom a concern for hepatotoxicity or DILI develops (i.e., any subject 
that meets criteria for close observation), a narrative summary will be provided to the chairman 
of the DSMB by the Sponsor (via the CRO DSMB manager) for review by the board. The initial 
narrative summary will be provided within 24 to 48 hours of Sponsor notification of identifying 
a subject that meets the close observation criteria and updated versions provided as additional 
information becomes available and/or is requested by the DSMB chairman. 
 
Contents of the narrative summary will be comparable to the information provided in each case 
submitted to the CEAC for review/adjudication. Tsumura will be responsible for collecting the 
information and developing the narrative summary for submission to the DSMB. Based on their 
findings, the DSMB will make recommendations to the Sponsor regarding management of the 
case at the patient, site, and/or study level(s) based on their responsibilities as defined in their 
charter (e.g., study drug continuation, additional clinical and/or diagnostic information/testing, 
need for medical specialty consultation [e.g., gastroenterology/hepatology]). 
 
Note: if transaminase elevations persist, subjects will be evaluated for other causes of 
transaminase elevations including tests of hepatic function (e.g., viral hepatitis, nonalcoholic 
fatty liver disease/NASH, ischemic hepatitis, thyroid disorders, occult celiac disease). The type 
and extent of testing will be determined via recommendations by the DSMB and PI (to include 
recommendations from clinical consults should they be performed). This may include, but is not 
limited to, diagnostic imaging procedures and liver biopsy. Recommended testing will be shared 
with the Sponsor’s medical director. 
 












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investigational drug/biologic, and use of supplemental ginger, ginseng, or Zanthoxylum fruit. 
Radiation therapy and chemotherapy is prohibited.  
 
Note: As part of the study ERAS protocol, gabapentinoids may be administered at a single low 
dose preoperatively; however, they should not be used in the postoperative setting as part of 
multimodal acute pain management unless indicated for postoperative neuropathic pain. 
 
Acute postoperative neuropathic pain is generally characterized by 1 or more of the following 
signs or symptoms in the absence of other likely causative factors (e.g., postoperative 
complications such as surgical site infection): 
• Pain that is difficult to manage and does not respond to traditional analgesic agents 
(e.g., opioids, nonsteroidal anti-inflammatory drugs [NSAIDs]) 
• Hyperalgesia (postoperative pain disproportionately higher in intensity than what would 
be expected) 
• Dysesthesia (constant burning, tingling, throbbing pain) 
• Allodynia (pain associated with a stimulus that would not be expected to cause pain 
[e.g., light touch or pressure]) 
These symptoms may be limited to or extend beyond the region of the surgical incision/site and 
may be persistent despite standard-of-care pain management. 
 
Refer to Section 10.2.1.1 for the standardized ERAS pathway for preoperative, intraoperative, 
and postoperative drugs/treatments that are allowed and to be used to enhance GI recovery. 
 
Concomitant medications allowed during the study include oral antibiotics, pain medications 
(acetaminophen, NSAIDs, opioids [used sparingly]), anesthesia/analgesia, and antiemetic 
prophylaxis in at-risk subjects. Based on the potential impact of opioids on GI recovery/POI, 
more details on concomitant opioid use may be required on the eCRF. 
 
Any prohibited medication or therapy that is taken by or administered to the subject during the 
course of the study must be recorded on the eCRF. The entry must include the dose, regimen, 
route, indication, and dates of use. 
 
The use of supplemental ginger or Zanthoxylum fruit within 72 hours or supplemental ginseng 
within 120 hours before randomization is prohibited. 


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10 STUDY PROCEDURES 
Table 1 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.5 specifies laboratory assessment samples to be obtained. See Section 11 and 
Section 12 for additional details regarding efficacy assessments and safety assessments, 
respectively. Details for PK analytical methodology are presented in Section 13. 
 


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Table 1. 
Schedule of Assessments 
Procedure 
Screening 
Day -28 to 
-1a 
Surgery 
Day -1 
Randomization 
Day 1 
 
Day 2 
to 10b 
Hospital Discharge or 
Study 
Withdrawal/Termination 
Follow-
up 
Contactc 
30 days 
(+15 days) 
After 
Discharge 
Follow-up 
Visitd 
 
 
Pre-
surgery 
Post-
surgery 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Study screening 
eligibility/ 
inclusion/exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
Randomization 
Eligibility Criteria 
 
 
 
X 
 
 
 
 
Demographics, 
medical history, 
including previous 
abdominal 
surgeries 
X 
X 
 
 
 
 
 
 
Medication 
history/ 
concomitant 
medications 
Xe 
X 
X 
X 
X 
X 
X 
X 
COVID-19 
screening 
questionsf 
X 
X 
 
 
 
 
 
 
COVID-19 test 
X 
 
 
 
 
 
 
 
Pregnancy testg 
X 
X 
 
 
 
 
 
 
Physical 
examinationh 
X 
 
 
 
 
X 
 
X 
Vital signsi 
X 
 
 
X 
 
X 
 
X 


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Procedure 
Screening 
Day -28 to 
-1a 
Surgery 
Day -1 
Randomization 
Day 1 
 
Day 2 
to 10b 
Hospital Discharge or 
Study 
Withdrawal/Termination 
Follow-
up 
Contactc 
30 days 
(+15 days) 
After 
Discharge 
Follow-up 
Visitd 
 
 
Pre-
surgery 
Post-
surgery 
 
 
 
 
 
12-lead ECGj 
X 
 
 
X 
 
X 
 
 
Serologyk: HBV, 
HCV  
X 
 
 
 
 
 
 
 
Hematology, 
serum chemistry, 
urinalysisl 
X 
 
 
X 
 
X 
 
 
LFTsm 
X 
X 
 
X 
X 
X 
 
X 
Record surgery 
start and stop time 
 
 
X 
 
 
 
 
 
Record estimated 
blood loss 
 
 
X 
 
 
 
 
 
Record need for 
blood transfusion 
 
 
X 
 
 
 
 
 
Record total 
intraoperative IV 
fluid type and 
volume 
 
 
 
 
 
 
 
 
Record NGT 
removal, if used 
intraoperatively 
 
 
X 
 
 
 
 
 
Record 
information on 
postoperative NGT 
insertion, if used 
 
 
 
X 
X 
X 
 
 
Randomization 
 
 
 
X 
 
 
 
 


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Procedure 
Screening 
Day -28 to 
-1a 
Surgery 
Day -1 
Randomization 
Day 1 
 
Day 2 
to 10b 
Hospital Discharge or 
Study 
Withdrawal/Termination 
Follow-
up 
Contactc 
30 days 
(+15 days) 
After 
Discharge 
Follow-up 
Visitd 
 
 
Pre-
surgery 
Post-
surgery 
 
 
 
 
 
Administration of 
study medication 
TID every 6 hoursn 
 
 
 
X 
X 
X 
 
 
Perform GI 
assessments twice 
dailyo 
 
 
 
X 
X 
X 
 
 
Subject eDiary 
assessmentsp 
 
 
 
X 
X 
X 
 
 
Ready for 
discharge based 
solely on GI 
recovery (when 
applicable) 
 
 
 
X 
X 
X 
 
 
Hospital discharge 
order written 
 
 
 
 
 
X 
 
 
Time to 
discontinue IV 
fluids and 
transition to oral 
liquids (when 
applicable) 
 
 
 
X 
X 
X 
 
 
Time to transition 
to oral analgesics 
(when applicable) 
 
 
 
X 
X 
X 
 
 
Monitoring of AEs 
 
X 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
Day -28 to 
-1a 
Surgery 
Day -1 
Randomization 
Day 1 
 
Day 2 
to 10b 
Hospital Discharge or 
Study 
Withdrawal/Termination 
Follow-
up 
Contactc 
30 days 
(+15 days) 
After 
Discharge 
Follow-up 
Visitd 
 
 
Pre-
surgery 
Post-
surgery 
 
 
 
 
 
Monitoring of 
prespecified 
postoperative 
complications 
 
 
X 
X 
X 
X 
X 
X 
Review of data for 
hepatobiliary AEsq 
 
 
X 
X 
X 
X 
X 
X 
Hospital 
readmission 
assessment 
 
 
 
 
 
 
X 
X 
PK samplingr 
 
 
 
X 
X 
X 
 
 
Abbreviations: AE = adverse event; BM = bowel movement; CAEC = clinical endpoint adjudication committee ; ECG = electrocardiogram; eCRF = electronic 
case report form; GI = gastrointestinal; HBV = hepatitis B virus; HCV = hepatitis C virus; INR = International Normalized Ratio; IV = intravenous; LFTs = liver 
function tests; NGT = nasal gastric tube; PCR = polymerase chain reaction; PK = pharmacokinetic; PT = prothrombin time; RBC = red blood cells; TID = 3 times 
per day (i.e., 6 hours ± 1 hour apart). 
• 
a 
Exceptional measure for COVID-19: Depending on the COVID-19 situation, measures below may be considered for the screening: 
• 
Consider performing laboratory testing, urine pregnancy tests, and safety laboratory tests at a local hospital, or regional independent laboratory located 
near the subject. 
• 
Telephone conversation or video conferencing may be used for obtaining information on demography, medical and surgical history, and prior and 
concomitant medications. 
• 
Local at-home services performed by trained non-study personnel may be used for measurement of vital signs, physical examinations, and ECG. 
• 
b 
Study drug is to be administered up to Day 10 or hospital discharge, whichever is earlier. 
• 
c 
Subjects are to be contacted via telephone (or visited in-person if still in the hospital) 10 to 14 days after the last dose of study medication. 
Need for hospital readmission will be determined. 
• 
d 
Depending on the COVID-19 situation or if there are any reasonable restrictions, measures below may be considered for the 30-day follow-up 
visit. 
• 
If subject is unable to come to clinic for in-person visit, then consider performing LFT laboratory tests (if needed) at a local hospital, or regional 
independent laboratory located near the subject. Telephone conversation or video conferencing may be used for other procedures at this visit. 
Additionally, local at-home services performed by trained non-study personnel may be used for measurement of vital signs and physical examinations. 


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• 
e 
Medications taken within 30 days before screening are to be recorded on the eCRF. 
• 
f 
Additional screening questions for COVID-19 will be asked by the investigator or site staff: 1) Has the subject traveled to countries known to 
be COVID-19 hotspots as well as US cities with high COVID-19 case densities, within the last 14 days before screening? 2) Does the subject currently 
or did the subject have flu-like symptoms within the past 72 hours, e.g., fever, cough, shortness of breath? 3) Has the subject had any close contact with 
any person exhibiting flu-like symptoms within the past 14 days? and 4) Has the subject been exposed to anyone who has been diagnosed with 
COVID-19 within the past 14 days? 
• 
g 
A serum pregnancy test must be performed during screening unless done within 28 days of the screening visit. A urine pregnancy test may be 
performed on the day before or the day of surgery. A local laboratory should be used for screening and pre-surgery Day 1 pregnancy tests. If a serum 
pregnancy test has been performed within 28 days before surgery, but before consent is obtained, serum pregnancy test need not be repeated unless 
deemed appropriate by the investigator. 
• 
h 
Physical examinations are to include measurement of weight; height is to be measured at the screening visit only. If a physical examination has 
been performed within 28 days before surgery, but before consent is obtained, the full physical examination need not be repeated unless deemed 
appropriate by the investigator. A review of the physical examination with revision or addition of any changes, if required, will be performed after the 
consent has been signed. 
• 
i 
Vital signs to include blood pressure, heart rate, respiratory rate, and body temperature. On Day 1, vital signs should be taken before study drug 
administration to represent baseline values. 
• 
j 
Additional ECGs may be conducted as clinically warranted. On Day 1, this should be done before study drug administration to represent 
baseline ECG. If a 12-lead ECG has been performed within 28 days before surgery, but before consent is obtained, the 12-lead ECG need not be 
repeated unless deemed appropriate by the investigator. 
• 
k 
If the subject has a previous test result for HCV and/or has previously tested positive for HCV, an HCV RNA (PCR) test should be done, with 
a negative result confirmed. If the subject has a history of HBV or has previously tested positive for HBV, a hepatitis B surface antibody test needs to be 
performed and negative results confirmed. If these tests have been performed within 28 days before surgery, but before consent is obtained, the HBV/ 
HCV test need not be repeated unless deemed appropriate by the investigator. 
• 
l 
Blood and urine samples will be obtained. Tests for routine hematology tests will include red blood cell count, hemoglobin, hematocrit, platelet 
count, and white blood cell count with differential. Tests for routine serum chemistry include glucose, electrolytes (sodium, potassium, calcium, 
chloride, bicarbonate), blood urea nitrogen or urea, creatinine, creatinine clearance, total protein, and albumin. A urinalysis includes appearance, pH, 
glucose, ketones (by dipstick), RBCs (by dipstick), specific gravity, and microscopy if needed. If these tests have been performed within 28 days before 
surgery, but before consent is obtained, the hematology, serum chemistry, urinalysis tests need not be repeated unless deemed appropriate by the 
investigator. On Day 1, this should be taken prior to study drug administration to represent baseline values. A local laboratory should be used for 
screening and before pre-surgery Day -1. A central laboratory should be used after randomization on Day 1 and Hospital Discharge/Study Termination. 
• 
m 
Samples for routine clinical liver function tests will include alkaline phosphatase, aspartate transaminase, alanine transaminase, total and direct 
bilirubin, prothrombin time and INR. If these tests have been performed within 28 days before surgery, but before consent is obtained, the LFTs need 
not be repeated unless deemed appropriate by the investigator. On Day-1 LFT do not have to be repeated if done within 14 days of Surgery and the LFT 
were within normal limits. On Day 1, this should be taken before study drug administration to represent baseline values. Liver functions tests to include 
PT/INR and will be obtained during screening, pre-surgery, Randomization Day 1, Day 4, Day 7, and Day 10 (if remaining in the hospital), and the day 
of hospital discharge. Liver function tests are needed at the 30-day follow-up visit only if LFTs were elevated at discharge and trending down. If a 
subject remains in the hospital for an AE of elevated tests, then levels will be followed until resolution. A local laboratory should be used for screening 
and before pre-surgery Day -1. A central laboratory should be used after randomization on Day 1 and future visits. 
• 
n 
Subjects will be randomized 1:1:1 (TU-100 15 g: TU-100 7.5 g: placebo) and stratified by surgical approach (open versus laparoscopic). Study 
drug will be administered TID (3 times per day [i.e., 6 hours ± 1 hour apart]). 


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• 
o 
GI assessments are to be performed twice daily, morning and afternoon with assessments separated by at least 6 hours. 
• 
p 
Subjects will record the following items in their eDiaries on all postoperative in-hospital study days: first flatus (record in real time), first BM 
(record in real time), nausea occurrence and bothersomeness (24-hour reflection), vomiting/retching occurrence/number of episodes (24-hour reflection), 
abdominal bloating occurrence and bothersomeness (24-hour reflection). 
• 
q 
Blinded review and assessment of hepatobiliary AEs by an independent CEAC will be performed on an ongoing basis during the conduct of the 
study. 
• 
r 
PK samples will be drawn only at designated sites at the following times below, and at early termination (not needed at hospital discharge). If a 
subject is terminating early on a day scheduled for a blood draw, a second sample on the day of termination should be taken if possible. If a subject is 
terminating early on a day not scheduled for a blood draw, at least 1 sample should be obtained that day if possible. 
• 
1 hour (± 30 min) after first dose on Day 1 
• 
4 hours (± 1 hour) after the first dose on Day 1 
• 
Predose on Day 3 (if not discharged yet) 
• 
2 hours (± 1 hour) on Day 3 (if not discharged yet) 
• 
Predose on Day 5 (if not discharged yet) 
• 
2 hours (± 1 hour) on Day 5 (if not discharged yet) 




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permitted in the preoperative period (See Section 9.6.1) 
• Preemptive, multimodal antiemetic prophylaxis (i.e., ondansetron and dexamethasone) 
must be used for all at-risk subjects (i.e., ≥ 2 risk factors [female gender at birth, 
nonsmoker, history of motion sickness or postoperative nausea and vomiting (PONV), 
postoperative opioid use]). 
• A multimodal, opioid-sparing, pain management plan should be planned as appropriate 
(e.g., combination of acetaminophen and NSAIDs, gabapentin administered at a low 
dose). 
o Note: although an opioid-sparing approach should be used for postoperative pain 
management, opioid analgesics use is not prohibited. 
• Alvimopan, methylnaltrexone, naloxone (except for treatment of known or suspected 
opioid overdose), and prophylactic or routine use of metoclopramide are prohibited for 
the purposes of this protocol in order to reduce confounding of the effect of TU-100 on 
the primary outcome measure. 
10.2.1.2 Intraoperative Elements 
• Excess fluid administration and volume overload should be avoided. 
• Transverse abdominis plane (TAP) blocks (with bupivacaine or bupivacaine liposome 
injectable) are permitted. 
• Epidural anesthesia should not be used for the purposes of this protocol in order to reduce 
confounding of the effect of TU-100 on the primary outcome measure. 
10.2.1.3 Postoperative Elements 
• A multimodal, opioid-sparing, pain management plan should be implemented as 
appropriate (e.g., combination of acetaminophen and NSAIDs). 
o Gabapentinoids (i.e., gabapentin, pregabalin) should not be used unless indicated 
for postoperative neuropathic pain. (See Section 9.6.1) 
o Note: although an opioid-sparing approach should be used for postoperative pain 
management, opioid analgesics use is not prohibited. 
• Indwelling NGTs for prophylaxis cannot be used. 
• Protocol guidelines for selective postoperative nasogastric intubation for the management 
of clinical events should be followed, as shown below. 
o Occurrence of one or more of the following events:  
▪ ≥ 2 low-volume (e.g., < 300 cc) episodes of emesis 
▪ ≥ 1 high-volume (e.g., ≥ 300 cc) episode of emesis 
▪ Moderate to severe abdominal distension 
• IV fluids are to be discontinued as soon as the subject can tolerate oral liquids and 
maintain adequate hydration. 




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• Please follow your local testing guidelines for SARS-CoV-2. If testing is mandatory at 
your institution, a positive result would be exclusionary 
• Subjects with prior history of COVID-19 must be confirmed recovered per CDC criteria 
and have a SARS-CoV-2 negative test result 
• If a subject contracts COVID-19 during the interval between screening and pre-surgery 
Day -1 (and falls out of the screening window), he or she may be rescreened once 
recovered, assuming the subject meets all other inclusion/exclusion criteria and per 
investigator clinical judgement 
Depending on the COVID-19 situation (and/or to reduce burden of patient travel as needed, 
e.g., need to travel long distances to the site), measures below may be considered for the 
screening: 
• Consider performing laboratory testing, urine pregnancy tests, and safety laboratory tests 
at a local hospital, or regional independent laboratory located near the subject. 
• Telephone conversation or video conferencing may be used for obtaining information on 
demography, medical and surgical history, and prior and concomitant medications. 
• Local at-home services performed by trained non-study personnel may be used for 
measurement of vital signs, physical examinations, and ECG. 
If physical examination, screening day laboratory tests, 12-lead ECG, and serum pregnancy test 
have been performed within 28 days before surgery, but before consent is obtained, the full 
physical examination, screening laboratory tests, 12-lead ECG, and serum pregnancy test will be 
reviewed and need not be repeated unless deemed appropriate by the investigator. A review of 
the physical examination with revision or addition of any changes, if required, will be performed 
after the consent has been signed. 
 
The Schedule of Assessments is located in Table 1. 
 
Day -1 (Day of surgery) 
LFTs will be assessed pre-surgery, unless performed within 14 days of Day-1and results were 
within normal limits. 
The following procedures will be completed on the day of surgery: 
• Capture additional medical history since screening 
• Record concomitant medications (pre- and post-surgery) 
• Perform a urine pregnancy test for WOCBP only 
• Monitor prespecified postoperative complications 
• Record surgery start (as noted from operating room records) and stop dates and times (time 
of the last suture or staple) 
• Record need for blood transfusion 
• Record estimated blood loss 
• Record total intraoperative IV fluid type and volume 




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• Perform GI assessments (twice daily, morning and afternoon; assessments must be 
separated by at least 6 hours) 
• Record time of GI assessment, and also: 
o Record time of first: 
▪ Clear liquid toleration 
▪ Solid diet toleration 
▪ Absence of distention and presence of bowel sounds and flatus (i.e., time of 
when all 3 conditions have been achieved) 
o Record time subject is ready for hospital discharge (based solely upon recovery of 
GI function as determined by the treating medical team) 
• Time of discontinue IV fluids and transition to oral liquids 
• Time of transition to oral analgesics 
• Record concomitant medications 
• If an NGT is inserted, record date, time, and reason for insertion 
• Monitor AEs 
• Review of hepatobiliary AEs 
• Monitor prespecified postoperative complications (See Section 11.7) 
• Collect LFT samples on Day 4, Day 7, and Day 10 (if subject remains in the hospital) per 
Table 1.  
• Collect blood samples for PK analyses only at designated sites at: 
o 1 hour (± 30 minutes) after the first dose on Day 1 
o 4 hours (± 1 hour) after the first dose of Day 1 
o Predose on Day 3* 
o 2 hours (± 1 hour) on Day 3* 
o Predose on Day 5* 
o 2 hours (± 1 hour) on Day 5* 
*if not discharged yet 
 
In addition, PK samples should be taken at early termination. If a subject is terminating early on 
a day scheduled for a blood draw, a second sample on the day of termination should be taken if 
possible. If a subject is terminating early on a day not scheduled for a blood draw, at least 1 
sample should be obtained that day if possible. 
 
All subjects will be managed with an ERAS protocol as per hospital SOC. However, elements 
within ERAS protocols intended to manage GI recovery will be standardized and compliance 
measured to the extent possible within this trial. (Section 10.2.1). 
 




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All subjects will be contacted via telephone (or in-person if still in the hospital) within 10 to 
14 days after the last dose of study medication for follow-up that will include: 
• Record concomitant medications 
• Monitor AEs 
• Review of data for hepatobiliary AEs 
• Monitor prespecified postoperative complications 
• Determine whether hospital readmission occurred and reason for readmission 
A certified letter will be sent to any subject not contacted after 3 attempts by telephone. 
 
Follow-up visit (30 days + 15 days after hospital discharge) 
All subjects are to return for a follow-up visit 30 days (+ 15 days). Procedures to be conducted at 
this visit include: 
• Perform physical examination, including weight. Any clinically relevant physical 
abnormalities (with the exception of surgical scars) that were not present at screening 
should be recorded as AEs. 
• Record vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• Record concomitant medications 
• Monitor AEs 
• Monitor prespecified postoperative complications 
• Determine whether hospital readmission occurred and reason for readmission 
• If elevated at discharge and trending down, then liver tests will be completed at the 
30-day follow-up visit. If a subject remains in the hospital for an AE of elevated tests, 
then levels will be followed until resolution. 
If a patient does not return for a scheduled visit, all necessary measures should be taken to 
contact the patient and document the patient’s outcome.  
Reasonable efforts should be made to contact subjects who are lost to follow-up. A certified 
letter will be sent to any subject not contacted after 3 attempts by telephone. These efforts must 
be documented in the subject’s file. 
 
Exceptional measure for COVID-19 
Depending on the COVID-19 situation (and/or to reduce burden of patient travel as needed), 
measures below may be considered for the 30-day follow-up visit.  
• Window for the 30 day follow-up can be extended to +15 days after hospital discharge.  
• If subject is unable to come to clinic for in-person visit, then performing LFT laboratory 
tests (if needed) at a local hospital, or regional independent laboratory located near the 
subject will be considered. Local laboratory results should be documented in subject’s 
file. 


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• Telephone conversation or video conferencing may be used for other procedures at this 
visit. Additionally, local at-home services performed by trained non-study personnel may 
be used for measurement of vital signs and physical examinations. 
 


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11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 1) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
 
11.1 Surgery Data Collection 
During the surgery, the following information should be collected and recorded on the eCRF: 
• Surgery start and stop times (stop time is defined as the time of the last stitch or staple) 
• Any estimated blood loss 
• Need for blood transfusion 
• Total intraoperative IV fluid type and volume 
• NGT removal time, if used 
11.2 Gastrointestinal Assessments 
Gastrointestinal assessments will be performed twice daily in the morning and afternoon, starting 
on randomization Day 1, and continuing until hospital discharge or study termination. 
Assessments must be separated by at least 6 hours. Gastrointestinal assessments will include: 
• Recording time of first: 
o Clear liquid toleration (i.e., time at which the subject transitions from clear liquids 
to the next diet stage [full liquids or solids]) 
o Solid diet toleration (i.e., able to eat a meal that requires chewing without a 
vomiting episode by the time the next consecutive meal is offered) 
▪ Note, if the first solid meal is consumed on the day of hospitalization 
(i.e., the day of surgery), the time to toleration of solids is as stated (e.g., 
the time to eat solids without a vomiting episode by the time the next 
consecutive meal is offered). Further, if the first solid meal is consumed 
on the day of discharge, the time to toleration of solids criteria is met if 
there is no vomiting prior to discharge. In all cases, the actual time that 
should be recorded on the eCRF is the time the meal was consumed by the 
subject, not the cutoff time for vomiting prior to next consecutive meal or 
discharge.  
o Absence of distention + presence of bowel sounds + flatus (time of when all 
3 conditions have been achieved) 
• Record time subject is ready for hospital discharge (based solely upon recovery of GI 
function as determined by the treating medical team) 
11.3 Electronic Diary Assessments 
Subjects will record in their eDiaries on all postoperative in-hospital days. They should record 
the following: 
• First flatus (record in real time) 
• First BM (record in real time) 


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• Nausea occurrence and bothersomeness (a 24-hour reflection) 
• Vomiting/retching occurrence/number of episodes (a 24-hour reflection) 
• Abdominal bloating occurrence and bothersomeness (a 24-hour reflection) 
The investigator will assess eDiary entries at study visits starting on Randomization Day 1 and 
continuing daily until hospital discharge or study termination. 
 
11.4 Time to Writing of Discharge Order 
The time when the discharge order is written should be noted on the eCRF by the investigator. 
 
11.5 Time to Discontinuation of IV Fluids 
The time of discontinuation of IV fluids and the transition to oral liquids should be noted on the 
eCRF by the investigator. 
 
11.6 Time to Transition of Oral Analgesics 
The time when the subject is able to transition from IV to oral analgesics should be noted on the 
eCRF by the investigator. 
 
11.7 Prespecified Postoperative Complications 
Any postoperative complications should be recorded on the eCRF by the investigators. These 
prespecified complications include: 
• Need for blood transfusion information (recorded as part of in-surgery information) 
• Readmission to hospital within 7 days and 30 days of discharge 
• POI-related morbidity as evidenced by: 
o POI that required readmission within 7 days of discharge, or 
o Need for postoperative NGT insertion to manage symptoms of POI (i.e., 
vomiting/retching, abdominal distension) per protocol guidelines 
• Other postoperative complications including: 
o Prolonged POI 
▪ Minimal incision BR (laparoscopic or robotically-assisted or hand-
assisted): Unresolved POI by postoperative Day 3 
▪ Laparotomy (open) BR: Unresolved POI by postoperative Day 5 
Note: POI = primary POI (i.e., POI that is not secondary to surgical 
complication, such as anastomotic leak, abscess formation, or sepsis) 
o Recurrent POI (prolongs hospital stay or results in readmission – based on 
investigator assessment) 
o Surgical site infection 
o Anastomotic leak 
o EPSBO 


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▪ Confirmed by the presence of a transition point between dilated and 
decompressed bowel demonstrated on abdominal imaging 


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12 SAFETY ASSESSMENTS 
Safety assessments (vital signs, physical examinations, ECG recording, AEs, clinical laboratory 
results [routine hematology and biochemistry]) are to be performed at protocol-specified visits, 
as specified in the Schedule of Assessments (Table 1). 
 
12.1 Medical History 
Medical history will be recorded at screening. Investigators should document the occurrence, 
signs, and symptoms of the subject’s ongoing pre-existing conditions present at the time when 
informed consent is given and up to the time of first dosing, significant surgeries (i.e., cardiac, 
vascular, or general thoracic surgery), and GI-related conditions/surgeries. Medical history will 
include alcohol consumption, illicit drug use, and smoking history, if applicable. 
 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 12.6. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
 
Additionally, demographic data will be collected for all subjects and include age at study entry, 
gender, race, ethnicity, weight, and height, according to applicable regulations. 
 
12.2 Vital Signs 
Vital signs (body temperature, respiratory rate, heart rate, and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the Schedule of Assessments 
(Table 1). All vital signs will be measured after the subject has been resting in a sitting position 
for at least 5 minutes. Blood pressure measurements are to be taken in the same arm for the 
duration of the study. Day 1 (Postoperative Day 1) vital signs should be taken before study drug 
administration. 
 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be repeated 
at the investigator’s discretion. Any confirmed, clinically significant vital sign measurements 
must be recorded as AEs. 
 


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12.3 Physical Examination 
A complete physical examination (head, eyes, ears, nose and throat; heart; lungs; abdomen; skin; 
cervical and axillary lymph nodes; and neurological and musculoskeletal systems) will be 
performed at screening (Day -28 to Day -1). Body weight (without shoes) will be recorded at 
screening and at the follow-up visit (30 days + 15 days after hospital discharge) and height 
(without shoes) will be recorded at screening only. Physical examinations will be performed by a 
physician. 
 
If a physical examination has been performed within 28 days before surgery, but before consent 
is obtained, the full physical examination does not need to be repeated unless deemed 
appropriate by the investigator; however, this should be assessed.  
 
Symptom-driven, limited physical examinations will be performed as clinically indicated at any 
study visit. 
 
12.4 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 1).  
 
At screening, the investigator will examine the ECG traces for signs of cardiac disease that could 
exclude the subject from the study. If an ECG has been performed within 28 days before surgery, 
but before consent is obtained, it does not need to be repeated unless deemed appropriate by the 
investigator but should be reviewed by the site PI. 
 
The ECG on Day 1 should be performed before study drug administration.  
 
An assessment of normal or abnormal will be recorded; if the ECG is considered abnormal, the 
abnormality will be documented on the eCRF. Electrocardiograms will be repeated if clinically 
significant abnormalities are observed, or artifacts are present. 
 
12.5 Laboratory Assessments 
Laboratory assessment samples (Table 2) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 1).  
 
If laboratory assessments have been performed within 28 days before surgery, but before consent 
is obtained, they do not need to be repeated unless deemed appropriate by the investigator, but 
should be reviewed by the site PI. 
 
The blood samples taken on Day 1 should be taken before study drug administration. The 
calculation of eGFR is necessary for screening of subject eligibility per entry criteria (see 
Section 8.2). 
 
A urine pregnancy test may also be performed on the day before or the day of surgery. 
 


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Table 2. 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Liver Function Tests 
Hct 
Hb 
Platelet count 
RBC count 
WBC count with 
differential 
 
Total protein 
Albumin 
BUN or urea 
Creatinine 
Creatinine clearance 
Electrolytes (sodium, potassium, calcium, 
chloride, and bicarbonate) 
Glucose 
 
ALT 
ALP 
AST 
Total and direct bilirubin 
Coagulation 
PT 
INR 
 
Serology 
Urinalysis 
 
HBV 
HCV 
 
Appearance 
pH 
Protein 
Glucose 
Ketones (dipstick) 
RBCs (dipstick) 
Specific gravity 
Microscopy (if needed) 
Pregnancy test: A serum pregnancy test will be performed on all women of childbearing potential at screening. A 
urine pregnancy test may be performed on the day before or the day of surgery. 
eGFR calculationa: GFR = 141 × min(Scr/κ,1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black], where Scr = serum creatinine (mg/dL), κ = 0.7 for females and 0.9 for males, α = -0.329 for females and -
0.411 for males, min = minimum of Scr/κ or 1, and max = maximum of Scr/κ or 1. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; 
eGFR = estimated glomerular filtration rate; Hb = hemoglobin; HBV = hepatitis B virus; Hct = hematocrit; 
HCV = hepatitis C virus; INR = international normalized ratio; PT = prothrombin time; RBC = red blood cell; 
WBC = white blood cell. 
• 
a 
eGFR calculation is known as the CKD-EPI formula (Levy, 2009). 
 
Blood taken at screening or pre-surgery on Day -1 will be analyzed at a local laboratory facility. 
Blood taken post-surgery on Day 1 (Postoperative Day 1, before study drug administration), and 
Day 2 through Day 10 will be analyzed at the central laboratory facility. All laboratory reports 
must be reviewed, signed, and dated by the investigator. A legible copy of all reports must be 
filed with both the subject’s eCRF and medical record (source document) for that visit. Any 
laboratory test result considered by the investigator to be clinically significant should be 
considered an AE (clinically significant AEs include those that require an intervention). 
Clinically significant abnormal values occurring during the study will be followed up until repeat 
test results return to normal, stabilize, or are no longer clinically significant. 
 












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The Sponsor will create narrative summary and will contact the site to obtain relevant 
information for this summary. The Sponsor will provide the narrative summary to the DSMB.  




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14 STATISTICAL ANALYSIS 
14.1 General Considerations 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. The SAP will serve as a compliment to the protocol 
and supersedes it in case of differences. 
 
The statistical evaluation will be performed using Statistical Analysis Software (SAS)® version 
9.4 or higher (SAS Institute, Cary, NC). All summaries will be presented by cohort and overall 
for each part, when appropriate. Summary statistics will be presented by dose group. For 
continuous variables, data will be summarized with the number of subjects (N), mean, standard 
deviation, median, minimum, and maximum by treatment group. For categorical variables, data 
will be tabulated with the number and proportion of subjects for each category by treatment 
group. 
 
The precision of the measurement units for each continuous variable will be used to determine 
the number of decimal places used to report these summary statistics. Minimum and maximum 
values will be reported with the same precision as the units of measure. The mean and median 
will be reported to 1 greater decimal place, and the standard deviation will be reported to 2 
additional decimal places. Any values that require transformation to standard units (metric or 
international [SI]) will be converted with the appropriate corresponding precision. Percentages 
will be presented to 1 decimal place. For statistical analyses, baseline is defined as the most 
recent measurement before initiation of first study drug administration. 
 
The SAP will provide specific details on the analytical methods and data displays. Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol. Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
CSR. Additional exploratory analyses of the data will be conducted as deemed appropriate. 
 
14.2 Determination of Sample Size 
The study is expected to enroll approximately 402 eligible subjects (with expected loss to 
follow-up or censorship of primary endpoint) with 1:1:1 randomization ratio over a post-surgery 
period (up to 10 days). The study is sized to achieve approximately 87% power to detect a hazard 
ratio (HR; TU-100 versus placebo) of 1.428 for GIR, which translates into an improvement in 
median time to GIR from 48 hours (2.0 days) for placebo (reference) to 34 hours (1.4 days) for 
TU-100 at a 0.05 significance level of one-sided log-ranked test for equality of time to GIR 
survival curve.  
 
Based on historical evidence, it is assumed that a small proportion of subjects will be lost to 
follow-up or will have events censored due to required analytical methods. To account for this 
anticipated loss in contribution of events to the primary endpoint, an additional 36 subjects 
(approximately 10% of 366) will be enrolled to achieve a final sample size of 402 subjects 
(134 per group). 


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14.3 Analysis Sets 
Safety analysis set 
The Safety Analysis Set will consist of all randomized subjects who receive at least 1 dose of 
study medication. The Safety Analysis Set will be used primarily for the analysis of safety data. 
Subjects will be classified based upon the treatment received. 
 
Full analysis set (FAS) 
The FAS will include all randomized subjects who receive at least 1 dose of study medication, 
who underwent an elective BR surgery as specified in the protocol, and who provided at least 
1 post-surgery assessment of the primary endpoint (GIR) during the treatment period. The FAS 
will be used primarily for the analysis of efficacy data. Participants will be analyzed according to 
the treatment group to which they are randomized. 
 
Per-protocol analysis (PP) set 
The PP set is a subset of the FAS who: 
• Had a protocol-specified surgery 
• Did not take prohibited medications during the treatment period that could affect the 
primary endpoint 
• Had otherwise complied with the protocol without any other major protocol deviation 
(any exceptions for inclusion/exclusion criteria granted by the Sponsor/medical monitor 
will not be considered protocol violations) 
Details of the evaluability criteria will be determined before study unblinding and specified in 
the SAP. 
 
PK analysis set: The PK Analysis set will include all subjects who have available PK data for at 
least 1 dose of TU-100. 
 
14.4 Handling of Missing Data and Outliers 
For incomplete date in safety data such as prior and concomitant medication and AEs, the 
following rules will be applied. 
 
For partial start date: 
• If the month and year are provided and day is missing, and the month and year match the 
month and the year of the first dose date of TU-100, the day of the first dose date of 
TU-100 will be imputed. 
• If the year is provided and the month and day are missing and the year matches the year 
of the first dose date of TU-100, the month and day of the first dose date of TU-100 will 
be imputed. Otherwise, January will be used. 
• If the start date is completely missing, the start date will not be imputed. 
• If the stop date is complete and the imputed start date is after the actual stop date, then 
the start date will be imputed as the stop date. 










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14.8 Pharmacokinetic/Pharmacodynamic Analysis 
Plasma concentrations of the HAS and HBS (the major constituents of TU-100) will be 
summarized for each treatment group. Plasma concentrations of other constituents of TU-100 
may also be summarized based on the ability to detect their presence in the collected blood 
samples. Exploratory population PK/pharmacodynamic analyses may be conducted to 
understand the exposure response relationships between TU-100 and efficacy and safety data. 
Data may be used for future population PK analyses which, if conducted, will be reported 
separately. 
 
14.9 Interim Analysis 
No interim analysis is planned. 
 
14.10 Data Independent Committees 
There will be 2 independent committees. Each will have a formal charter and their specific roles 
will be discussed within the protocol. 
• DSMB for clinical trial safety oversight 
• CEAC for assessment of hepatobiliary AEs 
An independent DSMB will be established to conduct safety reviews on periodic safety data cuts 
and will follow an approved DSMB charter. The DSMB will communicate back to Tsumura 
about their assessments. Detailed information on the role of the DSMB and frequency of 
meetings will be provided in the DSMB charter separate from this protocol. The DSMB will be 
responsible for safety review and oversight of aggregate data from participants. They are not 
responsible for review of individual participant efficacy data (i.e., GIR determination). 
 
The CEAC blinded to treatment assignment is distinct from the DSMB and will only focus on 
assessment of hepatobiliary AEs. The CEAC adjudicated hepatobiliary AE database will be used 
to determine the risk for hepatobiliary AEs. Detailed information on the role of the CEAC and 
frequency of meetings will be provided in the CEAC charter separate from this protocol. 
 




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Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained by 
Syneos Health. Access to the EDC system is available to only authorized users via the study’s 
internet website, where a user unique assigned username and password are required for access. 
 
Any changes made to data after collection will be made through the use of the EDC system. 
Electronic case report forms (eCRFs) will be considered complete when all missing and/or 
incorrect data have been resolved. 
 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IEC/IRB, and regulatory inspections. 
 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
 
15.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
investigator shall ensure that study subjects authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to the 
Sponsor. 
 




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15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; EU 536/2014, Annex 1, D, 17 (a); and in compliance with 
GCP guidelines. 
 
The IEC/IRB will review and approve this protocol and the ICF. All subjects are required to give 
written informed consent before participation in the study. 
 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
 
15.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 


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16 REFERENCES 
Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 
2009;58(9):1300-1311. 
Carmichael JC, Keller DS, Baldini G, Bordeianou L, Weiss E, Lee L, Boutros M, McClane J, 
Feldman LS, Steele SR. Clinical practice guidelines for enhanced recovery after colon and 
rectal surgery from the American society of colon and rectal surgeons and society of American 
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Doorly MG, Senagore AJ. Pathogenesis and clinical and economic consequences of 
postoperative ileus. Surg Clin North Am. 2012;92(2):259-272, viii. 
Gustafsson UO, Scott MJ, Schwenk W, Demartines N, Roulin D, Francis N, McNaught CE, 
MacFie J, Liberman AS, Soop M, Hill A, Kennedy RH, Lobo DN, Fearon K, Ljungqvist O; 
Enhanced Recovery After Surgery Society. Guidelines for perioperative care in elective 
colonic surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations. Clin 
Nutr. 2012;31(6):783-800. 
Johnson MD, Walsh RM. Current therapies to shorten postoperative ileus. Cleve Clin J Med. 
2009;76(11):641-648. 
Katsuno H, Maeda K, Kaiho T, Kunieda K, Funahashi K, Sakamoto J, Kono T, Hasegawa H, 
Furukawa Y, Imazu Y, Morita S, Watanabe M. Clinical efficacy of Daikenchuto for 
gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, 
placebo-controlled study (JFMC39-0902). Jpn J Clin Oncol. 2015;45(7):650-656. 
Kelliher LJS, Jones CN, Fawcett WJ. Enhanced recovery for gastrointestinal surgery. BJA 
Education. 2015;15(6):305-310. 
Kono T, Shimada M, Nishi M, Morine Y, Yoshikawa K, Katsuno H, Maeda K, Koeda K, Morita 
S, Watanabe M, Kusano M, Sakamoto J, Saji S, Sokuoka H, Sato Y, Maehara Y, Kanematsu T, 
Kitajima M. Daikenchuto accelerates the recovery from prolonged postoperative ileus after 
open abdominal surgery: a subgroup analysis of three randomized controlled trials. Surg 
Today. 2019;49(8):704-711. 
Lassen K, Coolsen MM, Slim K, Carli F, de Aguilar-Nascimento JE, Schäfer M, Parks RW, 
Fearon KC, Lobo DN, Demartines N, Braga M, Ljungqvist O, Dejong CH; ERAS® Society; 
European Society for Clinical Nutrition and Metabolism; International Association for Surgical 
Metabolism and Nutrition. Guidelines for perioperative care for pancreaticoduodenectomy: 
Enhanced Recovery After Surgery (ERAS®) Society recommendations. Clin Nutr. 
2012;31(6):817-830. 
Levy AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, Kusek JW, Eggers P, 
Van Lente F, Greene T, Coresh J. A new equation to estimate glomerular filtration rate. Ann 
Intern Med. 2009;150:604-612. 
Luchey A, Livingston E, Taché Y, Mechanisms and treatment of postoperative ileus. Arch. Surg. 
2003;138(2):206-214. 
Melloul E, Hübner M, Scott M, Snowden C, Prentis J, Dejong CH, Garden OJ, Farges O, 
Kokudo N, Vauthey JN, Clavien PA, Demartines N. Guidelines for Perioperative Care for 
Liver Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations. World J 
Surg. 2016;40(10):2425-2440. 
Miettinen OS, Nurminen MM. Comparative analysis of two rates. Statistics in Medicine. 
1985;4(2):213–226. 
Murphy MM, Tevis SE, Kennedy GD. Independent risk factors for prolonged postoperative ileus 
development. J Surg Res. 2016;201(2):279-285. 


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Pecorelli N, Nobile S, Partelli S, Cardinali L, Crippa S, Balzano G, Beretta L, Falconi M. 
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Pedziwiatr M, Mavrikis J, Witowski J, Adamos A, Major P, Nowakowski M, Budzyński A. 
Current status of enhanced recovery after surgery (ERAS) protocol in gastrointestinal surgery. 
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Shimada M, Morine Y, Nagano H, Hatano E, Kaiho T, Miyazaki M, Kono T, Kamiyama T, 
Morita S, Sakamoto J, Kusano M, Saji S, Kanematsu T, Kitajima M. Effect of TU-100, a 
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a multi-center, phase III trial (JFMC40-1001). Int J Clin Oncol. 2015;20(1):95-104. 
Stakenborg N, Gomez-Pinilla PJ, Boeckxstaens GE. Postoperative ileus: pathophysiology, 
current therapeutic approaches. Handb Exp Pharmacol. 2017;239:39-57. 
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17 APPENDICES 
APPENDIX 1 describes the contraception guidelines applicable for this study. 
APPENDIX 2 presents an opioid conversion chart. 


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APPENDIX 1. 
CONTRACEPTION GUIDELINES 
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must 
use at least 1 highly effective method of contraception during the study and for 30 days after the 
last dose of study treatment. 
 
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
 
Highly effective methods of contraception are those which have a failure rate of < 1% (when 
implemented consistently and correctly) and include: 
• combined (containing estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal ligation or occlusion 
• vasectomy (provided that the male has a medical assessment of surgical success) 
• condom in combination with contraceptive cream, jelly, or foam 
• sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical trial, in line with the preferred and 
usual lifestyle of the subject) 
All subjects will be strongly advised that they (or the female partners of male subjects) should 
not become pregnant while on study treatment or for 30 days after the last dose. A female subject 
will be advised that she must report immediately to the study site for pregnancy testing and 
appropriate management in the event that she may be pregnant. 
 
Reference 
1. [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. Recommendations related to 
contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. September 15, 2014. 


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APPENDIX 2. 
OPIOID CONVERSION CHART 
Generic Opioid 
Name 
Unit 
Route 
Conversion 
Factor  
Oral MME Conversion 
Factor 
Morphine 
MG 
IV 
1 
3 
Morphine 
MG 
PO 
0.333 
1 
Methadone 
MG 
IV 
1 
 
Methadone 
MG 
PO 
0.333  
3 (variable with dose) 
Nalbuphine 
MG 
IV 
1 
 
Nalbuphine 
MG 
PO 
0.333 
1 
Buprenorphine 
MG 
IV 
25 
 
Buprenorphine 
MCG 
Transdermal 
 
12.6 
Fentanyl 
MCG 
IV 
0.125 
0.2 
Fentanyl 
MCG 
Transdermal 
 
7.2 
Sufentanil 
MCG 
IV 
1.25 
 
Alfentanyl 
MCG 
IV 
0.02 
15 
Oxycodone 
MG 
PO 
 
1.5 
Hydromorphone 
MG 
IV 
6.67 
17.5 
Hydromorphone 
MG 
PO 
2.22 
4  
Codeine 
MG 
PO 
0.05 
0.15 
Dihydrocodeine 
MG 
PO 
 
0.25 
Tramadol 
MG 
PO 
 
0.1 
Meperidine 
MG 
PO 
0.03 
0.1  
Meperidine 
MG 
IV/IM 
 
0.4 
Pentazocine 
MG 
PO 
0.06 
 
Pentazocine 
MG 
IV/IM 
 
0.37 
• 
Abbreviations: IV = intravenous; IM = intramuscular; MME = morphine mg equivalent; PO = orally.