Conditions: Ileus Gastro-Intestinal Disorder
Keywords: post operative ileus return of bowel function return of gastrointestinal function enterotomy colon surgery colorectal surgery intestinal surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of LB1148 in subjects undergoing planned bowel resection.

Detailed description:
This will be a multicenter, randomized, double-blind, placebo-controlled, study to evaluate the safety and efficacy of LB1148 in return to bowel function for subjects undergoing planned bowel resection.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: LB1148 intervention 2: Placebo
Intervention descriptions: intervention 1: A total of 700 mL of drug product will be administered orally as a split dose before surgery. intervention 2: A total of 700 mL of placebo will be administered orally as a split dose before surgery.

Protocol document:
Prot_002.pdf: 
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CLINICAL TRIAL PROTOCOL  
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate 
the Safety and Efficacy of LB1148 in Accelerating the Time to Return 
of Bowel Function in Subjects Undergoing Planned Bowel Resection 
(INTEGRITY) 
Study Number: 
PBI-POI-301 
Study Phase: 
3 
Test Product: 
LB1148 
IND Number: 
158008 
Indication: 
Accelerate the time to return of bowel function in patients undergoing 
abdominal surgery 
Sponsor: 
Palisade Bio, Inc.  
5800 Armada Drive, Suite 210 
Carlsbad, CA 92008 
Study Director: 
 
 
 
Medical Monitor: 
 
 
 
 
 
Version 
Date 
Original Protocol, v1.0 
February 10, 2022 
Protocol v2.0 
March 9, 2022 
Protocol v3.0 
May 20, 2022 
Protocol v4.0 
June 10, 2022 
 
 
Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without 
written authorization from SPONSOR, except to the extent necessary to obtain informed 
consent from persons receiving the investigational product or their legal guardians, or for 
discussions with local regulatory authorities, Institutional Review Boards, Ethics Committees, 
or persons participating in the conduct of the study.  


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..................................................................................................6 
INVESTIGATOR SIGNATURE PAGE......................................................................................7 
SYNOPSIS ......................................................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
1 
INTRODUCTION............................................................................................................14 
1.1 
Return of Bowel Function and Ileus ..................................................................................14 
1.2 
Limitations of Current Therapy .........................................................................................14 
1.3 
LB1148 ..............................................................................................................................15 
1.3.1 Nonclinical Pharmacology Studies ........................................................................15 
1.3.2 Toxicology .............................................................................................................15 
1.3.3 Clinical Trials of LB1148 ......................................................................................17 
1.4 
Rationale for Use of LB1148 for the Return of Bowel Function ......................................20 
1.5 
Risk/Benefit Assessment for this Study .............................................................................20 
2 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................22 
2.1 
Study Objectives ................................................................................................................22 
2.1.1 Primary Objective ..................................................................................................22 
2.1.2 Secondary Objectives .............................................................................................22 
2.1.3 Exploratory Objectives ..........................................................................................22 
2.1.4 Safety Objectives ...................................................................................................22 
2.2 
Study Endpoints .................................................................................................................22 
2.2.1 Primary Endpoint ...................................................................................................22 
2.2.2 Secondary Endpoints .............................................................................................23 
2.2.3 Exploratory Endpoints ...........................................................................................23 
2.2.4 Safety .....................................................................................................................23 
3 
STUDY DESIGN ..............................................................................................................24 
3.1 
Overall Study Design .........................................................................................................24 
3.2 
Rationale for Study Design ................................................................................................25 
3.2.1 General Design Issues ............................................................................................25 
3.2.2 Selection of Population ..........................................................................................25 
3.2.3 Selection of Dose ...................................................................................................25 
3.3 
Data Monitoring Committee ..............................................................................................25 
3.4 
Subject Participation and Study Duration ..........................................................................26 
4 
SUBJECT POPULATION ..............................................................................................27 
4.1 
Inclusion Criteria ...............................................................................................................27 
4.2 
Exclusion Criteria ..............................................................................................................27 
4.3 
Subject and Study Discontinuation ....................................................................................28 
4.3.1 Screening Failures ..................................................................................................28 
4.3.2 Premature Discontinuation from Investigational Product ......................................28 
4.3.3 Premature Discontinuation from Study .................................................................28 
4.3.4 Replacement of Subjects ........................................................................................28 


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4.3.5 Study or Site Termination ......................................................................................29 
5 
INVESTIGATIONAL PRODUCT.................................................................................30 
5.1 
LB1148 ..............................................................................................................................30 
5.1.1 Description .............................................................................................................30 
5.1.2 Packaging and Labeling .........................................................................................30 
5.2 
Placebo ...............................................................................................................................30 
5.2.1 Description .............................................................................................................30 
5.2.2 Packaging and Labeling .........................................................................................31 
5.3 
Glucose Packaging and Labeling .......................................................................................31 
5.4 
Storage of Investigational Product .....................................................................................31 
5.5 
Preparation of Investigational Product for Dispensing to Subjects ...................................31 
5.6 
Subject Self-Administration of Investigational Product ....................................................31 
5.7 
Blinding and Unblinding....................................................................................................31 
5.8 
Concomitant Medications ..................................................................................................32 
5.9 
Restrictions ........................................................................................................................32 
5.9.1 Prohibited Medications ..........................................................................................32 
5.9.2 Perioperative Surgical Preparation ........................................................................32 
5.9.3 Birth Control ..........................................................................................................33 
5.10 
Treatment Compliance .......................................................................................................33 
6 
STUDY PROCEDURES .................................................................................................34 
6.1 
Definitions and Descriptions of Assessments and Procedures ..........................................34 
6.2 
Study Activities by Visit ....................................................................................................36 
6.2.1 Screening................................................................................................................36 
6.2.2 Randomization .......................................................................................................36 
6.2.3 Study Day 1 (IP administration) ............................................................................37 
6.2.4 Study Day 2 (Day of Surgery) ...............................................................................37 
6.2.5 Study Days 3 through Discharge (or Day 16, whichever is sooner) ......................37 
6.2.6 Hospital Discharge .................................................................................................38 
6.2.7 Study Day 30 (± 2 days) ........................................................................................38 
6.2.8 Study Day 90 / End of Study (± 7 days) ................................................................38 
6.3 
Storage of Research Samples .............................................................................................38 
7 
ADVERSE EVENTS .......................................................................................................39 
7.1 
Reporting Responsibilities .................................................................................................39 
7.2 
Definitions..........................................................................................................................40 
7.2.1 Adverse Event ........................................................................................................40 
7.2.2 Serious Adverse Event ...........................................................................................40 
7.2.3 Relatedness (Causality) ..........................................................................................40 
7.2.4 Severity ..................................................................................................................41 
7.3 
Clinical Laboratory Abnormalities ....................................................................................41 
7.4 
Physical Exam Abnormalities ............................................................................................41 
7.5 
Pregnancy ...........................................................................................................................41 
7.6 
Reporting of Serious Adverse Events ................................................................................42 
8 
STATISTICAL CONSIDERATIONS ...........................................................................43 
8.1 
Sample Size ........................................................................................................................43 
8.2 
Analysis Populations ..........................................................................................................43 


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8.3 
Analysis Conventions ........................................................................................................43 
8.4 
Control for Multiplicity......................................................................................................44 
8.5 
Subject Disposition ............................................................................................................44 
8.6 
Demographic, Baseline, and Surgical Characteristics .......................................................45 
8.7 
Medical History .................................................................................................................45 
8.8 
Concomitant Medications ..................................................................................................45 
8.9 
Drug Exposure ...................................................................................................................45 
8.10 
Efficacy Analyses ..............................................................................................................45 
8.10.1 Primary Endpoint - Time to GI-2 ...........................................................................45 
8.10.2 Secondary Endpoints .............................................................................................47 
8.10.3 Exploratory Endpoints ...........................................................................................49 
8.11 
Safety Analyses ..................................................................................................................50 
8.11.1 Adverse Events ......................................................................................................50 
8.11.2 Laboratory Evaluations and Vital Signs ................................................................50 
9 
ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES ....................................51 
9.1 
Ethical Conduct of the Study .............................................................................................51 
9.2 
Institutional Review Board Approval ................................................................................51 
9.3 
Informed Consent...............................................................................................................51 
9.4 
Confidentiality ...................................................................................................................51 
9.5 
Protocol Amendments ........................................................................................................51 
9.6 
Case Report Forms .............................................................................................................52 
9.7 
Source Document Maintenance .........................................................................................52 
9.8 
Retention of Records ..........................................................................................................52 
9.9 
Study Monitoring ...............................................................................................................52 
9.10 
Protocol Deviations ............................................................................................................53 
9.11 
Financial Disclosure ...........................................................................................................53 
9.12 
Publication and Disclosure Policy .....................................................................................53 
REFERENCE LIST .....................................................................................................................55 
APPENDIX 1 
SCHEDULE OF ACTIVITIES ..............................................................57 
APPENDIX 2 
AMERICAN COLLEGE OF CHEST PHYSICIANS (ACCP) 
GUIDELINES - CAPRINI RISK FACTOR SCORE...................................................58 
APPENDIX 3 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS 
CLASSIFICATION SYSTEM ........................................................................................59 
APPENDIX 4 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI-CTCAE) ...............................................60 
APPENDIX 5 
AMENDMENTS TO THE PROTOCOL ..............................................61 
 
 
 


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LIST OF FIGURES 
Figure 1 
Kaplan-Meier Curve of Time to GI-2 ....................................................................19 
Figure 2 
Study Schematic.....................................................................................................24 
LIST OF TABLES 
Table 1 
Tranexamic Acid Pharmacokinetic Parameters after a Single Oral Dose of 
LB1148 in Healthy Subjects ..................................................................................17 
Table 2 
LB1148 Solution Components by Weight and Concentration ..............................30 
Table 3 
Blinded IP Bottle Label Content ............................................................................30 
Table 4 
Glucose Bottle Label Content ................................................................................31 
Table 5 
Intercurrent Events for Time to GI-2 .....................................................................46 
Table 6 
Intercurrent Events for Time to First Bowel Movement .......................................47 
Table 7 
Intercurrent Events for LOS...................................................................................49 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SPONSOR SIGNATURE PAGE 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the 
Safety and Efficacy of LB1148 in Accelerating the Time to Return of Bowel Function in 
Subjects Undergoing Planned Bowel Resection (INTEGRITY)  
Protocol Number: 
PBI-POI-301 
This clinical study protocol was subject to critical review and has been approved by the Sponsor. 
The following personnel contributed to writing and/or approving this protocol: 


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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: 
 
A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the 
Safety and Efficacy of LB1148 in Accelerating the Time to Return of Bowel Function in 
Subjects Undergoing Planned Bowel Resection (INTEGRITY)  
Protocol Number: 
 
PBI-POI-301 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
Signed: 
 
Date: 
 
 
 
Print Name: 
 
 
Site Name: 
 
 


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SYNOPSIS 
Sponsor:  Palisade Bio, Inc. 
Study Title:  A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Safety and 
Efficacy of LB1148 in Accelerating the Time to Return of Bowel Function in Subjects Undergoing 
Planned Bowel Resection (INTEGRITY) 
Test Product:  LB1148 
Name of Ingredients: Tranexamic acid (TXA), polyethylene glycol (PEG) 3350, glucose, electrolytes 
Study Number:  PBI-POI-301 
Study Phase:  Phase 3 
Study Centers: 30-60 US sites 
Objectives:   
Primary Objective:  
The primary objective is to compare the time to gastrointestinal (GI) 2 (GI-2), defined as the time from 
the end of surgery to the time of recovery of the upper GI tract (toleration of solid food) and the lower 
GI tract (first bowel movement) following surgery, whichever occurs last, among subjects treated with 
LB1148 or placebo. 
Secondary Objectives:  
Compare the following among subjects treated with LB1148 or placebo: 
• 
Time to first bowel movement. 
• 
Hospital length of stay (LOS) Ready 
• 
LOS Discharge Order Written (DOW) 
• 
LOS Actual 
Exploratory  Objectives:  
Compare the following among subjects treated with LB1148 or placebo: 
• 
Time to GI-3 
• 
Incidence of the following events at Day 90: 
- 
Hospital readmission 
- 
Post-operative ileus (POI) 
• 
Opiate use by morphine milligram equivalent (MME) 
Safety Objectives: 
• 
Evaluate the incidence, severity and potential causal association of treatment emergent adverse 
events following exposure to LB1148. 
Study Design: 
This is a Phase 3, randomized, double-blind, placebo-controlled, study to evaluate the safety and 
efficacy of LB1148 in subjects undergoing planned bowel resection. Subjects scheduled for planned 
bowel resection, aged 18 to 80 years inclusive, will be screened within 42 days of randomization. 
Subjects who meet all inclusion and no exclusion criteria, and provide written informed consent, will 
be stratified by 1) surgical approach (minimally invasive or laparotomy) and 2) with or without a 
planned stoma. Subjects will then be randomized to receive LB1148 or placebo in a in a 1:1 ratio. 
All subjects will receive 700 mL of Investigational Product (IP) as split, oral doses of 350 mL 
beginning the evening prior to surgery (Day 1), the first at 6-10 hours and the second 2-6 hours prior. 
Subjects will then undergo surgery (Day 2).   


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Subjects will be assessed for safety and tolerability, including adverse events (AEs) and vital signs 
from time of dosing on Study Day 1 through discharge or Study Day 16, whichever is sooner.  Subjects 
will be monitored for return of bowel function following surgery, from Study Day 3 through discharge 
or Study Day 16, whichever is sooner.  Subjects will have clinical lab tests (chemistry, coagulation, 
and hematology) on Study Day 3. Subjects will be monitored for serious AEs (SAEs) through Study 
Day 30. Subjects will be monitored for hospital readmission and POI through Study Day 90.   
 
Data Monitoring Committee 
An independent DMC will be commissioned for this study.  The DMC will be comprised of 3 
physicians with expertise in therapeutic areas pertinent to this protocol; all will have clinical trial 
experience.  The DMC safety monitoring plan will be detailed in the DMC Charter. 
Number of Subjects Planned:  600 
Diagnosis and Main Eligibility Criteria: 
Inclusion Criteria 
1. Adults age 18 to 80 years, inclusive. 
2. Scheduled to undergo a planned (non-emergent) bowel resection via minimally invasive technique 
or laparotomy.  This includes any subject in which a resection of the small intestine, colon, or 
rectum is performed for any elective indication. 
3. Willing to perform and comply with all study procedures including, being hospitalized until 
achieving GI-2 and responding to telephone follow-up visits as scheduled. 
4. Willing and able to provide written informed consent. 
Exclusion Criteria 
1. History of total colectomy. 
2. Has a preexisting ostomy. 


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3. History of radiation enteritis. 
4. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. 
5. History of seizure disorder.  
6. History of myeloproliferative disorders. 
7. American Society of Anesthesiologists (ASA) Class IV or V (Appendix 3).  
8. Inability to take IP orally or consume solid food. 
9. Planned treatment with alvimopan (Entereg®) during hospitalization period. 
10. Chronic opioid usage, defined by the American Pain Society as daily or near-daily use of opioids 
for at least 90 days.   
11. Men and women of child bearing potential (WOCBP) who are unwilling to practice a highly 
effective method of contraception that may include, but is not limited to, abstinence, sex only with 
persons of the same sex, monogamous relationship with vasectomized partner, vasectomy, 
hysterectomy, bilateral tubal ligation, licensed hormonal methods (but not combination hormonal 
methods), intrauterine device, or use of spermicide combined with a barrier method (e.g., condom, 
diaphragm) for 28 days before Day 1 and through Day 30. 
12. Women who will not agree to stop combined hormonal contraceptive and or combined hormonal 
replacement therapy (including combined hormonal pill, patch or vaginal ring) during the 7 day 
period prior to Surgery (Study Day 2) through the 7 day period following surgery (Study Days 3 
through 9). 
13. Has contraindications or potential risk factors to taking TXA.  These include subjects with: 
- 
Known sensitivity to TXA 
- 
Recent craniotomy (past 30 days) 
- 
Active cerebrovascular bleed 
- 
Active thromboembolic disease (such as deep vein thrombosis, pulmonary embolism, cerebral 
thrombosis, ischemic stroke, or acute coronary syndrome) 
- 
Acute promyelocytic leukemia taking all-trans retinoic acid for remission induction 
14. Receipt of any investigational drug within 28 days or 5 half-lives prior to Day 1. 
15. Any other condition that, in the opinion of the Investigator would make the subject unsuitable for 
the study or unable to comply with the study requirements. 
Duration of Treatment: Subjects will receive a split dose of IP over the 10 hours prior to surgery.  
The total duration for subject participation is approximately 4.5 months (Screening through Day 90). 
Test Product; Mode of Administration; and Dose:   
A total of 700 mL of LB1148 solution will be administered orally as a split dose (350 mL 6-10 hours 
before surgery and another 350 mL 2-6 hours before surgery).   
LB1148 in sterile water contains 7.5 g (68 mM) TXA, 28 g glucose, 32.5 g PEG 3350, and electrolytes 
(sodium sulfate anhydrous, sodium bicarbonate, sodium chloride, sodium sulfate anhydrous). 
Reference Product; Mode of Administration; and Dose:  
A total of 700 mL of placebo solution will be administered orally as a split dose (350 mL 6-10 hours 
before surgery and another 350 mL 2-6 hours before surgery).   
Placebo in sterile water contains 28 g glucose, 32.5 g PEG 3350, and electrolytes (sodium sulfate 
anhydrous, sodium bicarbonate, sodium chloride, sodium sulfate anhydrous). 


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Endpoints/Criteria for Evaluation: 
Efficacy 
Primary Endpoint:  
• 
Time to GI-2, defined as the time from the end of surgery to the time of recovery of the upper GI 
tract (toleration of solid food) and the lower GI tract (first bowel movement) following surgery, 
whichever occurs later up to 14 days post-surgery (Study Day 16). 
- 
End of surgery is defined as the time the last skin staple or suture was placed by the surgeon. 
- 
Toleration of solid food is defined as the time a subject finished a meal that required chewing 
and experienced no significant nausea/vomiting for 4 hours after the solid meal. 
o Nausea and vomiting must be severe enough to completely interfere with the subject’s 
ability to tolerate food.  This does not include expected post-surgical nausea that does not 
interfere with solid meal ingestion. 
Secondary Endpoints: 
• 
Time in hours from placement of the last skin staple or suture to the time of first bowel movement. 
• 
LOS Ready - Time subject is ready for discharge, defined as the time from the end of surgery to the 
time the subject is ready for hospital discharge solely based on the recovery of GI function, as 
determined by the surgeon.  
• 
LOS DOW - Time discharge order written, defined as the time from the end of surgery to the time 
that the hospital discharge order is written.  
• 
LOS Actual - Time of actual discharge, defined as the time from the end of surgery to the time the 
subject is actually discharged from the hospital. 
Exploratory Endpoints: 
• 
Time to GI-3, defined as the time from the end of surgery to the time of toleration of solid food and 
either first flatus or bowel movement, whichever occurs later up to 14 days post-surgery (Study 
Day 16). 
• 
Proportion of subjects not readmitted to the hospital following actual discharge by Study Day 90. 
• 
Proportion of subjects without POI: 
- 
During the planned hospitalization – POI is defined as the inability to tolerate liquid or solids 
greater than expected post-operative period, confirmed by imaging studies.   
- 
Following initial discharge – POI is defined as having clinical symptoms (e.g., abdominal 
cramps, bloating, nausea, vomiting, constipation, difficulty passing gas, and difficulty 
tolerating a normal diet) and ileus confirmed by imaging studies. 
• 
Total opiate use by aggregate MME from the end of surgery until Actual discharge or Day 16, 
whichever is earlier. 
Safety:   
• 
AEs and serious AEs (SAEs); clinically significant abnormal physical exam findings and 
laboratory results will be reported as AEs 
• 
Vital signs 
• 
Serum chemistries, coagulation, and hematology 


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Statistical Methods:  
Sample Size:  
A total sample size of 600 subjects, randomized in a 1:1 ratio, provides 90% power to detect a 
difference in median time to GI-2 between groups of 22 hours, assuming a median time to return of 
bowel function of 70 hours in the LB1148 group and 92 hours in the placebo group, using a 2-sided 
log-rank test with a significance level of 0.05.  
Enrolling 650 subjects allows for 7.8% of subjects to be excluded from the Per Protocol (PP) 
population. 
Primary Efficacy Analyses: 
Time to GI-2 will be a time to event analysis involving the production of non-parametric Kaplan-Meier 
survival curves for the two treatment groups and their comparison via the stratified log-rank test. As a 
sensitivity/supportive analysis, a Cox proportional-hazard model (PH) analysis with a main effect of 
treatment and stratified by surgery type (laparotomy versus minimally invasive approaches) and stoma 
(stoma versus no stoma) will be performed. Inference between the treatment groups for this analysis 
will be evaluated using the Wald chi-square test. 
Control for Multiplicity 
Multiplicity will be controlled through a combination of gate keeping and the Hochberg procedure 
(Multiple Endpoints in Clinical Trials Guidance for Industry, Draft Guidance 2017). 
The primary endpoint will be evaluated a significance level of 0.05.  If there is significance then the 
secondary endpoints will be evaluated, otherwise all secondary endpoints will be considered as 
exploratory.  
If the primary endpoint is significant at 0.05, the four secondary endpoints (time to first bowel, LOS 
Ready, LOS DOW, LOS Actual) will be considered using the Hochberg procedure. The significance 
level/α critical values are 0.0125, 0.0167, 0.025, and 0.05.  
Using the Hochberg procedure, the p-values for each secondary endpoint will be computed and then 
ordered from largest to smallest. The largest computed p-value will be compared against the largest 
critical value. If it does not show significance, then the next largest p-value is compared to the next 
largest critical value. Testing continues until a p-value for an endpoint is statistically significant when 
compared to its respective critical value. Once an ordered p-value is significant, that endpoint and all 
endpoints with p-values smaller than that endpoint are considered to have a statistically significant 
treatment effect. 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term or 
Abbreviation  
Definition 
AE 
Adverse event  
ADL 
Activities of daily living 
ASA 
American Society of Anesthesiologists 
BP 
Blood pressure 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DOW 
Discharge order written 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HDPE 
High-density polyethylene 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IXRS 
Interactive response system used for randomization 
LOS 
Length of stay 
MME 
Morphine milligram equivalent 
NCI 
National Cancer Institute 
NG 
Nasogastric tube 
NPO 
Nothing by mouth (nil per os) 
NPRS 
Numeric Pain Rating Scale 
OG 
Orogastric tube 
PEG 
Polyethylene glycol 
PH 
Proportional-hazard 
PK 
Pharmacokinetics 
POI 
Post-operative ileus 
PP 
Per Protocol 
REMS 
Risk Evaluation and Mitigation Strategies 
RR 
Respiratory Rate 
SAE 
Serious adverse event 
T 
Temperature 
TXA 
Tranexamic acid 
VTE 
Venous thromboembolism 
WOCBP 
Women of child bearing potential 


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1 INTRODUCTION 
1.1 
Return of Bowel Function and Ileus 
Gastrointestinal (GI) hypomotility is expected after major surgery.  However, for some patients 
undergoing common abdominal surgeries, there is a delay in return of normal bowel function. 
This is associated with significant discomfort, nausea, vomiting, and the inability to advance the 
diet postoperatively. If unresolved, this can predispose patients to nosocomial complications, 
infections, malnutrition, electrolyte derangements, and poor wound healing.  
Palliative treatments such as nasogastric (NG) tube placement and extending observation can be 
uncomfortable and costly.  Possible interventions such as total parenteral nutrition expose 
patients to additional risk. Postoperative ileus is associated with a prolonged length of ICU and 
hospital stay, increased resource utilization, and risk for readmission due to GI dysmotility or 
bowel obstruction (Goldstein 2007).  In a retrospective study of colon resections, prolonged 
postoperative ileus was directly associated with the serious complications of intra-abdominal 
infections, anastomotic leak and a significantly higher mortality risk (3.7 vs. 0.9%, p <0.01) 
(Moghadamyeghaneh 2016).  Treating the root cause of GI hypomotility caused by abdominal 
surgery has the potential to lower the risk of morbidity and mortality for the over 6 million 
patients undergoing abdominal surgeries each year in the US (CDC 2010). 
GI surgical intervention (incisions, surgical manipulation, and mesenteric hypoperfusion) leads 
to a breakdown of the intestinal mucosal barrier, and subsequent translocation of intraluminal 
proteases into the parenchyma of the intestinal tissues and peritoneum where they initiate 
autodigestion.  Protease activity damages tissues, cell surface receptors, activates immune cells 
and initiates a pro-inflammatory cascade leading to pathology in the intestine and peritoneum 
(Chang 2012, Delano 2013, Altshuler 2014).  
1.2 
Limitations of Current Therapy 
The mechanisms affecting post-surgical bowel function and inducing a delay in return of normal 
bowel function are multifactorial, involving the neurologic, inflammatory, proteolytic, hormonal, 
cell signaling, anesthetic, and narcotic mechanisms (Goldstein 2007). The single approved 
therapeutic for acceleration of time to GI recovery following surgery is alvimopan 
(ENTEREG®), a µ-opioid receptor antagonist that helps mitigate the effects of opioids on GI 
motility (ENTEREG Prescribing Information 2020). Alvimopan is approved only for surgeries 
that include partial bowel resection with primary anastomosis, has a black box warning for 
increased incidence of myocardial infarction, and is only available through a Risk Evaluation and 
Mitigation Strategies (REMS) program for short-term use. There are no approved therapeutics 
for the acceleration of return of GI function that arise from any of the other etiologies. There are 
no directed available therapies for patients who are using nonopioid analgesics during surgery, 
patients undergoing all abdominal surgeries other than partial bowel resection, and patients with 
cardiac risks that outweigh the benefits of alvimopan treatment. In a retrospective study of 
14,781 patients undergoing elective colorectal surgery at 51 hospitals in Washington State from 
2009 to 2013, only 11% of patients received alvimopan (Ehlers 2016). In a retrospective study of 
patients undergoing colon resection in 2012-2013 after alvimopan was widely available, 12.7% 
experienced prolonged ileus, indicating that patients still face morbidity and mortality risks with 


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only a single limited available therapy (Moghadamyeghaneh 2016).  Hence, delay in return of 
bowel function in the post-operative setting remains an important unmet medical need. 
1.3 
LB1148 
LB1148 contains tranexamic acid (TXA), polyethylene glycol (PEG) 3350, glucose, and 
electrolytes.  It is reconstituted in water and administered as a split, oral dose (350 mL 6-10 
hours and 2-6 hours prior to surgery). TXA is currently approved for its plasminogen inhibition 
effects in patients with hemophilia who are undergoing tooth extraction and patients with heavy 
menstrual bleeding (Dubber 1965) demonstrated that TXA also inhibits trypsin, a key digestive 
protease, at concentrations 4-fold higher than that required for plasminogen inhibition.  In 
addition to trypsin inhibition, TXA is a broad-spectrum serine protease inhibitor with inhibitory 
activity against chymotrypsin, elastase, enterokinase, as well as others.  This activity appears to 
be independent of plasminogen inhibition.   
Summarized below are nonclinical pharmacology studies, toxicology, and clinical trials of 
LB1148.  More detail can be found in the LB1148 Investigator’s Brochure. 
1.3.1 
Nonclinical Pharmacology Studies 
Several studies have been performed to demonstrate the mechanism of action and efficacy of 
TXA and LB1148.  When enterally administered in animal studies, LB1148 inhibits key 
digestive enzymes in the lumen of the small intestine and helps preserve the gut barrier during 
acute periods of perturbation, shock, hypoperfusion, and ischemia (Chang 2012, Delano 2013, 
Altshuler 2014).  Oral (enteral) administration of LB1148 allows TXA to inhibit the digestive 
enzymes in the lumen of the bowel and to halt the digestive enzymes proteolytic activity against 
the intestine and villi.   
1.3.2 
Toxicology 
TXA, PEG 3350, glucose, and electrolytes are substances approved for use in the United States 
(US).   
Tranexamic Acid 
The dose of TXA contained in LB1148 is 7.5 g. 
TXA is currently approved for its plasminogen inhibition effects in patients with hemophilia who 
are undergoing tooth extraction (CYKLOKAPRON® injection, for intravenous use) and patients 
with heavy menstrual bleeding (LYSTEDA® tablets, for oral use).  The approved dose for 
LYSTEDA is 1.3 g three times a day (3.9 g/day) for a maximum of 5 days (LYSTEDA 
Prescribing Information).  The dose of TXA in LB1148 is 7.5 g, administered as a single split 
dose of 3.75 g 6-10 hours prior to surgery and again, 2-6 hours prior to surgery.   
Single dose and repeat dose studies have been performed in more than 5 species, including rats, 
dogs, and monkeys.  In single dose studies the lethal dose 50 (LD50) ranged from 5 g/kg in dogs 
(human equivalent dose [HED] of 162 g) in a dog to 12.5 g/kg in mice (HED of 60 g). 


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Adverse ocular effects were observed in a 9-month toxicology study in dogs.  Animals were 
administered TXA in food at doses of 0, 2, 6, or 12 g/kg/day. These doses are approximately 2, 
5, and 6 times, respectively, the recommended human oral dose of 3.9 g/day based on AUC and 
the same, 2.6, and 3.12 times the dose of TXA in LB1148. 
At 6 times the human dose (3.12 times the TXA in LB1148), some dogs developed reversible 
reddening and gelatinous discharge from the eyes. Ophthalmologic examination revealed 
reversible changes in the nictitating membrane/ conjunctiva. In some female dogs, the presence 
of inflammatory exudate over the bulbar conjunctival mucosa was observed. Histopathological 
examinations did not reveal any retinal alteration. No adverse effects were observed at 5 times 
the human dose (2.6 times the TXA in LB1148). 
In other studies, focal areas of retinal degeneration were observed in cats, dogs and rats 
following oral or intravenous TXA doses at 6-40 times the recommended usual human dose 
based on mg/m2 (actual animal doses between 250-1600 mg/kg/day). 
Carcinogenicity – Carcinogenicity studies with TXA in male mice at doses as high as 6 times 
(5000 mg/kg/day) the recommended human dose of 3.9 g/day showed an increased incidence of 
leukemia which may have been related to treatment. This is 3.12 times the dose of TXA in 
LB1148.  Female mice were not included in this experiment.   
Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary 
system have been reported in one strain of rats after dietary administration of doses exceeding 
the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were 
reported at lower doses. Subsequent long-term dietary administration studies in a different strain 
of rat, each with an exposure level equal to the maximum level employed in the earlier 
experiment, have failed to show such hyperplastic/neoplastic changes in the liver. 
Mutagenesis - TXA was neither mutagenic nor clastogenic in the in vitro Bacterial Reverse 
Mutation Assay (Ames test), in vitro chromosome aberration test in Chinese hamster cells, and in 
in vivo chromosome aberration tests in mice and rats.  
Impairment of Fertility - Reproductive studies performed in mice, rats and rabbits have not 
revealed any evidence of impaired fertility or adverse effects on the fetus due to TXA. 
PEG 3350 
The amount of PEG 3350 in LB1148 is 32.5 g total.  However, each split dose of LB1148 
contains 16.25 g of PEG 3350 which is comparable to the over the counter, osmotic laxative 
MiraLAX dose, which contains 17g of PEG 3350.  Published PK studies of PEG 3350, including 
MiraLAX, demonstrate that it is minimally absorbed, and is rapidly excreted and primarily 
eliminated via feces (Pelham 2008).  
Glucose and Electrolytes 
LB1148 contains 28 g of glucose; about the same as a cup of apple juice.   


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LB1148 contains electrolytes as follows: sodium sulfate anhydrous - 3.98 g; sodium bicarbonate 
- 1.18 g; sodium chloride - 1.03 g, and potassium chloride - 0.52 g.  These electrolytes are also 
found in PEG 3350 containing mechanical bowel preparations in amounts 2-4 times higher than 
those in LB1148. 
1.3.3 
Clinical Trials of LB1148 
Palisade Bio, Inc. (Palisade) and its partner 
 
have completed or terminated 3 clinical trials of LB1148.  One study is ongoing in the US. 
LB1148-PK-101 
Study LB1148-PK-101 was a Phase 1 single dose, open label study where LB1148 was 
administered to healthy adults following a 10-hour fast.  Blood samples for measuring TXA 
levels were obtained, just prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6,  8, 10, 12, 24, 48, 72, 96 
and 144 hours after dosing. 
Among the 12 healthy subjects who participated and completed the trial, 6 were men and 6 were 
women. The average age was 33.3 years (SD = 7.62). The average weight and BMI were 60.1 kg 
(SD = 4.68) and 22.4 kg/m2 (SD = 1.35), respectively. The average weights of male and female 
subjects were 63.2 kg and 57.0 kg, respectively, and the BMI was 22.0 kg/m2 and 22.8 kg/m2 
respectively. 
PK parameters were calculated and analyzed using Phoenix™ WinNonlin® 8.1 (Pharsight Corp., 
Mountain View, CA USA). 
Table 1 below summarizes the PK parameters of TXA following a single oral dose. 
Table 1 
Tranexamic Acid Pharmacokinetic Parameters after a Single Oral 
Dose of LB1148 in Healthy Subjects 
 
C max
T max
AUC 0-t
AUC 0-∞
%AUC ex
t ½
λ z
CL/F
V Z /F
(µg/mL)
(h)
(µg 
·h/mL)
(µg 
·h/mL)
%
(h)
(1/h)
(L/h)
(L)
N
12
12
12
11 *
11 *
11 *
11 *
11 *
11 *
Mean
31.4
2.81
178.57
181.42
2.89
7.9
0.1
44.42
499.16
SD
7.97
0.58
52.07
53.59
1.45
2.43
0.03
11.75
187.77
CV%
25.4
20.52
29.16
29.54
50.03
30.77
27.22
26.46
37.62
Median
29.15
2.98
175.41
158.79
2.63
7.4
0.09
47.23
471.02
Min
21.47
1.98
123.05
127.09
1.27
5.16
0.05
25.7
268.75
Max
46.36
3.98
287.84
291.87
5.86
13.33
0.13
59.01
951.56
GeoMean
30.53
2.76
172.02
174.79
2.59
7.6
0.09
42.91
470.45
GeoSD
1.28
1.24
1.33
1.33
1.64
1.34
1.34
1.33
1.43
GeoCV%
24.8
21.83
28.89
28.78
53.01
29.56
29.56
28.78
36.99
Note: * The R 2 adj of subject 1001 is <0.8 , so the subject was not included in the statistics of pharmacokinetic 
parameters related to λz .


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LBS-POI-201-CN 
Study LBS-POI-201-CN, was a randomized, double-blind, placebo-controlled proof-of-concept 
study designed to evaluate LB1148 to improve the recovery of gastrointestinal function 
(measured in hours to achieve GI-2) and to reduce post-operative ileus (POI) in subjects 
undergoing elective bowel resection (PROFILE).  This study enrolled 131 subjects from 6 sites 
in 
   
The patient population included subjects aged 18 to 80 years who were scheduled for non-
emergent bowel surgery, with or without planned stoma. This included any subject undergoing 
small bowel, colon or rectal resection for any indication. 
Subjects were randomized into 2 treatment groups (LB1148 or placebo) at a ratio of 1:1. Subjects 
were stratified by: 1) surgical method (minimally invasive or laparotomy), and 2) whether there 
was a planned stoma.  Subjects received a split, oral dose of LB1148 or placebo: 350 mL 6-10 
and 350 mL 2-6 hours before surgery.  Perioperative care was standardized at all sites per study 
protocol. 
GI function, including POI, was evaluated each day while subjects were hospitalized.  While in 
the hospital subjects were monitored closely for venous thrombosis and surgical complications.  
Adverse events (AEs) were reported from the time of dosing through discharge or Day 14, 
whichever came first.  Serious AEs (SAEs) including POI and hospital readmission were 
reported through Day 30.   
Subjects who required a second surgery (e.g., takedown of a stoma) were evaluated for the 
presence, extent and severity of adhesions upon opening of the abdomen for the second surgery. 
The primary objective was to evaluate the efficacy of oral LB1148 in improving GI function 
recovery and reducing POI in subjects undergoing elective bowel resection. 
Secondary objectives included: 
• Safety 
• Time to GI-3 
• Length of hospital stay (LOS, in hours) to discharge or 14th day (whichever is earlier) 
• Presence of intra-abdominal adhesions at time of second surgery (following the initial 
surgery) 
For the LB1148 group, the median and 95% confidence interval of the time to the GI-2 event 
was 67.0 hours (57.0, 73.0), the mean was 81.4 ± 65.81 hours. Both were lower than the median 
92.0 hours (86.0, 106.0) and the mean 107.3 ± 68.88 hours of the placebo group. The median 
time difference between the two groups was -25.0 hours, that is, the median time from the 
LB1148 group to the GI-2 event was 25 hours less than the placebo group. The log-rank test 
results in P values of 0.0015 (with or without stoma stratification) and 0.0098 (without 
stratification), reaching statistically significant differences. The hazard ratio and the 
corresponding 95% CI estimated by the stratified (with or without stoma) Cox proportional-
hazards (PH) model is 1.800 (1.246, 2.600), and the unstratified value is 1.605 (1.117, 2.307), 


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indicating that the LB1148 group reached the endpoint event 1.800 times (stratified) or 1.605 
times (unstratified) faster than the placebo group.  
There was a significant difference in the Kaplan-Meier curve of GI-2 between the two groups 
(Figure 1), that is, the time required for a GI-2 event to occur in the LB1148 group was shorter 
than that in the placebo group.  
Figure 1 
Kaplan-Meier Curve of Time to GI-2 
 
Among subjects dosed there were 46 AEs (71.9%) in the LB1148 group and 50 (79.4%) in the 
placebo group.  Subjects with at least one AE related to the drug was 7 (10.9%) in the LB1148 
and 3 (4.8%) in placebo group. A total of 13 subjects had serious adverse events (SAE), 
including 5 (7.8%) in the LB1148 group and 8 (12.7%) in the placebo group. No SAE related to 
the drug occurred in the trial, and there was no adverse event that led to drug discontinuation or 
withdrawal of subjects from the trial.  No subject had a venous thrombotic event. 
AEs reported in 3 or more subjects receiving LB1148 included: fever (15.6%), nausea (14.1%), 
hypoalbuminemia (14.1%), vomiting (9.4%), bloating (9.4%), constipation (7.8%), abdominal 
pain (7.8%), diarrhea (6.3%), decreased blood sugar (6.3%), expectorant cough (6.3%), cough 
(6.3%), hypotension (6.3%), anemia (4.7%), and increased fibrin D dimer (4.7%). 
Overall, AEs are balanced between the groups and there are no apparent trends for type or 
severity of AEs. 
LBS-SS201 
LBS-SS201was a Phase 2 study entitled, “Treatment of Septic Shock by Inhibiting 
Autodigestion and Preserving Gut Integrity with Enteric LB1148 (SSAIL Study).” The study 
commenced in 2016 and was prematurely terminated the same year due to lack of enrollment.   
A total of 8 subjects were enrolled into the study: 5 subjects received LB1148 and 3 received 
placebo.  On average, subjects were exposed to approximately 6 days of study drug (LB1148 or 


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placebo) with 700 mL administered per day.   A total of 3 (60.0%) subjects receiving LB1148 
reported 20 AEs and all 3 (100.0%) subjects receiving placebo reported 12 AEs.  There were no 
observed trends for type or severity of AEs. No subject had a venous thrombotic event. 
There were 4 SAEs reported in the study, none of which were related to study drug.    
LBS-POI-201 
LBS-POI-201 is a multicenter, randomized, double-blind, parallel, placebo-controlled, proof-of-
concept, adaptive design, Phase 2 study to evaluate LB1148 for return of GI function, reduction 
of POI and intra-abdominal adhesions in subjects undergoing elective bowel resection with a 
planned stoma.  This study is similar in design to study LBS-POI-201-CN described above.  The 
study is ongoing and to date, 75 subjects have been enrolled. 
Among subjects dosed there were 29 AEs (64.4%) in Group A and 25 (83.3%) in Group B.  A 
total of 14 subjects had SAEs none of which were related to the drug, per the investigator.  No 
subject had a venous thrombotic event. 
AEs reported in 3 or more subjects included: nausea (28%), vomiting (10.7%), procedural pain 
(9.3%), urinary retention (5.3%), gastrooesophageal reflux disease (4%), pyrexia (4%), and  
anaemia (4%). 
Overall, AEs are balanced between the groups and there are no apparent trends for type or 
severity of AEs. 
1.4 
Rationale for Use of LB1148 for the Return of Bowel Function 
As noted above, oral administration of LB1148 allows TXA to inhibit the digestive enzymes in 
the lumen of the bowel and to halt the digestive enzymes proteolytic activity against the 
intestine’s mucosal barrier, intestinal villi and the peritoneum.  In nonclinical models of GI 
injury, Palisade has demonstrated the ability of LB1148 to protect the intestine from damaging 
proteolytic activity and thereby enhance the return of bowel function.   
Additionally, in a Phase 2 study of LB1148, “A Randomized, Double-Blind, Placebo-Controlled 
Proof-of-Concept Study Designed to Evaluate LB1148 to Improve the Recovery of 
Gastrointestinal Function and to Reduce Post-Operative Ileus in Subjects Undergoing Elective 
Bowel Resection (PROFILE);” conducted in 
 subjects receiving LB1148 had a statistically 
significant 25 hour improvement (p = 0.0015) in the return of bowel function following GI 
surgery compared to subjects receiving placebo. 
Nonclinical and clinical findings to date form the rationale for proceeding into this well-powered 
Phase 3 trial. 
1.5 
Risk/Benefit Assessment for this Study 
More than 100 adult clinical trial subjects have received at least one dose of LB1148.  No subject 
has experienced a SAE thought by the investigator to be related to LB1148.  No subject has 
experienced a venous thrombotic event. 


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AEs reported in 5 or more clinical trial subjects receiving LYSTEDA (oral TXA) for up to 5 
days for the treatment of heavy menstrual bleeding include: headache, nasal and sinus symptoms, 
back pain, abdominal pain, musculoskeletal pain, arthralgia, muscle cramps and spasms, 
migraine, anemia, and fatigue (LYSTEDA Prescribing Information). 
Warnings and Precautions for the use of LYSTEDA (LYSTEDA Prescribing Information), 
include:  
- 
Venous and arterial thrombosis or thromboembolism, as well retinal artery and retinal 
vein occlusions 
- 
Severe allergic reactions 
- 
Cerebral edema and cerebral infarction in patients with subarachnoid hemorrhage 
- 
Ligneous conjunctivitis 
The eligibility criteria for this study (Section 4) have been established to limit the risks to 
subjects, specifically those for whom TXA is contraindicated.  Additionally, women are 
prohibited from using combined hormonal contraception or treatment for 7 days prior to dosing 
and for 7 days after dosing (Section 5.9.1).  During the period of hospitalization (after dosing 
with LB1148), subjects will be monitored daily for AEs and signs of venous thromboembolism 
(VTE).  The study Medical Monitor will also review safety data continuously throughout the 
study. 
Other than alvimopan, which has limited use in this population (see Section 1.2), there are no 
approved therapies that accelerate the return of bowel function in subjects undergoing planned 
bowel resection.  Subjects may benefit from shorter time to return of bowel function.  Subjects 
may also benefit from the knowledge that study participation will contribute to the body of 
knowledge return of bowel function. 
The overall benefit-risk assessment for LB1148 is favorable at this time. 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective  
The primary objective is to compare the time to gastrointestinal (GI) 2 (GI-2), defined as the 
time from the end of surgery to the time of recovery of the upper GI tract (toleration of solid 
food) and the lower GI tract (first bowel movement) following surgery, whichever occurs last, 
among subjects treated with LB1148 or placebo. 
2.1.2 
Secondary Objectives 
Compare the following among subjects treated with LB1148 or placebo: 
• Time to first bowel movement 
• LOS Ready 
• LOS DOW 
• LOS Actual 
2.1.3 
Exploratory Objectives 
Compare the following among subjects treated with LB1148 or placebo: 
• Time to GI-3 
• Incidence of the following events at Day 90: 
- 
Hospital readmission 
- 
POI 
• Opiate use by MME 
2.1.4 
Safety Objectives 
Evaluate the incidence, severity and potential causal association of treatment emergent adverse 
events following exposure to LB1148. 
2.2 
Study Endpoints  
2.2.1 
Primary Endpoint 
• Time to GI-2, defined as the time from the end of surgery to the time of recovery of the upper 
GI tract (toleration of solid food) and the lower GI tract (first bowel movement) following 
surgery, whichever occurs later up to 14 days post-surgery (Study Day 16). 
 


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2.2.2 
Secondary Endpoints 
• Time in hours from placement of the last skin staple or suture to the time of first bowel 
movement. 
• LOS Ready - Time subject is ready for discharge, defined as the time from the end of surgery 
to the time the subject is ready for hospital discharge solely based on the recovery of GI 
function, as determined by the surgeon.  
• LOS DOW - Time discharge order written, defined as the time from the end of surgery to the 
time that the hospital discharge order is written.  
• LOS Actual - Time of actual discharge, defined as the time from the end of surgery to the 
time the subject is actually discharged from the hospital. 
2.2.3 
Exploratory Endpoints 
• Time to GI3, defined as the time from the end of surgery to the time of toleration of solid 
food and either first flatus or bowel movement, whichever occurs later up to 14 days post-
surgery (Study Day 16). 
• Proportion of subjects not readmitted to the hospital following initial discharge by Study Day 
90. 
• Proportion of subjects without POI: 
- 
During the planned hospitalization – POI is defined as the inability to tolerate liquid or 
solids greater than expected post-operative period, confirmed by imaging studies.  
Following initial discharge – POI is defined as having clinical symptoms (e.g., abdominal 
cramps, bloating, nausea, vomiting, constipation, difficulty passing gas, and difficulty 
tolerating a normal diet) and ileus confirmed by imaging studies. 
• Total opiate use by aggregate MME from the end of surgery until Actual discharge or Day 
16, whichever is earlier.  
2.2.4 
Safety  
• AEs and SAEs; clinically significant abnormal physical exam findings and laboratory results 
will be reported as AEs 
• Vital signs 
• Serum chemistries, coagulation, and hematology 
 


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3 STUDY DESIGN 
3.1 
Overall Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, study to evaluate the safety and 
efficacy of LB1148 in subjects undergoing planned bowel resection. Subjects scheduled for 
planned bowel resection, aged 18 to 80 years inclusive, will be screened within 42 days of 
randomization. Subjects who meet all inclusion and no exclusion criteria, and provide written 
informed consent, will be stratified by 1) surgical approach (minimally invasive or laparotomy) 
and 2) with or without a planned stoma. Subjects will then be randomized to receive LB1148 or 
placebo in a 1:1 ratio. 
All subjects will receive 700 mL of Investigational Product (IP) as split, oral doses of 350 mL 
beginning the evening prior to surgery (Day 1), the first at 6-10 hours and the second 2-6 hours 
prior. Subjects will then undergo surgery (Day 2). Subjects will then undergo surgery (Study Day 
2).   
Subjects will be assessed for safety and tolerability, including AEs and vital signs from time of 
dosing on Study Day 1 through discharge or Study Day 16, whichever is sooner.  Subjects will 
be monitored for return of bowel function following surgery, from Study Day 3 through 
discharge or Study Day 16, whichever is sooner.  Subjects will have clinical lab tests (chemistry, 
coagulation, and hematology) on Study Day 3. Subjects will be monitored for serious AEs 
(SAEs) through Study Day 30. Subjects will be monitored for hospital readmission and POI 
through Study Day 90.  
Figure 2 
Study Schematic 
 


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The Schedule of Activities is provided in Appendix 1.   
3.2 
Rationale for Study Design 
3.2.1 
General Design Issues 
This study is intended to be a confirmatory trial to provide evidence that LB1148 is safe and 
effective in accelerating the time to return of bowel function in subjects undergoing abdominal 
surgery.  Therefore, it is designed as a randomized, double-blind, placebo-controlled, superiority 
trial.  
3.2.2 
Selection of Population 
The population for this study includes adult patients scheduled to undergo a planned (non-
emergent) bowel resection via minimally invasive technique or laparotomy.  This includes any 
subject in which a resection of the small intestine, colon, or rectum is performed for any elected 
indication.  The exclusion criteria include underlying conditions that might put a subject at risk 
(i.e. where treatment with TXA is contraindicated) or so serious that their inclusion might make 
either safety or efficacy analyses difficult to interpret. 
The study population is the target population for LB1148 and the eligibility criteria allow 
sufficient homogeneity in terms of co-morbidities to permit precise estimation of treatment 
effects. 
3.2.3 
Selection of Dose 
As noted in Section 1 of this protocol, TXA inhibits trypsin, a key digestive protease, at 
concentrations 4-fold higher than that required for plasminogen inhibition (Dubber 1965).  In 
addition to trypsin inhibition, TXA is a broad-spectrum serine protease inhibitor with inhibitory 
activity against chymotrypsin, elastase, enterokinase, as well as others.  Palisade demonstrated 
that the 90% inhibitory concentration (IC90) was ~68 mM TXA.  Nonclinical in vivo studies 
demonstrated that TXA inhibits the digestive enzymes in the lumen of the bowel and halt the 
proteolytic activity against the intestine and villi. Concentrations of 68 mM repeatedly 
demonstrated protection of the bowel in nonclinical animal studies. LB1148 containing 7.5 g of 
TXA allows for a 68 mM concentration in the intestine.   
3.3 
Data Monitoring Committee 
An independent DMC will be commissioned for this study.  The DMC will be comprised of 3 
physicians with expertise in therapeutic areas pertinent to this protocol; all will have clinical trial 
experience.  The DMC safety monitoring plan will be detailed in the DMC Charter. 
The primary responsibility of the DMC is to safeguard study subjects by reviewing and assessing 
the clinical safety data being collected during the performance of the study.  At scheduled 
intervals detailed in the DMC charter, the DMC will review all AE data. SAEs (Section 7.2.2) 
and ≥ Grade 3 AEs that are “Likely” (Section 7.2.3) to be related to IP will be communicated to 
the DMC in a timely manner, which may result in an ad hoc meeting of the DMC.     


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Based on these evaluations of the data, the DMC will make recommendations to the Sponsor to 
continue the study as planned, or to modify, temporarily suspend, or terminate the study.  The 
DMC will also be responsible for identifying issues and making recommendations regarding the 
monitoring of subjects for safety, including collection of additional safety data. 
The Sponsor will be responsible for notifying Investigators and Regulatory Authorities of any 
DMC recommendations, as appropriate. 
3.4 
Subject Participation and Study Duration 
The duration of the study for an individual subject is 90 days, plus up to a 42-day screening 
window.  The estimated duration of the entire study (i.e., first subject screened to last subject off 
study) is approximately 18 months. 


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4 SUBJECT POPULATION 
Approximately 600 subjects who meet the eligibility criteria will be enrolled at approximately 30-
60 sites in the US and multinational. 
4.1 
Inclusion Criteria 
1. Adults age 18 to 80 years, inclusive. 
2. Scheduled to undergo a planned (non-emergent) bowel resection via minimally invasive 
technique or laparotomy.  This includes any subject in which a resection of the small 
intestine, colon, or rectum is performed for any elective indication. 
3. Willing to perform and comply with all study procedures including, being hospitalized until 
achieving GI-2 and responding to telephone follow-up visits as scheduled. 
4. Willing and able to provide written informed consent. 
4.2 
Exclusion Criteria 
1. History of total colectomy. 
2. Has a preexisting ostomy. 
3. History of radiation enteritis. 
4. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. 
5. History of seizure disorder.  
6. History of myeloproliferative disorders. 
7. American Society of Anesthesiologists (ASA) Class IV or V.  
8. Inability to take IP orally or consume solid food. 
9. Planned treatment with alvimopan (Entereg®) during hospitalization period. 
10. Chronic opioid usage, defined by the American Pain Society as daily or near-daily use of 
opioids for at least 90 days.   
11. Men and women of child bearing potential (WOCBP) who are unwilling to practice a highly 
effective method of contraception that may include, but is not limited to, abstinence, sex only 
with persons of the same sex, monogamous relationship with vasectomized partner, 
vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal methods (but not 
combination hormonal methods), intrauterine device, or use of spermicide combined with a 
barrier method (e.g., condom, diaphragm) for 28 days before Day 1 and through Day 30. 
12. Women who will not agree to stop combined hormonal contraceptive and or combined 
hormonal replacement therapy (including combined hormonal pill, patch or vaginal ring) 
during the 7 day period prior to Surgery (Study Day 2) through the 7 day period following 
surgery (Study Days 3 through 9). 
13. Has contraindications or potential risk factors to taking TXA.  These include subjects with: 
- 
Known sensitivity to TXA 
- 
Recent craniotomy (past 30 days) 


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- 
Active cerebrovascular bleed 
- 
Active thromboembolic disease (such as deep vein thrombosis, pulmonary embolism, 
cerebral thrombosis, ischemic stroke, or acute coronary syndrome) 
- 
Acute promyelocytic leukemia taking all-trans retinoic acid for remission induction 
14. Receipt of any investigational drug within 28 days or 5 half-lives prior to Day 1. 
15. Any other condition that, in the opinion of the Investigator would make the subject 
unsuitable for the study or unable to comply with the study requirements. 
4.3 
Subject and Study Discontinuation 
4.3.1 
Screening Failures 
Subjects who sign and date the informed consent form (ICF) but who fail to meet the eligibility 
criteria are defined as screen failures.  The site shall maintain a screening log, that documents the 
subject’s initials, demographics, and reason(s) for screen failure.  A copy of the log should be 
retained in the Investigator’s study files.   
4.3.2 
Premature Discontinuation from Investigational Product 
Any subject who does not self-administer the entire contents of both bottles of IP will be 
considered “prematurely discontinued from IP.”  The reason for not taking IP as intended by 
protocol will be reported to the study team and collected in the eCRF.  If the reason is due to an 
AE, it will be reported in accordance with Section 7 - Adverse Events of the protocol (including 
relatedness and severity). 
Subjects who discontinue IP for any reason should remain in the study.  All efforts will be made 
to ensure appropriate follow up, including all relevant evaluations for safety, clinical 
assessments, and collection of laboratory study results as described in this protocol. 
4.3.3 
Premature Discontinuation from Study  
A subject may be prematurely discontinued from the study for any of the following reasons: 
• Subject wishes to withdraw consent 
• Subject is lost to follow-up 
• Subject is non-compliant or unwilling to comply with the procedures required by the protocol 
• Investigator discretion 
• Sponsor request 
4.3.4 
Replacement of Subjects 
Subjects who are randomized but do not receive study IP or have the planned surgery will be 
replaced to ensure the study enrolls sufficient numbers of subjects for the primary analysis. 


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4.3.5 
Study or Site Termination 
Conditions may arise during the study that could prompt the study to be halted or the study site 
to be terminated.  Conditions that may prompt such considerations include, but are not limited to, 
the following: 
• The discovery of unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study. 
• A decision on the part of Sponsor to suspend, discontinue, or shorten the study. 
• Study conduct at the study site may warrant termination under conditions that include the 
following: 
- 
Failure of Investigator(s) to enroll eligible subjects into the study 
- 
Failure of Investigator(s) to comply with International Conference of Harmonisation-
Good Clinical Practice (ICH-GCP) guidelines, or FDA guidelines and regulations 
- 
Submission of false information from the research facility to the Sponsor, the Clinical 
Monitor, the FDA, or Institutional Review Board (IRB) 
- 
Insufficient adherence to protocol requirements 
- 
A conflict of interest of the Investigator, his/her institution, or site personnel that would 
negatively impact the integrity of the clinical trial 
- 
Institution or IRB under investigation for cause by a regulatory agency 
 
 


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5 INVESTIGATIONAL PRODUCT 
5.1 
LB1148 
5.1.1 
Description 
LB1148 contains TXA, PEG 3350, glucose, and electrolytes.  It is formulated in a powder for 
reconstitution in 640 mL of water (total volume upon reconstitution is 700 mL) and administered 
as a single split dose.  The quantities and concentrations of the individual components of LB1148 
are shown in Table 2 below: 
Table 2 
LB1148 Solution Components by Weight and Concentration 
Component 
Weight (g) 
Concentration (mM) 
Tranexamic acid  
7.5 g 
68.15 
Glucose (carbohydrate)† 
28 g 
222.03 
Polyethylene glycol 3350 
32.5 g 
N/A 
Sodium Sulfate Anhydrous 
3.98 g 
40.06 
Sodium Bicarbonate 
1.18 g 
20.12 
Sodium Chloride 
1.03 g 
25.15 
Potassium Chloride 
0.52 g 
9.83 
Water † 
640 mL 
NA 
† packaged separately 
 
5.1.2 
Packaging and Labeling 
LB1148 powder for reconstitution is packaged in single dose 120 mL high-density polyethylene 
(HDPE) bottles.  Bottles are blinded (contain either LB1148 or placebo) and identified with a 
“Med #” as shown in Table 3 below. 
Table 3 
Blinded IP Bottle Label Content 
Blinded TXA Active or Placebo Powder For Reconstitution 
Med #: XXXXXX 
RECONSTITUTE AS INSTRUCTED IN PHARMACY MANUAL 
Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 
30°C (59°F to 86°F). DO NOT FREEZE. 
CAUTION: NEW DRUG - LIMITED BY FEDERAL LAW TO INVESTIGATIONAL USE ONLY 
Re-labeled by: Thermo Fisher Scientific, 699 N Wheeling Rd, Mount Prospect, 60056 
Manufactured for: Palisade Bio, Inc. 5800 Armada Drive, Suite 210, Carlsbad, CA 92008 
5.2 
Placebo 
5.2.1 
Description 
The placebo for this study is comprised of the same ingredients listed in Table 1 above, except 
for TXA. 


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5.2.2 
Packaging and Labeling 
Placebo powder for reconstitution is packaged in single dose 120 mL HDPE bottles.  Bottles are 
blinded (contain either LB1148 or placebo) and identified with a “Med #” as shown in Table 3 
above. 
5.3 
Glucose Packaging and Labeling 
Glucose powder for reconstitution is provided in single dose, open label 60 mL HDPE bottles. 
The label for the glucose powder is shown in Table 4 below. 
Table 4 
Glucose Bottle Label Content 
Glucose Powder for Reconstitution Lot #: XXXXXX  
RECONSTITUTE AS INSTRUCTED IN PHARMACY MANUAL  
Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 
30°C (59°F to 86°F). DO NOT FREEZE.  
CAUTION: NEW DRUG - LIMITED BY FEDERAL LAW TO INVESTIGATIONAL USE ONLY  
Re-labeled by: Thermo Fisher Scientific, 699 N Wheeling Rd, Mount Prospect, 60056 
Manufactured for: Palisade Bio, Inc. 5800 Armada Drive, Suite 210, Carlsbad, CA 92008 
5.4 
Storage of Investigational Product  
LB1148, Placebo, and glucose should be stored at controlled, room temperature 20°C-25°C 
(68°F-77°F).  Excursions are permitted from 15°C-30°C (59°F-86°F).   
5.5 
Preparation of Investigational Product for Dispensing to Subjects 
Preparation of the IP must be performed by a designated site pharmacist (or otherwise 
qualified personnel) in accordance with the Pharmacy Manual provided by the Sponsor.   
Do not freeze powder or reconstituted product.  The Sponsor does not have stability data 
under frozen storage conditions.   
5.6 
Subject Self-Administration of Investigational Product  
Site staff will dispense the subject’s IP within 48 hours prior to the subject’s scheduled surgery.  
Subjects will be instructed to consume a bottle of IP at 6-10 hours and the second bottle at 2-6 
hours prior to surgery. 
5.7 
Blinding and Unblinding 
Investigators, subjects, and all study staff will be blinded to treatment assignment.   
Unblinding of treatment assignment is discouraged.  In the event of a medical emergency for 
which the identity of the treatment assignment is critical to the care of a subject, the Investigator 
should call the Medical Monitor to discuss.  In the event that unblinding is deemed necessary, an 
unblinded statistician will provide the treatment assignment to the Medical Monitor who will 


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provide the information to the Investigator.  A decision to discontinue a subject from further IP 
administration is not a rationale to unblind the treatment assignment. 
5.8 
Concomitant Medications 
The following concomitant medications and therapies will be documented in the subject’s source 
document from the morning of Study Day 1 (prior to dosing) through Hospital Discharge or 
Study Day 16, whichever comes first: 
• Prescription and over-the-counter medications, including opioids, bowel prep, and nutritional 
supplements  
• Blood products 
• Use of Adhesion Barrier Products including:  
o SEPRAFILM® Adhesion Barrier 
o ADEPT® Adhesion Reduction Solution 
o GYNECARE INTERCEED® Absorbable Adhesion Barrier 
5.9 
Restrictions 
5.9.1 
Prohibited Medications 
Subjects may not: 
• Receive other medication containing TXA from Screening through the 7 day period 
following surgery (Study Day 9) 
• Receive pancreatic enzyme replacement therapy from Day 2 through hospital discharge or 
Study Day 16, whichever comes first 
• Use a combined hormonal contraceptive and or combined hormonal replacement therapy 
(including combined hormonal pill, patch or vaginal ring) during the 7 day period prior to 
Surgery (Study Day 2) through the 7 day period following surgery (Study Day 9) 
• Use alvimopan (Entereg®) from Day 2 through hospital discharge or Study Day 16, 
whichever comes first 
5.9.2 
Perioperative Surgical Preparation 
• Subjects may not eat, drink, or take oral medications, including drinking bowel preparations, 
1 hour before and 1 hour after IP administration. 
• Subjects may not consume solid food within 8 hours prior to induction of surgical anesthesia 
• Subjects may not drink a carbohydrate containing drink within 8 hours prior to induction of 
surgical anesthesia; the IP contains glucose and will replace this drink during this time period 
• Subjects may not consume anything by mouth (NPO) within 2 hours prior to induction of 
surgical anesthesia, except for daily oral medication such as anti-hypertensive may be taken 
with small volume of water as directed by physician 


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• Subjects must receive prophylaxis for VTE according to each site’s standard of care 
5.9.3 
Birth Control 
Men and WOCBP must be willing to practice a highly effective method of contraception that 
may include, but is not limited to, abstinence, sex only with persons of the same sex, 
monogamous relationship with vasectomized partner, vasectomy, hysterectomy, bilateral tubal 
ligation, licensed hormonal methods (but not combination hormonal methods), intrauterine 
device or use of spermicide combined with a barrier method (e.g., condom, diaphragm) for 28 
days before and after receiving the IP. 
5.10 Treatment Compliance 
To ensure compliance with the dosing regimen, the IP will be prepared by the site pharmacist or 
otherwise qualified personnel.  Any member of the study team may dispense the blinded, 
reconstituted dose to the subject or it may be couriered to the subject.  Subjects will be instructed 
to return their used IP bottles for a compliance check prior to surgery on the morning of surgery 
(Study Day 2). 
 


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6 STUDY PROCEDURES 
Refer to Appendix 1 for the Schedule of Activities. 
6.1 
Definitions and Descriptions of Assessments and Procedures 
General – results of all of the assessments and procedures described below should be recorded 
in the subject’s electronic medical record or study-specific source document.  The following 
section, Section 6.2 details when these assessments and procedures are to be performed. 
AEs and SAEs (see Section 7) 
Bowel function – the following information should be collected: 
- 
Time solid food is tolerated (i.e., no significant nausea/vomiting for 4 hours after the 
solid meal; significant nausea is the inability to tolerate solid food over a 4 hour period) 
- 
nausea/vomiting) 
o Nausea and vomiting must be severe enough to completely interfere with the subject's 
ability to tolerate food.  This does not include expected post-surgical nausea that does 
not interfere with solid meal ingestion. 
- 
Time of first flatus 
- 
Time of first bowel movement 
- 
POI  
During the planned hospitalization - defined as the inability to tolerate liquid or solids 
greater than expected post-operative period, confirmed by imaging studies.  Resolution of 
POI, defined as having resolved when all of the following criteria are met:     
o Absence of vomiting for 12 hours without a NG/OG tube  
o Ability to tolerate a solid or liquid oral diet 
o Passage of flatus OR stool over the preceding 24 hours 
Following initial discharge - defined as having clinical symptoms (e.g., abdominal 
cramps, bloating, nausea, vomiting, constipation, difficulty passing gas, and difficulty 
tolerating a normal diet) and ileus confirmed by imaging studies 
Concomitant Medications (see Section 5.8) 
Discharge – the following information should be collected to assess LOS: 
- 
Time discharge is order written 
- 
Time the subject is ready for hospital discharge solely based on the recovery of GI 
function, as determined by the surgeon (“ready” for discharge) 
- 
The time the subject is actually discharged from the hospital 
Laboratory Tests – sites will use their local laboratory for this study 
- 
Serum chemistries – chloride, creatinine, glucose, sodium, potassium, carbon dioxide 
(CO2), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bilirubin, and estimation of glomerular filtration rate (eGFR) 


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- 
Hematology - hemoglobin, hematocrit, red blood cell count, white blood cell count, and 
platelet count. 
- 
Coagulation studies - partial thromboplastin time (PTT), prothrombin time (PT), and 
International Normalized Ratio (INR) 
- 
Pregnancy test – WOCBP must have a serum pregnancy test (serum human chorionic 
gonadotropin [hCG]) within 14 days prior to randomization and a urine hCG test prior to 
surgery on the morning of Study Day 2.  For this study, WOCBP is defined as not 
surgically sterile or post-menopausal defined as age > 40 years without menses for ≥ 2 
years. 
- 
Serum for cytokine and cortisol measurements (see Section 6.3) 
Informed consent – written informed consent must be obtained from each subject or legal 
representative designee (if subject is unable to sign) after the study has been fully explained in 
accordance with (ICH-GCP). Informed consent must be obtained prior to performing any study-
specific procedures. A copy of the signed and dated ICF should be provided to the subject or 
legal representative, and a copy maintained in the subject’s record.  The consent process must 
also be documented in the subject’s record. 
Medical history, including demographics, GI history and reason for surgery – demographics 
and a complete medical history of clinically significant diagnoses, including past and present GI 
diagnoses, and reason for surgery should be obtained from each subject and documented in the 
medical record.  Additionally, the Caprini Risk Factor Score (Appendix 2) will be calculated at 
the time the Medical History is obtained. Any clinically significant diagnoses occurring from 
Screening until the subject doses on Study Day 1 should be recorded as Medical History. 
Perioperative Surgical Preparation (see Section 5.9.2) 
Physical exam: 
- 
Complete physical exam – examination of the following systems: cardiovascular, 
dermatological, ear, nose, and throat, extremities, gastrointestinal, musculoskeletal. 
ophthalmological, neurological, and respiratory 
- 
Targeted physical exam – brief, focused examination of the subject following medical 
history, and include an assessment of lower extremities for possible VTE, and an 
assessment for AEs  
Surgery information – the following information should be collected: 
- 
Type of operation  
- 
Surgical approach (minimally invasive or laparotomy) 
- 
Location of the incision 
- 
Extent of bowel resection 
- 
Start time and stop time (placement of the last skin staple or suture) of surgery 
- 
Surgical complications should be reported as AEs/SAEs 
Telephone Contacts - Every effort must be made to contact the subject or legally authorized 
representative on Study Days 30 and 90. Documentation of contact and/or attempts at contacting 
the subject must be recorded in the subject’s record. 


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Vital signs – temperature (T), respiratory rate (RR), heart rate (HR), blood pressure (BP). HR 
and BP should be obtained after subject is resting for 5 minutes.   
6.2 
Study Activities by Visit 
Each subject who enters Screening will be assigned a subject ID number for traceability. The 
subject ID will consist of a 3-digit site number and a 3-digit subject number (i.e. 301-001, etc.). 
Subjects who sign and date the ICF but who fail to meet the eligibility criteria are defined as 
Screen Failures. Screen Failure subjects should have their demographic information captured 
with the reason for screen failure specified. 
6.2.1 
Screening 
The purpose of the screening visit is to determine the subject’s trial eligibility by assessing all 
inclusion/exclusion criteria based on available medical information, clinical assessment, clinical 
laboratory testing, and subject interview.  All subjects will be screened to within 42 days prior to 
Study Day 1 (dose of IP).   
The following assessments and procedures must be performed: 
• Obtain written informed consent 
• Obtain demographics 
• Complete the Caprini risk factor (Appendix 2) 
• Complete the ASA Classification (Appendix 3) 
• Review medical history, including GI history, reason for surgery, and concomitant 
medications 
• Perform a complete physical exam, including vital signs, height and weight 
• Collect laboratory samples for the following: 
- 
Serum chemistries 
- 
Hematology 
- 
Coagulation studies 
- 
Serum pregnancy test for WOCBP should be collected within 14 days of randomization 
• Confirm eligibility; note that if it becomes apparent anytime during screening that the subject 
is not eligible, do not complete additional procedures and document the reason for screen 
failure 
6.2.2 
Randomization 
Upon determination that a subject meets all eligibility criteria, the subject will be stratified by 1) 
surgery type (laparotomy versus minimally invasive approaches) and planned stoma (yes or no), 
then randomized to a specific treatment assignment.  Randomization should occur via IXRS 
within 48 hours of Study Day 1.  


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6.2.3 
Study Day 1 (IP administration) 
Blinded IP can be dispensed up to 48 hours prior to surgery. All subjects will take 700 mL of IP 
as the following split, oral doses: 
• 350 mL 6-10 hours prior to surgery, and 
• 350 mL 2-6 hours prior to surgery.  
Eating, drinking, consuming bowel preparation, and taking oral medications should be held 1 
hour before and 1 hour after IP administration. 
All subjects will be provided a Dosing Instruction Form that includes date and windows for 
dosing, and room for the subject to document actual time of dosing and any problems with 
dosing.   
6.2.4 
Study Day 2 (Day of Surgery)  
The following assessments and procedures must be performed prior to surgery: 
• Review concomitant medications including the Dosing Instruction Form to ensure the subject 
took IP as instructed 
• Perform urine pregnancy test for WOCBP 
• Perform targeted physical exam, including vital signs 
• Obtain blood pre-operatively for cytokine and cortisol measurements (use serum separator 
tube, spin and mail to the lab the same day. Do not freeze.)  
• Assess AEs (or update Medical History in the case of a physical exam finding not previously 
reported) 
Perform surgery and document the appropriate surgical information per Section 6.1. 
6.2.5 
Study Days 3 through Discharge (or Day 16, whichever is sooner) 
• Perform targeted physical exam, including vital signs 
• Assess adverse events 
• Review concomitant medications 
• Complete bowel function assessments per Section 6.1 
• On Study Day 3 ONLY, collect laboratory samples for the following: 
- 
Serum chemistries 
- 
Hematology 
- 
Coagulation studies 
- 
Obtain blood for cytokine and cortisol measurements (use serum separator tube, spin and 
mail to the lab the same day. Do not freeze.) 


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• On Study Day 7 ONLY or day of discharge, whichever is sooner, obtain blood for cytokine 
and cortisol measurements (use serum separator tube, spin and mail to the lab the same day. 
Do not freeze.) 
6.2.6 
Hospital Discharge 
Subjects should not be discharged until the following criteria are met: 
- 
Passage of stool 
- 
Ability to tolerate solid food and drink liquids 
• Perform all activities listed above in Section 6.2.5 
• Document discharge information per Section 6.1 
6.2.7 
Study Day 30 (± 2 days) 
Site study staff will contact the subject or their legally authorized representative to determine if 
the subject experienced POI or any SAE, including hospital readmission. 
6.2.8 
Study Day 90 / End of Study (± 7 days) 
Site study staff will contact the subject or their legally authorized representative to determine if 
the subject experienced POI or hospital readmission. If readmission did occur, this event should 
be recorded as a SAE.  
Additionally, complete subject disposition form and exit the subject from the study. 
6.3 
Storage of Research Samples 
Approximately 8.5 mL of blood will be collected into an appropriate tube on Study Day 2 prior 
to surgery, Study Day 3, and Study Day 7/ day of discharge, whichever is sooner.  Samples will 
be processed and stored until shipment to the lab. Stored samples may be used by the Sponsor or 
its research partners for better understanding of how LB1148 and/or safety analyses. No human 
genetic testing will be performed on these samples without expressed consent of study subjects. 
At the conclusion of this study, these samples may be retained in storage by the Sponsor or its 
research partners for a period up to 15 years. 
 


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7 ADVERSE EVENTS  
AEs will be reported in a manner consistent with the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (link provided in Appendix 4).  
Adverse events that are expected to occur during this study are as follows: 
• Acute Kidney Failure 
• Anastomotic leak 
• Dehydration 
• Intra-abdominal abscess 
• Peritonitis 
• Post-operative ileus 
• Small bowel obstruction 
• Urinary Retention 
 
Adverse events listed in the labeling of marketed TXA products (Lysteda™, Cyklokapron™) 
include: 
• Anemia 
• Fatigue 
• Headache, including migraine 
• Muscle cramps 
• Pain (back, abdominal, joint, musculoskeletal) 
• Sinus and nasal symptoms 
 
Adverse events that have been observed with other TXA products and are therefore of particular 
concern for the DMC are: 
• Ligneous conjunctivitis 
• Seizures 
• Thromboembolism (including stroke, renal occlusion) 
7.1 
Reporting Responsibilities 
All AEs will be recorded in the eCRF, from Study Day 1 through Hospital Discharge or Day 16, 
whichever is earlier.  SAEs will be reported through Study Day 30.  Hospital readmissions will 
be reported as an SAE through Study Day 90.  It is the responsibility of the Investigator or Sub-
investigator(s) to perform assessment of all AEs/SAEs.  Data describing AEs, including SAEs, 
will be entered in the subject’s medical record and eCRF.  In addition, SAEs will be reported to 
the Sponsor as described in Section 7.6. 
Subjects who experience AEs, whether serious or not serious, should receive appropriate 
treatment and medical supervision as clinically indicated.  All AEs must be followed until 
resolution/stabilization or until a time that is mutually agreed upon between the Medical Monitor 
and the Investigator. 


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7.2 
Definitions 
7.2.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, 
whether or not related to the IP. 
7.2.2 
Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” (SAE) if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening  
• An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, 
its occurrence places the patient or subject at immediate risk of death. It does not include an 
AE that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room (ER) or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
If it is not certain that an event meets the above definitions of an SAE, contact the Medical 
Monitor to discuss. 
7.2.3 
Relatedness (Causality) 
Causality assessment is required for AEs (and SAEs) that occur during clinical investigations.  
There is currently no standard international nomenclature to describe the degree of causality or 
relatedness of an AE with the IP.  The following terms will be used during this study:  
• Likely - Reasons to consider an AE likely related to treatment may include, but are not 
limited to the following: 
- 
Timing of the event relative to the administration of the IP 


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- 
There is a biologically plausible explanation based on the mechanism of action or mode 
of delivery of the treatment 
- 
No other explanation is likely 
• Unlikely - An AE with no temporal association with the IP but rather related to other 
etiologies such as concomitant medications or conditions, procedures, or subject's known 
clinical state. 
7.2.4 
Severity 
Severity will be reported in accordance with the NCI-CTCAE (Appendix 4).   
If an appropriate listing is not present in this table for an AE, the AE will be graded as follows: 
• Grade 1 Mild - asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Grade 2 Moderate - minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL) 
• Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL 
• Grade 4 Life-threatening consequences; urgent intervention indicated 
• Grade 5 Death related to AE 
7.3 
Clinical Laboratory Abnormalities 
Any laboratory abnormality deemed clinically significant by the Investigator at Screening should 
be reported as medical history. Any new clinically significant laboratory findings following 
Study Day 1 should be reported as an AE.  A clinically significant abnormality is a confirmed 
abnormality (by repeat test) that is changed sufficiently from Screening so that in the judgment 
of the Investigator a change in management is warranted.  This alteration may include 
monitoring the laboratory test further, initiating other diagnostic tests or procedures, changing 
ongoing treatment, or administering new treatment.   
Whenever possible, the underlying medical diagnosis (e.g., anemia) should be reported as the AE 
term.  Repeated additional tests and/or other evaluations required to establish the significance 
and etiology of an abnormal result should be obtained when clinically indicated.  
7.4 
Physical Exam Abnormalities 
Any physical exam abnormality deemed clinically significant by the Investigator at Study Day 1 
should be reported as medical history. Any new physical exam abnormality deemed clinically 
significant by the Investigator during the study should be reported as an AE.  
7.5 
Pregnancy 
All pregnancies that occur –including female partners of male subjects – during the study 
must be reported to the Sponsor and followed to conclusion. The outcome of each 


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pregnancy must be reported.  The subject should be followed per study protocol.  Pregnancy 
alone is not a reason for premature discontinuation from the study. 
Pregnancy alone is not an AE, nor is an induced elective abortion to terminate a pregnancy 
without medical reason.  However, an induced therapeutic abortion to terminate a pregnancy due 
to complications or medical reasons must be reported as an SAE.  The underlying medical 
diagnosis for this procedure should be reported as the SAE term.  A spontaneous abortion is 
always considered an SAE. 
7.6 
Reporting of Serious Adverse Events  
SAEs must be reported to the Sponsor or designee within 1 business day of becoming aware of 
the event by entering the data on the AE eCRF. If at the time the Investigator submits an initial 
SAE report the event has not resolved, the Investigator must provide a follow-up as soon as it 
resolves (or upon receipt of significant information if the event is still ongoing). All SAEs must 
be followed until resolution/stabilization or until a time that is mutually agreed upon between the 
Medical Monitor and the Investigator. Upon checking “serious” on the AE eCRF, a notification 
will be sent to the Medical Monitor and/or designee. Relevant eCRFs (including Medical 
History, Concomitant Medications, and Adverse Events) must also be completed to provide 
supporting documentation for the SAE. If there are additional documents that support the SAE 
(e.g., clinic or hospital records or procedure reports), they should be uploaded to the AE eCRF.   
The Sponsor is responsible for notifying the relevant Regulatory Authorities of certain events. It 
is the Investigator’s responsibility to notify the IRB of all SAEs that occur at his or her site. 
Investigators will also be notified of all unexpected, serious, IP-related events that occur during 
the clinical trial. Each site is responsible for notifying its IRB of these additional SAEs.  
 
 
 


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8 STATISTICAL CONSIDERATIONS 
8.1 
Sample Size 
A total sample size of 600 subjects, randomized in a 1:1 ratio, provides 90% power to detect a 
difference in median time to GI-2 between groups of 22 hours, assuming a median time to return 
of bowel function of 70 hours in the LB1148 group and 92 hours in the placebo group, using a 2-
sided log-rank test with a significance level of 0.05.  
Enrolling 650 subjects will allow for 7.8% of subjects not included in the Per Protocol (PP) 
population. 
8.2 
Analysis Populations 
Intent-to treat (ITT): The ITT population includes all randomized subjects who receive any 
amount of IP and have the scheduled surgery. Subjects will be analyzed according to the 
treatment to which they were randomized to receive. It should be noted that although this 
analysis population definition technically modifies the strict definition of ITT (i.e., all 
randomized subjects without any other conditions), this analysis population as defined is still 
consistent with the ITT principle given the context of this clinical trial. All analyses 
corresponding to the primary endpoint and all secondary endpoints will be formally assessed 
using the ITT population. 
Per Protocol Population (PP): The PP population consists of those subjects in the ITT 
population who meet all inclusion and no exclusion criteria, complete full IP dose, and have no 
important protocol deviations (Section 9.10). All analyses corresponding to the primary endpoint 
and all secondary endpoints will be additionally assessed using the PP population for sensitivity 
analysis purposes. 
Safety Population: All randomized subjects who receive any amount of IP.  Subjects will be 
analyzed according to the treatment that they actually received. 
8.3 
Analysis Conventions 
Planned statistical analyses will be detailed in the Statistical Analysis Plan (SAP).  This plan will 
be finalized prior to locking of the final data set and unblinding of results.  The general principles 
are outlined below.  Ad hoc exploratory analyses may be performed in addition to those 
specified, but no claims or conclusions will be drawn other than hypotheses to be tested in future 
clinical trials.  
In general, descriptive statistics for continuous variables will consist of subject count (n), mean 
(or geometric mean), median, standard deviation (SD), and range; and descriptive statistics for 
categorical variables will consist of subject counts and percentages.   
No imputation of missing data will be performed except for selected times when dates are present, 
but times are not. The times to impute are tabled below. 


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Time 
Condition 
Imputation 
Time of final staple or suture 
Date Present/Time absent 
1. 
Time 
Surgery 
began 
2. 
12:00 
am 
Time of first bowel movement 
Date Present/Time absent 
11:59 pm 
Time first toleration of solid food 
Date Present/Time absent 
11:59 pm 
Time subject is ready for hospital discharge solely 
based on the recovery of GI function, as determined by 
the surgeon 
Date Present/Time absent 
1. 
TDO 
2. 
TAD 
3. 
11:59 
pm 
TDO 
Date Present/Time absent 
1. 
TAD 
2. 
11:59 
pm 
TAD 
Date Present/Time absent 
11:59 pm 
Time of first flatus 
Date Present/Time absent 
11:59 pm 
Listings will not be imputed. 
All efficacy and safety data will be included in data listings and summaries. 
8.4 
Control for Multiplicity 
Multiplicity will be controlled through a combination of gate keeping and the Hochberg 
procedure (Multiple Endpoints in Clinical Trials Guidance for Industry, Draft Guidance 2017). 
The primary endpoint will be evaluated at a significance level of 0.05, if there is significance 
then the secondary endpoints will be evaluated, otherwise all secondary endpoints will be 
considered exploratory (Wiens 2003).  
If the primary endpoint is significant at 0.05, the four secondary endpoints (time to first bowel 
movement, LOS Ready, LOS DOW, LOS Actual) will be considered using the Hochberg 
procedure. The α critical values are 0.0125, 0.0167, 0.025, and 0.05.  
Using the Hochberg procedure, the p-values for each secondary endpoint will be computed and 
then ordered from largest to smallest (Hochberg 1988). The largest computed p-value will be 
compared against the largest critical value. If it does not show significance, then the next largest 
p-value is compared to the next largest critical value. Testing continues until a p-value for an 
endpoint is statistically significant when compared to its respective critical value. Once an 
ordered p-value is significant, that endpoint and all endpoints with p-values smaller than that 
endpoint are considered to have a statistically significant treatment effect. 
8.5 
Subject Disposition 
The number of subjects who are randomized, treated, complete the study, and reasons for 
discontinuation from the study will be summarized in tabular format for the safety population. 
Subject disposition will also be displayed for the safety population in a subject listing. 


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8.6 
Demographic, Baseline, and Surgical Characteristics 
Demographics, baseline, and surgical characteristics will be summarized by treatment group and 
consist of (but not limited to) the following: age, height, weight, sex, ethnicity/race, GI history, 
reason for surgery, surgical approach, duration of surgery, stoma or no stoma.  
Quantitative variables will be summarized by summary statistics (n, mean, SD, minimum, 
median, and maximum). Qualitative variables will be summarized as counts and percentages. 
Demographics and characteristics will be summarized for both the safety population and ITT 
population.  
8.7 
Medical History 
All medical history (past and current medical disorders), including GI history, will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in use at the 
start of the study.  Medical history will be summarized by MedDRA System Organ Class (SOC) 
and Preferred Term, and results presented by treatment group for the safety population. 
8.8 
Concomitant Medications 
All medications will be coded using the World Health Organization (WHO) drug dictionary 
version currently in use at the start of the study and summarized by treatment group, drug class, 
and medication term. 
8.9 
Drug Exposure 
The number and percent of subjects who consumed all or part of their IP will be summarized by 
treatment group for the ITT population.  
8.10 Efficacy Analyses 
8.10.1 
Primary Endpoint - Time to GI-2 
Analyses 
The primary endpoint is the time to GI-2, defined as the time in hours from the end of surgery to 
the time of recovery of the upper GI tract (toleration of solid food) and the lower GI tract (first 
bowel movement) following surgery, whichever occurs later up to 14 days post-surgery. 
• End of surgery is defined as the time the last skin staple or suture was placed by the surgeon. 
• Toleration of solid food is defined as the time a subject finished a meal that required chewing 
and experienced no significant nausea/vomiting for 4 hours after the solid meal. 
Time to GI-2 will be presented using descriptive statistics by treatment group. Non-parametric 
Kaplan-Meier survival curves will be produced for the two treatment groups and compared 
between treatment groups using a log-rank test adjusted with the following stratification factors: 
• Type of surgery (laparotomy versus minimally invasive approaches), and  


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• Stoma construction (Y/N)  
In addition to the non-parametric survival curves, a semi-parametric, stratified Cox PH model 
will be performed for sensitivity analysis purposes, with treatment as the main effect, and 
surgery type (laparotomy versus minimally invasive) and stoma construction (Y/N) as strata. 
Comparison of treatment groups and assessment of the significance of the parameter estimates 
for surgery type and stoma will be made using the Wald chi-square test. Interactions between 
treatment and the stratification factors will considered as part of the model building process. In 
order to further investigate the sensitivity of the analysis, a second run of the stratified Cox PH 
model will add the additional strata “Any opiates” taken after surgery (Y/N).  
Ties will be accounted for in the analyses above by selecting the Fleming -Harrington (FH) 
option in lieu of the default Kaplan Meir estimates. If there are no ties FH estimates are 
equivalent to Breslow estimates. Likewise, Breslow estimates will be selected for the Cox PH 
model. 
All results will be summarized and listed by treatment group for the ITT and PP populations.  
Estimand and Associated Intercurrent Events 
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E9(R1) guidance [E9-R1_Step4_Guideline_2019_1203.pdf (ich.org)] defines 
Intercurrent Events (IcE) as “Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the clinical question of 
interest.” The clinical question of interest addressed here is the estimand associated with the 
primary endpoint, i.e., the difference in the time to return of normal GI function, as measured by 
GI-2 (as defined above), between subjects receiving LB1148 and subjects receiving placebo for 
the treatment of return of bowel function after GI surgery. As described above, this difference 
will be measured by Kaplan-Meier (log rank test) and its sensitivity ascertained with two Cox 
PH models (Wald chi square). The timeframe of reference is Study Day 2 through discharge or 
14 days after surgery (Study Day 16), whichever is earlier.  
The IcEs that may affect the interpretation or the occurrence of this estimand are tabulated below 
in Table 5, along with the related censoring rules for each analysis. 
Table 5 
Intercurrent Events for Time to GI-2 
 
 
Primary Analysis Approach (Kaplan-
Meier and Cox Models) 
Further Sensitivity Analyses  
(Kaplan-Meier Model Only)  
Intercurrent Event 
First Run of Cox 
Model 
Second Run of 
Cox Model 
#1 
#2 
No GI-2 but death 
report 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the 
date of death 
*Descending Event 
Dates (Controls) 
No GI-2 and the 
subject is lost to 
follow-up or 
withdrew informed 
consent 
Censoring at 
Study Day 16  
Censoring at 
Study Day 16  
Censoring at the 
date consent 
withdrawn 
*Descending Event 
Dates (Controls) 


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No GI-2 within 14 
days after surgery 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
*Descending Event 
Dates (Controls) 
Opiate use 
Not applicable 
Add strata “any 
opiates” (Y/N) 
to the Cox PH 
model 
Not applicable 
Not applicable 
*Descending Event Dates: All missing values for subjects on placebo due to intercurrent events tabled above 
should be replaced with day of event as date corresponding to Study Day 15 and compute the log rank and 
Wald Chi square tests as above, then replace with the date corresponding to Study Day 14 unless Study Day 
15 was the actual date of the event and hence should be left as Study Day 15 and then compute the log rank 
and Wald Chi square tests. Likewise for Study Day 12. Treatment subjects with missing data will be 
censored using the Primary Analysis Approach at Study Day 16 
Further details for handing partial dates and times will be provided in the Statistical Analysis 
Plan (SAP). 
8.10.2 
Secondary Endpoints 
Time to First Bowel Movement 
Analysis 
The secondary endpoint, time to first bowel movement, is defined as the time from the end of 
surgery to the time of the first bowel movement.  Time to first bowel movement will be analyzed 
using time to event methods described above for the primary endpoint, time to GI-2.  Time to 
first bowel movement will be presented in summary tables with descriptive statistics for the ITT 
and PP populations. 
Estimand and Associated Intercurrent Events 
The clinical question of interest here is the estimand associated with this secondary endpoint, i.e., 
the difference in the time of first bowel movement, (as defined above), between patients 
receiving LB1148 and patients receiving placebo for the treatment of return of bowel function 
after GI surgery. As described above, this difference will be measured by Kaplan-Meier (log 
rank test) and its sensitivity ascertained with two Cox PH models (Wald chi square). The 
timeframe of reference is Study Day 2 through discharge or 14 days after surgery (Study Day 
16), whichever is earlier.  
The IcEs that may affect the interpretation or the occurrence of this estimand are tabulated below 
in Table 6, along with the related censoring rules for each analysis. 
Table 6 
Intercurrent Events for Time to First Bowel Movement 
Intercurrent Event 
Primary Analysis Approach 
(Kaplan-Meier and Cox Models) 
Further Sensitivity Analysis  
(Kaplan-Meier) Model Only) 
First Run of Cox 
Model 
Second Run of 
Cox Model 
#1 
No bowel movement 
but death report 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the date of death 
No bowel movement 
and the subject is lost 
to follow-up or 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the date consent 
withdrawn 


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Intercurrent Event 
Primary Analysis Approach 
(Kaplan-Meier and Cox Models) 
Further Sensitivity Analysis  
(Kaplan-Meier) Model Only) 
First Run of Cox 
Model 
Second Run of 
Cox Model 
#1 
withdrew informed 
consent 
No bowel movement 
within 14 days after 
surgery 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at Study Day 16 
Opiate use 
Not applicable 
Add strata “any 
opiates” (Y/N) to 
the Cox PH model 
Not applicable 
Length of Stay – Ready, DOW, and Actual 
Analysis 
The secondary endpoints, for LOS are defined as follows: 
• LOS Ready, is defined as the time from the end of surgery to the time subject is ready for 
hospital discharge solely based on the recovery of GI function, as determined by the surgeon. 
• LOS DOW, defined as the time from the end of surgery to the time that the hospital 
discharge order is written. 
• LOS Actual, is the time of actual discharge, defined as the time from the end of surgery to 
the time the subject is actually discharged from the hospital. 
LOS will be analyzed using time to event methods described above for the primary endpoint, 
time to GI-2. The second Cox PH model adding “Any opiates” use will be performed only if the 
strata was significant for the primary endpoint analyses.  LOS Ready, DOW, and Actual will be 
presented in summary tables with descriptive statistics for the ITT and PP populations. 
Estimand and Associated Intercurrent Events 
The clinical questions of interest here are the estimands associated with these secondary 
endpoints, i.e., the difference in the time to: 
- 
when the subject is ready for discharge, 
- 
when the discharge order is written, and 
- 
actual discharge, 
between patients receiving LB1148 and patients receiving placebo for the treatment of return of 
bowel function after GI surgery.   
As described above, this difference will be measured by Kaplan-Meier (log rank test) and its 
sensitivity ascertained with at least one Cox PH models (Wald chi square). The timeframe of 
reference is Study Day 2 through discharge or 14 days after surgery (Study Day 16), whichever 
is earlier. 


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The IcEs that may affect the interpretation or the occurrence of these estimands are tabulated 
below in Table 7, along with the related censoring rules for each analysis. 
Table 7 
Intercurrent Events for LOS 
Intercurrent Event 
Primary Analysis Approach  
(Kaplan-Meier and Cox Models) 
Further Sensitivity Analyses  
(Kaplan-Meier Model Only) 
First Run of Cox 
Model 
Second Run of 
Cox Model* 
#1 
Failure to meet 
discharge criteria 
(Ready, DOW, Actual) 
but have a death 
report 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the date of death 
Failure to meet 
discharge criteria 
(Ready, DOW, Actual) 
and the subject is lost 
to follow-up or 
withdrew informed 
consent 
Censoring Study 
Day 16 
Censoring at 
Study Day 16 
Censoring at the date consent 
withdrawn 
Failure to meet 
discharge criteria 
(Ready, DOW, Actual) 
within 14 days after 
surgery 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at Study Day 16 
Opiate use 
Not applicable 
Add strata “any 
opiates” (Y/N) to 
the Cox PH model 
Not applicable 
*The second Cox PH model adding “Any opiates” use will be performed only if the strata was significant 
for the primary endpoint analyses. 
8.10.3 
Exploratory Endpoints 
Exploratory endpoints and their analysis methods are described below.  All analyses will use the 
ITT population, and no statistical testing will be formal in nature. 
• Time to GI3, defined as the toleration of solid food and either first flatus or bowel movement 
will be analyzed using time to event methods described above for the primary endpoint, time 
to GI-2.   
• Proportion of subjects not readmitted to the hospital following initial discharge by Study Day 
90. 
• Proportion of subjects without POI: 
- 
During the planned hospitalization – POI is defined as the inability to tolerate liquid or 
solids greater than expected post-operative period, confirmed by imaging studies  
Resolution of POI, defined as having resolved when all of the following criteria are met:     
o Absence of vomiting for 12 hours without a nasogastric (NG)/orogastric (OG) tube  
o Ability to tolerate a solid or liquid oral diet 
o Passage of flatus OR stool over the preceding 24 hours. 
- 
Following initial discharge – POI is defined as having clinical symptoms (e.g., abdominal 
cramps, bloating, nausea, vomiting, constipation, difficulty passing gas, and difficulty 
tolerating a normal diet) and ileus confirmed by imaging studies. 


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• Opiate use will be summed using MME. Opiate use will be summarized by treatment group 
using summary statistics (n, mean, SD, SEM, minimum, first quartile, median, third quartile, 
and maximum). Comparisons will be made using the Wilcoxon rank sum test. 
8.11 Safety Analyses 
8.11.1 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA).  
Frequency tables will be presented by treatment group for all AEs and SAEs by System Organ 
Class (SOC) and Preferred Term (PT).  Frequency tables will also be produced by treatment 
group for AEs leading to discontinuation from IP and study, by severity, and by causality.  No 
formal statistical testing will be done. 
Clinically significant physical exam and lab abnormalities will be reported as AEs and 
summarized as described above. 
8.11.2 
Laboratory Evaluations and Vital Signs 
Laboratory results and vital signs will be summarized by mean, median, SD, and range.  
Laboratory abnormalities will be analyzed as safety outcomes by summarizing frequency, 
severity, and changes from baseline.  Other analyses may include but are not limited to the 
following: examination of shift tables and pre-established severity grades. 


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9 ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES 
9.1 
Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor, its authorized US 
representative, and Investigator abide by good ICH-GCP guideline E6, and in US regulations 
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56, and 312.  Compliance with 
these regulations also constitutes compliance with the ethical principles that have their origins in 
the Declaration of Helsinki. 
9.2 
Institutional Review Board Approval 
This protocol and the ICF and any subsequent modifications will be reviewed and approved by 
the relevant IRB responsible for oversight of the study.  A letter from the IRB indicating 
approval of the study to be conducted by the Investigator will be provided to the Sponsor prior to 
initiation of any enrollment at that site.  All reviews and approvals by the IRB will be in 
accordance with 21 CFR part 56. 
9.3 
Informed Consent 
The ICF document must be signed and dated prior to the initiation of study-related tests, and 
prior to administration of IP.  The original signed ICF for each participating subject shall be filed 
with records kept by the Investigators.  A copy of the ICF must be provided to the subject.  If 
applicable, the ICF will be provided in a certified translation of the local language. 
9.4 
Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, and in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors and other authorized agents of the Sponsor, the IRB approving this research, 
and any applicable regulatory authorities will be granted direct access to the study subjects’ 
original medical records for verification of clinical trial procedures and/or data, without violating 
the confidentiality of the subjects, to the extent permitted by the law and regulations.  In any 
presentation of the results of this study at meetings or in publications, the subjects’ identity will 
remain confidential.    
9.5 
Protocol Amendments 
Any changes to the protocol will be made in writing by the Sponsor in the form of a protocol 
amendment.  All protocol amendments will be sent to the Investigator, who is responsible for 
submitting the amendment to the IRB for approval. 


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9.6 
Case Report Forms  
An electronic Case Report Form (eCRF) will be used to record subject data specified by this 
protocol.  The eCRF must be completed by designated and trained study personnel.  The eCRF 
will be signed by the Investigator or a Sub-Investigator listed on the Form FDA 1572.  It is the 
responsibility of the Investigator to ensure the eCRFs are completed and submitted to the 
Sponsor (or designee) in an accurate and timely manner.  The processing of eCRFs will include 
an audit trail (to include changes made, reason for change, date of change and person making 
change).   
9.7 
Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents may include, but are not limited to, study progress notes, e-
mail correspondences, computer printouts, laboratory data, and drug accountability records.  All 
source documents produced in this study will be maintained by the Investigator(s) and made 
available for inspection by the Sponsor’s representatives, the IRB, the FDA, or other regulatory 
authorities. 
9.8 
Retention of Records 
US regulations (21 CFR part 312.62) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drugs including medical records, 
eCRFs, ICFs, test results, and IP records be kept on file by the Investigator for 2 years after a 
marketing application is approved for the drug for the indication for which it is being studied.  If 
no application is filed or approved, these records must be kept for 2 years after the investigation 
has been discontinued and the FDA has been notified.  ICH guidelines indicate that documents 
should be retained until at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region, or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the IP.  No study records should be destroyed without prior authorization from the Sponsor. 
9.9 
Study Monitoring 
Site visits will be conducted by an authorized Sponsor representative (the monitor) to inspect 
study data, subjects’ medical records, and eCRFs in accordance with ICH guidelines, GCPs, and 
the respective US or national regulations and guidelines, as applicable.  It will be the monitor’s 
responsibility to inspect the eCRFs at regular intervals throughout the study, to verify the 
adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered.  The monitor should have access to laboratory test reports and other subject records 
needed to verify the entries on the eCRFs. 
The Investigator will permit representatives of the Sponsor, the IRB, the FDA, and/or respective 
health authorities to inspect facilities and records relevant to this study. 


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9.10 Protocol Deviations 
Sites are responsible for abiding by their IRB rules and regulations for reporting protocol 
deviations.  Additionally, the following important protocol deviations will be reported in the 
eCRF: 
• Subject did not meet study eligibility criteria 
• Subject did not receive the correct treatment assignment 
• Subject did not consume 100% of the assigned dose 
• Subject did not have planned surgery 
• Subject received a prohibited concomitant medication 
• Subject discharged from the hospital prior to achieving GI-2, the primary endpoint  
A subject who has 1 of the above deviations will be followed for safety per protocol. 
9.11 Financial Disclosure 
Investigators participating in this study will provide accurate financial disclosure information to 
the Sponsor as required by 21 CFR Part 54. Investigators will update the financial information if 
any relevant changes occur during the study and for 1 year following completion of the study. 
9.12 Publication and Disclosure Policy 
Investigators and their staff shall hold confidential, and not disclose directly or indirectly to any 
third party other than those persons involved in the study who have a need to know, the protocol, 
the data arising out of the study, and any other information related to the study or to Sponsor’s 
products or research programs that is provided to the Investigator. All such persons must be 
instructed not to further disseminate this information to others. Investigators shall not use the 
Confidential Information for any purpose other than the study. The foregoing obligations of 
confidence and non-use assumed by the Investigator shall not apply to: (a) information which at 
the time of disclosure is in the public domain; (b) information which thereafter lawfully becomes 
part of the public domain other than disclosure by or through the Investigator; (c) information 
which, as evidenced by the Investigator’s written records, was known by the Investigator prior to 
the Sponsor’s disclosure; (d) information which is lawfully disclosed to the Investigator by a 
third party not under any obligation of confidence to the Sponsor; or (e) information which is 
required to be disclosed by law or government regulatory agency, provided reasonable advance 
notice of such disclosure is given to the Sponsor.  
All data and discoveries arising out of the study, patentable or non-patentable, shall be the sole 
property of the Sponsor.  The Sponsor reserves the right of prior review of any publication or 
presentation of information related to the study. The Sponsor reserves the right of prior review of 
any publication or presentation of information related to this study. The Sponsor may use these 
data now or in the future for presentation or publication at the Sponsor’s discretion or for 
submission to government regulatory agencies. 


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The Sponsor adheres to the general principles of publication of scientific data as articulated by 
the International Committee of Medical Journal Editors and acknowledges its responsibility to 
publish results of clinical trials.  Persons that fulfill the criteria for authorship 
(http://www.icmje.org/recommendations/) may be authors on publications based on their 
contributions to the design, conduct, results, and/or analysis of this clinical trial.  Investigators 
will have access to the data from this clinical trial for the preparation of scientific presentations 
and publications subject to the requirements of confidentiality.  The Sponsor reserves the right to 
review, within a reasonable time frame, results or analyses from data generated in this study that 
are intended for public presentation, including scientific meetings. 
In signing this protocol, Investigator agrees to the release of the data from this study and 
acknowledges the above confidentiality and publication policy. The provisions of this Statement 
shall survive the completion of the study.  


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program comparative effectiveness research translation network collaborative. J Am Coll Surg. 
2016 May;222(5):870-7.  
Cronin M, Dengler N, Krauss ES, Segal A, Wei N, Daly M, Mota F, Caprini JA. Completion of 
the Updated Caprini Risk Assessment Model (2013 Version). Clin Appl Thromb Hemost. 2019 
Jan-Dec;25:1076029619838052. doi: 10.1177/1076029619838052. PMID: 30939900; PMCID: 
PMC6714938. 
DeLano FA, Hoyt DB, Schmid-Schönbein GW. Pancreatic digestive enzyme blockade in the 
intestine increases survival after experimental shock. Sci Transl Med. 2013 Jan 
23;5(169):169ra11. 
Dubber AH, McNicol GP, Douglas AS. Amino methyl cyclohexane carboxylic acid (AMCHA), 
a new synthetic fibrinolytic inhibitor. Br J Haematol. 1965 Mar;11:237-45. 
Ehlers AP, Simianu VV, Bastawrous AL, Billingham RP, Davidson GH, Fichera A, et al. 
Alvimopan use, outcomes, and costs: a report from the surgical care and outcomes assessment 
program comparative effectiveness research translation network collaborative. J Am Coll Surg. 
2016 May;222(5):870-7.  
ENTEREG® (alvimopan) capsules, for oral use [prescribing information]. Whitehouse Station, 
NJ. Merck & Co., Inc., 2020 
Goldstein JL, Matuszewski KA, Delaney CP, Senagor A, Chiao EF, Shah M, et al.  Inpatient 
economic burden of postoperative ileus associated with abdominal surgery in the United States.  
P T.  2007 Feb;32:82-90.   
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance, Biometrika, 
Volume 75, Issue 4, December 1988, Pages 800–802, https://doi.org/10.1093/biomet/75.4.800 
LYSTEDA® (tranexamic acid) tablets, for oral use [prescribing information]. Parsippany, NJ. 
Ferring Pharmaceuticals Inc., 2020 
Moghadamyeghaneh Z, Hwang GS, Hanna MH, Phelan M, Carmichael JC, Mills S, et al. Risk 
factors for prolonged ileus following colon surgery. Surg Endosc. 2016 Feb;30(2):603-609.  


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NCI-CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm accessed on 08 
August 2016. 
Pelham RW, Nix LC, Chavira RE, Cleveland MV, Stetson P. Clinical trial: single- and multiple-
dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects. 
Aliment Pharmacol Ther. 2008 Jul;28(2):256-65. doi: 10.1111/j.1365-2036.2008.03727.x. Epub 
2008 Apr 30. PMID: 18462266. 
Wiens, B.L. (2003), A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceut. Statist., 2: 211-215. https://doi.org/10.1002/pst.64 
  


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Appendix 1 Schedule of Activities 
Study Day/ 
Assessment 
Screening 
Dosing 
Surgery 
Hospitalization 
Follow-Up 
Day -42 to  
-2 
Day 1 
Day 2 
Day 3 to 16/ 
Discharge a 
Day 30 
(±2 Days) 
Day 90       
(±7 Days) 
Informed consent 
X 
 
 
 
 
 
Medical history, including 
diagnosis leading to surgery 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Confirm eligibility criteria 
X 
X b 
 
 
 
 
Complete physical exam 
X 
 
 
 
 
 
Caprini Risk Factor 
X 
 
 
 
 
 
ASA Classification 
X 
 
 
 
 
 
Targeted physical exam 
 
 
X 
Daily 
 
 
Vital signs  
X 
 
X 
Daily 
 
 
Laboratory Tests 
 
 
 
Day 3 only 
 
 
Serum chemistries 
X 
 
 
X 
 
 
Hematology 
X 
 
 
X 
 
 
Coagulation studies 
X 
 
 
X 
 
 
Pregnancy test  
S c 
 
U c 
 
 
 
Central lab sample 
 
 
X d 
Day 3, Day 7 e 
 
 
Randomization 
 
X f 
 
 
 
 
Dosing 
 
X g 
 
 
 
 
Bowel function assessment 
 
 
 
Daily 
 
 
POI assessment 
 
 
 
Daily 
X 
X 
Concomitant medication 
assessment, including 
opiates 
X 
 
X 
Daily 
 
 
AE, SAE, Hospital 
Readmission Assessments 
 
 
X 
Daily 
SAEs / 
Hospital 
Readmission 
Hospital 
Readmission 
AE=adverse event, DC=discharge, POI=post-operative ileus, S=serum, U=urine 
a. Subjects will be followed in the hospital through Day 16 or discharge, whichever occurs first 
b. Eligibility should be confirmed at Screening and just prior to randomization 
c. For WOCBP a serum hCG test should be performed 14 days prior to randomization and a urine hCG 
test prior to surgery on the morning of Study Day 2 
d. Prior to surgery 
e. Day 7 or day of discharge, whichever comes sooner 
f. 
Randomization and IP preparation should occur within 48 hours prior to dosing  
g. Subjects will consume 700 mL of IP in a split dose of 350 mL 6-10 hours prior to surgery and 350 mL 
2-6 hours prior to surgery 
 


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Appendix 2 American College of Chest Physicians (ACCP) Guidelines - Caprini 
Risk Factor Score 
https://capriniriskscore.org/assessment/  
 
  
 
Abbreviations:  BMI = Body Mass Index; COPD = Chronic Obstructive Pulmonary Disease; DVT = Deep 
Vein Thrombosis; PE = Pulmonary Embolism. 
 
Sources: Caprini 2010, Cronin 2019 
 
 


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Appendix 3 American Society of Anesthesiologists Classification System 
Approved by the ASA House of Delegates on October 15, 2014, and last amended on December 
13, 2020 
Current Definitions and ASA-Approved Examples for Adults 
ASA PS 
Classification 
Definition 
Examples, Including but not Limited to: 
ASA I 
A normal healthy patient 
Healthy, non- smoking, no or minimal alcohol 
use 
ASA II 
A patient with mild systemic disease 
Mild diseases only without substantive 
functional limitations.  
Current smoker, social alcohol drinker, 
pregnancy, obesity (30<BMI<40), well-
controlled DM/HTN, mild lung disease 
ASA III 
A patient with severe systemic disease 
Substantive functional limitations;  
One or more moderate to severe diseases: 
Poorly controlled DM or HTN, COPD, morbid 
obesity (BMI ≥40), active hepatitis, alcohol 
dependence or abuse, implanted pacemaker, 
moderate reduction of ejection fraction, ESRD 
undergoing regularly scheduled dialysis, history 
(>3 months) of MI, CVA, TIA, or CAD/stents. 
ASA IV 
A patient with severe systemic disease that 
is a constant  threat to life 
Recent (<3 months) MI, CVA, TIA or 
CAD/stents, ongoing cardiac ischemia or severe 
valve dysfunction, severe reduction of ejection 
fraction, shock, sepsis, DIC, ARD or ESRD not 
undergoing regularly scheduled dialysis 
ASA V 
A moribund patient who is not expected to 
survive without the operation 
Ruptured abdominal/thoracic  aneurysm, 
massive trauma, intracranial bleed with mass 
effect, ischemic bowel in the face of significant 
cardiac pathology or multiple organ/system 
dysfunction 
ASA VI 
A declared  brain- dead patient whose 
organs are being removed for donor 
purposes 
 
Abbreviations:  ARD = advanced renal disease; BMI = body mass index; CAD = coronary artery disease; 
COPD = chronic obstructive pulmonary disease; CVA = cerebrovascular accident; DIC = disseminated 
intravascular coagulation; DM= diabetes mellitus; ESRD = end stage renal disease; HTN = hypertension; 
MI = myocardial infarction; TIA = transient ischemic attack.   
 
Source: ASA website - https://www.asahq.org/standards-and-guidelines/asa-physical-status-classification-system  


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Appendix 4 National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) 
The following is a link to the full CTCAE, v 5: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
 
 
 


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Appendix 5 Amendments to the Protocol 
Amendment 1, Protocol Version 2.0, March 9, 2022 
The overall purpose of this amendment is to: 
• Add a Data Monitoring Committee  
• Add an exclusion criteria for subjects with severe renal impairment 
• Specify when a subject may be discontinued prematurely from IP  
• Clarify perioperative surgical preparation restrictions   
Effect on Informed Consent Form 
• Add perioperative surgical preparation restrictions 
Summary of Changes to make v2.0 
Section 
Change 
Rationale 
Synopsis – Data Monitoring 
Committee 
Added 
An independent DMC will be 
commissioned for this study.  The 
DMC will be comprised of 3 
physicians with expertise in 
hematology, pulmonology or 
intensive care, and internal 
medicine; all will have clinical trial 
experience.  The DMC safety 
monitoring plan will be detailed in 
the DMC Charter. 
FDA recommendation  
Section 3.3 – Data Monitoring 
Committee 
Added entire section 
An independent DMC will be 
commissioned for this study.  The 
DMC will be comprised of 3 
physicians with expertise in 
hematology, pulmonology or 
intensive care, and internal 
medicine; all will have clinical trial 
experience.  The DMC safety 
monitoring plan will be detailed in 
the DMC Charter. 
The primary responsibility of the 
DMC is to safeguard study 
subjects by reviewing and 
assessing the clinical safety data 
being collected during the 
performance of the study.  The 
DMC will review SAEs (Section 
7.2.2) and ≥ Grade 3 AEs that 
are “Likely” (Section 7.2.3) to be 
related to IP as these events may 
occur.  They will also meet 
FDA recommendation  


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Section 
Change 
Rationale 
periodically throughout the study 
to review cumulative safety data.   
Based on these evaluations of 
the data, the DMC will make 
recommendations to the Sponsor 
to continue the study as planned, 
or to modify, temporarily 
suspend, or terminate the study.  
The DMC will also be responsible 
for identifying issues and making 
recommendations regarding the 
monitoring of subjects for safety, 
including collection of additional 
safety data. 
The Sponsor will be responsible 
for notifying Investigators and 
Regulatory Authorities of any 
DMC recommendations, as 
appropriate. 
Synopsis and Section 4.2  - 
Exclusion Criteria 
Added Exclusion Criteria: 
5. Estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73 
m2 
FDA request 
Section 4.3.2 – Premature 
Discontinuation from 
Investigational Product 
Added entire section 
Any subject who does not self-
administer the entire contents of 
both bottles of IP will be 
considered “prematurely 
discontinued from IP.”  The 
reason for not taking IP as 
intended by protocol will be 
reported to the study team and 
collected in the eCRF.  If the 
reason is due to an AE, it will be 
reported in accordance with 
Section 7 - Adverse Events of the 
protocol (including relatedness 
and severity). 
All efforts will be made to follow 
subjects who discontinue IP for 
any reason.  Such follow up will 
include all relevant evaluations 
for safety including clinical 
assessments and collection of 
laboratory study results as set out 
in this protocol. 
FDA request 
Section 5.9.2 – Perioperative 
Surgical Preparation 
Modified first bullet 
• Subjects may not eat, drink, or 
take oral medications, 
including drinking bowel 
preparations, 1 hour before 
FDA request 


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Section 
Change 
Rationale 
and 1 hour after IP 
administration. 
Section 6.1 – Laboratory Tests 
Added 
eGFR to be included with the 
chemistry panel 
FDA request 
Section 6.2.3 – Study Day 1 (IP 
Administration) 
Modified second paragraph 
Eating, drinking, consuming 
bowel preparation, and taking 
oral medications should be held 
1 hour before and 1 hour after IP 
administration. 
FDA request 
Amendment 2, Protocol Version 3.0, May 20, 2022 
The overall purpose of this amendment is to improve the clarity of the protocol and to add 
specific information regarding a blood draw for research. 
Summary of Changes to make v3.0 
Section 
Change 
Rationale 
Administrative 
Corrected typos, grammatical 
errors and errors in references, 
updated version number and 
date, updated this table 
 
Synopsis – Study Centers 
Removed 
and multinational 
This study will be conducted only 
at US sites 
Synopsis – Secondary Objectives Definitions were removed, as 
they are provided in the 
endpoints 
Safety was moved to a separate 
objective 
Safety is listed separately in the 
statistics section 
Synopsis – Secondary Objectives Definitions were removed, as 
they are provided in the 
endpoints 
 
Synopsis – Study Design 
The timing of dosing was clarified  As written it could be inferred that 
the entire dose needed to be 
completed on Day 1 
Synopsis – I/E Criteria 
• 
Willingness to forgo 
alvimopam treatment was 
moved to an affirmative 
choice, rather than an 
exclusion criterion 
• 
Exclusion regarding 
emergency surgery was 
deleted, as it is covered by 
inclusion criterion #2 
• 
“or current” deleted from 
exclusion criteria as 
redundant to “history of” 
• 
This should be a choice 
made by the subject in 
consultation with their 
physician 
 
• 
Redundant 
 
 
• 
Timeframe of “history” is not 
defined and therefore 
includes current time 


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• 
Exc#10 added missing text 
• 
typo 
 
Synopsis – Test Product 
added “solution”, qualified water 
as “sterile” for both IPs 
To distinguish drug product from 
reconstituted product 
Synopsis –Endpoints 
Reworded 
For clarity 
Synopsis – Data Monitoring 
Committee 
Edited 
An independent DMC will be 
commissioned for this study.  The 
DMC will be comprised of 3 
physicians with expertise in 
therapeutic areas pertinent to this 
protocol hematology, 
pulmonology or intensive care, 
and internal medicine; all will 
have clinical trial experience. The 
DMC safety monitoring plan will 
be detailed in the DMC Charter. 
DMC members may have 
alternate backgrounds  
Body of the protocol 
All changes to the synopsis are 
also made in the body of the 
protocol 
 
Section 1.3.3 – LBS-POI-201-CN Added italicized text: “…to 
improve the recovery of 
gastrointestinal function 
(measured in hours to achieve 
GI-2) and…” 
for clarity 
Section 3.2.2 – Selection of 
Population 
added italicized text: “…sufficient 
homogeneity in terms of co-
morbidities to permit 
To avoid implying that race, 
gender or ethnicity will be 
homogeneous by design 
Section 3.3 – Data Monitoring 
Committee 
Edited 
An independent DMC will be 
commissioned for this study.  The 
DMC will be comprised of 3 
physicians with expertise in 
therapeutic areas pertinent to this 
protocol hematology, 
pulmonology or intensive care, 
and internal medicine; all will 
have clinical trial experience.  
The DMC safety monitoring plan 
will be detailed in the DMC 
Charter. 
The primary responsibility of the 
DMC is to safeguard study 
subjects by reviewing and 
assessing the clinical safety data 
being collected during the 
performance of the study.  At 
scheduled intervals detailed in 
the DMC charter, the DMC will 
review all AE data. SAEs 
(Section 7.2.2) and ≥ Grade 3 
FDA recommendation  


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AEs that are “Likely” (Section 
7.2.3) to be related to IP will be 
communicated to the DMC in a 
timely manner, which may result 
in an ad hoc meeting of the DMC. 
The DMC will review SAEs 
(Section 7.2.2) and ≥ Grade 3 
AEs that are “Likely” (Section 
7.2.3) to be related to IP as these 
events may occur.  They will also 
meet periodically throughout the 
study to review cumulative safety 
data. 
Synopsis and Section 4.2 - 
Exclusion Criteria 
Renumbered Exclusion Criterion 
5 to be 4: 
4. Estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73 
m2 
Administrative 
Section 4.3.2 – Premature 
Discontinuation from 
Investigational Product 
Edited this section 
Any subject who does not self-
administer the entire contents of 
both bottles of IP will be 
considered “prematurely 
discontinued from IP.”  The 
reason for not taking IP as 
intended by protocol will be 
reported to the study team and 
collected in the eCRF.  If the 
reason is due to an AE, it will be 
reported in accordance with 
Section 7 - Adverse Events of the 
protocol (including relatedness 
and severity). 
Subjects who discontinue IP for 
any reason should remain in the 
study.  All efforts will be made to 
ensure appropriate follow up, 
including all relevant evaluations 
for safety, clinical assessments, 
and collection of laboratory study 
results as described in this 
protocol. All efforts will be made 
to follow subjects who 
discontinue IP for any reason.  
Such follow up will include all 
relevant evaluations for safety 
including clinical assessments 
and collection of laboratory study 
results as set out in this protocol. 
Improved clarity 
Section 5.1.1 - Description 
Added “solution” to table 
description and highlighted the 
components that are packaged 
separately 
For added clarity – LB1148 drug 
product is not itself a solution 


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Section 6.1 – Laboratory Tests 
Changed 
“future research”  
to 
 “Serum for cytokine and cortisol 
measurements” 
 
Added 
“respiratory rate (RR)” to vital 
signs 
A decision was made to measure 
inflammatory cytokines and 
serum cortisol 
Section 6.2.1 – Screening 
Revised the order of procedures 
to have simple, potentially 
disqualifying gradings precede 
more laborious tasks 
Removed “Serum for future 
research” 
The timing of the serum collection 
was adjusted to match an ERAS 
study 
Section 6.2.4 – Study Day 2 
Revised the serum collection 
instructions 
Added 
“in the case of a physical exam 
finding not previously reported” 
Addition explains how a potential 
AE can become medical history 
Section 6.2.5 – Study Day 3 
Added 
Clarification regarding serum 
collection for cytokine and cortisol 
analysis 
 
Section 6.3- Storage of Research 
Samples 
Edits made to days of collection, 
volume and handling 
 
Section 7 – Adverse Events 
Added 
A listing of adverse events that 
can be expected in the patient 
population or have been seen 
with TXA according to existing 
drug labels 
To avoid declaring adverse 
events as unexpected 
Section 8.3 
Added: 
“No imputation of missing data 
will be performed except for 
selected times when dates are 
present, but times are not. The 
times to impute are tabled 
below.” 
The table was added. 
Added: 
“Listings will not be imputed.” 
 
 
Sections 8.7 & 8.8 
Clarified that coding of AEs and 
concomitant medications will be 
done using the version of 
MedDRA and WHO Drug 
To avoid requiring recoding each 
time the version changes 


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currently in use at the start of the 
study 
Section 8.10.1 – Analyses 
Added 
“in hours” 
Added: 
“Interactions between treatment 
and the stratification factors will 
considered as part of the model 
building process.” 
Added: 
“Ties will be accounted for in the 
analyses above by selecting the 
Fleming -Harrington (FH) option 
in lieu of the default Kaplan Meir 
estimates. If there are no ties FH 
estimates are equivalent to 
Breslow estimates. Likewise, 
Breslow estimates will be 
selected for the Cox PH model.” 
Tables 5, 6 and 7 were revised 
for clarity. 
To define the unit of time 
 
 
For clarification 
Appendix 1 – Schedule of 
Activities 
Changed the heading from 
Assessments to Activities 
 
Updated collection times for the 
research blood sample 
Not all activities are assessments 
 
 
The sample will be for cytokine 
and cortisol measurements  
Amendment 3, Protocol Version 4.0, June 7, 2022 
The overall purpose of this amendment is to improve the clarity of the protocol. 
Summary of Changes to make v3.0 
Section 
Change 
Rationale 
Synopsis – I/E Criteria 
• 
Willingness to forgo 
alvimopam treatment was 
moved back to an exclusion 
criterion  
• 
Men and women of child 
bearing potential (WOCBP) 
who are unwilling to practice 
a highly effective method of 
contraception that may 
include, but is not limited to, 
abstinence, sex only with 
persons of the same sex, 
monogamous relationship 
with vasectomized partner, 
vasectomy, hysterectomy, 
bilateral tubal ligation, 
• 
This should be a choice 
made by the physician with 
subject agreement to forgo 
alvimopam treatment  
• 
Moved to exclusion criterion if 
the subject is unwilling to 
practice a highly effective 
method of contraception from 
Day 1 through Day 30 
 
 
 
 
 


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licensed hormonal methods 
(but not combination 
hormonal methods), 
intrauterine device, or use of 
spermicide combined with a 
barrier method (e.g., condom, 
diaphragm) for 28 days 
before Day 1 and through 
Day 30 moved to an 
exclusion criterion. 
• 
Updated to specify ‘women’ 
who will not agree to stop 
combined hormonal 
contraceptive and or 
combined hormonal 
replacement therapy 
 
 
 
 
 
 
 
 
• 
For clarification  
 
Synopsis –Endpoints 
Reworded 
For clarity 
Body of the protocol 
All changes to the synopsis were 
also made in the body of the 
protocol 
 
Synopsis and Section 4.2 - 
Exclusion Criteria 
• 
Added back ‘willingness to 
forgo alvimopam treatment’ 
as an exclusionary criterion 
• 
Moved and updated wording 
that men and women of child 
bearing potential unwilling to 
practice a highly effective 
method of contraception 
would be excluded 
• 
Updated exclusion 12 to 
specify women who will not 
agree to stop combined 
hormonal contraceptive and 
or combined hormonal 
replacement therapy would 
be excluded  
Administrative updates per 
changes made to the synopsis 
 

SAP_003.pdf: 
Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
Protocol Number: 
PBI-POI-301 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Study to Evaluate the Safety and Efficacy of LB1148 in 
Accelerating the Time to Return of Bowel Function in 
Subjects Undergoing Planned Bowel Resection 
(INTEGRITY) 
Product Name or Number: 
LB1148 
Sponsor: 
 
Palisade Bio, Inc. 
5800 Armada Drive, Suite 210  
Carlsbad, CA 92008 
 
SAP Prepared by: 
 
 
Biostatistician 
Innovative Analytics, Inc. 
161 East Michigan Ave. 
Kalamazoo, MI 49007 
USA 
 
SAP Version Number (Date): 
Version 0.2 (July 14, 2022) 
Protocol Version Number (Date) 
Version 4.0 (June 10, 2022) 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
2 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................4 
2 
STUDY OVERVIEW ..........................................................................................................5 
3 
STUDY OBJECTIVES ........................................................................................................5 
3.1 
Primary Objective ............................................................................................................5 
3.2 
Secondary Objectives ......................................................................................................6 
3.3 
Exploratory Objectives ....................................................................................................6 
3.4 
Safety Objectives .............................................................................................................6 
4 
GENERAL METHODS.......................................................................................................6 
4.1 
Analysis Populations ........................................................................................................6 
4.2 
Summarization of Data ....................................................................................................7 
4.3 
Sample Size Justification and Randomization .................................................................7 
4.4 
Data Handling ..................................................................................................................8 
4.4.1 Method for Handling Missing Data .............................................................................8 
4.4.2 Definition of Baseline Values ......................................................................................8 
4.4.3 Windowing of Visits ....................................................................................................8 
4.4.4 Control for Multiplicity ................................................................................................8 
4.5 
Output Production and Validation ...................................................................................9 
5 
SUBJECT DISPOSITION ...................................................................................................9 
6 
DEMOGRAPHIC CHARACTERISTICS ...........................................................................9 
7 
MEDICAL HISTORY .........................................................................................................9 
8 
SURGICAL PLANS AND ASSESSMENTS .....................................................................9 
9 
PRIOR AND CONCOMITANT MEDICATIONS ...........................................................10 
10 
DRUG EXPOSURE...........................................................................................................10 
11 
EFFICACY ANALYSIS ...................................................................................................10 
11.1 
Primary Efficacy Endpoint ............................................................................................10 
11.1.1 Time to GI-2 ..............................................................................................................10 
11.2 
Secondary Efficacy Endpoints .......................................................................................12 
11.2.1 Time to First Bowel Movement .................................................................................12 
11.2.2 LOS – Ready, DOW, and Actual ...............................................................................14 
11.3 
Exploratory Efficacy Endpoints .....................................................................................15 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
3 
12 
SAFETY ANALYSIS ........................................................................................................16 
12.1 
Adverse Events ..............................................................................................................16 
12.2 
Laboratory Tests ............................................................................................................17 
12.3 
Physical Examinations ...................................................................................................17 
12.4 
Vital Signs ......................................................................................................................17 
13 
SUBJECT LISTINGS ........................................................................................................18 
14 
INTERIM ANALYSES .....................................................................................................18 
15 
FINAL SIGN-OFF FOR PALISADE BIO, INC PROTOCOL PBI-POI-301 
STATISTICAL ANALYSIS PLAN ..................................................................................19 
16 
REVISIONS TO STATISTICAL ANALYSIS PLAN ......................................................20 
 
 
 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
4 
1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE 
adverse event 
CMH 
Cochran-Mantel-Haenszel 
DOW 
discharge order written 
GI 
gastrointestinal 
IcE 
intercurrent events 
ICH 
International Council for Harmonization 
IP 
investigational product 
ITT 
intent-to-treat 
LB1148 
investigational product - the active ingredient, TXA, is formulated in a 
solution containing PEG, glucose, electrolytes, and water 
LOS 
length of stay 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MME 
morphine milligram equivalent 
PH 
proportional hazards 
POI 
post-operative ileus 
PP 
per protocol 
PT 
preferred term 
SAE 
serious adverse event 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
SOP 
standard operating procedure 
TAD 
time the subject is actually discharged from the hospital 
TDO 
time that the hospital discharge order is written 
Y/N 
Yes/No 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
5 
2 STUDY OVERVIEW 
This is a Phase 3, randomized, double-blind, placebo-controlled, study to evaluate the safety and 
efficacy of LB1148 in subjects undergoing planned bowel resection. Subjects scheduled for 
planned bowel resection, aged 18 to 80 years inclusive, will be screened within 42 days of 
randomization. Subjects who meet all inclusion and no exclusion criteria, and provide written 
informed consent, will be stratified by 1) surgical approach (minimally invasive or laparotomy) 
and 2) with or without a planned stoma. Subjects will then be randomized to receive LB1148 or 
placebo in a 1:1 ratio. 
All subjects will receive 700 mL of Investigational Product (IP) as split, oral doses of 350 mL 
beginning the evening prior to surgery (Day 1), the first at 6-10 hours and the second 2-6 hours 
prior to surgery. Subjects will then undergo surgery (Study Day 2). 
Subjects will be assessed for safety and tolerability, including adverse events (AEs) and vital signs 
from time of dosing on Study Day 1 through discharge or Study Day 16, whichever is sooner. 
Subjects will be monitored for return of bowel function following surgery, from Study Day 3 
through discharge or Study Day 16, whichever is sooner. Subjects will have clinical lab tests 
(chemistry, coagulation, and hematology) on Study Day 3. Subjects will be monitored for serious 
AEs (SAEs) through Study Day 30. Subjects will be monitored for hospital readmission and post-
operative ileus (POI) through Study Day 90. 
The study will evaluate return of gastrointestinal (GI) function, as provided in the primary 
objective (Section 3.1), in order to determine the overall study drug effect. Additionally, an 
evaluation of the secondary (Section 3.2) and exploratory objectives (Section 3.3) related to return 
of GI function, length of stay (LOS), POI, and opiate use will be performed. 
The Schedule of Assessments is provided in Appendix 1 of the protocol.  
This study is to be conducted at up to approximately 30-60 sites in the United States, with planned 
enrollment of 650 subjects. Unless required for safety reasons or protocol compliance, Sponsor 
personnel, all subjects, Investigators, Pharmacists, and persons performing assessments, will 
remain blinded to the identity of the treatment from time of randomization until final database 
lock. 
An independent data monitoring committee (DMC) will be commissioned for this study. The DMC 
will be comprised of 3 physicians with expertise in therapeutic areas pertinent to this protocol; all 
will have clinical trial experience. The DMC safety monitoring plan will be detailed in the DMC 
Charter. 
3 STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective is to compare the time to GI-2, defined as the time from the end of surgery 
to the time of recovery of the upper GI tract (toleration of solid food) and the lower GI tract (first 
bowel movement) following surgery, whichever occurs last, among subjects treated with LB1148 
or placebo.   


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3.2 Secondary Objectives 
The secondary objectives of this study are to compare the following among subjects treated with 
LB1148 or placebo: 
• Time to first bowel movement 
• LOS Ready, defined as the time from the end of surgery to the time subject is ready for 
hospital discharge solely based on the recovery of GI function, as determined by the 
surgeon 
• LOS Discharge Order Written (DOW) defined as the time from the end of surgery to the 
time that the hospital discharge order is written (TDO) 
• LOS Actual - defined as the time from the end of surgery to the time the subject is actually 
discharged from the hospital (TAD) 
3.3 Exploratory Objectives 
The exploratory objectives of this study are to compare the following among subjects treated with 
LB1148 or placebo: 
• Time to GI-3, defined as the time from the end of surgery to the time as the of toleration 
of solid food and either first flatus or bowel movement, whichever occurs last  
• Incidence of the following events at Day 90: 
o Hospital readmission 
o POI 
• Opiate use by morphine milligram equivalent (MME) 
3.4 Safety Objectives 
Evaluate the incidence, severity and potential causal association of treatment emergent AEs 
following exposure to LB1148. 
4 GENERAL METHODS 
4.1 Analysis Populations 
Intent-to-Treat Population (ITT): The ITT population includes all randomized subjects.  
modified Intent-to-Treat Population (mITT): The mITT population includes all randomized 
subjects who receive any amount of IP and have the scheduled surgery. Subjects will be analyzed 
according to the treatment to which they were randomized to receive. It should be noted that 
although this analysis population definition technically modifies the strict definition of ITT (i.e., 
all randomized subjects without any other conditions), this analysis population as defined is still 
consistent with the ITT principle given the context of this clinical trial, The surgery must occur for 


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the efficacy endpoints to be measured and meaningful. All analyses corresponding to the primary 
endpoint and all secondary endpoints will be formally assessed using the mITT population. 
Safety Population: Ideally, the safety population will be defined as all randomized subjects who 
receive any amount of IP. If a subject were to receive IP without being randomized, then they 
would be included in the Safety population also. Subjects will be analyzed according to the 
treatment actually received. 
Per Protocol Population (PP): The PP population consists of those subjects in the mITT  
population who meet all inclusion and no exclusion criteria, complete full IP dose, and have no  
important protocol deviations (as defined in Section 9.10 of the Study Protocol). All analyses 
corresponding to the primary endpoint and all secondary endpoints will be additionally assessed 
using the PP population for sensitivity analysis purposes. 
4.2 Summarization of Data 
Study results will be summarized in tabular format by treatment group, with descriptive statistics 
and/or in subject listings. In general, descriptive statistics for continuous variables will consist of 
subject count (n), mean (or geometric mean), standard deviation (SD), standard error of the mean 
(SEM), minimum, first quartile, median, third quartile and maximum. Descriptive statistics for 
categorical variables will consist of subject counts and percentages. 
All available safety and efficacy data will be included in data listings.  
The efficacy analyses described in this Statistical Analysis Plan will be performed for the ITT (all 
efficacy endpoints) and PP populations (primary and secondary efficacy endpoints), while the 
safety analyses will be performed for the safety population. All statistical tests will be 2-sided with 
an alpha of 0.05. 
4.3 Sample Size Justification and Randomization  
A total sample size of 600 subjects, randomized in a 1:1 ratio, provides 90% power to detect a 
difference in median time to GI-2 between groups of 22 hours, assuming a median time to return 
of bowel function of 70 hours in the LB1148 group and 92 hours in the placebo group, using a 2-
sided log-rank test with a significance level of 0.05. 
The table below displays the results of sample size calculations for the differences between 
treatment groups in median times to return of bowel function ranging from 25 to 18 hours; all for 
a 2-sided 0.05 significance level and the log-rank test: 
Assumed MTTRBF (hrs) 
 
Diff (hrs) 
 
   HR 
Required n per group 
Placebo 
LB1148 
80% power 
90% power 
92 
67 
25 
1.373 
167 
223 
92 
68 
24 
1.353 
183 
245 
92 
69 
23 
1.333 
202 
271 
92 
70 
22 
1.314 
224 
300 
92 
71 
21 
1.296 
250 
334 
92 
72 
20 
1.278 
279 
373 
92 
73 
19 
1.260 
313 
419 


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92 
74 
18 
1.243 
354 
474 
MTTRBF = median time to return of bowel function 
HR = hazard ratio = MTTRBF (Placebo) / MTTRBF (LB1148) (assuming exponential survival curves for 
both treatment groups) 
For randomization purposes, subjects will be stratified by 1) surgery type (laparotomy versus 
minimally invasive approaches) and 2) planned stoma (Yes/No) (Y/N)). 
4.4 Data Handling 
4.4.1 Method for Handling Missing Data 
No imputation of missing data will be performed except for selected times when dates are present, 
but times are not. The times to impute are tabled below. 
Time 
Condition 
Imputation 
Time of final staple or suture 
Date Present/Time absent 
1. Time Surgery 
began 
2. 12:00 am 
Time of first bowel movement 
Date Present/Time absent 
11:59 pm 
Time first toleration of solid food 
Date Present/Time absent 
11:59 pm 
Time subject is ready for hospital discharge solely 
based on the recovery of GI function, as 
determined by the surgeon 
Date Present/Time absent 
1. TDO 
2. TAD 
3. 11:59 pm 
TDO 
Date Present/Time absent 
1. TAD 
2. 11:59 pm 
TAD 
Date Present/Time absent 
11:59 pm 
Time of first flatus 
Date Present/Time absent 
11:59 pm 
Listings will not be imputed. 
4.4.2 Definition of Baseline Values 
Unless otherwise specified, Baseline values for vital signs, physical examinations, and 
concomitant medications are defined as the last values collected before the first dose of IP. Unless 
specified otherwise, the efficacy endpoints begin at the end of surgery.    
4.4.3 Windowing of Visits 
All data will be categorized based on the scheduled visit at which it was collected. These visit 
designators are pre-defined values indicated in the Schedule of Assessments (Appendix 1 of the 
protocol). 
4.4.4 Control for Multiplicity 
Multiplicity will be controlled through a combination of gate keeping and the Hochberg 
procedure (Multiple Endpoints in Clinical Trials Guidance for Industry, Draft Guidance 2017). 
The primary endpoint will be evaluated at a significance level of 0.05, if there is significance 
then the secondary endpoints will be evaluated, otherwise all secondary endpoints will be 
considered exploratory (Wiens 2003). 


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If the primary endpoint is significant at 0.05, the four secondary endpoints will be considered 
using the Hochberg procedure. The p-values for each secondary endpoint will be computed and 
then ordered from largest to smallest (Hochberg 1988). These ordered p-values will then be 
compared to the α critical values 0.05, 0.025, 0.0167, and 0.0125, respectively. If the first p-
value does not show significance, then the next largest p-value is compared to the next largest 
critical value. Testing continues until a p-value for an endpoint is statistically significant when 
compared to its respective critical value. Once an ordered p-value is significant, that endpoint 
and all endpoints with p-values smaller than that endpoint are considered to have a statistically 
significant treatment effect. 
4.5 Output Production and Validation 
All analyses will be performed using SAS V 9.3 or higher (SAS Institute, Inc, Cary, North 
Carolina, USA). Validation and quality control of the tables, listings, and figures which display 
the results of the statistical analysis of the data from this study, will follow the appropriate 
Innovative Analytics standard operating procedures (SOPs). 
5 SUBJECT DISPOSITION  
The number of subjects who are randomized, treated, complete the study, and reasons for 
discontinuation from the study will be summarized in tabular format for the safety population. 
Subject disposition will also be displayed for the safety population in a subject listing. 
6 DEMOGRAPHIC CHARACTERISTICS 
Demographics, baseline, and surgical characteristics will be summarized by treatment group and 
consist of (but are not limited to) the following: age, height, weight, sex, ethnicity/race, GI history, 
reason for surgery, surgical approach, duration of surgery, stoma or no stoma.  
Quantitative variables will be summarized by summary statistics (n, mean, SD, minimum, median, 
and maximum). Qualitative variables will be summarized as counts and percentages.  
Demographics, baseline, and surgical characteristics will be summarized for both the safety 
population and ITT population. 
7 MEDICAL HISTORY  
All medical history (past and current medical disorders), including GI history, will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) version currently in use at the start 
of the study. Medical history will be summarized by MedDRA System Organ Class (SOC) and 
Preferred Term (PT), and results presented by treatment group for the safety population. All 
medical history events will be displayed for the safety population in a subject listing. 
8 SURGICAL PLANS AND ASSESSMENTS 
Frequency tables will be presented by treatment group for initial surgical plan information and 
surgery assessments. All surgery information will be listed for the safety population. 


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9 PRIOR AND CONCOMITANT MEDICATIONS 
All medications will be coded using the World Health Organization Drug Dictionary (WHODrug) 
version currently in use at the start of the study. Frequency tables will be presented by treatment 
group for prior and concomitant medications taken during the study.  
• Prior medications are defined as those taken with a start date prior to the first dose of study 
medication. 
• Concomitant medications are defined as those with a start date on or after the first dose of 
study medication, or those with a start date before the first dose of study medication and a 
stop date on or after the first dose of study medication (including those medications which 
are classified as ongoing). 
All prior and concomitant medications will be listed for the safety population. 
10 DRUG EXPOSURE 
The number and percent of subjects who consumed all or part of their IP will be summarized by 
treatment group for the ITT population. All findings will be displayed in subject listings. 
11 EFFICACY ANALYSIS 
11.1 Primary Efficacy Endpoint 
11.1.1 Time to GI-2 
The primary endpoint is the time to GI-2, defined as the time from the end of surgery to the time 
of recovery of the upper GI tract (toleration of solid food) and the lower GI tract (first bowel 
movement) following surgery, whichever occurs later up to 14 days post-surgery (Study Day 
16).  
• End of surgery is defined as the time the last skin staple or suture was placed by the 
surgeon. 
• Toleration of solid food is defined as a subject finished a meal that required chewing and 
experienced no significant nausea/vomiting for 4 hours after the solid meal. 
o Nausea and vomiting must be severe enough to completely interfere with the 
subject’s ability to tolerate food.  This does not include expected post-surgical 
nausea that does not interfere with solid meal ingestion. 
 Analysis Methods 
Time to GI-2 will be presented using descriptive statistics by treatment group. Non-parametric 
Kaplan-Meier survival curves will be produced for the two treatment groups and compared 
between treatment groups using a log-rank test adjusted with the following stratification factors: 
• Type of surgery (laparotomy versus minimally invasive approaches), and  


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• Stoma construction (Y/N) 
In addition to the non-parametric survival curves, a semi-parametric, stratified Cox proportional 
hazards (PH) model will be performed for sensitivity analysis purposes, with treatment as the main 
effect, and surgery type (laparotomy versus minimally invasive) and stoma construction (Y/N) as 
strata. Comparison of treatment groups and assessment of the significance of the parameter 
estimates for surgery type and stoma will be made using the Wald chi-square test. Interactions 
between treatment and the stratification factors will considered as part of the model building 
process. In order to further investigate the sensitivity of the analysis, a second run of the stratified 
Cox PH model will add the additional strata “Any opiates” taken after surgery (Y/N). 
Ties will be accounted for in the analyses above by selecting the Fleming -Harrington (FH) option 
in leu of the default Kaplan Meir estimates. If there are no ties FH estimates are equivalent to 
Breslow estimates. Likewise, Breslow estimates will be selected for the Cox PH model.  
All results will be summarized and listed by treatment group for the ITT and PP populations. 
 Estimand and Associated Intercurrent Events (IcE) 
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E9(R1) guidance [E9-R1_Step4_Guideline_2019_1203.pdf (ich.org)] defines 
IcE as “Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest.” The clinical 
question of interest addressed here is the estimand associated with the primary endpoint, i.e., the 
difference in the time to return of normal GI function, as measured by GI-2 (as defined above), 
between subjects receiving LB1148 and subjects receiving placebo for the treatment of return of 
bowel function after GI surgery. As described above, this difference will be measured by 
Kaplan-Meier (log rank test) and its sensitivity ascertained with two Cox PH models (Wald chi 
square). The timeframe of reference is Study Day 2 through discharge or 14 days after surgery 
(Study Day 16), whichever is earlier. 
The IcEs that may affect the interpretation or the occurrence of this estimand are tabulated below 
in Table 1, along with the related censoring rules for each analysis. 
Table 1 
IcE for Time to GI-2 
 
Primary Analysis Approach 
(Kaplan-Meier1 and Cox 
Models2) 
Supplemental Analyses  
(Kaplan-Meier1 Model Only)  
Intercurrent 
Event 
First Run of 
Model 
Second Run of 
Model 
First Run of 
Model 
Second Run of 
Model 
No GI-2 but death 
report 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the 
date of death 
*Descending Event 
Dates (Controls) 
No GI-2 and the 
subject is lost to 
follow-up or 
withdrew 
informed consent 
Censoring at 
Study Day 16  
Censoring at 
Study Day 16  
Censoring at the 
date consent 
withdrawn 
*Descending Event 
Dates (Controls) 


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Primary Analysis Approach 
(Kaplan-Meier1 and Cox 
Models2) 
Supplemental Analyses  
(Kaplan-Meier1 Model Only)  
No GI-2 within 14 
days after surgery 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
*Descending Event 
Dates (Controls) 
Opiate use 
Not applicable 
Add strata “any 
opiates” (Y/N) 
to the Cox PH 
model 
Not applicable 
Not applicable 
1Kaplan-Meier with log rank test  
2Cox PH model with Wald chi square 
*Descending Event Dates: All missing values for subjects on placebo due to IcE tabled above 
should be replaced with day of event as date corresponding to Study Day 15 and compute the log 
rank and Wald Chi square tests as above, then replace with the date corresponding to Study Day 
14 unless Study Day 15 was the actual date of the event and hence should be left as Study Day 15 
and then compute the log rank and Wald Chi square tests. Likewise for Study Day 12. Treatment 
subjects with missing data will be censored using the Primary Analysis Approach at Study Day 
16. 
Descending event dates for the controls with missing intercurrent event data will document what 
would happen if the missing data in the treatment group subjects had worse outcomes to that of 
the missing data in the control group. The treatment group data is censored at Day 16 while the 
censoring dates for the control group subjects are systematically decreased (Study Day 15, Study 
Day 14, and Study Day 12). 
 Tabulation of Patterns of Missing Data 
To visualize any patterns present in the missing data, the following table will be constructed: The 
number of subjects with no GI-2 data due to death, lost to follow-up or withdrew, or not achieved 
within 14 days will be cross tabulated by treatment (LB1148 or placebo) within the four cells 
making up the randomization strata, e.g., type of surgery (laparotomy versus minimally invasive 
approaches) crossed with stoma construction (Y, N). 
 Partial Dates and Times 
All components of the primary endpoint, time to GI-2, are collected while the subject is in the 
hospital, so the dates should be available. See Section 4.4.1 for times which may be imputed. 
11.2 Secondary Efficacy Endpoints 
11.2.1 Time to First Bowel Movement 
The secondary endpoint, time to first bowel movement, is defined as the time in hours from 
placement of the last skin staple or suture to the time of first bowel movement. 


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 Analysis Methods 
Time to first bowel movement will be analyzed using time to event methods described above for 
the primary endpoint, time to GI-2. Time to first bowel movement will be presented in summary 
tables with descriptive statistics for the ITT and PP populations. 
 Estimand and Associated IcE 
The clinical question of interest here is the estimand associated with this secondary endpoint, i.e., 
the difference in the time of first bowel movement, (as defined above), between patients 
receiving LB1148 and patients receiving placebo for the treatment of return of bowel function 
after GI surgery. As described above, this difference will be measured by Kaplan-Meier analysis 
(which includes a log rank test) and its sensitivity ascertained with two Cox PH models (Wald 
chi square). The timeframe of reference is Study Day 2 through discharge or 14 days after 
surgery (Study Day 16), whichever is earlier. 
The IcEs that may affect the interpretation or the occurrence of this estimand are tabulated below 
in Table 2, along with the related censoring rules for each analysis. 
Table 2 
IcE for Time to First Bowel Movement 
Intercurrent Event 
Primary Analysis Approach 
(Kaplan-Meier1 and Cox Models2) 
Supplemental Analysis  
(Kaplan-Meier1) Model 
Only) 
First Run of Cox 
Model 
Second Run of 
Cox Model 
 
No bowel movement 
but death report 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the date of death 
No bowel movement 
and the subject is lost 
to follow-up or 
withdrew informed 
consent 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the date consent 
withdrawn 
No bowel movement 
within 14 days after 
surgery 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at Study Day 16 
Opiate use 
Not applicable 
Add strata “any 
opiates” (Y/N) to 
the Cox PH 
model 
Not applicable 
1Kaplan-Meier with log rank test  
2Cox PH model with Wald chi square 
*The second Cox PH model adding “Any opiates” use will be performed only if the strata are significant 
for the primary endpoint analyses 
 Tabulation of Patterns of Missing Data 
To visualize any patterns, present in the missing data the following table will be constructed: The 
number of subjects with no bowel movement due to death, lost to follow-up or withdrew, or not 
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four cells making up the randomization strata, e.g., type of surgery (laparotomy versus minimally 
invasive approaches) crossed with stoma construction (Y/N). 
 Partial Dates and Times 
All components of the secondary endpoint, time to first bowel movement, are collected while the 
subject is in the hospital, so the dates should be available. See Section 4.4.1 for times which may be 
imputed. 
11.2.2 LOS – Ready, DOW, and Actual 
 Analysis Methods 
LOS will be analyzed using time to event methods described above for the primary endpoint, 
time to GI-2. The second Cox PH model adding “Any opiates” use will be performed only if the 
strata was significant for the primary endpoint analyses. LOS Ready, DOW, and Actual will be 
presented in summary tables with descriptive statistics for the ITT and PP populations. 
 Estimand and Associated IcE 
The clinical questions of interest here are the estimands associated with these secondary 
endpoints, i.e., the difference in the time to: 
- 
when the subject is ready for discharge, 
- 
when the discharge order is written, and 
- 
actual discharge, 
between patients receiving LB1148 and patients receiving placebo for the treatment of return of 
bowel function after GI surgery.  
As described above, this difference will be measured by Kaplan-Meier (log rank test) and its 
sensitivity ascertained with at least one Cox PH models (Wald chi square). The timeframe of 
reference is Study Day 2 through discharge or 14 days after surgery (Study Day 16), whichever 
is earlier. 
The IcEs that may affect the interpretation or the occurrence of these estimands are tabulated 
below in Table 3, along with the related censoring rules for each analysis. 
Table 3 
IcE for LOS 
Intercurrent Event 
Primary Analysis Approach  
(Kaplan-Meier1 and Cox Models2) 
Supplemental Analyses  
(Kaplan-Meier1` Model 
Only) 
First Run of 
Cox Model 
Second Run of 
Cox Model* 
 
Failure to meet 
discharge criteria 
(Ready, DOW, 
Actual) but have a 
death report 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at the date of death 


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Intercurrent Event 
Primary Analysis Approach  
(Kaplan-Meier1 and Cox Models2) 
Supplemental Analyses  
(Kaplan-Meier1` Model 
Only) 
First Run of 
Cox Model 
Second Run of 
Cox Model* 
 
Failure to meet 
discharge criteria 
(Ready, DOW, 
Actual) and the 
subject is lost to 
follow-up or 
withdrew informed 
consent 
Censoring Study 
Day 16 
Censoring at 
Study Day 16 
Censoring at the date consent 
withdrawn 
Failure to meet 
discharge criteria 
(Ready, DOW, 
Actual) within 14 
days after surgery 
Censoring at 
Study Day 16 
Censoring at 
Study Day 16 
Censoring at Study Day 16 
Opiate use 
Not applicable 
Add strata “any 
opiates” (Y/N) to 
the Cox PH 
model 
Not applicable 
1Kaplan-Meier with log rank test  
2Cox PH model with Wald chi square 
*The second Cox PH model adding “Any opiates” use will be performed only if the strata are 
significant for the primary endpoint analyses. 
 Tabulation of Patterns of Missing Data 
To visualize any patterns, present in the missing data the following table will be constructed: The 
number of subjects with failure to meet discharge criteria (Ready, DOW, Actual) data due to 
death, lost to follow-up or withdrew, or not achieved within 14 days will be cross tabulated by 
treatment (LB1148 or placebo) within the four cells making up the randomization strata, e.g., 
type of surgery (laparotomy versus minimally invasive approaches) crossed with stoma 
construction (Y, N). 
 Partial Dates and Times 
All components of the secondary endpoint(s), failure to meet discharge criteria (Ready, DOW, 
Actual), are collected while the subject is in the hospital, so the dates should be available. See 
Section 4.4.1 for times which may be imputed. 
11.3 Exploratory Efficacy Endpoints 
Exploratory endpoints and their analysis methods are described below. All analyses will use the 
ITT population, and no statistical testing will be formal in nature. 
• Time to GI-3, defined as the time from the end of surgery to the time of toleration of solid 
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surgery (Study Day 16).  Time to GI-3 will be analyzed using time to event methods 
described above for the primary endpoint, time to GI-2. If a date is present but a time is 
absent, time may be imputed as described in Section 4.4.1. 
• Proportion of subjects not readmitted to the hospital following initial discharge by Study 
Day 90 will be analyzed using counts and percentages with comparisons made using the 
Cochran-Mantel-Haenszel (CMH) chi-square test, which allows for the inclusion of the 
stratification factors type of surgery (laparotomy versus minimally invasive approaches) 
crossed with stoma construction (Y, N). 
• Proportion of subjects without POI will be analyzed using counts and percentages with 
comparisons made using the CMH chi-square test, which allows for the inclusion of the 
stratification factors type of surgery (laparotomy versus minimally invasive approaches) 
crossed with stoma construction (Y, N). The following definitions of POI will be used: 
- 
During the planned hospitalization, POI is defined as the inability to tolerate liquid or 
solids greater than expected post-operative period, confirmed by imaging studies. 
Resolution of POI is defined as having resolved when all of the following criteria are 
met:  
o Absence of vomiting for 12 hours without a nasogastric (NG)/orogastric (OG) tube  
o Ability to tolerate a solid or liquid oral diet 
o Passage of flatus OR stool over the preceding 24 hours. 
- 
Following initial discharge, POI is defined as having clinical symptoms (e.g., 
abdominal cramps, bloating, nausea, vomiting, constipation, difficulty passing gas, and 
difficulty tolerating a normal diet) and ileus confirmed by imaging studies. 
• Total opiate use by aggregate MME from the end of surgery until Actual discharge or Day 
16, whichever is earlier. Opiate use will be summarized by treatment group using summary 
statistics (n, mean, SD, SEM, minimum, first quartile, median, third quartile, and 
maximum). Comparisons will be made using the Wilcoxon rank sum test. 
All results will be listed for the ITT population. 
12 SAFETY ANALYSIS 
12.1 Adverse Events 
All AEs will be coded using the MedDRA coding system. Frequency tables will be presented by 
treatment group for all AEs by SOC and PT for the safety population. Frequency tables will also 
be presented for AEs leading to discontinuation of IP and study, AEs by maximum severity, AEs 
by causality, and serious AEs. Subject listings of all AEs will also be provided for the safety 
population. 
In all displays, AEs will be displayed by MedDRA SOC and PT. Subjects who have the same AE 
occur more than once will be counted only once for that event. Subjects who have more than one 
AE within a SOC will be counted only once in that SOC. No formal statistical testing will be done. 


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12.2 Laboratory Tests 
Safety labs are performed at Screening and on post-operative Day 3. For hematology, chemistry, 
and coagulation, summary statistics (n, mean, SD, SEM, minimum, median, and maximum) will 
be presented for the observed values at each time point for the safety population. Summary 
statistics will also be presented for the change from baseline values to each post-baseline time 
point. In these displays, baseline will be defined as the last values obtained prior to the first dose. 
Laboratory abnormalities will be analyzed as safety outcomes by summarizing frequency, severity, 
and changes from baseline. 
Pregnancy tests are performed at Screening and before surgery. 
For all tests, including pregnancy tests, results will be displayed in subject listings for the safety 
population. Laboratory reference ranges will be provided by the laboratory site and will be 
included in an appendix of the clinical study report. 
12.3 Physical Examinations 
Complete physical examinations are performed at Screening, and targeted physical exams are 
performed at Day 2, then daily through post-operative Day 16 (or for as long as the patient remains 
hospitalized), including at hospital discharge. Complete physical examinations include 
examination of the following systems: cardiovascular, dermatological, ear, nose, and throat, 
extremities, GI, musculoskeletal. ophthalmological, neurological, and respiratory. Targeted 
physical examinations are brief, focused examinations of the subject following medical history 
and include an assessment of lower extremities for possible venous thromboembolism and an 
assessment for AEs. 
Height and weight are measured at the Screening visit only. 
Any physical exam abnormality deemed clinically significant by the Investigator at Study Day 1 
will be reported as medical history. Any new physical exam abnormality deemed clinically 
significant by the Investigator during the study will be reported as an AE. 
All findings will be displayed in subject listings for the safety population. 
12.4 Vital Signs 
Vital signs will be collected at Screening, Day 2, then daily through post-operative Day 16 (or for 
as long as the patient remains hospitalized), including at hospital discharge. Summary statistics (n, 
mean, SD, SEM, minimum, median, and maximum) will be presented for the observed values at 
each time point for systolic and diastolic blood pressure, heart rate, respiratory rate and temperature 
at each time point for the safety population. Summary statistics will also be presented for the 
change from baseline values to each post-baseline time point. In these displays, baseline will be 
defined as the last value obtained prior to the first dose. 
All vital signs results will be displayed in subject listings for the safety population. 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
18 
13 SUBJECT LISTINGS  
All data that are collected and entered into the study database will be presented in subject listings.   
14 INTERIM ANALYSES 
No interim analysis is planned. 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
19 
15 FINAL SIGN-OFF FOR PALISADE BIO, INC PROTOCOL PBI-POI-
301 STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Biostatistician 
Innovative Analytics 
 
Date 
 
 
 
 
 
 
 
 
 
Chief Medical Officer 
Palisade Bio, Inc.  
 
Date 
 
 
 
 


Statistical Analysis Plan 
Version 0.2 
Palisade Bio, Inc. PBI-POI-301 
July 14, 2022 
 
CONFIDENTIAL 
 
 
 
20 
16 REVISIONS TO STATISTICAL ANALYSIS PLAN 
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