Clinical trial NCT02836470
Conditions: Ileus Post-Operative Adhesions
Keywords: Post-operative Ileus Post-Operative Abdominal Adhesions Return of Gastrointestinal Function Anastomosis Enterotomy Enterostomy Colorectal Surgery Intestines Surgery
Sponsor: Palisade Bio
Start date: 2019-10-01; Completion date: 2023-09-08
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to establish preliminary evidence of the efficacy, safety, and tolerability of LB1148 for the treatment of post-operative ileus and intra-abdominal adhesions in subjects undergoing elective bowel resection.

Detailed description:
This will be a multicenter, randomized, double-blind, parallel, placebo-controlled, proof-of-concept, adaptive design, Phase 2 study to evaluate LB1148 for return of gastrointestinal function and reduction of post-operative ileus and intra-abdominal adhesions in subjects undergoing elective bowel resection surgery with or without a planned stoma.

Arms: arm 1: Active arm 2: Placebo
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 documents:
Prot_002.pdf: 
Clinical Study Protocol: LBS-POI-201 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Proof of Concept 
Study to Evaluate LB1148 for Return of Gastrointestinal Function, Post-
Operative Ileus and Intra-Abdominal Adhesions in Subjects Undergoing 
Elective Bowel Resection (PROFILE) 
Study Number: 
LBS-POI-201 
Study Phase: 
2 
Product Name: 
LB1148 
Indication: 
Post-Operative Ileus and Adhesions 
Investigators: 
Multicenter across the United States 
Sponsor: 
Palisade Bio, Inc. 
7750 El Camino Real, Suite 5200 
Carlsbad, CA 92009 
Medical Monitor: 
 
 
 
 
 
Date 
Original Protocol: 
11 July 2016 
Amendment #1: 
17 August 2016 
Amendment #2: 
18 August 2016 
Amendment #3: 
13 June 2019 
Amendment #4: 
17 June 2021 
Amendment #5: 
24 August 2021 
Amendment #6: 
26 August 2022 
 
 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for the use of 
Investigators and Palisade Bio, Inc. or its designees.  It is the property of Palisade Bio, Inc. 
and should not be copied by or distributed to persons not involved in the clinical 
investigation of LB1148 unless such persons are bound by a confidentiality agreement with 
Palisade Bio, Inc.  
 


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SPONSOR SIGNATURE 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Proof of Concept 
Study to Evaluate LB1148 for Return of Gastrointestinal Function, Post-
Operative Ileus and Intra-Abdominal Adhesions in Subjects Undergoing 
Elective Bowel Resection (PROFILE) 
Study Number: 
LBS-POI-201 
Version Date: 
26 August 2022 
 
 
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: 
 
Name: 
 
 
 
Title: VP, Clinical Operations 
 
 
Signature:  
 
Date:  
 
 
Name: 
 
 
 
Title: Chief Medical Officer 
 
 
Signature:  
 
Date:  
 
 
 
 


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INVESTIGATOR’S SIGNATURE 
 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Proof of Concept 
Study to Evaluate LB1148 for Return of Gastrointestinal Function, Post-
Operative Ileus and Intra-Abdominal Adhesions in Subjects Undergoing 
Elective Bowel Resection (PROFILE) 
Study Number: 
LBS-POI-201 
Version Date: 
26 August 2022 
 
I have read the LBS-POI-201 protocol and agree to conduct the study as outlined.   
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.   
I agree to conduct the study in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, are consistent with the Good Clinical Practices guidelines of the 
International Conference on Harmonization, and according to applicable regulatory 
requirements.  
 
Principal Investigator: 
                            
(Print Name/Title) 
 
 
Signature of Principal Investigator:  
 
 
 
 
 
Date: 
 
 
Affiliation/Company:  
 
 
 
 
 
 
 
 
 


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SYNOPSIS 
Study Title:  A Randomized, Double-Blind, Placebo-Controlled Proof of Concept Study to 
Evaluate LB1148 for Return of Gastrointestinal Function, Post-Operative Ileus and Intra-
Abdominal Adhesions in Subjects Undergoing Elective Bowel Resection (PROFILE) 
Name of Finished Product:   
LB1148  
Name of Active Ingredient: 
Tranexamic acid (TXA) 7.5 g 
Study Number:  LBS-POI-201 
Study Phase: 2 
Clinical Sites: 
Approximately 15 sites in the United States  
Study Rationale:  
The purpose of this study is to establish preliminary evidence of the efficacy, safety, and 
tolerability of LB1148 for the treatment of post-operative ileus and intra-abdominal adhesions 
in subjects undergoing elective bowel resection. 
Primary Objective:  
To compare the change from baseline in extent and severity of intra-abdominal adhesions 
among subjects treated with LB1148 or placebo. 
Secondary Objectives: 
The secondary objectives of this study are to determine the following among subjects treated 
with LB1148 or placebo: 
• Compare time from surgical closure to resolution or appearance, as appropriate, of 1 or 
more of the components common to gastrointestinal (GI) dysfunction following elective 
bowel resection with a planned stoma. 
• Compare number of hours to GI2. 
• Compare number of hours to GI3. 
• Compare number of hours to resolution of POI.   
• Compare hospital length of stay (LOS, recorded in hours) through Discharge or Day 14 
(whichever comes first).   
• Compare the incidence of intra-abdominal adhesions following the second surgery among 
subjects treated with LB1148 or placebo. 
• Compare the extent and severity of intra-abdominal adhesions following the second 
surgery among subjects treated with LB1148 or placebo. 
• Compare change from baseline in incidence, extent, and severity of intra-abdominal 
adhesions among subjects treated with LB1148 or placebo who had adhesions observed at 
the time of the first surgery. 
• Assess the safety and tolerability of LB1148 in subjects undergoing elective bowel 
resection.  
 
 


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Exploratory Objectives:   
The exploratory objectives of this study are to determine if LB1148 reduces the: 
• Post-operative abdominal pain. 
• Incidence of bowel obstruction through 30 days post-operatively. 
• Incidence of hospital re-admittance through 30 days post-operatively. 
• Volume of blood product transfusions on the day of surgery. 
Study Design: 
This 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.   
Subjects scheduled for elective bowel resection, aged 18 to 80 years inclusive, will be 
screened within 42 days of randomization (Study Day -1).  Subjects who meet all inclusion 
and no exclusion criteria, and provide written informed consent, will be stratified by: 1) 
surgical approach (either minimally invasive technique or laparotomy) and 2) with or without 
a planned stoma, and then randomized to receive a split oral liquid dose of LB1148 or placebo 
(polyethylene glycol [PEG], glucose, and electrolytes) in a in a 1:1 ratio. 
All subjects will receive 350 mL of study drug 6-10 and 2-6 hours prior to surgery (Study Day 
1/2).  Subjects will then undergo the first surgery.  At the time of surgical closure, the 
investigator will determine the incidence, extent, and severity of adhesions using the Intra-
Abdominal Adhesion Extent and Severity Assessment Worksheet (Appendix 5). 
Subjects will be assessed for safety and tolerability, including AEs, physical exam, vital signs, 
clinical lab tests (chemistry, coagulation, and hematology) while in the hospital and on Day 
30.  Subjects will be monitored for return of bowel function while in the hospital and 
discharged following tolerance of solid food and first bowel movement. 
Within 8 months of enrollment, subjects will undergo a second surgery for the purpose of 
ostomy takedown or other planned abdominal surgery, at which time the surgeon will 
determine the incidence, extent, and severity of adhesions. If a subject is not ready for the 
second surgery by 8 months, the investigator may consult with Medical Monitor to obtain 
window approval. 
Unless required for safety reasons or protocol compliance, all subjects, Investigators, and 
study site personnel will remain blinded to the identity of the treatment from time of 
randomization until final database lock.   
Study Population:  
Inclusion Criteria: 
Subjects will be eligible for participation in the study only if they meet ALL of the following 
inclusion criteria:  


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1. Scheduled to undergo an elective (non-emergent) bowel resection with a planned stoma via 
laparotomy or minimally invasive technique.  This includes any subject in which a 
resection of the small intestine, colon, or rectum is performed for any elected indication.  
2. Planned stoma takedown or other planned abdominal surgery within 8 months of the initial 
surgery. 
3. Willing to perform and comply with all study procedures including attending clinic visit as 
scheduled and completion of a second surgery for stoma takedown or other abdominal 
surgery and to determine the presence of intra-abdominal adhesions. 
4. Has been informed of the nature of the study (either the subject or their legal 
representative), agrees to its provisions, and has provided written informed consent.  
Exclusion Criteria: 
Subjects will not be eligible for participation in the study if they meet ANY of the following 
exclusion criteria: 
1. <18 or >80 years of age. 
2. Requires emergency bowel surgery. 
3. Has had 1 or more abdominal surgeries, excluding the current, for inflammatory bowel 
disease, including, but not limited to, inflammatory bowel disease (IBD), Crohn’s Disease, 
or ulcerative colitis.   
Note: This does not apply to previous surgery such as hernia repair unrelated to IBD. 
4. American Society of Anesthesiologists (ASA) Class 4 or 5.  
5. Known inability to take the study drug orally (i.e. complete small bowel obstruction). 
6. Has contraindications or potential risk factors to taking TXA.  These include subjects with: 
a. Known sensitivity to TXA 
b. Recent craniotomy (past 30 days) 
c. Active cerebrovascular bleed 
d. Active thromboembolic disease (such as deep vein thrombosis, pulmonary embolism, 
cerebral thrombosis, ischemic stroke, or acute coronary syndrome) 
e. Acute promyelocytic leukemia taking all-trans retinoic acid for remission induction, or 
f. Continuing use of a combined hormonal contraceptive and or combined hormonal 
replacement therapy (including combined hormonal pill, patch, or vaginal ring) 
7. Has peritoneal carcinomatosis. 
8. History of or current seizure disorder.  
9. Patients with myeloproliferative disorders. 
10. Any other condition that, in the opinion of the Investigator, would preclude the subject 
from being an appropriate candidate for the study, including severe renal or hepatic 
impairment. 


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11. Planned treatment with alvimopan (Entereg®) during study participation period. 
12. Planned use of 4% icodextrin (Adept®) or SEPRAFILM during the first surgery. 
13. Received any other investigational therapy within 4 weeks prior to Randomization 
14. Female subjects of childbearing potential with a positive urine or serum pregnancy test or 
who are not taking (or not willing to take) acceptable birth control measures (abstinence, 
intrauterine devices, contraceptive implants or barrier methods) through Day 30.  
Additionally, those women who are lactating and insist on breast feeding within 5 days of 
the last dose of study drug.   
15. Known history of radiation enteritis. 
Planned Number of Subjects:   
Enrolled:  Planned 120 subjects; adaptive design may allow for up to 200 subjects.   
Test Product, Dose, and Mode of Administration:  
A total of 700 mL of LB1148 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 contains 7.5 g TXA, polyethylene glycol (PEG), glucose, and electrolytes.  
Reference Product, Dose, and Mode of Administration:  
A total of 700 mL of placebo will be administered orally as a split dose (350 mL 6-10 hours 
before surgery and another 350 mL 2-6 hours before surgery).   
The placebo contains PEG, glucose, and electrolytes. 
Duration of Treatment:  
Subjects will receive study drug over the 10 hours prior to surgery.   
Administration:  
A total of 700 mL of study drug should be completely consumed orally 2-10 hours prior to 
induction of surgical anesthesia as a split dose: 
• Subject will consume 350 mL 6-10 hours prior to surgery.   
• Subject will consume the remaining 350 mL 2-6 hours prior to surgery.   
Perioperative Standardization of Care:  
Subjects must receive:   
• Venous thromboembolism (VTE) prophylaxis according to each institute’s regional 
antithombotic guidelines. 
Subjects must not receive:   
• Solid foods consumed for the 8 hours prior to induction of surgical anesthesia; 
• Alternative carbohydrate drinks 8 hours prior to induction of surgical anesthesia; study 
drug will replace carbohydrate drinks within that time period, and 


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• Anything by mouth for the 2 hours prior to induction of surgical anesthesia (exception: 
daily oral medication such as anti-hypertensive may be taken with small volume of water 
as directed by physician) 
Duration of Subject Study Participation: 
The total duration for subject participation is up to 10 months (screen through second surgery). 
Efficacy Assessments: 
Intra-Abdominal Adhesions:   
• Incidence of intra-abdominal adhesions as determined by the surgeon. 
• Extent and severity of intra-abdominal adhesions as determined by the surgeon using the 
Intra-Abdominal Adhesion Extent and Severity Assessment Worksheet (Appendix 5). 
Bowel Function: 
• GI2, defined as the time from the end of surgery (the time the last skin staple or suture was 
placed by the surgeon) to the time of toleration of solid food (the time a patient finished 
meal that required chewing and experienced no significant nausea/vomiting for four hours 
after the solid meal) AND the time to first bowel movement.  
• GI3, defined as the toleration of solid food and either first flatus or bowel movement. 
• Ability to tolerate a liquid oral diet (time subject is able to sustain oral liquid intake 
without need for IV fluid administration). 
• Ability to tolerate a solid oral diet (time subject is able to ingest solid food without 
significant nausea/vomiting for four hours).   
• Flatus. 
• Bowel movement. 
• Insertion, reinsertion, and/or removal of nasogastric (NG)/orogastric (OG) tube. 
• Nausea with a Verbal Rating Score (VRS) ≥3 (moderate to severe). 
• Vomiting or retching. 
• POI, 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 nausea AND 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. 
Other Endpoints:   
• Hospital LOS defined as time of admission to time that discharge order is written. NOTE: 
Subjects may not be discharged until all of the following criteria are met:  
o Passage of stool 
o Ability to tolerate solid food and drink comfortably 
o Adequate oral analgesia  
o Subject’s willingness to be discharged. 
• Pain values will be evaluated using  


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o Values recorded from the Numeric Pain Rating Scale (NPRS);  
o Analgesia consumption, including totals for opioid use and morphine equivalents;  
• The number of subjects with a recorded bowel obstruction; 
• The number of subjects with a hospital re-admission, and 
• Blood product transfusion volume on the day of surgery.   
Safety Endpoints: 
Safety and tolerability will be assessed based on the incidence and severity of treatment 
emergent adverse events (AE), serious adverse events (SAEs), vital signs, clinical laboratory 
results.  Specific safety sub-analyses will be performed to assess the safety of LB1148 in the 
following patient populations:  
• patients who are on chemotherapy; 
• patients with a venous port or catheter; 
• patients with varicose veins and superficial vein thrombosis;  
• patients with varying degrees of obesity;  
• patients who are smokers; 
• patients with varying degrees of renal function; and 
• patient age groups, including 65-80 years old.  
Statistical Methods: 
Intra-Abdominal Adhesions: 
Comparisons between the LB1148 and placebo groups with respect to change from baseline in 
extent and severity of intra-abdominal adhesions will be made using the Wilcoxon rank sum 
test. 
Bowel Function:  
Bowel function analyses will be a time to event analysis (e.g., Cox proportional hazard model) 
with a main effect of treatment and stratified by surgery type (laparotomy versus minimally 
invasive approaches) and stoma (planned stoma versus no stoma).  The p-values between the 
treatment groups will be evaluated using the Wald chi-square test.  The magnitude of the 
treatment effect will be presented as the difference between the LB1148 and placebo groups in 
mean time to event (estimated by area under the Kaplan-Meier survival curve). 
Interim Analyses: 
An interim analysis of efficacy, safety, and tolerability will be performed after enrollment of 
approximately 50-60 subjects.  Results from this interim analysis will permit a clearer 
determination of effect size and may trigger an increase in overall study sample size to up to 
200 subjects enrolled.   
 
 
 


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TABLE OF CONTENTS 
 
SPONSOR SIGNATURE ..........................................................................................................2 
INVESTIGATOR’S SIGNATURE ...........................................................................................3 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................14 
1. 
INTRODUCTION .......................................................................................................16 
1.1. 
Summary ................................................................................................................16 
1.2. 
Post-Operative Ileus ...............................................................................................17 
1.3. 
Intra-abdominal Adhesion Formation and Impact .................................................17 
1.4. 
Rationale for Use of LB1148 .................................................................................18 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...............................................................20 
2.1. 
Study Objectives ....................................................................................................20 
2.1.1. 
Primary Objective ........................................................................................20 
2.1.2. 
Secondary Objectives ...................................................................................20 
2.1.3. 
Exploratory Objectives ................................................................................20 
2.2. 
Study Endpoints .....................................................................................................20 
2.2.1. 
Intra-Abdominal Adhesions .........................................................................20 
2.3. 
Bowel Function ......................................................................................................21 
2.3.1. 
Other Endpoints ...........................................................................................21 
2.3.2. 
Safety Endpoints ..........................................................................................22 
3. 
INVESTIGATIONAL PLAN ......................................................................................23 
3.1. 
Overall Study Design and Plan ..............................................................................23 
3.2. 
Rationale for Study Design, Control Group, and Perioperative Standardization ..24 
3.3. 
Study Duration and Dates ......................................................................................25 
4. 
STUDY POPULATION SELECTION .......................................................................26 
4.1. 
Study Population ....................................................................................................26 
4.2. 
Inclusion Criteria ...................................................................................................26 
4.3. 
Exclusion Criteria ..................................................................................................26 
5. 
STUDY TREATMENTS .............................................................................................28 
5.1. 
Description of Treatments ......................................................................................28 
5.1.1. 
Study Drug ...................................................................................................28 


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5.1.2. 
Placebo .........................................................................................................28 
5.2. 
Treatment Administration ......................................................................................28 
5.3. 
Selection and Timing of Dose for Each Subjects ..................................................28 
5.4. 
Method of Assigning Subjects to Treatment Groups .............................................29 
5.5. 
Blinding..................................................................................................................29 
5.6. 
Concomitant Therapy.............................................................................................29 
5.7. 
Restrictions ............................................................................................................30 
5.7.1. 
Fluid and Food Intake ..................................................................................30 
5.7.2. 
Reproduction ................................................................................................30 
5.8. 
Treatment Compliance ...........................................................................................30 
5.9. 
Packaging and Labeling .........................................................................................30 
5.10. Study Drug Storage, Preparation, Dispensing, and Accountability .......................31 
6. 
STUDY PROCEDURES .............................................................................................32 
6.1. 
Informed Consent...................................................................................................32 
6.2. 
Demographics and Medical History ......................................................................32 
6.3. 
Physical Examination.............................................................................................32 
6.4. 
Surgery Assessment ...............................................................................................32 
6.5. 
Concomitant Medication Assessments ..................................................................33 
6.6. 
Vital Signs ..............................................................................................................33 
6.7. 
Laboratory Tests ....................................................................................................33 
6.7.1. 
Pregnancy Test .............................................................................................33 
6.7.2. 
Local Laboratory Tests ................................................................................34 
6.8. 
Study Drug Administration ....................................................................................34 
6.9. 
Perioperative Surgical Preparation ........................................................................34 
6.10. Taste Assessment ...................................................................................................35 
6.11. Opioid Use .............................................................................................................35 
6.12. Pain Assessment.....................................................................................................35 
6.13. Gastrointestinal Function Assessment ...................................................................35 
6.14. Hospital Discharge .................................................................................................36 
6.15. Day 30 Follow-Up .................................................................................................36 
6.16. Adhesions Assessment (Day 0 and at time of second surgery) .............................37 
6.17. Appropriateness of Measurements .........................................................................37 
7. 
ADVERSE EVENTS ASSESSMENTS ......................................................................38 
7.1. 
Adverse Events ......................................................................................................38 


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7.2. 
Serious Adverse Events .........................................................................................39 
7.3. 
Adverse Events of Special Interest ........................................................................40 
7.4. 
Venous Thrombosis ...............................................................................................40 
7.5. 
Post-Operative Ileus ...............................................................................................40 
7.6. 
Post-Surgical Complications ..................................................................................40 
7.7. 
Unexpected Adverse Event ....................................................................................40 
7.8. 
Unexpected Adverse Drug Reaction ......................................................................40 
7.9. 
Adverse Event Reporting Period ...........................................................................41 
7.10. Recording Adverse Events .....................................................................................41 
7.11. Assessing Adverse Event Severity .........................................................................42 
7.12. Assessing Adverse Event Relationship to Study Drug ..........................................42 
7.13. Reporting Serious or Unexpected Adverse Events ................................................43 
7.14. Pregnancy ...............................................................................................................43 
7.15. Discontinuation or Withdrawal ..............................................................................44 
7.15.1. 
Discontinuation of Study Drug ....................................................................44 
7.15.2. 
Withdrawal from the Study ..........................................................................44 
7.15.3. 
Discontinuation of Study Sites.....................................................................45 
7.15.4. 
Institutional Review Board/Independent Ethics Committee Approval .......45 
7.15.5. 
Discontinuation of the Study .......................................................................45 
8. 
QUALITY CONTROL AND ASSURANCE .............................................................46 
9. 
PLANNED STATISTICAL METHODS ....................................................................47 
9.1. 
General Considerations ..........................................................................................47 
9.2. 
Determination of Sample Size ...............................................................................47 
9.3. 
Statistical Methods .................................................................................................47 
9.3.1. 
Adhesions .....................................................................................................47 
9.3.2. 
Bowel Function ............................................................................................47 
9.4. 
Interim Analysis .....................................................................................................47 
10. 
ADMINISTRATIVE CONSIDERATIONS ................................................................48 
10.1. Regulatory Considerations .....................................................................................48 
10.2. Institutional Review Board or Independent Ethics Committee Approval .............48 
10.3. Subject Information and Consent...........................................................................48 
10.4. Subject Confidentiality ..........................................................................................49 
10.5. Case Report Forms and Study Records .................................................................49 
10.6. Safety Monitoring ..................................................................................................50 


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10.7. Protocol Deviations ................................................................................................50 
10.8. Study Monitoring and Access to Source Documentation ......................................50 
10.9. Retention of Data ...................................................................................................51 
11. 
REFERENCE LIST .....................................................................................................52 
APPENDIX 1 SCHEDULE OF ASSESSMENTS PROTOCOL LBS-POI-201 ...................55 
APPENDIX 2 LIST OF LABORATORY TESTS ................................................................58 
APPENDIX 3 NAUSEA VERBAL RATING SCORING (VRS) SCALE ...........................59 
APPENDIX 4 PAIN SCORING ............................................................................................60 
APPENDIX 5 INTRA-ABDOMINAL ADHESION EXTENT AND SEVERITY 
ASSESSMENT WORKSHEET .....................................................................61 
APPENDIX 6 AMERICAN SOCIETY OF ANESTHESIOLOGISTS CLASSIFICATION 
SYSTEM ........................................................................................................62 
APPENDIX 7 NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI-CTCAE) ................................63 
APPENDIX 8 AMERICAN COLLEGE OF CHEST PHYSICIANS (ACCP) GUIDELINES 
- CAPRINI RISK FACTOR SCORE .............................................................64 
APPENDIX 9 PROTOCOL AMENDMENT SUMMARY ..................................................65 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term or 
Abbreviation  
Definition 
AE 
adverse event  
ASA 
American Society of Anesthesiologists 
BP 
blood pressure 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
electronic case report form 
ERAS 
Enhanced Recovery After Surgery Society 
GCP 
good clinical practice 
GI 
gastrointestinal 
HR 
heart rate 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
Investigative 
Team 
Investigator and/or designated study site team 
IRB 
Institutional Review Board 
IV 
intravenous 
IXRS 
interactive response system used for randomization.   
LBS 
Leading BioSciences (the Sponsor) 
LB1148 
investigational product – the active ingredient, TXA, is formulated in a 
solution containing PEG, glucose, electrolytes and water. 
LOS 
length of stay 
NCI 
National Cancer Institute 
NG 
nasogastric tube 
NPO 
nothing by mouth (nil per os) 
NPRS 
Numeric Pain Rating Scale 


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Term or 
Abbreviation  
Definition 
OG 
orogastric tube 
PEG 
polyethylene glycol 
POI 
post-operative ileus 
PCA 
patient-controlled analgesia  
RR 
respiratory rate 
SAE 
serious adverse event 
TAP 
transverse abdominis plane 
TXA 
tranexamic acid – the active ingredient in LB1148 
UADR 
unexpected adverse drug reaction  
VRS 
Verbal Rating Scale (used for nausea) 
VTE 
venous thromboembolism 
 
 


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INTRODUCTION 
1.1. 
Summary 
During abdominal surgery, surgeons handle, manipulate, and often make incisions in the bowel.  
These actions can create bruising, lesions, and microscopic damage to the bowel (Thomas et al., 
2004), which may allow digestive enzymes to cross the intestinal mucosal barrier potentially 
resulting in injury both locally and remotely.  Although normally not life threatening, this 
digestive enzyme leak during surgery exacerbates local tissue and organ damage.  Due to 
proximity to the leak, the bowel is one of the most seriously affected organs.  Leaking digestive 
enzymes may delay return of normal gastrointestinal (GI) function, lead to a lack of motility in 
the intestine (ileus), and promote the formation of intestinal scar tissue (adhesions).   
LB1148 contains tranexamic acid (TXA) as the active ingredient, a synthetic lysine amino acid 
derivative that is best known as a plasminogen activator inhibitor (DeLano et al., 2013) in the 
antifibrinolytic pharmaceutical class.  In addition to being an anti-fibrinolytic, TXA is also a 
broad-spectrum serine protease inhibitor with inhibitory activity against trypsin, chymotrypsin, 
elastase, enterokinase, as well as others.  This activity appears to be independent of plasminogen 
inhibition or activity.  The pharmacology as a serine protease inhibitor is what is believed to 
allow TXA to preserve GI integrity during periods of mucosal barrier disruption.  When 
administered enterally in preclinical 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 (refer to the LB1148 Investigator’s Brochure 
[IB] for further detail).  The key is the oral/enteral administration of LB1148 allowing 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.  Intravenous (IV) administration of TXA does 
not allow TXA to reach therapeutic levels in the lumen of the small intestine and does not 
demonstrate a therapeutic benefit to preserving the mucosal barrier during times of perturbation.   
All of the components in the LB1148 formulation are approved for use in humans and have 
well-characterized and established safety profiles.  As of April 2016, PubMed lists 534 published 
clinical trials with TXA in humans.  Some of these studies are quite large, such as the CRASH-2 
study, which enrolled over 20,000 patients in over 40 countries.  Furthermore, oral and parenteral 
formulations of TXA have 30 years of post-marketing experience.  TXA is routinely given in 
doses up to 10 g by IV and over 8 days of consecutive oral administration in patients undergoing 
dental surgery with an acceptable safety and tolerability profile (Section 1.4).   
The components of LB1148 are reconstituted in water (700 mL final volume) prior to oral or 
enteral administration.  For this study, LB1148 will be orally administered once via a split dose 
prior to surgery.  This clinical study is designed to determine if administration of LB1148 prior 
to surgery will reduce the GI complications and GI dysfunction following elective bowel 
resection. 


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1.2. 
Post-Operative Ileus 
All patients undergoing bowel resection experience some degree of post-operative ileus (POI), a 
transient cessation of bowel motility.  Prolonged POI is a serious complication of abdominal 
surgery, resulting in increased morbidity, hospital length of stay, and costs.  Post-surgical 
hospital stays for patients who develop POI are 4-6 days longer than for patients who do not 
develop POI, resulting in a major burden on patients and health care providers each year (Berger 
et al., 2015; Goldstein et al., 2007; Iyer et al., 2009; Jakobsen et al., 2014). 
Although POI is common after abdominal surgery, there is no widely agreed upon definition in 
the literature.  The 2006 Clinical Consensus defines POI as “transient cessation of coordinated 
bowel motility after surgical intervention, which prevents effective transit of intestinal contents 
or tolerance of oral intake”.  The 2006 Clinical Consensus defines primary POI as occurring in 
the absence of any precipitating complication, whereas secondary POI occurs in the presence of 
a precipitation complication (bowel obstruction, infection, etc.).  The 2006 Clinical Consensus 
also defined 3 types of POI:  
1. Panintestinal ileus (no flatus or bowl movement, presence of nausea and vomiting);  
2. Upper GI symptoms (nausea, vomiting and flatus present), and  
3. Lower GI (no flatus or bowel movement, tolerance of diet). 
The mechanism of POI remains elusive and is likely multifactorial, involving the central nervous 
system (CNS, specifically the autonomic nervous system), inflammation (mast cell inflammatory 
process), the enteric nervous system, hormones, neuropeptides, anesthesia, narcotics and 
digestive enzymes (2006 Clinical Consensus; Gan et al., 2015; Iyer et al., 2009; Jakobsen et al., 
2014; Kalff et al., 1998; Kraft et al., 2010; Ludwig et al., 2008; Vather et al., 2013; Vather et al., 
2014; Vather et al., 2015; Wolthius et al., 2016).   
POI prevention strategies include the type of opioid (Gan et al., 2015; Berger et al., 2015) and 
anesthesia used (Goldstein et al., 2007).  Nursing prevention strategies include early patient 
ambulation, early introduction of a peroral diet, selective use of a NG tube, and the use of 
non-opioid analgesics (2006 Clinical Consensus).  Additionally, Entereg® (alvimpan) has been 
approved for use in the US as a gut motility stimulator to restore gut function after surgery. 
1.3. 
Intra-abdominal Adhesion Formation and Impact 
The post-operative intra-abdominal adhesions (referenced as adhesions herein) develop in the 
abdomen following abdominal or pelvic surgery and are found in up to 95% of patients who have 
subsequent surgery.  Adhesions are a normal response to injury of the tissue surfaces during 
surgery, and although adhesions may have some beneficial effects, they can increase risk for 
complications, cause significant morbidity, and impose technical difficulties for subsequent 
abdominal surgeries.  Adhesions are fibrous ‘bridges’ or bands that join intra-abdominal organs 


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(Ghonge and Ghonge, 2014).  Traditionally, adhesion formation is thought to be a result of a 
complex interaction of cytokines, growth factors, cell adhesion molecules, neuropeptides, and 
numerous other factors secreted by cells in or near the area of trauma tissue perturbation during 
surgery.   
Adhesions are known to have a significant impact on post-surgical quality of life for people 
worldwide.  Adhesions may result in small bowel obstruction, female infertility, chronic 
abdominal pain, and increased difficulty with subsequent surgery and intervention costs (Ghonge 
and Ghonge, 2014; Ward and Panitch, 2011; DeCherney and Kumar, 2015).  A number of 
animal studies and human interventional studies have evaluated a variety of techniques and 
materials designed to reduce and prevent postsurgical adhesions.  Prevention strategies include 
mechanical (solid), liquid and gel, and pharmaceutical barriers (Ward, 2011).  To date, only a 
handful of agents have been proven safe and effective in clinical trials, and few have generated 
abundant evidence to be adopted for routine use. 
1.4. 
Rationale for Use of LB1148  
The intestinal mucosal barrier plays a key role in both acute critical care medical conditions as 
well as burdensome chronic diseases.  Healthy maintenance of the intestinal mucosal barrier 
requires oxygenation and blood flow and avoidance of mechanical or physical injury.  Potent 
digestive enzymes are maintained within the intestine as long as normal blood flow continues 
and no damage or disturbances to the wall occur.   
Breakdown of the intestinal mucosal barrier can be produced by wide variety of events.  These 
include prolonged low blood pressure ([BP] e.g. during shock), disruption of blood flow (e.g. 
during ischemia), and physical and mechanical perturbations (e.g. during trauma or abdominal 
surgery).   
One of the key advances toward the use of LB1148 to reduce post-operative complications was 
the learning that with more subtle perturbations of the mucosal barriers, such as during 
abdominal surgery, intraluminal pancreatic digestive enzymes played a role in the pathology of 
GI dysfunction.  When the mucosal barrier was disturbed, the pancreatic digestive enzymes had a 
profound effect on the tissue the enzymes contacted first, namely, the intestine.  Importantly, the 
enterotomy into the bowel during resection and anastomosis is sufficient to release pancreatic 
digestive enzymes, which delays the return of gut function.  Perioperative enteral administration 
of LB1148 in preclinical models was sufficient to reduce the delayed return of GI function.  
Furthermore, the reduction in pancreatic digestive enzyme-induced tissue damage had a 
profound reduction in post-operative adhesion formation.  Together, these preclinical studies 
provide evidence that blocking pancreatic digestive enzymes with LB1148 in the intestinal 
lumen reduces local tissue damage, preserves GI function, and reduces adhesion formation.   


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LB1148 was designed to stop the downstream effects of a disruption of the intestinal mucosal 
barrier by inhibiting digestive enzymes only in the lumen of the bowel and not systemically.  
One of the objectives of this study is to determine if a single split dose of LB1148 reduces the 
mucosal barrier breakdown and the leakage of digestive enzymes, thereby preventing local tissue 
damage and ultimately decreasing the number of hours from surgical closure to return of normal 
GI function.   
All of the components of LB1148 are approved for use in man, having been administered to tens 
of thousands of subjects in controlled clinical trials, and used in hundreds of thousands of 
patients during routine medical care, most notably in the surgical setting.  From a safety and 
tolerability perspective, the use of a single oral, 7.5 g dose is within the amount of TXA routinely 
used in medical practice.  The Canadian Cyklokapron Monograph indicates an oral dose of 
100 mg/kg for 8 days for patients undergoing dental surgery.  Assuming a patient weighs 75 kg, 
this would equate to a 7.5 g dose.  Since LB1148 contains TXA as the active ingredient, relevant 
TXA-related safety information from the Canadian Cyklokapron Monograph, the Lysteda 
Package Insert (oral administration), and the Australian Public Assessment is provided in the 
LB1148 Investigator’s Brochure (IB).  Information related to the pharmacokinetics (including 
absorption, distribution, metabolism and excretion), as well as supporting nonclinical data are 
provided in detail in the LB1148 IB.    
Additionally, Palisade Bio has sponsored a Phase 2 study evaluating the use of LB1148.  This 
was a multicenter, randomized, double blind, parallel, placebo-controlled study evaluating 
enteral administration of LB1148 in subjects with septic shock.  A total of 8 subjects were 
enrolled and completed the study through Day 28, however the Sponsor terminated this study 
due to slow enrollment.  Details from this study are also provided in the LB1148 IB.  


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STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
To compare the change from baseline in extent and severity of intra-abdominal adhesions among 
subjects treated with LB1148 or placebo. 
2.1.2. 
Secondary Objectives  
The secondary objectives of this study are to determine the following among subjects treated 
with LB1148 or placebo: 
• Compare time from surgical closure to resolution or appearance, as appropriate, of 1 or more 
of the components common to gastrointestinal (GI) dysfunction following elective bowel 
resection with a planned stoma. 
• Compare number of hours to GI2. 
• Compare number of hours to GI3. 
• Compare number of hours to resolution of POI.   
• Compare hospital length of stay (LOS, recorded in hours) through Discharge or Day 14 
(whichever comes first).   
• Compare the incidence of intra-abdominal adhesions following the second surgery among 
subjects treated with LB1148 or placebo. 
• Compare the extent and severity of intra-abdominal adhesions following the second surgery 
among subjects treated with LB1148 or placebo. 
• Compare change from baseline in incidence, extent, and severity of intra-abdominal 
adhesions among subjects treated with LB1148 or placebo who had adhesions observed at 
the time of the first surgery. 
• Assess the safety and tolerability of LB1148 in subjects undergoing elective bowel resection.  
2.1.3. 
Exploratory Objectives 
The exploratory objectives of this study are to determine if LB1148 reduces the: 
• Post-operative abdominal pain. 
• Incidence of bowel obstruction through 30 days post-operatively. 
• Incidence of hospital re-admittance through 30 days post-operatively. 
• Volume of blood product transfusions on the day of surgery. 
2.2. 
Study Endpoints  
2.2.1. 
Intra-Abdominal Adhesions  
• Incidence of intra-abdominal adhesions as determined by the surgeon. 


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• Extent and severity of intra-abdominal adhesions as determined by the surgeon using the 
• Intra-Abdominal Adhesion Extent and Severity Assessment Worksheet (Appendix 5). 
2.3. 
Bowel Function 
• GI2, defined as the time from the end of surgery (the time the last skin staple or suture was 
placed by the surgeon) to the time of toleration of solid food (the time a patient finished meal 
that required chewing and experienced no significant nausea/vomiting for four hours after the 
solid meal) AND the time to first bowel movement.  
• GI3, defined as the toleration of solid food and either first flatus or bowel movement. 
• Ability to tolerate a liquid oral diet (time subject is able to sustain oral liquid intake without 
need for IV fluid administration). 
• Ability to tolerate a solid oral diet (time subject is able to ingest solid food without 
significant nausea/vomiting for four hours).   
• Flatus. 
• Bowel movement. 
• Insertion, reinsertion, and/or removal of nasogastric (NG)/orogastric (OG) tube. 
• Nausea with a Verbal Rating Score (VRS) ≥3 (moderate to severe). 
• Vomiting or retching. 
• POI, 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 nausea AND 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. 
2.3.1. 
Other Endpoints 
• Hospital LOS defined as time of admission to time that discharge order is written. NOTE: 
Subjects may not be discharged until all of the following criteria are met:  
o Passage of stool 
o Ability to tolerate solid food and drink comfortably 
o Adequate oral analgesia  
o Subject’s willingness to be discharged. 
• Pain values will be evaluated using: 
o Values recorded from the Numeric Pain Rating Scale (NPRS);  
o Analgesia consumption, including totals for opioid use and morphine equivalents;  
• The number of subjects with a recorded bowel obstruction; 
• The number of subjects with a hospital re-admission, and 
• Blood product transfusion volume on the day of surgery.   


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2.3.2. 
Safety Endpoints 
Safety and tolerability will be assessed based on the incidence and severity of treatment 
emergent adverse events (AEs), serious adverse events (SAEs), vital signs, clinical laboratory 
results.   
Specific safety sub-analyses will be performed to assess the safety of LB1148 in the following 
patient populations:  
• patients who are on chemotherapy; 
• patients with a venous port or catheter; 
• patients with varicose veins and superficial vein thrombosis;  
• patients with varying degrees of obesity;  
• patients who are smokers; 
• patients with varying degrees of renal function; and 
• patient age groups, including 65-80 years old.  


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INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This 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.   
Figure 1  
Illustration of Study Design for Protocol LBS-POI-201 
 
Subjects scheduled for elective bowel resection, aged 18 to 80 years inclusive, will be screened 
within 42 days of randomization (Study Day -1).  Subjects who meet all inclusion and no 
exclusion criteria, and provide written informed consent, will be stratified by: 1) surgical 
approach (either minimally invasive technique or laparotomy) and 2) with or without a planned 
stoma, and then randomized to receive a split oral liquid dose of LB1148 or placebo 
(polyethylene glycol [PEG], glucose, and electrolytes) in a in a 1:1 ratio. 
All subjects will receive 350 mL of study drug 6-10 and 2-6 hours prior to surgery (Study Day 
1/2).  Subjects will then undergo the first surgery.  At the time of surgical closure, the 
investigator will determine the incidence, extent, and severity of adhesions using the Intra-
Abdominal Adhesion Extent and Severity Assessment Worksheet (Appendix 5). 
Subjects will be assessed for safety and tolerability, including AEs, physical exam, vital signs, 
clinical lab tests (chemistry, coagulation, and hematology) while in the hospital and on Day 30.  
Subjects will be monitored for return of bowel function while in the hospital and discharged 
following tolerance of solid food and first bowel movement. 


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Within 8 months of enrollment, subjects will undergo a second surgery for the purpose of ostomy 
take down or other planned abdominal surgery, at which time the surgeon will determine the 
incidence, extent, and severity of adhesions.  If a subject is not ready for the second surgery by 8 
months, the investigator may consult with Medical Monitor to obtain window approval. 
Unless required for safety reasons or protocol compliance, all subjects, Investigators, and study 
site personnel will remain blinded to the identity of the treatment from time of randomization 
until final database lock.   
The Schedule of Assessments is provided in Appendix 1 and the study endpoints are in 
Section 2.2.   
3.2. 
Rationale for Study Design, Control Group, and Perioperative Standardization 
Study Design:  This 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.  The study is randomized to control for factors known and unknown 
between the treatment groups, and neither the Investigator nor the subject will know which 
treatment the subject will receive in order to avoid any bias in the study assessments. 
Control Group:  Placebo, superimposed on current standard of care, is an appropriate control 
for this study.   
Perioperative Standardization of Care:  There are no internationally recognized perioperative 
standards of care for general bowel resection subjects.  Although the Enhanced Recovery After 
Surgery (ERAS) Society has provide suggestions for improved perioperative care for GI surgical 
patients, these standards have been inconsistently adopted by surgical centers 
(ERAS website).  Often each surgical center has its own, site-specific practices that best fit its 
patients and standards of care.  This has led to heterogeneous perioperative care across sites and 
countries.  To improve the homogeneity of perioperative care in this study and improve the 
opportunity to detect the effect of treatment, the following standards are being set forth: 
• Subjects must receive:   
o Venous thromboembolism (VTE) prophylaxis according to each institute’s regional 
antithombotic guidelines. 
• Subjects must not receive:   
o Solid foods consumed for the 8 hours prior to induction of surgical anesthesia; 
o Alternative carbohydrate drinks 8 hours prior to induction of surgical anesthesia; study 
drug will replace carbohydrate drinks within that time period;   


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o Anything by mouth for the 2 hours prior to induction of surgical anesthesia (exception: 
daily oral medication such as anti-hypertensive may be taken with small volume of water 
as directed by physician), and     
3.3. 
Study Duration and Dates 
The total duration for subject participation is  up to10 months (screen through second surgery). 


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STUDY POPULATION SELECTION 
4.1. 
Study Population 
Inclusion and exclusion criteria are provided below.  As stated earlier (Section 3.1), this is an 
adaptive design study.  Currently, 120 subjects are planned for randomization at approximately 
15 sites in the United States.  Based on the interim analysis results, the adaptive design of this 
study may allow for up to 200 total subjects enrolled at study completion.   
4.2. 
Inclusion Criteria 
Subjects will be eligible for participation in the study only if they meet ALL of the following 
inclusion criteria:  
1. Scheduled to undergo an elective (non-emergent) bowel resection with a planned stoma via 
laparotomy or minimally invasive technique.  This includes any subject in which a resection 
of the small intestine, colon, or rectum is performed for any elected indication.  
2. Planned stoma takedown or other planned abdominal surgery within 8 months of the initial 
surgery. 
3. Willing to perform and comply with all study procedures including attending clinic visit as 
scheduled and completion of a second surgery for stoma takedown or other abdominal 
surgery and to determine the presence of intra-abdominal adhesions. 
4. Has been informed of the nature of the study (either the subject or their legal representative), 
agrees to its provisions, and has provided written informed consent.  
4.3. 
Exclusion Criteria 
Subjects will not be eligible for participation in the study if they meet ANY of the following 
exclusion criteria: 
1. <18 or >80 years of age. 
2. Requires emergency bowel surgery. 
3. Has had 1 or more abdominal surgeries, excluding the current, for inflammatory bowel 
disease, including, but not limited to, inflammatory bowel disease (IBD), Crohn’s Disease, or 
ulcerative colitis.   
Note: This does not apply to previous surgery such as hernia repair unrelated to IBD. 
4. American Society of Anesthesiologists (ASA) Class 4 or 5.  
5. Known inability to take the study drug orally (i.e. complete small bowel obstruction). 
6. Has contraindications or potential risk factors to taking TXA.  These include subjects with: 
a. Known sensitivity to TXA 


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b. Recent craniotomy (past 30 days) 
c. Active cerebrovascular bleed 
d. Active thromboembolic disease (such as deep vein thrombosis, pulmonary embolism, 
cerebral thrombosis, ischemic stroke, or acute coronary syndrome) 
e. Acute promyelocytic leukemia taking all-trans retinoic acid for remission induction, or 
f. Continuing use of a combined hormonal contraceptive and or combined hormonal 
replacement therapy (including combined hormonal pill, patch, or vaginal ring) 
7. Has peritoneal carcinomatosis.  
8. History of or current seizure disorder.  
9. Patients with myeloproliferative disorders. 
10. Any other condition that, in the opinion of the Investigator, would preclude the subject from 
being an appropriate candidate for the study, including severe renal or hepatic impairment. 
11. Planned treatment with alvimopan (Entereg®) during study participation period. 
12. Planned use of 4% icodextrin (Adept®) or SEPRAFILM during the first surgery. 
13. Received any other investigational therapy within 4 weeks prior to Randomization 
14. Female subjects of childbearing potential with a positive urine or serum pregnancy test or 
who are not taking (or not willing to take) acceptable birth control measures (abstinence, 
intrauterine devices, contraceptive implants or barrier methods) through Day 30.  
Additionally, those women who are lactating and insist on breast feeding within 5 days of the 
last dose of study drug.   
15. Known history of radiation enteritis. 


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STUDY TREATMENTS 
5.1. 
Description of Treatments 
5.1.1. 
Study Drug 
LB1148 contains 7.5 g TXA, polyethylene glycol (PEG), glucose, and electrolytes.  A dose of 
700 mL of LB1148 will be administered orally (refer to Section 5.2). 
5.1.2. 
Placebo 
The placebo contains PEG, glucose, and electrolytes.  A dose of 700 mL of placebo will be 
administered orally (refer to Section 5.2). 
5.2. 
Treatment Administration 
Eating, bowel prep, and drinking will be held 1 hour before and 1 hour after study drug 
administration. 
A total of 700 mL of study drug should be completely consumed orally 2-10 hours prior to 
induction of surgical anesthesia.  Study drug will be provided to subjects in 2 bottles, 
approximately 350 mL in each bottle: 
• Subject will consume the first 350 mL 6-10 hours prior to surgery.   
• Subject will consume the second 350 mL 2-6 hours prior to surgery. 
5.3. 
Selection and Timing of Dose for Each Subjects 
The 7.5 g dose was chosen for safety and efficacy reasons.  The minimally effective 
concentrations of TXA in the lumen of the small intestine were 45 mM (Delano et al., 2013) and 
56.5 mM (Chang et al., 2012).  LB1148 is formulated at a concentration of 68.2 mM (7.5 g TXA 
per 700 mL solution).    
In preclinical testing, LB1148 demonstrated efficacy when administered 2 hours prior to 
abdominal surgery.  For this study, study drug will be administered 2-10 hours prior to 
abdominal surgery (refer to Section 5.2 and Section 6.8).  Additional information regarding dose 
selection, safety, and preclinical efficacy can be found in the LB1148 IB.   
The ASA Practice Guidelines for Preoperative Fasting are based on a synthesis and analysis of 
the current literature, expert and practitioner opinion, open forum commentary, and clinical 
feasibility data.  These Guidelines are recommendations to assist the practitioner and patient in 
making health care decisions.  The guidelines currently read that patients should fast from clear 
liquids for 2 hours pre-operatively and fast from regular meals for 8 hours pre-operatively 
(ASA, 2011; Korpman et al., 2012).  This protocol was designed to be in alignment with ASA 
Practice Guidelines.   


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5.4. 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet all study criteria for enrollment will be randomly assigned to either the 
investigational drug (LB1148) or placebo treatment group.  Assignment to treatment groups will 
be determined by a computer-generated randomized sequence using an interactive response 
system (IXRS).  All randomized subjects will be divided between the 2 treatment groups 
(LB1148 or placebo) in a 1:1 ratio, stratified by: 1) surgical approach (either minimally invasive 
technique or laparotomy) and 2) with or without a planned stoma.   
5.5. 
Blinding 
This is a randomized double-blind study.  The subject’s coded treatment assignment will be 
provided to the blinded pharmacist or designee by an IXRS.  The randomization code for 
treatment assignment will be retained by the IXRS. 
Unless required for safety reasons or protocol compliance, it is anticipated that there will be little 
need to unblind a subject’s treatment assignment at the site level.  Treatment code must not be 
broken except in medical emergencies when the appropriate management of the subject 
necessitates knowledge of the treatment randomization.  Because no known antidote for LB1148 
exists, there should be no medical reason for unblinding at the site.   
The Medical Monitor should be contacted if the Investigator requests unblinding a subject's 
treatment assignment.  Emergency unblinding for AEs may be performed through the IXRS.  If 
the treatment code is broken, then the Investigator(s) must document and report it to the Sponsor.   
The Sponsor retains the right to break the code for SAEs that are unexpected and suspected to be 
causally-related to treatment, and that potentially require expedited reporting to regulatory 
authorities.   
The Sponsor or its designee intends to unblind the treatment assignment at the time of the interim 
analysis; however, the study double blind (subject, Investigator, and/or designated study site 
team [investigative team]) will remain intact.  Care will be taken such that unblinded Sponsor 
representative will have no contact with the site in regards to any subject data that are not yet 
collected by the investigative team.  Further, the contract research organization (CRO) 
representatives in direct contact with the investigative team will remain blinded to treatment 
assignment throughout the study.   
5.6. 
Concomitant Therapy 
The subject must not perform any of the following during study participation:  
• Receive other medication containing TXA while receiving study drug;   
• Receive pancreatic enzyme replacement therapy during the Surgical Period;   


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• 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 through the 7 day period following surgery;   
• Consume solid foods 8 hours prior to induction of surgical anesthesia; 
• Receive alternative carbohydrate drinks.  Study drug will replace carbohydrate drinks within 
8 hours prior to induction of surgical anesthesia. 
• Consume anything by mouth (NPO) for the 2 hours prior to induction of surgical anesthesia.  
(Exception: daily oral medication such as anti-hypertensive may be taken with small volume 
of water as directed by physician).   
• Receive 4% icodextrin (Adept®) or SEPRAFILM during the first surgery  
• Use post-operative alvimopan (also known as Entereg®).  
Otherwise, there are no restrictions with respect to concomitant therapies for this study.  All 
concomitant medications should be listed in the electronic case report form (eCRF) along with 
the date therapy was initiated and, if applicable, terminated.   
5.7. 
Restrictions 
5.7.1. 
Fluid and Food Intake  
There is no co-administration of food or drink with the study drug.  Eating, bowel preparation, 
and drinking will be held 1 hour before and 1 hour after study drug administration. 
5.7.2. 
Reproduction 
Subjects of reproductive capability must agree to use contraception throughout the Follow-Up 
Period of the study (through Day 30).  Acceptable methods include abstinence, intrauterine 
devices, contraceptive implants, and barrier methods (condom, diaphragm with spermicide).   
5.8. 
Treatment Compliance 
Study drug will be administered either by site personnel at the study hospital or by the subject at 
home prior to surgery.  Location for administration is dependent on time of surgery and location 
for surgical preparation by the subject, and may differ for participating subjects.   
5.9. 
Packaging and Labeling 
The Sponsor will provide study materials to the study pharmacy in 120 mL bottles of either 
active or placebo powder for reconstitution.  Glucose powder will be provided in a clearly 
labeled 60 mL bottle.  Reconstitution and labeling instructions are provided in the Pharmacy 
Manual.   


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5.10. Study Drug Storage, Preparation, Dispensing, and Accountability 
Study drug will be sent to the clinical study site pharmacy.  Instructions for requesting additional 
supplies of product will be provided in the Pharmacy Manual.   
Both LB1148 and placebo are to be stored at room temperature.  Study drug should be stored 
carefully at the clinical study site, safely and separately from other drugs.  Instructions for the 
reconstitution of study drug are provided in the Pharmacy Manual. 
The site research pharmacist or other authorized site study team personnel will dispense the 
reconstituted blinded study drug to each subject.  The Investigator (or designated pharmacist) 
will maintain records of: 
• The receipt of study drug at the clinical study site;  
• The inventory at the site dispensing product to each subject, and 
• The return of unused cartons to the Sponsor or destruction at the clinical study site. 
During the course of the study, or upon completion or termination of the study, the 
Investigator/pharmacist will return all unused medication to the Sponsor or destroy all unused 
medication at the site according to institutional procedures after recording the relevant 
accountability information.  For drug accountability records, the site will provide the Clinical 
Monitor with a copy of the inventory record and a record of destroyed clinical supplies (on a 
Drug Accountability Log).  The record of destroyed clinical supplies will include information on: 
• All dispensed bottles; 
• All used and unused bottles returned to the pharmacy;  
• All unused bottles; 
• All used and unused bottles destroyed in the course of the study; 
• Date(s) of destruction, and 
• Name and signature of the Investigator/pharmacist. 
During and at the end of the study, all study drug will be reconciled against current inventory and 
the dispensing records as part of routine monitoring visits.  After reconciliation, unused (full) 
bottles will be destroyed at the site per institutional standard operating procedure.  At the end of 
the study, unused, unopened cartons of study drug will be returned or destroyed as instructed by 
the Sponsor, or its designees. 


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STUDY PROCEDURES 
The schedule of assessments and treatments is provided in Appendix 1.  While the subject is in 
the hospital, all assessments and treatments are to be performed on the study day as indicated.   
6.1. 
Informed Consent  
Written informed consent must be obtained from each subject or legal representative designee if 
subject is unable to sign after the nature of the study has been fully explained in accordance with 
International Conference on Harmonization (ICH) Good Clinical Practices (GCP).  Informed 
consent must be obtained prior to performing any study-specific procedures.   
6.2. 
Demographics and Medical History 
Medical history will include significant medical conditions and surgical history, as well as 
baseline signs and symptoms occurring within 2 weeks of randomization.  Additionally, the 
subject’s diagnosis and reason for requiring a bowel resection will be documented, the planned 
surgical approach for the bowel resection, the planned use of stoma, and the need for a planned, 
second surgery.  The subject’s medical history will be collected during the Screening Period; 
during this review, a Caprini risk factor score will be calculated (Appendix 8).  Each subject’s 
risk factors for VTE will be assessed in order to determine the appropriate VTE regimen 
according to each institute’s regional antithombotic guidelines. The subject’s prior or current use 
of tobacco will also be collected.  
On the day of the first surgery (the Surgical Period), any changes to subject’s condition that 
affect inclusion/exclusion criteria will be documented.  Subject must meet all inclusion/exclusion 
criteria at time of the first surgery.   
6.3. 
Physical Examination 
A complete physical examination (except for genitourinary unless indicated) will be performed 
at Screening.  Height will be measured at the Screening visit only.    
From Day 0 through Post-Operative Day 14, and at Hospital Discharge, or study termination, 
whichever comes first – a brief, focused examination of the subject will be performed, including 
lower extremity assessments to identify any clinical symptoms of VTE and assessment for AEs.  
Each focused examination will include weight measurements.  
6.4. 
Surgery Assessment 
During surgery (where applicable), the following data should be recorded:   
• The type of operation. 
• The type of surgical approach (minimally invasive technique or laparotomy). 


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• The location of the surgical incision(s). 
• Surgical time, recorded as:  
o Surgery start time, defined as the time when the initial incision is made, and 
o Surgery end time, defined as when the last suture or staple was placed.   
• Ileostomy mobilization time (defined as the time from skin incision to completion of 
circumferential mobilization and start of preparation of ileostomy for closure). 
6.5. 
Concomitant Medication Assessments 
Concomitant medications, including prescription and over-the-counter drugs, will be recorded 
within 2 weeks prior to randomization through Post-Operative Day 14, and at Hospital 
Discharge, or study termination, whichever comes first.  Additionally, any perioperative surgical 
preparation that was given or consumed will be documented, including mechanical bowel prep 
and nutritional supplements (refer to Section 3.2, Section 5.6, and Section 0).  
Blood products administered to the subject will be documented throughout the same timeframe 
on the Concomitant Medication eCRFs.  Documentation will include start and stop dates and 
reasons for the use. 
Unless otherwise specified in the protocol, administration of other concomitant investigational 
drugs or devices for any indication, other than study drug, is not permitted while on study.  
Additionally, receiving medication with TXA while taking the study drug is prohibited along 
with receiving pancreatic enzyme replacement therapy.  Any therapeutic or surgical procedures 
performed during the study period will be documented.  Documentation will include information 
regarding the date(s), indication(s), description of the procedure(s), and/or any clinical or 
pathological findings. 
6.6. 
Vital Signs 
Vital signs will include BP (systolic and diastolic measurements), heart rate (HR), respiratory 
rate (RR), oxygen saturation, and temperature.  Vital signs will be collected daily from Screening 
through Post-Operative Day 14, and at Hospital Discharge, or study termination, whichever 
comes first.  For study purposes, the vital signs taken the closest to 0800 will be used for data 
capture.  
6.7. 
Laboratory Tests 
6.7.1. 
Pregnancy Test 
A negative urine or serum pregnancy test must be obtained at Screening and confirmed prior to 
randomization for all females of childbearing potential.   


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6.7.2. 
Local Laboratory Tests 
Blood samples will be collected during the Screening Period and on Post-Operative Day 3.  A 
lab draw will be performed on Post-Operative Day 7 only if subject is still hospitalized. 
Appendix 2 lists the specific laboratory tests that will be performed for this study.   
All laboratory evaluations will be conducted at the laboratories located at or associated with the 
clinical site.  Each laboratory will be required to provide up-to-date reference ranges.  Laboratory 
values will be recorded on the eCRF(s).   
Unscheduled laboratory results, from tests pre-specified in this protocol, that are both abnormal 
and clinically significant, as decided by the Investigator, will be recorded on an additional eCRF 
page(s) and the data will be included in the assessment of out-of-range parameters.   
6.8. 
Study Drug Administration  
A total of 700 mL of study drug should be completely consumed orally 2-10 hours prior to 
induction of surgical anesthesia as a split dose: 
• For the first study drug administration, subject will consume 350 mL 6-10 hours prior to 
surgery.   
• For the second study drug administration, subject will consume the remaining 350 mL 2-6 
hours prior to surgery. 
Eating, bowel preparation, and drinking will be held 1 hour before and 1 hour after study drug 
administration. 
6.9. 
Perioperative Surgical Preparation 
All perioperative items the subject is given or consumed will be recorded during the Screening 
and Surgical Periods.  These include, but are not limited to, mechanical bowel prep, nutritional 
supplements, carbohydrate drinks, opioids, and analgesia.  As indicated in Section 3.2:   
• Subjects must receive:   
o VTE prophylaxis according to each institute’s regional antithombotic guidelines. 
• Subjects must not receive:   
o Solid foods consumed for the 8 hours prior to induction of surgical anesthesia; 
o Alternative carbohydrate drinks 8 hours prior to induction of surgical anesthesia; study 
drug will replace carbohydrate drinks within that time period;   
o Anything by mouth for the 2 hours prior to induction of surgical anesthesia (exception: 
daily oral medication such as anti-hypertensive may be taken with small volume of water 
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Additional information concerning restrictions are provided in Section 5.7. 
6.10. Taste Assessment 
In the first phase of the study, after the study drug has been consumed and before surgical 
anesthesia is administered during the Surgical Period, subject satisfaction with the taste of the 
study drug will be recorded.   
6.11. Opioid Use 
The use of opioid pain medications will be collected daily from Screening through Day 14, and 
at Hospital Discharge or study termination, whichever comes first.   
6.12. Pain Assessment 
The NPRS is an 11-point scale used to evaluate pain based on subject feedback.  This scale can 
be administered either verbally or graphically by the clinician where subjects is asked to rate 
their current pain intensity from 0 (“no pain”) to 10 (“worst possible pain imaginable”).  The 
NPRS is the method recommended by both the Initiative on Methods, Measurement and Pain 
Assessment in Clinical Trials as well as the Expert Working Group for the assessment of pain 
intensity during a clinical study (Breivik et al., 2008; Caraceni et al., 2002).  A change of 
approximately 30% (or 2 points) has been shown to represent a clinically meaningful change in 
pain (Farrar et al., 2001).   
Investigator or delegated site personnel should use the following statements to ask the subject to 
rate their post-operative abdominal pain: 
1. I would like you to rate your pain on a scale from 0 to 10.  
2. ‘0’ means you have no pain at all.  
3. ‘10’ means the worst possible pain you can imagine.  
4. What number would you give to your pain?  
A pain assessment will be collected daily starting after Surgery Day 0 through Day 14, and at 
Hospital Discharge, or study termination, whichever comes first (Appendix 4). 
6.13. Gastrointestinal Function Assessment 
Starting on Post-Operative Day 1, GI function will be assessed to determine return of GI 
function.  Daily GI assessments will be collected until either the subject has had return of GI 
function or Hospital Discharge.  If, while still in the hospital, GI function deteriorates to the 
point of no longer being able to tolerate an oral diet and pass stool, daily measurements should 
be collected again until the subject has had return of GI function.    


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Data for this assessment will include but not be limited to:   
• Nausea and vomiting (either subject reported or recorded as presence or absence, date and 
time, including VRS [Appendix 3]),   
• Passing of flatus (either subject reported or Investigator/delegated site personnel reported 
during a 24-hour calendar day; date and time of first flatus where only the first observance is 
recorded; in any instance where subject has post-operative complications and experiences 
ileus as decided by Investigator, the next flatus event should be recorded); 
• Passing of stool from anus or ostomy (recorded as presence or absence and date and time);  
• Presence of NG/OG tube (including date and time). 
• Ability to tolerate liquid diet (liquid diet ordered, subject is able to sustain oral liquid intake 
without need for IV fluid administration, and total liquid volume over a 24-hour calendar 
day); 
• Ability to tolerate a solid diet (solid diet ordered and date and time of solid food ingestion 
without significant nausea or vomiting for 4 hours).  
• If a subject experiences a POI event during hospitalization, this event will be recorded, 
including date and time as an AE/SAE.  
6.14. Hospital Discharge  
Subjects may not be discharged until all of the following criteria are met:  
• Passage of stool 
• Ability to tolerate solid food and drink comfortably 
• Adequate oral analgesia  
• Subject’s willingness to be discharged. 
Information related to Hospital Discharge after the first bowel resection will be recorded during 
the Post-Surgical period as:  
• When discharge order is written (date and time) 
• When subject departs from the hospital (date and time) 
6.15. Day 30 Follow-Up 
On Day 30 (+7 days), site study staff will contact the subject or their legally authorized 
representative to determine if the subject experienced a hospital readmission due to GI concerns 
and/or other medical reasons.  If readmission did occur, this event should be recorded as a SAE.   
As it is vital to obtain follow-up data, every effort must be made to contact the subject or legally 
authorized representative to collect this information.   


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6.16. Adhesions Assessment (Day 0 and at time of second surgery) 
The surgeon will determine the incidence, extent, and severity of adhesions at the time of 
surgical closure for the first surgery and at the time of opening for the second surgery.  Grading 
of the adhesions (extent and severity) will be performed by the surgeon during the surgical 
procedure (Appendix 5). 
For each abdominal region, the score of the extent and severity of adhesions are evaluated. The 
surgeon will grade the intra-abdominal adhesions at 9 abdominal region (right upper, 
epigastrium, left upper, left flank, left lower, pelvis, right lower, right flank and central) and 
when appropriate at 4 areas around the ostomy (superior, lateral, inferior, and medial).  
(Coccolini et al., 2013, Dabrowski et al., 2016, and the Seprafilm Package Insert). 
For each abdominal region, extent of adhesion formation is scored for adhesions from the 
abdominal wall to bowel (including abdominal wall to viscera) and for adhesions from bowel to 
bowel (including bowel to viscera) as follows: 
0 = no adhesion; 
1 = minimal (<1/3 of the site is covered); 
2 = moderate (1/3 to 2/3 of the site is covered), or 
3 = extensive (>2/3 of the site is covered). 
 
The severity of the adhesions in the region are graded using the following score:    
0 = no adhesions; 
1 = filmy thickness, avascular; 
2 = moderate thickness, limited vascularity, or  
3 = dense thickness, vascularized. 
At the second surgery visit the site study staff will determine if the subject experienced a hospital 
readmission due to GI concerns and/or other medical reasons.  If readmission did occur, this 
event should be recorded as a SAE. 
6.17. Appropriateness of Measurements 
All procedures used to measure the safety and efficacy of LB1148 in this study are considered to 
be appropriate and necessary to obtain the required safety, tolerability, and efficacy data.  The 
safety assessments used in this study, such as physical examination, vital signs, opioid use, 
laboratory assessments, and GI function assessments are widely used and are considered 
appropriate for monitoring subjects’ health and well-being in this type of study.  The measure 
used to evaluate pain levels is a validated and widely accepted rating scale used for clinical 
studies evaluating pain.   
 


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ADVERSE EVENTS ASSESSMENTS 
AE data will be collected from first administration of study drug through Day 14, Hospital 
Discharge, or study termination, whichever comes first.  Following discharge through the second 
surgery visit, any hospital readmissions will be recorded as SAEs. 
AEs/SAEs related to the second surgery will also be collected.   
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor or its designees to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject. 
The Investigator is responsible for the appropriate medical care of subjects during the study.  The 
Investigator remains responsible for following, through an appropriate health care option, SAEs 
or AEs that caused the subject to discontinue before completing the study.  The subject should be 
followed until the event is resolved or explained.  Frequency of follow-up evaluation is left to the 
discretion of the Investigator. 
7.1. 
Adverse Events  
An AE is any untoward medical occurrence in a subject administered a drug or biologic 
(medicinal) product; the event does not necessarily have a causal relationship with the 
administration of the study drug.  An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
This includes any side effect, injury, toxicity, or sensitivity reaction, and may include a single 
symptom or sign, a set of related symptoms or signs, or a disease.  An AE may also be any 
laboratory abnormality judged to be clinically significant by the Investigator that worsened when 
compared to baseline.   
AEs include the following: 
• All suspected adverse drug reactions. 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity. 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness. 
• Injury or accidents.   
Note:  If a medical condition is known to have caused the injury or accident (e.g., a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should be 
reported as 2 separate AEs.  
• Abnormalities in physiological testing or physical examination (findings that require clinical 
intervention or further investigation beyond ordering a repeat [confirmatory] test). 


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• Laboratory abnormalities that are clinically significant and require clinical intervention or 
further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event.   
An AE does not include: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an AE. 
• Pre-existing diseases or conditions present or detected at screening/baseline that do not 
worsen in severity or frequency. 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions). 
• Overdose of either study drug or concomitant medication without any signs or symptoms. 
Throughout the course of the study, every effort should be made to remain alert to possible AEs.  
Subjects should be encouraged to report AEs spontaneously or in response to general, non-
directed questioning. 
With the occurrence of an AE, the primary concern is the safety of the subject.  If necessary, 
appropriate medical intervention should be provided and the study drug discontinued.  Urgent 
safety issues may be discussed with Study Medical Monitor.  
7.2. 
Serious Adverse Events  
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:  
• Death. 
• A life-threatening AE (i.e., immediate risk of death)  
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
• Prolongation of existing hospitalization or re-hospitalization. 
• Results in persistent or significant disability/incapacity. 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
AE may jeopardize the 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 or at home; blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


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7.3. 
Adverse Events of Special Interest 
AEs of special interest can be either serious or non-serious.  For this study, 3 events will be 
calorized as Special Interest:  POI, thrombotic events, and conditions that cause a prolongation of 
existing hospitalization due to a post-surgical complication.  AEs of special interest will be 
reported as either an SAE (refer to Section 7.2) or as an AE (refer to Section 7.1).  
7.4. 
Venous Thrombosis 
As indicated in the LB1148 IB, nonclinical toxicology data indicates a possible association 
between the use of TXA and thrombosis events.  However, post-marketing AE reports in humans 
indicate thromboembolic events are relatively rare.  Since TXA is known to have an impact on 
blood clotting, thrombotic events will be recorded as an AE/SAE and followed to resolution.  
7.5. 
Post-Operative Ileus 
Resolution of POI-related symptoms are one of the focuses of this study.  As such, any instance 
of POI will be recorded as an AE/SAE and followed to resolution.  POI events post-discharge, 
but prior to Day 30, will also be recorded as an AE/SAE. 
7.6. 
Post-Surgical Complications  
The impact of study drug on LOS is a secondary endpoint for this study.  As such, any post-
surgical complication that prolongs discharge will be recorded as an AE/SAE.  
7.7. 
Unexpected Adverse Event 
An unexpected AE is any AE that is not identified in nature, severity, or frequency in the current 
LB1148 IB or product information.   
7.8. 
Unexpected Adverse Drug Reaction  
An unexpected adverse drug reaction (UADR) is an adverse reaction, the severity of which is not 
consistent with the applicable product information or IB.  All noxious and unintended responses 
to a medical product related to any dose should be considered an UADR.   
• The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility (meaning the relationship 
cannot be ruled out).   
• The expression “causal relationship” is meant to convey that in general there are facts, 
evidence, or arguments to suggest a reasonable causal relationship.  All serious and UADRs 
will have expedited reporting to regulatory agencies following ICH requirements.   


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7.9. 
Adverse Event Reporting Period 
AE data will be collected from first administration of study drug through Day 14, Hospital 
Discharge, or study termination, whichever comes first.  Following discharge through the Month 
3 visit, any hospital readmissions will be recorded as SAEs. 
AEs/SAEs related to the second surgery will also be collected.   
If a subject experiences an AE after signing informed consent, but prior to receiving study drug, 
the event will NOT be collected unless the Investigator feels the event may have been caused by 
a protocol procedure. 
In addition, any known untoward event that occurs subsequent to the AE-reporting period that 
the Investigator assesses as related to the study drug should also be reported as an AE.   
7.10. Recording Adverse Events 
All AEs will be documented in the appropriate section of the eCRFs.  Among these AEs, all 
SAEs (refer to Section 7.2) will be additionally documented in the SAE Report. 
The following will be recorded for each event in the eCRF: 
• A description of the AE in medical terms, not as reported by the subject.  Whenever possible, 
a diagnosis should be given when signs and symptoms are due to common etiology (e.g., 
cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper 
respiratory infection”). 
• The date of onset (start date). 
• The date of resolution (stop date). 
• The severity as assessed by the Investigator according to the definitions in Section 7.11. 
• The causal relationship to study drug as assessed by the Investigator; the decisive factor in 
the documentation is the temporal relation between the AE and the study drug (refer to 
Section 7.12).  
• Action taken for study drug (none, study drug discontinued, study drug dose reduction, study 
drug delayed). 
• Other action(s) taken (none, concomitant medication given, new or prolonged 
hospitalization, procedural surgery). 
• The outcome according to the following definitions: 
o Recovered with sequelae; 
o Recovered without sequelae; 
o Ongoing, no therapy; 
o Ongoing, therapy; 
o Died, and 
o Change in toxicity grade/severity. 


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• SAE (as defined in Section 7.2): Yes or No. 
If, in any 1 subject, the same AE occurs on several occasions (unless the AE is continuous and of 
stable grade), then the AE in question will be documented and assessed each time.  For an SAE, 
the information above recorded in the eCRF will also be recorded in the SAE Report.  Only AEs 
that fulfill the criteria for SAEs (refer to Section 7.2) should be recorded in the SAE Report. 
7.11. Assessing Adverse Event Severity 
To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe”, which are not synonymous, the following note of clarification is 
provided: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as “serious”, which is 
based on subject/event outcome or action criteria usually associated with events that pose a threat 
to a subject’s life or functioning.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
All AEs are to be evaluated with respect to severity using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) grading system (Appendix 7). 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline:  
• 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). Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
• Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Self-care ADL 
refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
• Grade 4 Life-threatening consequences; urgent intervention indicated.  
• Grade 5 Death related to AE. 
7.12. Assessing Adverse Event Relationship to Study Drug 
The Investigator must record his/her opinion concerning the relationship of the AE to study 
therapy on the eCRF.  Investigators will determine relatedness of an event to study drug based on 


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a temporal relationship as well as if the event is unanticipated or unexplained given the subject’s 
clinical course, previous medical conditions, and concomitant medications.  An event should be 
recorded as “drug related” if the Investigator believes it to be reasonably related to study drug. 
7.13. Reporting Serious or Unexpected Adverse Events 
Any SAE, irrespective of the relationship to study drug that occurs during the course of the study 
(from the first dose of study drug through Hospital Discharge, completion of Month 3 or early 
termination) will be reported on the eCRFs and SAE Report as soon as possible (within 24 hours 
after the site becomes aware of the event).   
The Investigator is encouraged to discuss with the Sponsor’s pharmacovigilance group any AE 
for which the issue of reportability is unclear or questioned.   
An SAE Report should be prepared containing as much information as is available concerning 
the event so that a written report can be filed with appropriate regulatory authorities.  If causality 
cannot be definitively assessed at the time of the SAE, it is important to notify Sponsor or its 
designees within the timelines stated above.  When new significant information is obtained and 
the outcome and attribution of the event is known, the Investigator will communicate this 
information to the Sponsor or its designees and/or on the appropriate eCRFs.  The relevant 
information will be provided in a timely manner to allow reporting to regulatory authorities 
within the required reporting period.  Any SAE follow-up information requested by the Sponsor 
or its designees should be provided in a timely manner. 
Additional information may be requested by the Sponsor or its designees to ensure that the initial 
reporting of SAEs is made to regulatory authorities within the requested timeframe.  For a 
follow-up report to the regulatory authorities, the Sponsor or its designees may be required to 
collect further information for a detailed description and a final evaluation of the case, including 
copies of hospital reports, autopsy reports, or other relevant documents. 
The Investigator, or Sponsor (or its designees) where applicable, will notify the relevant 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of any SAEs and safety 
reports according to local regulation requirements. 
7.14. Pregnancy  
All pregnancies that occur during the study must be reported to the Sponsor and followed to 
conclusion. The outcome of each pregnancy must be reported.   
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 


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diagnosis for this procedure should be reported as the SAE term.  A spontaneous abortion is 
always considered an SAE. 
7.15. Discontinuation or Withdrawal  
The criteria for study entry and enrollment must be followed explicitly.  If a subject who does 
not meet the study entry and enrollment criteria is inadvertently enrolled and study drug 
administration has been started, the Investigator should consult with the Sponsor or its designees 
regarding the termination or continuation of the study drug administration.   
If study drug is discontinued, the subject will continue in the study and undergo all study 
assessments per the protocol in order to provide the follow-up data needed for the analysis of the 
entire intent-to-treat population.  Investigator or delegated site personnel will make the effort to 
collect the necessary data per protocol; however, if the subject is to be completely off the study 
per the discretion of the subject, Investigator, or Sponsor, study procedures for Early 
Termination should be completed. 
7.15.1. 
Discontinuation of Study Drug 
Discontinuation of study drug administration is defined as termination of the study drug 
administration without the intent to re-administer at a later time.   
Subjects will discontinue the study drug administration in the following circumstances: 
• The Investigator decides that study drug should be discontinued.  If this decision is made due 
to a serious or intolerable AE or a clinically significant change in a laboratory value, the 
study drug is to be discontinued and appropriate measures taken (refer to Section 7.1).  The 
designated Medical Monitor is to be alerted. 
• The subject stops taking study drug.  If this decision is made because the subject’s condition 
has worsened, the surgical team (doctor) and the designated Medical Monitor should be 
alerted immediately.   
7.15.2. 
Withdrawal from the Study 
In the event that the subject, the subject’s legal representative, the Investigator, or the Sponsor 
decides that the subject should be withdrawn from the study, all scheduled study assessments 
will be discontinued. 
A subject may decide to withdraw from the study at any time.  If a subject refuses to take study 
drug, the subject should be withdrawn from study participation.  If the subject did take a portion 
of the study drug, the subject should remain in the study unless consent is withdrawn.   
The Sponsor or its designees must be alerted if a subject is withdrawn from the study.  A subject 
will be withdrawn from the study in the following situations: 


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• The subject or the subject’s legal representative withdraws consent. 
• The subject did not take any portion of study drug prior to surgery.   
• The Investigator or the Sponsor, for any reason, stops the subject’s participation in the study. 
7.15.3. 
Discontinuation of Study Sites 
Study site participation may be discontinued if the Sponsor, Investigator, or the IRB or IEC of 
the study site judges it necessary for any reason. 
7.15.4. 
Institutional Review Board/Independent Ethics Committee Approval 
The study protocol and Informed Consent Form (ICF), as well as any amendments, will be 
approved by an IRB or IEC as necessary for each study site. 
7.15.5. 
Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for any reason. 


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QUALITY CONTROL AND ASSURANCE 
Study training will be held for all sites prior to first subject enrollment.  To ensure accurate, 
complete, and reliable data, the Sponsor or its representatives will do the following: 
• Provide instructional material to the study sites, as appropriate. 
• Conduct a start-up training session/Site Invitation Visit to instruct the Investigators and 
appropriate site staff.  This session will give instruction on the protocol, the completion of 
the eCRFs, and study procedures. 
• Make periodic visits to the study site. 
• Be available for consultation and stay in contact with the study site personnel by mail, email, 
telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer edits and/or source verification to 
detect errors in data collection. 
• Conduct a quality review of the study database. 
In addition, the Sponsor or its representatives may periodically check subject data recorded 
against source documents at the study site.  The study may be audited by the Sponsor or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs. 
To ensure the safety of subjects in the study, and to ensure accurate, complete, and reliable data, 
the Investigator will keep records of laboratory tests, clinical notes, and subject medical records 
in the subject files as original source documents for the study.  If requested, the Investigator will 
provide the Sponsor, applicable regulatory agencies, and applicable ethical review boards with 
direct access to original source documents and supporting study documentation. 


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PLANNED STATISTICAL METHODS 
9.1. 
General Considerations 
This study employs an adaptive clinical study design feature (interim analyses with possible 
sample size re-estimation).  A comprehensive description of the statistical methods and analyses 
planned for this study will be provided in a Statistical Analysis Plan (SAP) prior to the planned 
interim analysis.   
9.2. 
Determination of Sample Size 
Although this study is not formally powered to detect a significant treatment effect, a sample size 
of 120 subjects is planned for enrollment/randomization and is considered adequate to establish 
proof-of-concept.  The adaptive design of this study may allow for up to 200 total subjects 
enrolled at study completion. 
9.3. 
Statistical Methods 
Specific details about the statistical methods for all assessments, the treatment of missing data, 
and the method of control of the Type I error rate will be provided in the Statistical Analysis Plan 
(SAP). 
9.3.1. 
Adhesions 
Comparisons between the LB1148 and placebo groups with respect to change from baseline in 
extent and severity of intra-abdominal adhesions will be made using the Wilcoxon rank sum test. 
9.3.2. 
Bowel Function 
The primary efficacy analysis will be a time to event analysis (e.g., Cox proportional hazard 
model) with a main effect of treatment and stratified by surgery type (laparotomy versus 
minimally invasive approaches) and stoma (planned stoma versus no stoma).  The p-values 
between the treatment groups will be evaluated using the Wald chi-square test.  The magnitude 
of the treatment effect will be presented as the difference between the LB1148 and placebo arms 
in mean time to event (estimated by area under the Kaplan-Meier survival curve). 
9.4. 
Interim Analysis 
The interim analysis serves to inform the Sponsor about the assumptions that underlie the trial 
procedures, endpoints, and sample size.  The interim analysis will be performed after enrollment 
of approximately 50-60 subjects.  The decision rules for increasing the sample size as well as the 
clinical and statistical considerations required for proper control and minimization of bias will be 
provided in the SAP. 


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ADMINISTRATIVE CONSIDERATIONS 
10.1. Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCPs and the applicable laws and 
regulations.  The Investigator, head of the medical institution, or designee will promptly submit 
the protocol to applicable ethical review boards. 
LB1148 is being studied in the U.S. under an IND application.  Study sites will include 
approximately up to 15 sites in the United States.   
All or some of the obligations of the Sponsor will be assigned to CRO(s). 
10.2. Institutional Review Board or Independent Ethics Committee Approval 
The study protocol and ICF, as well as any amendments, will be approved by the appropriate 
ethical review board (IRB or IEC) prior to initiation of the study at a particular site.  All subjects 
will sign an ICF prior to any study-specific procedures.  Site performance during the study will 
be routinely monitored by a study monitor (refer to Section 10.7).   
Documentation of ethical review board approval of the protocol and ICF must be provided to the 
Sponsor before the study may begin at the study sites.  The IRB/IEC will review the protocol and 
ICF as required in accordance with the ICH GCP guidelines.  Any member of the IRB/IEC who 
is directly affiliated with this study as an Investigator or as site personnel must abstain from the 
vote on the approval of the protocol.   
10.3. Subject Information and Consent 
Written informed consent must be obtained from each subject or legal representative designee if 
subject is unable to sign after the nature of the study has been fully explained in accordance with 
ICH GCPs.  Informed consent must be obtained prior to performing any study-specific 
procedures.   
The subject (or surrogate) and the individual explaining the study will sign the current IRB/IEC-
approved version of the consent form.  A copy of the signed ICF will be given to the subject.  
The date that consent was obtained will be recorded on the eCRF as well as in the subject’s 
chart.   
A copy of the IRB/IEC approved version of the consent form will be provided to the Sponsor.  
The original signed consent form must be maintained at the site and made available for 
inspection, as appropriate.   


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10.4. Subject Confidentiality 
The anonymity of subjects participating in this study must be maintained.  Subjects will be 
identified by their assigned subject number in all written communications between the 
Investigator and Sponsor or its designees.  Site documents that are not submitted to the Sponsor 
or its designees and that identify the subject (e.g., signed informed consent; source 
documents/charts) will be made available to the Sponsor (or its designees) or regulatory 
authorities for inspections, but will be maintained in confidence. 
All study-related information provided by the Sponsor or its designees to the Investigator and not 
previously published, including but not limited to the active study agent identity, the 
Investigator's Brochure, the study protocol, verbal and written communication, study data, assay 
methods and scientific data, will be considered confidential.  In addition, all information 
developed during the conduct of the clinical investigation of the study agent is also considered 
confidential.  Neither the Investigator nor any of his/her employees or agents shall disclose or 
use this information for any purpose other than the performance of the clinical study.  Such 
information shall remain the confidential and proprietary property of the Sponsor, and disclosure 
to others will be limited to other physicians who are conducting studies with the same active 
study agent, the IRB/IEC, and the applicable regulatory authorities except by prior written 
permission of the Sponsor or its agents.  At such time, that information becomes widely and 
publicly available through no fault of the Investigator, the obligation of nondisclosure toward 
that particular information will cease. 
10.5. Case Report Forms and Study Records 
Data collected through the completion of study procedures required by this protocol will be 
recorded in the subject’s chart as source documentation.  This data will then be transcribed onto 
the appropriate eCRFs.   
All information in the eCRFs must be supported by original data in the subject’s medical records.  
All medical records, laboratory printouts, notes made by the physician, and other materials will 
be considered source data and must be available for inspection by the Sponsor, the Sponsor’s 
designees, or governmental representatives.   
Appropriate site personnel training will occur prior to subject enrollment for the study.  The 
Investigator remains responsible for the accuracy and adequacy of all study data.   
Study data will be monitored as described in Section 10.6 and Section 10.7.   
Upon further data processing, queries may be generated and sent to the Investigator for 
clarification or correction.  The Investigator and/or delegated site personnel will address any 
queries and forward resolutions as directed by the site monitor.   


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10.6. Safety Monitoring 
The Sponsor or their designated Medical Monitor will review blinded safety data throughout the 
course of the study.  All SAEs will be reviewed within time frames mandated by company 
procedures and local regulatory requirements.  The Sponsor or their designee will review safety 
trends and laboratory analytes at periodic intervals.   
All deaths and SAE reports will be reviewed in a blinded manner by the Sponsor or its 
designee(s) during the study.  These reports will be reviewed to assure completeness and 
accuracy, but will not be unblinded to the clinical team during the study.  If a death or clinical 
AE is deemed serious, unexpected, and possibly related to study drug (refer to Section 0), only 
the Sponsor or its designees will be unblinded for regulatory reporting and safety monitoring 
purposes (refer to Section 5.5).  The clinical site will have the ability to do an emergency code 
break on an individual subject at their site.  These measures will preserve the integrity of the data 
collected during this study and minimize any potential for bias while providing for appropriate 
safety monitoring. 
10.7. 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 to the 
Sponsor: 
• Subject did not meet study eligibility criteria 
• Subject did not receive the correct treatment assignment 
• Subject received the wrong amount of a dose IP (i.e., ± 20% of assigned dose) 
• Subject received a prohibited concomitant medication 
• Subject was not assessed for intra-abdominal adhesions  
10.8. Study Monitoring and Access to Source Documentation 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study.  If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable ethical 
review boards with direct access to original source documents. 
The Sponsor or its designees (e.g., CRO) will assure the accuracy of data, the selection of 
qualified Investigators, appropriate study centers, and review protocol procedures with the 
Investigators and associated personnel prior to the study and during periodic monitoring visits.  
The Sponsor or its designee will review study data for accuracy and completeness during 
monitoring visits.  Discrepancies will be resolved with the Investigator as appropriate. 


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The Sponsor or its designees will monitor the study using any of the following methods: 
• Frequent telephone contacts; 
• Email; 
• Periodic site visits; 
• Review of original subject records, eCRFs, study drug accountability, and 
• Storage, and general study documentation. 
So that the study may be adequately monitored, the Investigator or delegated site personnel will 
cooperate in providing the Sponsor or its designees with all study documents (e.g., subject charts 
and study files) and responding to inquiries that may arise as a result of the document review. 
Review of these documents will usually occur during a routine monitoring visit, but may also be 
required during a visit by a quality assurance auditor.  The Sponsor reserves the right to 
terminate the study if access to source documentation is denied to the Sponsor or quality 
assurance representatives. 
10.9. Retention of Data 
Source documents are the original documents, data, and records from which the subject’s eCRF 
data are obtained.  These include, but are not limited to, hospital records, clinical and office 
charts, laboratory and pharmacy records, radiographs and correspondence.  eCRF entries may be 
considered source data if the eCRF is the site of the original data recording (i.e. no other written 
or electronic record of the data exists).  All source documents and study documentation will be 
kept by the Investigator for the appropriate retention period as stipulated by the site IRB or FDA 
guidelines, whichever is longer.   
Investigator shall retain study records required 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 study drug.  In the event that study records are relocated to a 
different location from the site location during this study retention period, Investigator must 
notify the Sponsor or its designees. 


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ASA website:  https://www.asahq.org/resources/clinical-information/asa-physical-status-
classification-system, accessed 02 April 2016.   
ASA.  Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce 
the risk of pulmonary aspiration:  application to healthy patients undergoing elective procedures.  
Anastesiol.  2011 March;114(3):495-511. 
Australian Public Assessment.  Report for Tranexamic Acid, December 2010.   
Bahl V, Hu HM, Henke PK, Wakefield TW, Campbell DA Jr, Caprini JA. A validation study of 
a retrospective venous thromboembolism risk scoring method. Ann Surg 2010;251:344-50. 
Berger NG, Ridolfi TJ, Ludwig KA.  Delayed gastrointestinal recovery after abdominal 
operation – role of alvimopan.  Clin Exp Gastroenterol.  2015 Aug;8:230-5.   
Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Breivik Hals EK, 
Kvarstein G, and Stubhaug A.  Assessment of pain.  BJA.  2008 May;100(1):17-24.   
Canadian Cyklokapron Monograph (500 mg tablets and 100 mg/mL injection).  June 2013.   
Caprini JA, Risk assessment as a guide for the prevention of the many faces of venous 
thromboembolism. Am J Surg. 2010 Jan;199(1 Suppl):S3-10.  
Caraceni A, Cherny N, Fainsinger R, Kaasa S, Poulain P, Radbruch L, De Conno F, and the 
Steering Committee of the EAPC Research Network.  Pain measurement tools and methods in 
clinical research in palliative care:  Recommendations of an expert working group of the 
European Association of Palliative Care.  J Pain Symptom Manage.  2002 Mar;23(3):239-55. 
Chang M, Kistler EB and Schmid-Schonbein GW.  Disruption of the mucosal barrier during gut 
ischemia allows entry of digestive enzymes into the intestinal wall.  Shock.  37:297-305, 2012.  
Coccolini F, Ansaloni L, Manfredi R, Campanati L, Poiasina E, Bertoli P et al.  Peritoneal 
adhesion index (PAI): proposal of a score for the “ignored iceberg” of medicine and surgery.  
Wor J Emerg Surg.  2013;8:6-11. 
Dabrowski A, Lepere M, Zaranis C, Coelio C, Hauters P.  Efficacy and safety of a resorbable 
collagen membrane COVA+™ for the prevention of postoperative adhesions in abdominal 
surgery.  Surg Endosc.  2016 Jun;30(6):2358-66.   


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DeCherney AH and Kumar S.  Postoperative peritoneal adhesions in adults and their prevention.  
UpToDate.  01 July 2015.   
DeLano FA, Hoyt DB, Schmid-Schonbein GW.  Pancreatic digestive enzyme blockade in the 
intestine increases survival after experimental shock.  Sci Transl Med.  2013 Jan;5(169):169ra11.   
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12 April 2016.   
Farrar JT, Young Jr. JP, LaMoreaux L, Werth JL and Poole RM.  Clinical importance of changes 
in chronic pain intensity measured on an 11-point numerical pain rating scale.  Pain.  2001 
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Gan TJ, Robinson SB, Oderda GM, Scranton R, Pepin J, Ramamoorthy S.  Impact of 
postsurgical opioid use and ileus on economic outcomes in gastrointestinal surgeries.  Curr Med 
Res Opin.  2015 Apr;31(4):644-86.    
Ghonge NP and Ghonge SD.  Computed tomography and magnetic resonance imaging in the 
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Imaging.  2014 Apr-Jun;24(2):149-55.   
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.   
Halpin A, Huckabay LM, Kozuki JL, Forsythe D.  Weight the benefits of using a 0-to-5 nausea 
scale.  Nurs.  2010 Nov:18-20.   
Iyer S, Saunders WB, Stemkowski S.  Economic burden of postoperative ileus associated with 
colectomy in the United States.  J Manag Care Pharm.  2009, Jul-Aug:15(6):485-94.   
Jakobsen T, Karjagin J, Vipp L, Padar M, Parik AH, Starkopf L, et al.  Postoperative 
complications and mortality after major gastrointestinal surgery.  Medicina (Kaunas).  
2014;50(2):111-7.   
Lobastov K, Barinov V, Schastlivtsev I, Laberko L, Rodoman G, Boyarintsev V. Validation of 
the Caprini risk assessment model for venous thromboembolism in high-risk surgical patients in 
the background of standard prophylaxis. J Vasc Surg Venous Lymphat Disord. 2016 
Apr;4(2):153-60. 
Kalff JC, Schraut WH, Simmons RL, Bauer AJ.  Surgical manipulation of the gut elicits an 
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Korpman TZ, Singleton M, and Zakowski M.  A trio of commentaries on preoperative fasting 
guidelines.  CSA Bulletin.  2012 Spring;61(2):40-5.  
Kraft M, Maclaren R, Su W, Owens G.  Alvimopan (Entereg) for the management of 
postoperative ileus in patients undergoing bowel resection.  P T.  2010 Jan;35(1):44-9.   
Ludwig K, Enker WE, Delaney CP, Wolff BG, Du W, Fort JG, et al.  Gastrointestinal tract 
recovery in patients undergoing bowel resection.  Arch Surg.  2008;143(1):1098-105.   
Lysteda Package Insert.  October 2013.   
NCI-CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm accessed on 08 
August 2016. 
NPRS website:  http://www.partnersagainstpain.com/printouts/A7012AS2.pdf accessed on 14 
April 2016. 
Seprafilm Package Insert.  December 2008.   
Thomas S, Kang G, Balasubramanian K.  Surgical manipulation of the intestine results in 
quantitative and qualitative alterations in luminal Escherichia coli.  Ann Surg. 2004 
Aug;240(2):248-54. 
Vather R, O’Grady G, Bissett IP, Dinning PG.  Pathophysiologic, translational and clinical 
aspects of postoperative ileus – a review.  Proc Aust Physiol Pharmacol Soc.  2013;44:85-99. 
Vather R, O’Grady G, Bissett IP, Dinning PG.  Postoperative ileus: mechanisms and future 
directions for research.  Clin Exp Pharmacol Physio.  2014 May;41(5):358-70.   
Vather R, Josephson R, Jaung R, Kahokehr A, Sammour T, Bissett I.  Gastrografin in prolonged 
postoperative ileus: a double-blinded randomized controlled trial.  Ann Surg.  2015 
Jul;262(1):23-30.   
Ward BC and Panitch A.  Abdominal adhesions:  current and novel therapies.  J Surg Res.  2011 
Jan;165(1):91-111.   
Wolthius AM, Bislenghi G, Fieuws S, de Buck van Overstraeten A, Boeckxstaens G, D’Hoore 
A.  Incidence of prolonged postoperative ileus after colorectal surgery: a systematic review and 
meta-analysis.  Colorectal Dis.  2016 Jan;18(1):O1-9.   
 


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Appendix 1 Schedule of Assessments Protocol LBS-POI-201  
Study Day 
Screening 
Surgical 
Post-Surgical 
Follow-
Up 
Second 
Surgery 
(-42 to -1 
Days)1,2 
Pre-Surgery / 
Surgery 
Day 02 
Post-
Operative 
Days 1-63 
Post-
Operative 
Day 73 
Post-
Operative 
Days 8-143 
Hospital 
Discharge 
(Early 
Termination) 
Day 30 
(+7 Days) 
Up to 8 
Months 
after Day 0 
Informed Consent 
X 
 
 
 
 
 
 
 
Surgery Assessment 
 
X 
 
 
 
 
 
X 
Study Eligibility Assessment4 
X 
X5 
 
 
 
 
 
 
Demographics & Medical 
History5 
X 
X 
 
 
 
 
 
 
Concomitant Medication and 
Blood Products Review5,6 
X 
X 
X 
X 
X 
X 
 
 
Randomization1 
X 
X 
 
 
 
 
 
 
Taste Assessment 
 
X 
 
 
 
 
 
 
Physical Exam7 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
  
X 
Study Drug Administration2,9,10 
X 
X 
 
 
 
 
 
 
Perioperative Surgical  
Preparation11 
X 
X 
 
 
 
 
 
 
Record Opioid Use 
X 
X 
X 
X 
X 
X 
 
 
Pain Assessment 
 
X 
X 
X 
X 
X 
 
X 


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Study Day 
Screening 
Surgical 
Post-Surgical 
Follow-
Up 
Second 
Surgery 
(-42 to -1 
Days)1,2 
Pre-Surgery / 
Surgery 
Day 02 
Post-
Operative 
Days 1-63 
Post-
Operative 
Day 73 
Post-
Operative 
Days 8-143 
Hospital 
Discharge 
(Early 
Termination) 
Day 30 
(+7 Days) 
Up to 8 
Months 
after Day 0 
GI Function Assessment 
 
 
 
 
 
 
 
 
Nausea 
 
 
X 
X 
X 
X 
 
 
Vomiting or Retching 
 
 
X 
X 
X 
X 
 
 
Flatus12 
 
 
X 
X 
X 
X 
 
 
Stools12 
 
 
X 
X 
X 
X 
 
 
NG/OG Tube 
 
 
X 
X 
X 
X 
 
 
Liquid Diet12 
 
 
X 
X 
X 
X 
 
 
Solid Diet12 
 
 
X 
X 
X 
X 
 
 
Adhesions Count 
 
X 
 
 
 
 
 
X 
Hospital Discharge 
 
 
 
 
 
 
 
 
Hospital Discharge Order 
Written 
 
 
X 
X 
X 
X 
 
 
Hospital Departure 
 
 
X 
X 
X 
X 
 
 
Subject’s Willingness To 
Discharge 
 
 
X 
X 
X 
X 
 
 
Adverse Events (AE) 
X 
X 
X 
X 
X 
X 
X13 
X14 
Local Laboratory Tests15 
 
 
 
 
 
 
 
 
Urine or Serum Pregnancy 
Test4,5 
X 
X 
 
 
 
 
 
 
Labs (CBC, coagulation, and 
metabolic)15  
X 
 
X 
X 
 
 
 
 
Abbreviations:  GI = gastrointestinal.   


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1 Screening and Day 0 (Pre-Operative/Pre-Surgery) can be combined if the visit is on the day of first surgery.  If this is the case, randomization will be performed 
during this study visit. 
2 Study Day 0 starts on the calendar day of the surgery; study dosing could occur Day -1 and/or up to 2 hours prior to surgery on Day 0.  
3 Subject will be monitored from Screening through Post-Operative Days 14 until Hospital Discharge or Study Termination (whichever occurs first).  
4 Eligibility assessment will include, if applicable, a negative pregnancy test.   
5 Document any changes to subject’s condition that affect inclusion/exclusion criteria.  Subject must meet all inclusion/exclusion criteria at time of the surgery.  
As part of medical history review, Caprini risk factor score will be calculated and tobacco use recorded.   
6 Concomitant medications taken within 14 days of randomization will be recorded during the Screening visit and through Post-Operative Day14 or Hospital 
Discharge or Study Termination (whichever comes first).   
7 Screening physical exam includes weight measurement and height measurements, lower extremity assessment to identify any clinical symptoms of VTE, 
assessment of venous port or venous catheter, varicose veins, superficial vein thrombosis, and BMI. Focused examinations include lower extremity assessment to 
identify any clinical symptoms of VTE and weight measurements from Day 0 through Post-Operative Days 14 until Hospital Discharge or Study Termination 
(whichever comes first). 
8 For data capture, use the vital signs (BP - systolic and diastolic measurements, HR, RR, oxygen saturation, and temperature) taken the closest to 0800 during 
the Surgical and Post-Surgical periods.  For the re-operation Adhesion Evaluation, vitals should be recorded prior to surgery. 
9 The study drug (a total of 700 mL) is administered orally prior to surgery as a split dose.  For the first study drug administration, subjects will consume 350 mL 
(at any rate of consumption) 6-10 hours prior to surgery.  The second study drug administration, subject will consume the remaining 350 mL (at any rate of 
consumption) 2-6 hours prior to surgery.  Note: There is no co-administration of food or drink with the study drug.  Eating, bowel preparation, and drinking 
should be withheld 1 hour before and 1 hour after study drug administration. 
10 Please refer to Section 9.4 for information regarding possible changes to the study after interim analysis evaluation.   
11 Capture all perioperative items the subject was given or consumed, including but not limited to, mechanical bowel prep, nutritional supplements, carbohydrate 
drinks, opioids, and analgesia.     
12 For flatus and stool, record the first noted event; if subject experiences POI, record the next event of flatus, and/or stool until resolution.  Diet changes (liquid, 
solid, NPO) will be monitored. 
13 Phone call for follow-up to gather any hospital readmission and vital status after initial hospital discharge information.  Only readmissions (SAEs) should 
recorded and reported. 
14 Only AE/SAEs related to the surgical procedure will be recorded and reported. 
15 Refer to Error! Reference source not found. for a list of Laboratory Tests.  Labs are collected on Screening and Post-Operative Day 3.  Post-Operative Day 7 
labs will only need to be performed only if subject is still hospitalized.  


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Appendix 2 List of Laboratory Tests 
 
Hematology (CBC) without differential: 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Red blood cell (RBC) count  
White blood cell (WBC) count 
  
Liver Function Tests: 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Bilirubin  
 
Urine or serum human chorionic 
gonadotropin (hCG) – collected only at 
Screening and prior to Surgery (Day 0) 
Basic Metabolic Panel (BMP):  
Serum chloride 
Creatinine 
Glucose 
Serum sodium 
Serum potassium 
Carbon dioxide (CO2) 
Blood urea nitrogen (BUN) 
 
Coagulation: 
Partial Thromboplastin Time (PTT) 
Prothrombin Time and International 
Normalized Ratio (PT-INR) 
 
  


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Appendix 3 Nausea Verbal Rating Scoring (VRS) Scale  
 
Score 
Measure 
Definition 
0 
None 
No nausea 
1 
Anticipated 
Nausea is anticipated and prophylaxis medications may be 
given. 
2 
Mild 
Nausea reported.  Able to tolerate food or medications by 
mouth. 
3 
Moderate 
Nausea persisting.  Lacks appetite.  Able to eat small meals 
occasionally. 
4 
Great 
Nausea ongoing.  No appetite.  Unable to tolerate 
food/medications by mouth. 
5 
Severe 
Nausea with dry heaves reported. 
 
Source:  Halpin et al., 2010.  
 


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Appendix 4 Pain Scoring  
 
Source:  NPRS website. 


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Appendix 5 Intra-Abdominal Adhesion Extent and Severity Assessment 
Worksheet  
 
 
 
 
 
References:  Coccolini et al., 2013, Dabrowski et al., 2016, and the Seprafilm Package Insert. 
Abdominal 
Wall to Bowel 
Abdominal 
Wall to Bowel 
Bowel to Bowel 
(or Viscera)
Bowel to Bowel 
(or Viscera)
Extent Score 
Severity Score
Extent Score
A Right upper
B Epigastrium
C Left upper
D Left flank
E Left lower
F Pelvis
G Right lower
H Right flank
I
Central
Severity Score
Abdominal 
Regions
3 = dense thickness, vascularized
Adhesion Extent Score 
Adhesion Severity Score 
0 = no adhesion
0 = no adhesions
1 = minimal (<1/3 of the site is covered)
1 = filmy thickness, avascular
2 = moderate (1/3 to 2/3 of the site is covered)
2 = moderate thickness, limited vascularity
3 = extensive (>2/3 of the site is covered)
Location of Abdominal Regions


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Appendix 6 American Society of Anesthesiologists Classification System 
The ASA Physical Status Classification System was last approved by the ASA House of 
Delegates on 15 October 2014.   
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.  
Examples: 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.  
Examples: 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, premature 
infant post-conceptional age <60 weeks, 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. 
Examples: recent (<3 months) MI, CVA, TIA, or 
CAD/stents, ongoing cardiac ischemia or severe 
valve dysfunction, severe reduction of ejection 
fraction, sepsis, DIC, ARD or ESRD not undergoing 
regularly scheduled dialysis.   
ASA V 
A moribund patient 
who is not expected to 
survive without the 
operation. 
Examples: 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.   
*The addition of “E” denotes Emergency surgery: An emergency is defined as existing when delay in treatment of 
the patient would lead to a significant increase in the threat to life or body part. 
Source:  ASA website.   


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Appendix 7 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 8 American College of Chest Physicians (ACCP) Guidelines - Caprini 
Risk Factor Score 
 
 
Abbreviations:  BMI = Body Mass Index; COPD = Chronic Obstructive Pulmonary Disease; DVT = Deep Vein 
Thrombosis; PE = Pulmonary Embolism. 
References:  Bahl et al., 2010, Caprini et al., 2010, and Lobostov et al., 2015. 
 


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Appendix 9 Protocol Amendment Summary 
Amendment #1 - 17 August 2016 
Amendment 1 to the protocol includes revisions requested by FDA. Changes are summarized as 
follows: 
• Assessments of respiratory rate and pluse oximetry were added to the vital signs to evaluate 
for respiratory signs associated with pulmonary embolism/thromboembolism. 
• Specific venous thrombosis examinations were added to the schedule of study events, such as 
lower extremity examination for DVT and other clinical signs of venous thrombosis in major 
organs, such as cardiac, cerebral, pulmonary and GI. 
• Exclusion criteria were updated to exclude patients with the following risk factors for 
thromboembolic disease: known medical history of thrombophilia (e.g. Factor V Leiden, 
prothrombin gene mutation); Stage IV malignant neoplasm; neurologic paresis, partial 
paralysis, or paralysis; pacemaker; and history of pulmonary embolism, deep vein 
thrombosis, cerebrovascular accident or rental venous/artierial occlusion. 
• Exclusion critieria updated to exclue patients patients with a history of or current seizure 
disorder. 
• Specific safety sub-analyses included to assess the safety of LB1148 in the following patient 
populations: patients who are on chemotherapy; patients with a venous port or catheter; 
patients with varicose veins and superficial vein thrombosis; patients with varying degrees of 
obesity; patients who are smokers; patients with varying degrees of renal function; and patient 
age groups, including 65-80 years old. 
• Calculation of Caprini risk factor score during the medical history collection. 
• Inclusion of weight measurements and lower extremity assessments to identify any clinical 
symptoms of venous thromboembolic. 
• Inclusion of respiratory rate, oxygen saturation and pulse rate during vital sign collection. 
• Adverse events to be evaluated with respect to severity using the National Cancer Institute 
Common Terminology criteria for Adverse Events grading system 
Amendment #2 - 18 August 2016 
Amendment 1 to the protocol includes revisions requested by FDA.  Changes are summarized as 
follows: 
• Exclusion criteria were updated to exclude patients with BMI >40.  
• Exclusion criteria were updated to exclude patients with congenital or acquired 
thrombophilia such as, but not limited to, patients with sickle cell disease, nephrotic 
syndrome, Factor V Leiden, prothrombin gene mutation, Protein C or S deficiency, 
antithrombin III deficiency, and antiphospholipid syndrome. 
• Exclusion criteria were updated to exclude patients with myeloproliferative disorders. 


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• Added assessment for risk factors of VTE to Demographics and Medical History. 
• Added VTE prophylaxis to perioperative standardization of care. 
 Amendment #3 - 13 June 2019 
Amendment 3 includes revisions to the study objectives and associated endpoints, as well as 
updates to perioperative care.  The objectives were change to be in alignment with other key 
clinical studies, and the perioperative care requirements were updated to be in alignment with 
current standard of care.  Changes are summarized as follows: 
• The time (hours) to recovery of GI function as defined by achieving GI2 was moved from a 
secondary objective to a primary objective.   
o The associated endpoints for GI2 were moved to be primary endpoints.   
• The previous primary objective was moved to a secondary objective (time [hours] from 
surgical closure to resolution or appearance, as appropriate, of 1 or more of the components 
common to GI dysfunction following elective bowel resection with or without a planned 
stoma).   
o The endpoints associated with GI dysfunction were moved to be secondary endpoints.   
• The requirement for the use of acetaminophen and a planned morphine or fentanyl PCA were 
removed from the perioperative care requirements for what a subject must receive.   
• The use of planned edidural anesthesia or TAP was removed from the perioperative care 
requirements for what a subject must not receive.   
Amendment #4 – 17 June 2021 
The overall purpose of the amendment is to: 
• Change the primary endpoint from return of bowel function to extent and severity of 
adhesions 
• Add a planned laproscopic surgery (second surgery) at Month 3 for the purpose of ostomy 
take down and/or adhesiolysis, and for the surgeon to determine the incidence, extent, and 
severity of adhesions. 
• Make Adverse Events Assessments its own section (Section 7) 
• Change the company name from Leading Biosciences, Inc. to Palisade Bio, Inc. 
• Add the name and contact information of the Medical Monitor. 
• Fix minor/administrative errors and inconsistencies. 
Impact on the Informed Consent Form: the ICF will be updated to reflect the planned laproscopic 
surgery at Month 3. 
Refer to the table below for a detailed list of changes. 


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Section 
Change 
Rationale 
General 
Changed company name from 
Leading Biosciences, Inc. to 
Palisade Bio, Inc. throughout the 
document 
• Reflects new company name 
Title Page 
Changed sponsor name and contact 
information to that of the Medical 
Monitor 
• Medical Monitor will be primary 
point of contact for the sponsor 
Synopsis – Clinical 
Sites 
• Changed North America and 
Europe to United States 
• Study will be performed in the 
United States only 
Synopsis – Primary 
Objective 
• Changed to: “To compare the 
change from baseline in extent 
and severity of intra-abdominal 
adhesions among subjects treated 
with LB1148 or placebo.” 
• Made original exploratory 
objective the primary 
Synopsis – 
Secondary 
Objectives 
• Moved original primary 
objective to secondary: 
“Compare time from surgical 
closure to resolution or 
appearance, as appropriate, of 1 
or more of the components 
common to gastrointestinal (GI) 
dysfunction following elective 
bowel resection with or without a 
planned stoma.” 
• Added the following secondary 
objectives: 
o Compare the extent and 
severity of intra-abdominal 
adhesions following the second 
surgery among subjects treated 
with LB1148 or placebo. 
o Compare change from baseline 
in incidence, extent, and 
severity of intra-abdominal 
adhesions among subjects 
treated with LB1148 or placebo 
who had adhesions observed at 
the time of the first surgery. 
• Minor edits to clarify objectives 
• Made original exploratory 
objective the primary 
 
 
 
 
 
 
 
 
• Additional analyses of adhesions 
Synopsis – 
Exploratory 
Objectives 
• Moved adhesion objective to 
primary 
• Removed language “For subjects 
who undergo a planned second 
abdominal reoperation, the 
• NA 
 
• All subjects will now undergo 
second surgery 


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Section 
Change 
Rationale 
exploratory objectives of this 
study are to determine if LB1148 
decreases….” 
Synopsis – Study 
Design 
• Provided additional detail to the 
study design description 
• Specified timing of adhesion 
determination by surgeon 
• Added a second surgery for all 
subjects, regardless of presence 
of stoma: “Within 3 months (± 1 
month) of enrollment, subjects 
will undergo a laproscopic 
surgery (second surgery) for the 
purpose of ostomy take down 
and/or adhesiolysis, the surgeon 
will determine the incidence, 
extent, and severity of 
adhesions.” 
• To specify procedures and 
timepoints 
• To provide specificity around 
timing of adhesion measurement 
• To obtain data for new primary 
endpoint 
Synopsis – Inclusion 
Criteria 
• Added: (2) “Willing to perform 
and comply with all study 
procedures including attending 
clinic visit as scheduled and 
completion of a second surgery 
for ostomy or adhesiolysis and to 
determine the presence of intra-
abdominal adhesions.” 
• To ensure subjects agree to 
second surgery 
Synopsis – 
Exclusion Criteria 
• Added (14) “Planned use of 4% 
icodextrin (Adept®) or 
SEPRAFILM during the first 
surgery.”  
• Use of these devices could 
confound interpretation of 
adhesion analyses 
Synopsis – Duration 
of Subject 
Participation 
• Changed to a total of 5 months: 
screen through second surgery) 
• All subjects will have a second 
surgery, therefore participation 
will be the same for all subjects 
Synopsis – Efficacy 
Assessments 
• Grouped by type (e.g., adhesion, 
bowel function) 
• Adhesions: added incidence 
 
• Bowel function: edited language 
for clarity 
• Added “Other Endpoints” 
category 
• Added “NOTE: Subjects may not 
be discharged until all of the 
following criteria are met:”  
• For clarity 
 
• Will now include analysis of 
adhesion incidence 
• For clarity 
 
• For clarity 
 
• To ensure data for secondary 
endpoints are collected before 
discharge 


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Section 
Change 
Rationale 
Synopsis – Safety 
Endpoints 
• Added vital signs and move 
clinical laboratory results to first 
paragraph 
• For clarity 
Synopsis – 
Statistical Methods 
• Added methods for analyzing 
adhesion data 
• To provide methods for 
analyzing new primary endpoint 
2. Study Obectives 
and Endpoints 
• Added “Endpoints” to section 
title 
• Updated per changes described 
for the synopsis above for 
primary, secondary, exploratory 
objectives  
• Updated per changes described 
for the synopsis above for 
primary, secondary, other, and 
safety endpoints  
• For clarity 
 
• See above 
 
 
• See above 
3.1 Overall Study 
Design and Plan 
• Updated per changes described 
for the synopsis above for study 
design 
• Revised schematic to show 
second surgery at Month 3 for 
adhesion assessment 
• See above 
 
 
• To reflect change to timing of 
adhesion assessment 
3.2 Rationale for 
Study Design, 
Control Group, and 
Perioperative 
Standardization 
• Added rationale for laproscopic 
surgery at Month 3 for 
assessment of adhesions 
• To support data collection for 
adhesion assessment 
3.3 Study Duration 
and Dates 
• Updated per changes described 
for the synopsis above for 
duration of subject participation 
• See above 
4.1 Study Population • Changed North America and 
Europe to United States 
• Study will be performed in the 
United States only 
4.2 Inclusion 
Criteria 
• Updated per changes described 
for the synopsis above for 
inclusion criteria 
• See above 
4.3 Exclusion 
Criteria 
• Updated per changes described 
for the synopsis above for 
exclusion criteria 
• See above 
5.6 Concomitant 
Therapy 
• Added prohibition of “Receive 
4% icodextrin (Adept®) or 
SEPRAFILM during the first 
surgery”  
• Use of these devices could 
confound interpretation of 
adhesion analyses 


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Section 
Change 
Rationale 
Original 6.5 Second 
Surgical Reoperation 
Assessment 
• Moved to Section 6.16 and 
combined with Adhesions 
Assessment 
• All subjects will have second 
surgery for adhesion assessment 
6.16 Adhesion 
Assessment (Day 0 
and Month 3 ± 1 
month 
• ¶-1 Added timing and purpose of 
adhesion assessment at first and 
second surgeries 
• ¶-2 Removed assessment of 
adhesions at ostomy 
• For clarity 
 
 
• To provide consistency in 
adhesion assessment among all 
subjects (not all will have 
ostomy) 
Original 6.18 
• Removed Adhesions Evaluation 
for Planned Second Reoperation 
• Replaced with updated section 
6.16 
New Section 7 
Adverse Events 
Assessments 
• Separated out Adverse Events 
Assessmentst to it’s own section 
• ¶-1 updated period of SAE 
reporting to first administration 
of study drug through Month 3 
visit 
• ¶-2 Edited to reflect all subjects 
will have AEs/SAEs related to 
second surgery reported 
• For clarity 
 
• To collect all SAEs, including 
hospital readmissions, through 
second surgery 
 
• For clarity 
7.9 Adverse Event 
Reporting Period 
• To make consistent with ¶-1 and 
2, as described above 
• For clarity 
7.13 Reporting 
Serious or 
Unexpected Adverse 
Events 
• Specified duration of reporting 
through Month 3 (second 
surgery) 
• For consistency throughout 
section 7 
9.3.1 Adhesions 
• Added methods for analyzing 
adhesion data (9.3.1) 
• To provide methods for 
analyzing new primary endpoint 
10.1 Regulatory 
Considerations 
• ¶-2 Changed North America and 
Europe to United States 
• Study will be performed in the 
United States only 
11 References 
• Added: 
o Adept Package Insert 
o Brown, et al. 2007 
• References relevant to second 
surgery 
Appendix 1 – 
Schedule of 
Assessments  
• Updated to relect Month 3 visit 
(second surgery) for all subjects 
• Edited footnote 14 to reflect 
AE/SAE reporting for second 
surgery 
• To reflect changes to protocol 
text 
Appendix 5 - Intra-
Abdominal 
Adhesion Extent and 
• Removed scoring for ostomy 
regions 
• No longer scoring ostomy 
regions 


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Section 
Change 
Rationale 
Severity Assessment 
Worksheet 
Appendix 7 -
National Cancer 
Institute Common 
Terminology 
Criteria for Adverse 
Events (NCI-
CTCAE) 
• Removed text and added 
hyperlink to the NCI-CTCAE 
website 
• For clarity 
Amendment #5 – 24 August 2021 
The overall purpose of the amendment is to: 
• Limit enrollment to only subjects who will undergo an elective (non-emergent) bowel 
resection with a planned stoma and a planned stoma takedown or other planned abdominal 
surgery within 8 months after the initial surgery 
• Clarified Physical Exam procedure 
• Added section on Pregnancy Reporting 
• Added section on Protocol Deviations 
• Removed references no longer referred to 
• Corrected minor typographical errors 
Impact on the Informed Consent Form: the ICF will be updated to reflect the changes to study 
population and planned second surgery 
Refer to the table below for a detailed list of changes. 
Section 
Change 
Rationale 
Synopsis – 
Secondary 
Objectives 
• Removed “or without”… a 
planned stoma 
• Excluding subjects who will not 
have a planned stoma and 
therefore will not have a planned 
second surgery 
Synopsis – Study 
Design 
• Changed ¶1 to reflect that only 
subjects with planned stoma or 
other planned abdominal surgery 
will be enrolled 
• Exclude subjects who will not 
have a planned stoma or other 
abdominal surgery and therefore 
will not have a planned second 
surgery 
• Changed ¶5 to address timing 
and purpose of second surgery 
• This time period allows for a 
subject to undergo and recover 
from cancer treatment prior to a 
second surgery for stoma 
takedown 


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Section 
Change 
Rationale 
Synopsis – Inclusion 
Criteria 
• Criteria #1 – removed subjects 
without a planned stoma 
• Exclude subjects who will not 
need a second surgery 
• Added criteria #2 for having a 
planned stoma takedown or other 
planned abdominal surgery 
(second surgery) within 8 months 
of the initial surgery 
• To ensure subjects will be 
evaluable for adhesions 
• Added to criteria #3 “…or other 
abdominal surgery” 
• Removed “and/or adhesiolysis” 
from criteria #3  
• Consistency with other criteria 
 
• No longer relevant 
Synopsis – Duration 
of Subject Study 
Participation 
• Changed from 5 months to “up to 
10 months” 
• To reflect change to timing in 
second surgery 
2.1.2 Secondary 
Objectives 
• Removed “or without”… a 
planned stoma 
• As stated above 
3.1 Overall Study 
Design and Plan 
• Changed ¶1 to reflect that only 
subjects with planned stoma or 
other planned abdominal surgery 
will be enrolled 
• As stated above 
• Changed ¶5 to address timing 
and purpose of second surgery 
• As stated above 
3.2.  Rationale for 
Study Design, 
Control Group, and 
Perioperative 
Standardization 
• Changed ¶1 to reflect that only 
subjects with planned stoma or 
other planned abdominal surgery 
will be enrolled 
• As stated above 
• Removed rational for second 
surgery in non-stoma subjects 
• No longer relevant 
3.3.  Study Duration 
and Dates 
• Changed from 5 months to “up 
to10 months” 
• As stated above 
4.2 Inclusion 
Criteria 
• Criteria #1 – removed subjects 
without a planned stoma  
• As stated above 
• Added criteria #2 for having a 
planned stoma takedown or other 
planned abdominal surgery 
within 8 months of the initial 
surgery 
• As stated above 
• Added to criteria #3 “…or other 
abdominal surgery” 
• Removed “and/or adhesiolysis” 
from criteria #3 
• As stated above 


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Section 
Change 
Rationale 
6.16 Adhesions 
Assessment 
• Changed ¶5 from “at the Month 
5-8 visit” to “At the second 
surgery” 
• Consistency 
6.3 Physical exam 
• To modify type of physical exam 
performed at Screening 
(Complete) and from Days 0-Day 
14/discharge from hospital 
(Focused) 
• To better reflect standard of care 
and required safety assessments 
6.16 Adhesion 
Assessment 
• Change second assessment 
timing to 5-8 months (Section 
Title and ¶5) 
• As stated above 
7 Adverse Events 
• Changed hospital readmission 
reporting period to the “second 
surgery” and removed “(Months 
5-8)”  
• Consistency 
7.14 Pregnancy 
• Added section to require 
reporting of pregnancies and 
clarify when a pregnancy is an 
AE 
• Data were being collected but not 
stated in original protocol 
10.7 Protocol 
Deviations 
• Added definition of “important 
protocol deviations” and 
reporting requirements 
• Not included in original protocol 
11. References 
• Removed ADEPT Package Insert 
and Brown reference 
• No longer relevant 
Appendix 1 – 
Schedule of 
Assessments 
• Changed “Adhesion Evaluation” 
column header to “Second 
Surgery 
• Adhesion Evaluation is required 
on Day 0 and second surgery 
• Changed timing of second 
surgery to  “Up to 8 Months after 
Day 0” 
• To reflect changes in amended 
protocol 
• Removed word “Complete” from 
physical exam row 
• To reflect change in amended 
protocol 
Amendment #6 – 26 August 2022 
The overall purpose of the this amendment was to: 
• Update the exclusion criteria to align this with the recently cleared phase 3 Return of Bowel 
Function clinical trial, IND #158008 
• Update typographical errors 
• Update Sponsor address  
Refer to the table below for a detailed list of changes. 


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Section 
Change 
Rationale 
Title Page 
• Removed ‘North America and 
Europe’and replaced with United 
States 
• Updated Sponsor address 
• This was updated per 
Amendment 4 but was not 
updated on this page 
• This is Sponsor’s current 
business address  
Sponsor Signature 
• Added 
and 
removed 
  
• Reflects Sponsor’s current 
process for protocol sign-off 
Synopsis – Study 
Design 
• Updated ¶2, 1st sentence to  
reflect when randomization 
should occur (Day -1 instead of 
Day 0) 
• Reflects the timing per the 
Schedule of Assessments when 
the site should randomize a 
subject 
Synopsis – 
Exclusion Criteria  
• Removed exclusion 5 ‘insulin 
dependent diabetes mellitus’ 
• Removed exclusion 8 ‘risk 
factors for thromboembolic 
events’ 
• Removed exclusion 11 ‘body 
mass index (BMI) > 40’ 
• Removed exclusion 16 ‘chronic 
opioid usage’ 
• Added new exclusion 7 ‘has 
peritoneal carcinomatosis’ 
• For the removal of exclusion 
criteria 5, 7 and 11, these were 
removed to align this with the 
recently cleared phase 3 
‘INTEGRITY’ clinical trial 
• Chronic opioid usage was 
removed as the study is enrolling 
only subjects that require a stoma 
and the primary endpoint is 
assessing adhesions per 
amendment 4 
• Added exclusion criteria 7, has 
peritoneal carcinomatosis, as this 
would not be suitable subject to 
receive study drug 
Synopsis – 
Perioperative 
Standardization of 
Care 
• Removed NPO and updated with 
‘Anything by mouth’ 
• The lead-in sentence started with 
‘not’ so removed the double 
negative  
3.1 Overall Study 
Design and Plan 
• Updated ¶2, 1st sentence to  
reflect when randomization 
should occur (Day -1 instead of 
Day 0) 
• Reflects the timing per the 
Schedule of Assessments when 
the site should randomize a 
subject 
3.2 Perioperative 
Standardization of 
Care 
• Removed NPO and updated with 
‘Anything by mouth’ 
• The lead-in sentence started with 
‘not’ so removed the double 
negative  
4.3 Exclusion 
Criteria 
• Removed exclusion 5 ‘insulin 
dependent diabetes mellitus’ 
• Removed exclusion 8 ‘risk 
factors for thromboembolic 
events’ 
• For the removal of exclusion 
criteria 5, 7 and 11, these were 
removed to align this with the 
recently cleared phase 3 
‘INTEGRITY’ clinical trial 


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Section 
Change 
Rationale 
• Removed exclusion 11 ‘body 
mass index (BMI) > 40’ 
• Removed exclusion 16 ‘chronic 
opioid usage’ 
• Added new exclusion 7 ‘has 
peritoneal carcinomatosis’ 
• Chronic opioid usage was 
removed as the study is enrolling 
only subjects that require a stoma 
and the primary endpoint is 
assessing adhesions per 
amendment 4 
• Added exclusion criteria 7, has 
peritoneal carcinomatosis, as this 
would not be suitable subject to 
receive study drug 
5.6 Concomitant 
Therapy 
• Removed ‘receive a planned 
epidural anesthesia or TAP block 
anesthesia  
• This was updated per 
Amendment 3 but was not 
previously removed on this page 
6.2 Demographic 
and Medical History  
• Added to collect the subject’s 
prior or current use of tobacco 
• This was to be collected per the 
original protocol’s Schedule of 
Assessments  
6.3 Physical 
Examination 
• Updated ¶1 to delineate height to 
collect at the Screening visit only 
• Updated ¶2 to delineate the 
focused physical exam 
• This was the intent of the original 
protocol and updates were made 
for clarification when each 
assessment should be completed  
6.6 Vital Signs 
• Removed pulse rate 
• The protocol is capturing heart 
rate so this is redundant  
6.7.1 Pregnancy Test • Removed the language after the 
1st sentence 
• Clarified when the pregnancy 
test, whether serum or urine, 
need to be completed 
6.9 Perioperative 
Surgical Preparation  
• Removed NPO and updated with 
‘Anything by mouth’ 
• The lead-in sentence started with 
‘not’ so removed the double 
negative  
6.12 Pain 
Assessment  
• Updated last paragraph for when 
the first pain assessment should 
be collected  
• Clarified when the first pain 
assessment should be collected 
post-surgery  
Appendix 1 
Schedule of 
Assessments  
• Removed physical exam at the 
2nd surgery 
• Removed collecting opiod use at 
the 2nd surgery 
• Removed collecting pregnancy 
test at the 2nd surgery  
• Updated footer note 4, 6, 7, and 9 
• This prior protocol amendment 4 
and 5 updates should have 
removed the physical exam, 
recording opioids and obtaining a 
pregnancy test at the 2nd surgery 
• Footers were updated for 
clarification and consistency  
Appendix 2 List of 
Laboratory Tests 
• Updated when the urine or serum 
hCG tests should be collected 
• Clarified for consistency  
 

SAP_003.pdf: 
Statistical Analysis Plan 
Palisade Bio, Inc. LBS-POI-201 
Version 3.0 
March 10, 2023 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Protocol Number: 
LBS-POI-201 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Proof 
of Concept Study to Evaluate LB1148 for Return of 
Gastrointestinal Function, Post-Operative Ileus and Intra- 
Abdominal Adhesions in Subjects Undergoing Elective 
Bowel Resection (PROFILE) 
Product Name or Number: 
LB1148 
Sponsor: 
Palisade Bio, Inc. 
5800 Armada Drive, Suite 210 
Carlsbad, CA 92008 
 
SAP Prepared by: 
[redacted] 
 
Innovative Analytics, Inc. 
161 East Michigan Ave. 
Kalamazoo, MI 49007 
USA 
 
SAP Version Number (Date): 
Version 3.0 (March 10, 2023) 
Protocol Version Number (Date) 
Amendment #6 (Aug 26, 2022) 


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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................... 4 
2 
STUDY OVERVIEW .......................................................................................................... 6 
3 
STUDY OBJECTIVES ........................................................................................................ 7 
3.1 
Primary Objective ............................................................................................................ 7 
3.2 
Secondary Objectives ....................................................................................................... 7 
3.3 
Exploratory Objectives ..................................................................................................... 7 
4 
GENERAL METHODS ....................................................................................................... 8 
4.1 
Analysis Populations ........................................................................................................ 8 
4.2 
Summarization of Data .................................................................................................... 8 
4.3 
Sample Size Justification and Randomization ................................................................. 9 
4.4 
Data Handling .................................................................................................................. 9 
4.4.1 Method for Handling Missing Data .............................................................................. 9 
4.4.2 Definition of Baseline Values ...................................................................................... 9 
4.4.3 Windowing of Visits .................................................................................................. 10 
4.4.4 Justification of Pooling ............................................................................................... 10 
4.5 
Output Production and Validation ................................................................................. 10 
5 
SUBJECT DISPOSITION ................................................................................................. 10 
6 
DEMOGRAPHIC CHARACTERISTICS ......................................................................... 10 
7 
MEDICAL HISTORY ....................................................................................................... 10 
8 
SURGICAL PLANS AND ASSESSMENTS .................................................................... 11 
9 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................... 11 
10 
DRUG EXPOSURE ........................................................................................................... 11 
11 
EFFICACY ANALYSIS .................................................................................................... 11 
11.1 
Primary Endpoints .......................................................................................................... 11 
11.1.1 Intra-Abdominal Adhesions ....................................................................................... 11 
11.2 
Secondary Endpoints ...................................................................................................... 13 
11.2.1 Intra-Abdominal Adhesions ....................................................................................... 13 
11.2.2 Bowel Function Endpoints ......................................................................................... 13 
11.3 
Exploratory Endpoints ................................................................................................... 15 


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11.4 
Censoring Rules ............................................................................................................. 16 
11.5 
Efficacy Time-to-Event Parameter by Analysis Type ................................................... 16 
12 
SAFETY ANALYSIS ........................................................................................................ 17 
12.1 
Adverse Events............................................................................................................... 17 
12.2 
Laboratory Tests ............................................................................................................ 18 
12.3 
Physical Examinations ................................................................................................... 18 
12.4 
Vital Signs ...................................................................................................................... 18 
13 
SUBJECT LISTINGS ........................................................................................................ 19 
14 
INTERIM ANALYSES ..................................................................................................... 19 
15 
APPENDIX A .................................................................................................................... 20 
16 
FINAL SIGN-OFF FOR Palisade BiO LBS-POI-201 STATISTICAL 
ANALYSIS PLAN ............................................................................................................. 23 
17 
REVISIONS TO STATISTICAL ANALYSIS PLAN ...................................................... 24 


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1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Term 
Definition 
 
AE 
adverse event 
BMI 
body mass index 
BP 
blood pressure 
CDC 
Centers for Disease Control 
CMS 
Centers for Medicare & Medicaid Services 
COVID-19 
coronavirus disease 2019 
GI 
gastrointestinal 
HR 
heart rate 
IV 
intravenous 
LBS 
Leading BioSciences (previous Sponsor name) 
LB1148 
investigational product - the active ingredient, TXA, is formulated in a 
solution containing PEG, glucose, electrolytes, and water 
LOS 
length of stay 
mcg 
microgram 
mg 
milligram 
mITT 
modified intent-to-treat 
MME 
Morphine milligram equivalent 
NG 
nasogastric tube 
NPRS 
Numeric Pain Rating Scale 
OG 
orogastric tube 
PAI 
Peritoneal Adhesion Index 
PD 
protocol deviation 
PEG 
polyethylene glycol 
PH 
proportional hazards 
PBI 
Palisade Bio, Inc. (Sponsor) 
POI 
post-operative ileus 
PP 
per protocol 
PV 
protocol violation 
SAE 
serious adverse event 
SD 
standard deviation 
SOP 
standard operating procedure 
TXA 
tranexamic acid - the active ingredient in LB1148 
VRS 
verbal rating score 
VTE 
venous thromboembolism 


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Abbreviation or Term 
Definition 
 
WHO 
World Health Organization 
 


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2 STUDY OVERVIEW 
This 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. 
The study is randomized to control for factors known and unknown between the treatment groups, 
and neither the Investigator nor the subject will know which treatment the subject will receive in 
order to avoid any bias in the study assessments. 
This study is composed of 5 periods: Screening, Surgical, Post-Surgical, Follow-Up, and Second 
Surgery. 
Subjects scheduled for elective bowel resection, aged 18 to 80 years inclusive, will be screened 
within 42 days of randomization (Study Day 1). Subjects who meet all inclusion and no exclusion 
criteria, and provide written informed consent, will be stratified by: 1) surgical approach (either 
minimally invasive technique or laparotomy) and 2) with or without a planned stoma, and then 
randomized to receive a split oral liquid dose of LB1148 or placebo (polyethylene glycol [PEG], 
glucose, and electrolytes) in a in a 1:1 ratio. (Note: Stratification factor #2 does not apply for 
subjects randomized after 01Jan2022 based on Protocol Amendment #5 updates because all 
subjects should have a stoma.) 
All subjects will receive 350 mL of study drug (test article) 6-10 and 2-6 hours prior to surgery 
(Study Day 1/2). Subjects will then undergo the first surgery. Prior to surgical closure, the 
investigator will determine the incidence, extent, and severity of adhesions using the Intra- 
Abdominal Adhesion Extent and Severity Assessment Worksheet (Study Protocol, Appendix 5). 
Subjects will be assessed for safety and tolerability, including AEs, physical exam, vital signs, 
clinical lab tests (chemistry, coagulation, and hematology) while in the hospital and on Day 30. 
Subjects will be monitored for return of bowel function while in the hospital and discharged 
following tolerance of solid food and first bowel movement. 
Within 8 months of enrollment, subjects will undergo a second surgery for the purpose of ostomy 
takedown or other planned abdominal surgery, at which time the surgeon will determine the 
incidence, extent, and severity of adhesions. If a subject is not ready for the second surgery by 8 
months, the investigator may consult with Medical Monitor to obtain window approval. 
Unless required for safety reasons or protocol compliance, all subjects, Investigators, and study 
site personnel will remain blinded to the identity of the treatment from time of randomization until 
final database lock. 
The Schedule of Assessments is provided in Appendix 1 of the protocol. 
The study will evaluate the extent and severity of adhesions, as provided in the primary objective 
(Section 3.1), in order to determine the overall test article effect. Additionally, an evaluation of the 
secondary (Section 3.2) and exploratory objectives (Section 3.3) related to return of GI function, 
pain, and POI will be performed. 


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3 STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective of this study is to compare the change from baseline in extent and severity 
of intra-abdominal adhesions among subjects treated with LB1148 or placebo. 
3.2 Secondary Objectives 
The secondary objectives of this study are to determine the following among subjects treated with 
LB1148 or placebo: 
• Compare time from surgical closure to resolution or appearance, as appropriate, of 1 or 
more of the components common to gastrointestinal (GI) dysfunction following elective 
bowel resection with a planned stoma. 
o Number of hours to GI2 (see Section 11.2.1 for definition) 
o Number of hours to GI3 (see Section 11.2.1 for definition) 
o Number of hours to resolution of POI 
• Compare hospital length of stay (LOS, recorded in hours) through Discharge or Day 14 
(whichever comes first). 
• Compare the incidence of intra-abdominal adhesions at the opening of the second surgery 
(operationally this occurs at the time of opening) 
• Compare the extent and severity of intra-abdominal adhesions at the opening the second 
surgery, (operationally this occurs at the time of opening) 
• Compare the change from baseline in incidence, extent, and severity of intra-abdominal 
adhesions among subjects who had adhesions observed at the time of the first surgery 
• An additional objective of this study is the evaluation of the safety and tolerability of 
LB1148 in subjects undergoing elective bowel resection. 
3.3 Exploratory Objectives 
The exploratory objectives of this study are to determine if LB1148 reduces the: 
• Post-operative abdominal pain (first surgery only) 
• Incidence of bowel obstruction through 30 days post-operatively (first surgery only) 
• Incidence of hospital re-admittance through 30 days post-operatively (first surgery only) 
• Volume of blood product transfusions needed on the day of surgery (first surgery only) 


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4 GENERAL METHODS 
4.1 Analysis Populations 
Due to coronavirus disease 2019 (COVID-19), some subjects enrolled and randomized prior to 
01Jan2022 were released from the hospital prior to achieving GI2. In addition, subjects were 
randomized based on whether the surgery was to include a stoma or not and a subject was 
considered completed at Study Day 30, e.g., the second surgery was optional. Protocol Amendment 
5 and 6 require subjects to have a stoma during the first surgery and require the second surgery for 
the subjects to be considered complete. The primary endpoint is now comparing the change from 
baseline in extent and severity of intra-abdominal adhesions rather than GI2 among subjects treated 
with LB1148 or placebo. These circumstances and changes require corresponding updates to the 
populations defined in the Study Protocol. 
The modified Intent-to-Treat (mITT) population includes all randomized subjects who received 
any investigational test article on or after 01Jan2022, where subjects will be analyzed according 
to the treatment to which they were randomized. 
Safety Population: The safety population will be defined as all subjects who receive any amount 
of investigational test article. Subjects will be analyzed according to the treatment actually 
received. 
The Per Protocol Population (PP) includes subjects in the mITT population who met all inclusion 
and no exclusion criteria, received the complete appropriate study dose, and had no important 
protocol deviations or violations, where subjects will be analyzed according to the treatment to 
which they were randomized. 
Study subjects may be replaced if found to be ineligible (violation of one or more 
inclusion/exclusion criteria), or if following randomization, did not go on to receive ANY amount 
of investigational test article. 
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, standard deviation (SD), 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 mITT 
(all efficacy endpoints) and PP Populations (primary efficacy endpoint and selected secondary 
efficacy endpoints), while the safety analyses will be performed for the Safety Population. All 
statistical tests will be 2-sided, with p-values considered nominal for this proof-of-concept study, 
although a p-value <0.05 will be highlighted. Unless otherwise specified, p-values will be reported 
to four (4) digits. No multiplicity adjustments will be performed. 


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4.3 Sample Size Justification and Randomization 
This proof-of-concept study was originally designed to utilize an adaptive sample size re- 
estimation to allow for sample size adjustment based on observed data from the interim analysis. 
No formal knowledge of the effect size is given; therefore, no power calculations were used to 
assess type I and type II error rates. The goal of this study is to assess the observed effect size at 
the interim and adjust sample size accordingly. 
Initially, subjects were randomized into an active or placebo group following a 1:1 ratio while 
stratified for surgery type (laparotomy or minimally invasive) and stoma (planned or unplanned). 
After the first 50-60 subjects were enrolled, an interim analysis was planned to assess GI2 and 
LOS (Discharge Order Written) endpoints. If the treatment effect size, conditional power, or 
reproducibility probability was deemed insufficient at the interim, then the sample size would be 
increased accordingly, from 120 up to 200 subjects. 
The sample size justification as originally designed no longer applies to the new primary endpoint 
(change from baseline in extent and severity of intra-abdominal adhesions among subjects treated 
with LB1148 or placebo). Enrolling up to 40 subjects is estimated to provide at least 30 randomized 
subjects, which should be adequate to explore the feasibility of the new endpoint. The data 
collected from the subjects in this study will be available to power a future study using this 
endpoint. 
Subjects randomized after 01Jan2022 were randomized by surgery type but within the planned 
stoma arm only. 
4.4 Data Handling 
4.4.1 Method for Handling Missing Data 
No imputation of missing data will be performed except for times when dates are present in “time 
to” analyses. In those occasions, the latest or earliest time in that day will be imputed (11:59 pm 
or 12:01 am) to obtain the worst case (longest) for the “time to” being analyzed. (i.e., longest when 
the endpoint is favorable and shortest when the endpoint is unfavorable.) Time fields in the listings 
will not include the imputation, however, the computed “time to” fields will. 
4.4.2 Day 
Start Date and End Date fields in the listings have a Day associated with them. Day = 1 will be 
determined by the date/time of when the first split dose of the test article is consumed. Days prior 
to this will be negative. 
In the tables and listings when referring to a specific Visit, e.g., Day 0, Day 1,…, ,Day 14, refer 
to Visit names given in Appendix 1 Schedule of Assessments in the study protocol. 
4.4.3 Definition of Baseline Values 
Unless otherwise specified, Baseline values are defined as the last values collected before the first 
split dose of test article. 


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4.4.4 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). 
4.4.5 Justification of Pooling 
Due to the expected low enrollment of subjects at each site, and the multitude of selected sites, 
data from all sites will be pooled. Study center or treatment-by-center interaction terms will not be 
included in statistical analyses. 
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 treated, complete the study, and reasons for discontinuation from 
the study will be summarized in tabular format for the safety population separately by subjects 
enrolled prior to 01Jan2022 and subjects enrolled after 01Jan2022. Subject disposition will also 
be displayed for the safety population in a subject listing. 
6 DEMOGRAPHIC CHARACTERISTICS 
Demographic and other characteristics will be summarized by treatment group and consist of (but 
will not be limited to) the following: age, sex, ethnicity, race, height, weight, and BMI. 
For quantitative variables, summary statistics (n, mean, SD, minimum, first quartile, median, third 
quartile, and maximum) will be presented for the safety population. For qualitative variables, 
results will be summarized as counts and percentages for the stratified safety population. 
Demographic and other characteristics will be tabulated also for the mITT population. 
Individual demographic and other characteristics for the safety population will be displayed in 
subject listings. A variable indicating enrollment stratification will be included in the listing. 
7 MEDICAL HISTORY 
All medical history events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding system (Version 25.0). Medical history events (past and current medical 
disorders) will be presented by treatment group for the safety population, summarized by MedDRA 
System Organ Class (SOC) and Preferred Term. 
Medical history events will be displayed for the safety population in a subject listing. Specific 
medical history will also be summarized and listed for the safety population. 


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8 SURGICAL PLANS AND ASSESSMENTS 
A frequency table will be presented by treatment group for first and second surgical approach and 
the presence (absence) of a stoma. The table will be sub-divided by subjects enrolled prior to 
01Jan2022 and subjects enrolled on or after 01Jan2022. All surgery information will be listed for 
the safety population. 
9 PRIOR AND CONCOMITANT MEDICATIONS 
All medications will be coded using the World Health Organization Drug Dictionary (WHO Drug) 
version March 2022. 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 split dose of 
study medication and ongoing is No and a stop date prior to the date of the first split dose 
of study medication. 
o Medications with an unknown stop date will be considered concomitant 
• 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. All concomitant 
treatments or procedures will be listed for the safety population. 
10 DRUG EXPOSURE 
The number and percent of subjects who consumed all of one or both doses will be presented by 
treatment group for the safety population. The estimated volume of each dose received will be 
summarized by treatment group. Subject satisfaction with the taste will also be presented by 
treatment group for the safety population. Additionally, subject satisfaction will be further 
classified by those who completed both doses and those who did not within treatment group. All 
findings will be displayed in subject listings. A symmetric scatter plot matrix will be used to 
display via histograms and scatter plots the relationship between Time to GI2, Change in Adhesion 
Score, and Time from last dose to start of surgery. There will be one cell in a plot matrix for each 
stratum surgery type (laparoscopic, minimally invasive) and for each of the test articles (LB1148, 
placebo). 
11 EFFICACY ANALYSIS 
11.1 Primary Endpoints 
11.1.1 Intra-Abdominal Adhesions 
The primary efficacy endpoint for this study involves intra-abdominal adhesions and is as follows: 


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• Extent and severity of intra-abdominal adhesions as determined by the surgeon using the 
Intra-Abdominal Adhesion Extent and Severity Assessment Worksheet (Appendix 5 of the 
protocol) 
If successful, this proof-of-concept study should provide necessary statistical information that 
when combined with information on clinical significance will allow for the computation of 
meaningful effect size and power calculations to support a subsequent phase 3 study(ies) with the 
following hypotheses: The null hypothesis for these primary efficacy endpoints is that there is no 
significant difference in intra-abdominal adhesions (extent and severity) between treatment 
groups; the alternative hypothesis is that there is a significant reduction in intra-abdominal 
adhesions (extent and severity) between treatment groups. 
The presence or absence of adhesions, surgeon-recorded values for the extent and severity of 
visible intra-abdominal adhesions using the Intra-Abdominal Adhesion Extent and Severity 
(Appendix 5 of the protocol) will be recorded at both the first and second surgeries. The following 
nine variables will be calculated at both the first and second surgeries and summarized: 
1. Summed Bowel-to-Abdominal Wall Adhesions Extent Score = bowel-to- 
abdominal wall extent scores summed across all 9 quadrants 
2. Summed Bowel-to-Abdominal Wall Adhesions Severity Score = bowel-to- 
abdominal wall severity scores summed across all 9 quadrants 
3. Bowel-to-Abdominal Wall Summed Extent and Severity Scores = add the Bowel- 
to-Abdominal Wall extent and severity scores together 
4. Summed Bowel-to-Bowel Adhesions Extent Score = bowel-to-bowel extent scores 
summed across all 9 quadrants 
5. Summed Bowel-to-Bowel Adhesions Severity Score = bowel-to-bowel severity 
scores summed across all 9 quadrants 
6. Bowel-to-Bowel Summed Extent and Severity Scores = add the Bowel-to-Bowel 
extent and severity scores together 
7. Bowel-to-Abdominal Wall and Bowel-to-Bowel Summed Extent and Severity 
Scores = add the Bowel-to-Abdominal Wall Summed Extent and Severity Scores 
(i.e., [3] above) to the Bowel-to-Bowel Summed Extent and Severity Scores (i.e., 
[6] above) 
8. Take the Maximum of the Bowel-to-Bowel Severity Scores over all 9 regions 
9. Bowel to Abdominal Wall Summed Severity Score added to the maximum Bowel 
to Bowel Severity Scores over the 9 regions, i.e., [2] and [8] are summed to obtain 
the Cocclini Peritoneal Adhesion Index (PAI) 
Descriptive statistics as detailed in Section 4.2 as well as 95% confidence intervals will be provided 
for the nine extent and severity score detailed above across treatment groups and stratified by 
surgery type. 
The summed extent and severity scores specified above (only # 7) will be compared between 
treatment groups at both the first and second surgeries, using a van Elteren test which allows for 


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the incorporation of the stratification factor type of surgery (laparotomy versus minimally invasive 
approaches) into the analysis. Additionally, the change from baseline in the summed extent and 
severity scores (i.e., from the first surgery to the second surgery) will be compared between 
treatment groups using a van Elteren test, again allowing control for surgery type. (This 
comparison will also be performed for that subgroup of subjects who had adhesions observed at 
the time of the first surgery.) 
As stated in Section 4.2, all p-values obtained will be considered nominal. 
All results will be summarized by treatment group for the mITT and PP populations. All findings 
will be presented in subject listings for the mITT population. 
11.2 Secondary Endpoints 
11.2.1 Intra-Abdominal Adhesions 
The secondary efficacy endpoints for this study involve intra-abdominal adhesions and are as 
follows: 
• Incidence of intra-abdominal adhesions at the second surgery 
Intra-abdominal lesions (Y/N) will be compared between treatment groups (LB1148 or 
Placebo) at both the first and second surgeries, analyzed using counts and percentages with 
comparisons made using the Cochran-Mantel-Haenszel (CMH) to obtain 95% Wald 
Confidence limits for the relative risk of adhesions along with the chi-square test, which 
allows for the incorporation of the stratification factor type of surgery (laparotomy versus 
minimally invasive approaches) into the analysis chi-square test for homogeneity of 
proportions. The change in proportion between the two surgeries will be evaluated across 
treatment and stratified by surgery type. 
• Extent and severity of adhesions at the second surgery (Incorporated into the tables leading 
to the primary endpoint) 
• Change from baseline in the incidence of intra-abdominal adhesions (Simple shift table) 
• Compare change from baseline in incidence, extent, and severity of intra-abdominal 
adhesions among subjects treated with LB1148 or placebo who had adhesions observed at 
the time of the first surgery. (A subset of the primary endpoint analysis.) 
• Compare number of adhesions between the LB1148 and placebo groups 
• Compare change between the two surgeries in the number of adhesions between the 
LB1148 and placebo groups 
11.2.2 Bowel Function Endpoints 
The secondary efficacy endpoints include the number of hours from surgical closure to 
resolution or presence, as appropriate, of: 
• Achievement of GI2, defined as the toleration of solid food (subject finished a meal that 
required chewing and experienced no significant nausea/vomiting for four hours) and the 


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recovery of the upper and lower GI tract (first bowel movement; passage of stool) 
following surgery (the time the last skin staple or suture was placed by the surgeon) 
• Nausea with a Verbal Rating Score (VRS) ≥3 (moderate to severe) (Listing only) 
• Vomiting or retching* (Listing only) 
• Presence of flatus (Listing only) 
• Bowel movement (presence of stool from anus or ostomy) 
• Insertion and reinsertion of nasogastric (NG)/orogastric (OG) tube* 
o Removal of NG/OG tube* (Listing only) 
• Ability to tolerate a liquid oral diet (liquid diet ordered, and subject is able to sustain oral 
liquid intake without need for IV fluid administration for hydration) 
• Ability to tolerate a solid oral diet (solid food ingestion without significant 
nausea/vomiting for four hours) 
• Achievement of GI3, identical to GI2 except recovery of the upper and lower GI tract is 
defined by either bowel movement or flatus 
• Resolution of POI, defined as having resolved when all of the following criteria are met: 
o Absence of nausea AND 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 
The following POI parameters will also be evaluated: 
• Incidence of POI (Within 14 days of first surgery, After Discharge), defined as the 
greater than expected inability to tolerate liquids or solids during the post-operative 
period 
o Within 14 days of first surgery subjects will be identified by AE preferred term 
(PT) and by a confirmatory imaging study within the start/stop dates of the POI 
▪ The AE PTs are ileus, post-operative ileus, small bowel obstruction, bowel 
obstruction, partial bowel obstruction, mechanical bowel obstruction, and 
non-mechanical bowel obstruction 
• Incidence of POI after hospital discharge 
o 
Subjects will be identified by AE PT as listed above 
*Vomiting and retching, as well as insertion, reinsertion, and removal of NG/OG tube will be 
treated as binary (yes/no) variables. 
Selected time-to-event secondary efficacy endpoints (See Table in Section 11.5) will be analyzed 
using a stratified Cox PH model with treatment as the main effect, stratified by surgery type 
(laparotomy versus minimally invasive). In addition to surgery type, a categorical age (<65 years, 
>= 65 years) will be included. Nominal p-values will be reported. Comparison of treatment groups 
and assessment of the significance of the parameter estimates for surgery type will be made using 
the Wald chi-square test. 


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In addition to the semi-parametric Cox PH model, non-parametric Kaplan-Meier survival curves 
will be produced for the two treatment groups and compared using a stratified log-rank test; results 
from this test will be considered nominal/hypothesis-generating in nature. The number of hours to 
each endpoint will be presented in summary tables with descriptive statistics for the mITT (all 
variables selected) and PP populations (POI, GI2, and GI3 variables only). 
Those endpoints defined as yes/no variables will be analyzed using a chi-square test for 
homogeneity of proportions. 
All findings will be presented in subject listings for the mITT population, including calculated 
time to event efficacy variables. 
11.3 Exploratory Endpoints 
The exploratory endpoints are: 
• 
Hospital LOS (number of days in the hospital, evaluated in hours) will be measured first 
by time to discharge order is written. The time will start at time of surgical closure and 
run until discharge order is written. 
• Pain values, evaluated using 
o Values recorded from the NPRS 
o Analgesia consumption, including totals for opioid use and morphine equivalents 
▪ See Section 15 APPENDIX A for conversion guidelines 
• The number of subjects with recorded bowel obstructions (Listing only) 
o AE Preferred Terms having the phrase ”bowel obstruction” in them e.g., small 
bowel obstruction 
• The number of subjects with a hospital re-admission 
• Blood product transfusion volume on the day of surgery (Listing only) 
The following LOS parameters will also be evaluated: 
• Time from surgical closure to actual discharge 
• Time from surgical closure to standard discharge (Listing only) The time will start at time 
of surgical closure and run until all four criteria for discharge have been met. The criteria 
are: 
o Passage of stool 
o Ability to tolerate solid food and drink comfortably 
o Adequate oral analgesia, and 
o Subject’s willingness to be discharged 
Selected time-to-event endpoints (See Table in Section11.5) will be analyzed using a stratified 
Cox PH model with treatment as the main effect, stratified by surgery type (laparotomy versus 
minimally invasive). Comparison of treatment groups and assessment of the significance of the 


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parameter estimates for surgery type will be made using the Wald chi-square test. In addition to 
the semi-parametric Cox PH model, non-parametric Kaplan-Meier survival curves will be 
produced for the two treatment groups and compared using a stratified log-rank test. The number 
of hours to each endpoint will be presented in summary tables with descriptive statistics for the 
mITT and PP populations. 
Pain assessments will be collected daily from surgery (Day 0) through post-operative Day 14 (or 
for as long as the patient remains hospitalized), at hospital discharge, and at the second surgery. 
All exploratory endpoints will be summarized by treatment group, except where it is indicated that 
only a listing will be provided. For continuous endpoints, summary statistics (n, mean, SD, 
minimum, first quartile, median, third quartile, maximum) will be presented for the mITT 
population, with comparisons of means made using the van Elteren test (Justification previously 
provided in Section 11.1.1.) For categorical endpoints, counts and percentages will be presented 
for the mITT population, with comparisons of proportions made using CMH with Wald 90% CIs 
(Justification previously provided in Section 11.1.111.1.1). 
All results will be listed for the mITT population, including calculated time to event efficacy 
variables. 
 
 
11.4 Censoring Rules 
 
Condition (within 14 days of surgery) 
Censoring 
No(t) Z1 but death report 
Censoring at Study Day 14 
No(t) Z1 and the subject is lost to follow-up or withdrew 
informed consent 
Censoring at Study Day 14 
No(t) Z1 within 14 days after surgery 
Censoring at Study Day 14 
1Where Z is GI2, GI3, bowel movement, liquid oral diet, solid oral diet, discharge order 
written, actually discharged from hospital 
11.5 Efficacy Time-to-Event Parameter by Analysis Type 
 
Number of hours 
to Analysis 
Cox PH 
Kaplan-Meier 
Other 
mITT 
PP 
mITT 
PP 
mITT 
PP 
GI2 
Yes 
Yes 
Yes 
Yes 
Frequency Table 
Frequency Table 
Bowel movement 
within 14 days 
Yes 
No 
Yes 
No 
Frequency Table 
No 
NG/OG 
use 
(insertion, 
reinsertion) 
No 
No 
No 
No 
Frequency Table 
only 
No 
NG/OG removal 
No 
No 
No 
No 
Listing only 
No 
Liquid oral diet 
No 
No 
Yes 
No 
Frequency Table 
No 
Solid oral diet 
Yes 
No 
Yes 
No 
Frequency Table 
No 
GI3 
Yes 
Yes 
Yes 
Yes 
Frequency Table 
Frequency Table 
POI within 14 
days 
Yes 
Yes 
Yes 
Yes 
Frequency Table 
Frequency Table 


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Number of hours 
to Analysis 
Cox PH 
Kaplan-Meier 
Other 
POI after 
discharge 
No 
No 
No 
No 
Included in 
Frequency Table 
for POI within 
14 days 
No 
Discharge 
order 
written 
Yes 
Yes 
Yes 
Yes 
No separate 
descriptive 
Frequency Table 
No separate 
descriptive 
Frequency Table 
Actual discharge 
Yes 
Yes 
Yes 
Yes 
No separate 
descriptive 
Frequency Table 
No separate 
descriptive 
Frequency Table 
Standard 
discharge 
No 
No 
No 
No 
Listing only 
No 
Nausea 
No 
No 
No 
No 
Listing only 
No 
Vomiting 
No 
No 
No 
No 
Listing only 
No 
Flatus 
No 
No 
No 
No 
Listing only 
No 
 
12 SAFETY ANALYSIS 
12.1 Adverse Events 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding system (Version 25.0). Frequency tables will be presented by treatment group 
for all adverse events (AEs) by system organ class and preferred term for the safety population. 
Frequency tables will also be presented for AEs leading to discontinuation of test article, AEs by 
maximum severity (per CTCAE Version 5.0 Section 7.11 Study Protocol), AEs related to test 
article, and serious AEs. Subject listings of all AEs will also be provided for the safety population. 
In all displays, adverse events will be displayed by MedDRA System Organ Class (SOC) and 
Preferred Terms. 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 system organ class will be counted 
only once in that system organ class. (The addition of severity or relatedness follow the same 
pattern.) 
In addition, frequency tables by treatment group for all AEs by system organ class and preferred 
term will be presented for the following populations: 
• Patients who have had chemotherapy in the last 60 days 
• Patients with a venous port or catheter 
• Patients with varicose veins and superficial vein thrombosis 
• Patients with varying degrees of obesity 
o Baseline BMI 30-35 
o Baseline BMI 35-40 
• Patients who are smokers 
• Patients with varying degrees of renal function 


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o Baseline eGFR 45-59 
o Baseline eGFR 30-44 
o Baseline eGFR 15-29 
o Baseline eGFR < 15 
• Patient age groups 
o 18-64 years 
o 65-80 years 
12.2 Laboratory Tests 
Safety labs are performed at Screening and on post-operative Day 3, and post-operative Day 7 (if 
subject is still hospitalized). For hematology, chemistry, and coagulation, summary statistics (n, 
mean, SD, 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. 
Pregnancy tests are performed at Screening and before each 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 from Screening through post-operative Day 14 (or 
for as long as the patient remains hospitalized), at hospital discharge, and at the second surgery (if 
applicable). Each physical examination includes weight measurements and lower extremity 
assessments to identify any clinical symptoms of venous thromboembolism (VTE). Height is 
measured at the Screening visit only. 
A frequency table of lower extremity assessment findings will be presented by treatment group for 
the safety population. 
All physical exam and lower extremity assessment findings will be displayed in subject listings 
for the safety population. 
12.4 Vital Signs 
Vital signs will be collected daily from Screening through post-operative Day 14 (or for as long as 
the patient remains hospitalized), at hospital discharge, and at the second surgery. Summary 
statistics (n, mean, SD, 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, 
oxygen saturation, 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. 


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All vital signs results will be displayed in subject listings for the safety population. 
13 SUBJECT LISTINGS 
All data that are collected and entered into the study database will be presented in subject listings. 
14 INTERIM ANALYSES 
An interim analysis of limited efficacy, safety, and tolerability was proposed in the initial study 
protocol. The purpose of the interim analysis was to allow for sample size adjustment based on 
observed data, e.g., an increase in sample size, if needed. An interim analysis with primary 
endpoints return of bowel function (GI2) and LOS (Discharge Order Written) was performed in 
the spring of 2020. Efficacy and safety tables were provided to the sponsor in May of 2020. 
The change in primary endpoint with Protocol Amendment #5 modified the emphasis of this study. 
No change in sample size was made because the endpoints reviewed were no longer the primary 
endpoints. As previously discussed in Section 4.1, the subjects used for this analysis are now 
included only in the safety population. 


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15 APPENDIX A 
MME Calculator Guidance 
1. Determine the total daily amount of each opioid the subject takes 
2. Convert each to MMEs by multiplying the dose for each opioid by the conversion factor 
(see table below) 
3. Add them together 
 
Use the formula: Strength per unit (units in table below) X (number of units/day) X MME factor 
= MME/day 
Example for Hydrocodone 5/325, 2 units BID: 5mg X 4 X 1 = 20 MME/day 
 
Type of Opioid (strength units) 
MME Conversion Factor 
Buprenorphine film/tabletiii (mg) 
Buprenorphineiii (mcg/hr) 
Buprenorphineiii (mcg) 
Butorphanol (mg) 
7 
Codeine (mg) 
0.15 
Dihydrocodeine (mg) 
0.25 
Fentanyl buccal or SL tablets, or lozenge/trocheiv (mcg) 
0.13 
Fentanyl film or oral sprayv (mcg) 
0.18 
Fentanyl nasal sprayvi (mcg) 
0.16 
Fentanyl patchvii (mcg) 
7.2 
Hydrocodone (mg) 
1 
Hydromorphone (mg) 
4 
Levorphanol tartrate (mg) 
11 
Meperidine hydrochloride (mg) 
0.1 
Methadoneviii (mg) 
3 
>0, ≤20 
4 
>20, ≤40 
8 
>40, ≤60 
10 
>60 
12 
Morphine (mg) 
1 
Opium (mg) 
1 
Oxycondone (mg) 
1.5 
Oxymorphone (mg) 
3 
Pentazocine (mg) 
0.37 
Tapentadolix (mg) 
0.4 
Tramadol (mg) 
0.1 
i The MME conversion factor is intended only for analytic purposes where prescription data are 
used to calculate daily MME. Use the formula: Strength per Unit X (Number of Units/ Days 


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Supply) X MME conversion factor = MME/Day. This value does not constitute clinical guidance 
or recommendations for converting patients from one form of opioid analgesic to another. Please 
consult the manufacturer’s full prescribing information for such guidance. Use of this file for the 
purposes of any clinical decision-making warrants caution. This is particularly true with regard 
to methadone (see viii below). 
ii National Center for Injury Prevention and Control. CDC compilation of benzodiazepines, 
muscle relaxants, stimulants, zolpidem, and opioid analgesics with oral morphine milligram 
equivalent conversion factors, 2017 version. Atlanta, GA: Centers for Disease Control and 
Prevention; Available at https://www.cdc.gov/drugoverdose/resources/data.html . For more 
information, send an email to Mbohm@cdc.gov" Mbohm@cdc.gov. 
iii Buprenorphine products are listed but do not have an associated MME conversion factor. 
These buprenorphine products, as partial opioid agonists, are not expected to be associated with 
overdose risk in the same dose-dependent manner as doses for full agonist opioids. The 
conversion factors for drugs prescribed or provided as part of medication-assisted treatment for 
opioid use disorder should not be used to benchmark against dosage thresholds meant for opioids 
prescribed for pain. 
iv The MME conversion factor for fentanyl buccal tablets, sublingual tablets, and 
lozenges/troche is 0.13. This conversion factor should be multiplied by the number of 
micrograms in a given tablet or lozenge/troche. 
v The MME conversion factor for fentanyl film and oral spray is 0.18. This reflects a 40% 
greater bioavailability for films compared to lozenges/tablets and 38% greater bioavailability for 
oral sprays compared to lozenges/tablets. 
vi The MME conversion factor for fentanyl nasal spray is 0.16, which reflects a 20% greater 
bioavailability for sprays compared to lozenges/tablets. 
vii The MME conversion factor for fentanyl patches is based on the assumption that one 
milligram of parenteral fentanyl is equivalent to 100 milligrams of oral morphine and that one 
patch delivers the dispensed micrograms per hour over a 24 hour day. Example: 25 ug/hr 
fentanyl patch X 24 hrs = 600 ug/day fentanyl = 60 mg/day oral morphine milligram equivalent. 
In other words, the conversion factor not accounting for days of use would be 60/25 or 2.4. 
However, since the fentanyl patch remains in place for 3 days, we have multiplied the conversion 
factor by 3 (2.4 X 3 = 7.2). In this example, MME/day for ten 25 µg/hr fentanyl patches 
dispensed for use over 30 days would work out as follows: Example: 25 ug/hr fentanyl patch X 
(10 patches/30 days) X 7.2 = 60 MME/day. Please note that because this allowance has been 
made based on the typical dosage of one fentanyl patch per 3 days, you should first change all 
Days Supply in your prescription data to follow this standard, i.e., Days Supply for fentanyl 
patches= # of patches X 3. 
viii The CDC MME conversion factor to calculate morphine milligram equivalents of methadone 
is 3. Calculating MME for methadone in clinical practice often involves a sliding-scale approach 
whereby the conversion factor increases with increasing dose since the conversion factor of 3 for 
methadone could underestimate MME for a given patient. CMS uses this conversion factor when 
analyzing Medicare population opioid use. CMS uses the graduated methadone MME conversion 
factors to calculate MME within the Overutilization Monitoring System (OMS) for identifying 


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and reporting potential opioid overutilizers. 
https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf. 
ix Tapentadol is a mu receptor agonist and norepinephrine reuptake inhibitor. Oral MMEs are 
based on degree of mu receptor agonist activity, but it is unknown if this drug is associated with 
overdose in the same dose-dependent manner as observed with medications that are solely mu 
receptor agonists. 


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16 FINAL SIGN-OFF FOR PALISADE BIO LBS-POI-201 STATISTICAL 
ANALYSIS PLAN 
 
 
[ redacted ] 
Biostatistician 
Innovative Analytics 
 
 
 
[ redacted ] 
VP Clinical Operations 
Palisade Bio 
Date 
 
 
 
 
 
 
 
 
 
 
Date 


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17 REVISIONS TO STATISTICAL ANALYSIS PLAN 
 
Date 
Revision 
October 11, 2022 
Version 2.0: Extensive revisions reflect the changes made to the study protocol 
covering Amendments 4, 5, and 6. The most significant change was the in the 
designation of the primary endpoint. The primary endpoint was changed from 
the number of hours from surgical closure to return of GI function as measured 
by GI2 to compare the change from baseline in extent and severity of intra- 
abdominal adhesions among subjects treated with LB1148 or placebo. Another 
significant change increased the alpha to 0.10 and changed the CIs from 95% to 
90%. 
March 10, 2023 
Version 3.0: The following statement was returned to this version of the SAP. 
“All statistical tests will be 2-sided, with p-values considered nominal. A p- 
value < 0.05 will be highlighted.” Gender and BMI added to models in specific 
efficacy analyses. An analysis was added regarding time between drug 
administration and actual surgery start time and efficacy between the two 
treatment groups. Confidence intervals were changed from 90% back to 95% 
throughout. Cocclini scoring system added to the primary endpoint. One shift 
table was added to better display the change in number of adhesions between 
the two surgeries.