Phase II, Multicentre, Randomized, Controlled, Two Arm, Single Blind Study to Assess Safety and Efficacy of D-PLEX Administered Concomitantly With SOC, Compared to SOC, in Prevention of Post Abdominal Surgery Incisional Infection.
Phase: PHASE2
Conditions: Abdominal Surgery, Colon Surgery, Post-Op Infection
Sponsor: PolyPid Ltd.



D-PLEX 310 Clinical Trial Protocol
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CONFIDENTIAL 
INVESTIGATOR SIGNATURE 
Protocol #: 
Study D-PLEX 310 
Protocol Title: 
Phase II, Prospective, Multicentre, Randomized, 
Controlled, Two arm, Single Blind, Study to 
assess 
Safety 
and 
Efficacy 
of 
D-PLEX 
Administered Concomitantly with the Standard 
of Care (SOC), compared to SOC treated control 
arm, in prevention of post abdominal surgery 
incisional infection. 
Protocol Version: 
04 
Protocol Date: 
27 Nov 2018 
I have read this clinical trial protocol and appendices and I agree to adhere to the 
requirements. I will provide copies of this clinical trial protocol and all pertinent 
information to the trial personnel under my supervision. I will discuss this material with 
them and ensure they are fully informed regarding the IP and the conduct of the trial. 
I will conduct the trial in accordance with the clinical trial protocol, ICH GCP guidelines, as 
well as local regulations. I also accept respective revisions to the clinical trial protocol 
approved by authorized personnel of the Sponsor and by regulatory authorities. 
This document contains proprietary and confidential information of PolyPid. Do not copy, 
distribute, or share with others without prior written authorization from PolyPid 
Principal Investigator (print) 
Principal Investigator (signature) 
Date 

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CONFIDENTIAL 
Clarification to Exclusion # 2 
Add inclusion criteria for survival 
expectancy after randomization 
 
 
x Addition of an inclusion criteria re 
survival expectancy post 
randomization 
x Adjustment to exclusion # 2 for 
greater clarity.  
Sections: Summary and 14.1 
Amendment to the statistical plan 
 
Addition of a blinded re-assessment after 
 recruited patients for 
evaluating the infection rate precision 
assumptions 
Sections: 8.1.9, 8.2.1 and 8.3 
Allow for blood tests and urinalysis 
for screening to be done within 90d 
prior to surgery 
 
To align with the sites standard practice re 
tests prior to surgery.  
Section 8.3 
Add a +1d window for V4 (D5) – if 
occurs on a Saturday/holiday 
 
To allow for tests to be done and avoid 
deviation. 
Sections: 8.1.11 
Removal of bodily systems 
description in physical examination  
 
 
 
To align with the sites standard practice re 
tests prior to surgery. 
Sections: Summary, 2.1.1.4 and 9.1.4 
Clarify the administration instruction 
for D-PLEX 
 
Greater clarity 
Section 10.2.3 
Removal of the option "LTFU" from 
AE outcome 
 
Was mistakenly left at last protocol 
update. 
Section: Appendix 1 
Amending time for storage prior to 
centrifuge 
 
Following new stability test, amending 
storage length from 12h to 18h for PK. 
Version 02 
Sections: opening pages, summary & 
throughout the protocol 
Adding and re-wording of study 
objectives 
 
 
To better describe the goal of the study 

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CONFIDENTIAL 
Section: opening page, sponsor and 
investigator signature pages 
Re-wording of study title 
To better describe the study design 
Sections: summary & 6 
Correction to number of study 
participants and centers 
Changes to the number of required 
subjects and sites 
Sections: Summary, 5.1, 6.1, 8.2.1 & 
10.1.3 
Adjustment of subject population 
description 
Adding "elective", enhancing the index 
surgery as "colorectal" and leaving out 
details to the study inclusion criteria. 
Sections: 2.1.2, 2.1.3, 2.2 & 2.3 
Re-written the pre-clinical and clinical 
sections 
To include new data from pre-clinical and 
clinical studies 
Sections: NA 
Deleted data on BonyPid product. 
Focusing on pre-clinical and clinical data 
from studies with D-PLEX 
Section 2.5 
Correction of mitigation "g" 
Re-wording of mitigation "k" 
Clarifying the instruction of re-allocation 
of an un-used study product. 
Changing "may" to "should" and amending 
instructions. 
Sections: summary, 4 & 8.1.5 - 
endpoints 
4.1 - Additional clarification re definition 
of superficial SSI, as per CDC guidelines 
- Adding death within 30 days post-    
operation as treatment failure 
- Adding requirement for a blinded
assessor for the surgical wound 
4.2 – adding secondary endpoints. 
4.3 & 8.1.5 – highlighting the role of the 
adjudication committee as a blinded and 
an independent one. 
Sections: Summary & 5 
Study design amendments to include 
different changes  
x 
Emphasizing requirement for at least 1 
X 5cm incision 
x 
Shortening the follow-up period to 60 
days 

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CONFIDENTIAL 
x 
Describing the minimal surgery 
requirements 
Sections: Summary, 5.1 & 8.2.2 
Determining the pre-operative 
standard of care treatment 
To align the pre-operation prophylactic 
treatment across all sites, as per 
standardizes MOH's and international 
guidelines 
Sections: Summary & 6 – entry 
criteria 
x 
Cancel the upper limit to patients 
age for study inclusion 
x 
Include "able and willing" 
subjects 
x 
Allow patients with active GI 
(only) infection to be included 
x 
Pending sponsor's approval, 
additional concomitant 
procedures, for the benefit of the 
subject, may be allowed during 
the index surgery 
x 
Restrict chemotherapy and 
radiation treatments 
x 
Removal of restriction for 
immunocompromised subjects 
x 
Following feasibility at new sites and 
an FDA comment 
x 
To also include patients with chronic 
GI illnesses 
x 
Following comments from the study 
PIs, in order not to exclude all patient 
requiring of a secondary procedure.  
 
x 
Due to inclusion of oncology patients. 
x 
To allow patients with immuno-gastric 
diseases.   
Section 8 – study procedures 
8.1.2 & 8.1.3 – Merge the definitions 
of randomization/enrollment  
8.1.4 - Adding requirement for a 
blinded assessor for the incisional 
wound 
8.1.4.1 - Adding description for 
emergency un-blinding 
8.1.16 – Adding infection assessment 
questionnaires  
8.1.9 – Adding a test (rectal swab) 
As per FDA comment, the 2 should be the 
same. 
To maintain blind as much as possible (in a 
single blinded study) 
Following requirement for a blinded 
assessor 
 
Adding a scoring questionnaire (ASEPSIS) 
to the visual assessment of wound 
infection. 
Following advice of an infectious disease's 
expert – to ensure resistance is not 
created.  

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8.1.10 – Adding a central lab 
8.1.14 – concomitant medications 
8.1.17 - Pharmacokinetics 
All suspected incisional-site-infection tests 
will be processed in a central lab to 
standardize process between all 
participating patients.  
Adjusting instruction following deletion of 
entry criteria # 13 
Amending the time point for PK collection 
and dividing the samples between the 3 
doses planned for the study. 
Adding guidance for case of re-application 
Section 8.2.3, 8.2.5 & table 1 – study 
visits 
x 
Removing visit No. 8 & amending visit 
7 to be a termination visit  
x 
Adding a rectal swab test to Screening 
& V7 as per secondary endpoint. 
x 
Adding infection assessment 
questionnaires to the visual check at 
all study visits. 
Section 8.3 – Table 1 (bullets) 
Adding description of the PK timelines and 
guidance to data collection in case of a 
patient no-show.  
Section 9 – study treatment  
9.1 – study treatment D-PLEX 
9.2 – concomitant medications 
9.4 – drug accountability 
Inserting data (description, composition, 
storage and preparation, application, 
contra-indications, warnings & packaging) 
from the Instruction For Use (IFU) into the 
protocol and cancelling the additional 
leaflet of IFU. 
Adjustment as per revised entry criteria 
and pre-operation SOC. 
Deletion of guide for destruction at site as 
not applicable for this study. 
Section 10.2.2 & 10.2.3 – Adverse 
Events 
Change in categories for causality and 
outcome  
Amending options for causality and 
outcome. 

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Sections summary & 14 – statistical 
analysis 
A statistical analysis plan was added. 
GENERAL 
Rephrasing, deletion of duplicates, 
correction of mis-spelled words or not 
clear enough instructions. 

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TABLE OF CONTENTS 
Table of Contents 
TABLE OF CONTENTS ............................................................................................................ 11 
1 
SUMMARY .................................................................................................................... 17 
2 
INTRODUCTION ............................................................................................................. 25 
2.1 
BACKGROUND .................................................................................................................................. 25 
2.1.1 
Background information on the product....................................................................................... 25 
2.1.2 
Unmet medical need for prevention of post abdominal surgery incisional infection ................... 26 
2.1.3 
Justification for the use of D-PLEX for prevention post abdominal surgery incisional infection .. 28 
2.2 
NON-CLINICAL DATA ......................................................................................................................... 29 
2.3 
CLINICAL DATA .................................................................................................................................. 30 
2.3.1 
Safety profile of Doxycycline ......................................................................................................... 31 
2.4 
POTENTIAL BENEFITS OF D-PLEX FOR PREVENTION OF POST ABDOMINAL SURGERY INCISIONAL 
INFECTION ................................................................................................................................................. 31 
2.5 
POTENTIAL RISKS OF D-PLEX FOR PREVENTION OF POST ABDOMINAL SURGERY INCISIONAL 
INFECTIONS AND THEIR MITIGATIONS ....................................................................................................... 31 
2.6 
SAFETY & EFFICACY SUMMARY ......................................................................................................... 33 
3 
OBJECTIVES ................................................................................................................... 33 
4 
STUDY ENDPOINTS ........................................................................................................ 34 
4.1 
PRIMARY EFFICACY ENDPOINT ......................................................................................................... 34 
4.2 
SECONDARY EFFICACY ENDPOINTS: .................................................................................................. 34 
4.3 
END-POINTS ADJUDICATION COMMITTEE (EPAC) ............................................................................. 35 
5 
TRIAL DESIGN ................................................................................................................ 35 
5.1 
OVERALL DESIGN .............................................................................................................................. 35 
5.2 
DESCRIPTION & JUSTIFICATION OF THE DURATION OF TREATMENT, SUBJECT PARTICIPATION AND 
TRIAL FOLLOW-UP...................................................................................................................................... 36 
6 
SELECTION OF SUBJECTS ............................................................................................... 36 
6.1 
INCLUSION CRITERIA ......................................................................................................................... 36 
6.2 
EXCLUSION CRITERIA ........................................................................................................................ 37 
7 
RECRUITMENT .............................................................................................................. 38 
8 
STUDY PROCEDURES & SCHEDULE OF ASSESSMENTS ................................................... 38 
8.1 
STUDY PROCEDURES ......................................................................................................................... 38 
8.1.1 
Informed consent procedure ........................................................................................................ 38 
8.1.2 
Screen failure ................................................................................................................................. 39 

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8.1.3 
Randomization / enrollment ......................................................................................................... 39 
8.1.4 
Blinding .......................................................................................................................................... 40 
8.1.5 
End point - assessment of infection rate ....................................................................................... 40 
8.1.6 
Management of suspected SSI ...................................................................................................... 42 
8.1.7 
Safety evaluation ........................................................................................................................... 42 
8.1.8 
Adverse events .............................................................................................................................. 43 
8.1.9 
Laboratory examinations ............................................................................................................... 43 
8.1.10 
Bacteriological testing - (Should be taken in any case of suspected infection before starting 
Antibiotic treatment) ................................................................................................................................... 43 
8.1.11 
Physical examination ................................................................................................................ 44 
8.1.12 
Vital signs .................................................................................................................................. 44 
8.1.13 
Electrocardiogram (ECG) .......................................................................................................... 44 
8.1.14 
Medical history and prior concomitant medications................................................................ 44 
8.1.15 
Allergy questionnaire ................................................................................................................ 45 
8.1.16 
Assessment of surgical site ....................................................................................................... 45 
8.1.17 
Pharmacokinetics ..................................................................................................................... 45 
8.2 
STUDY VISITS .................................................................................................................................... 46 
8.2.1 
Visit 1: Screening period (day -21 - 0) ........................................................................................... 46 
8.2.2 
Visit 2: Surgery – index procedure (day 0) .................................................................................... 47 
8.2.3 
Visits 3 – 6: follow up visits (Days 1, 5 ,14 & 30 post-surgery) ...................................................... 47 
8.2.4 
Unscheduled visit(s) ...................................................................................................................... 48 
8.2.5 
Visit 7 - end of study (60 days post-surgery) ................................................................................. 48 
8.3 
Table 1: Study assessments ............................................................................................................... 49 
8.4 
DEFINITION OF END OF TRIAL ........................................................................................................... 50 
8.5 
DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS & ‘STOPPING RULES’..................................... 50 
9 
NAME & DESCRIPTION OF ALL DRUGS USED IN THE TRIAL ............................................ 50 
9.1 
STUDY TREATMENT D-PLEX .............................................................................................................. 51 
9.1.1 
Product Description ....................................................................................................................... 51 
9.1.2 
Product Composition ..................................................................................................................... 51 
9.1.3 
Product Handling (storage & preparation) .................................................................................... 51 
9.1.4 
Product Usage and Dosage ............................................................................................................ 52 
9.1.5 
Contra-Indications ......................................................................................................................... 53 
9.1.6 
Use in Specific Populations ............................................................................................................ 53 
9.1.7 
Warnings and Precautions............................................................................................................. 53 
9.1.8 
Overdose ....................................................................................................................................... 54 
9.1.9 
Packaging ....................................................................................................................................... 54 
9.2 
CONCOMITANT MEDICATION ........................................................................................................... 54 

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9.2.1 
Medication(s)/Treatment(s) Permitted ......................................................................................... 54 
9.2.2 
Medication(s) prohibited during the trial ...................................................................................... 54 
9.3 
PREPARATION & LABELING OF INVESTIGATIONAL PRODUCT (IP) ..................................................... 55 
9.4 
DRUG ACCOUNTABILITY ................................................................................................................... 55 
10 RECORDING & REPORTING OF ADVERSE EVENTS & REACTIONS ................................... 55 
10.1 
DEFINITIONS ................................................................................................................................. 55 
10.1.1 
Adverse event (AE) ................................................................................................................... 55 
10.1.2 
Adverse drug reaction (ADR) .................................................................................................... 56 
10.1.3 
Serious adverse event (SAE) ..................................................................................................... 56 
10.1.4 
Unexpected adverse event ....................................................................................................... 57 
10.2 
ASSESSMENT OF ADVERSE EVENT ................................................................................................ 57 
10.2.1 
Severity ..................................................................................................................................... 57 
10.2.2 
Causality ................................................................................................................................... 58 
10.2.3 
Outcome ................................................................................................................................... 59 
10.2.4 
Expectedness ............................................................................................................................ 59 
10.2.5 
Seriousness ............................................................................................................................... 59 
10.3 
DOCUMENTATION AND REPORTING OF SAE ................................................................................ 60 
10.4 
TIME PERIOD AND FREQUENCY FOR DETECTING AEs, SAEs AND EVENTs OF SPECIAL INTEREST ... 60 
10.4.1 
Procedures for recording & reporting serious adverse events ................................................. 61 
10.4.2 
Notification of deaths ............................................................................................................... 61 
10.5 
REPORTING OF SUSARS ................................................................................................................ 61 
10.6 
DEVELOPMENT OF SAFETY UPDATE REPORTS .............................................................................. 62 
10.7 
THE TYPE & DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS .................... 62 
11 NOTIFICATION OF SERIOUS GCP BREACHES AND/OR PROTOCOL   VIOLATION ............. 62 
12 DATA MANAGEMENT & QUALITY ASSURANCE .............................................................. 63 
12.1 
CONFIDENTIALITY ......................................................................................................................... 63 
12.2 
DATA COLLECTION TOOLS & SOURCE DOCUMENT IDENTIFICATION ............................................. 63 
12.3 
DATA HANDLING & ANALYSIS ...................................................................................................... 63 
13 RECORD KEEPING & ARCHIVING ................................................................................... 63 
14 STATISTICAL ANALYSIS CONSIDERATIONS ..................................................................... 64 
14.1 
SAMPLE SIZE AND POWER ............................................................................................................ 64 
14.2 
ANALYSIS POPULATIONS .............................................................................................................. 64 
14.3 
STATISTICAL AND ANALYTICAL PLANS .......................................................................................... 65 
14.3.1 
Analysis of Demographics and Baseline Subject Characteristics .............................................. 65 
14.3.2 
Primary Endpoint Analysis ........................................................................................................ 65 
14.3.3 
Secondary Endpoint Analysis .................................................................................................... 65 

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14.3.4 
Safety Evaluations ..................................................................................................................... 65 
14.3.5 
Handling of Missing Data .......................................................................................................... 66 
14.3.6 
Interim Analyses ....................................................................................................................... 66 
15 DIRECT ACCESS TO SOURCE DATA DOCUMENTS ........................................................... 66 
16 ETHICS & REGULATORY REQUIREMENTS ...................................................................... 67 
17 QUALITY CONTROL (STUDY MONITORING) ................................................................... 67 
18 QUALITY ASSURANCE .................................................................................................... 67 
19 INSURANCE ................................................................................................................... 68 
20 PUBLICATION POLICY .................................................................................................... 68 
21 STATEMENT OF COMPLIANCE ....................................................................................... 68 
22 REFERENCES ................................................................................................................. 69 

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LIST OF ABBREVIATIONS 
AE
Adverse Event
ACS 
Acute Coronary Syndrome 
AR
Adverse Reaction
ASC/AST          
    Active Surveillance Culture/Testing 
ASEPSIS 
Additional treatment, Serous discharge, Erythema, 
Purulent exudate, Separation of deep tissue, Isolation of 
bacteria, Stay duration as inpatient 
ALT(SGPT)
Alanine Aminotransferase
AST(SGOT)
Aspartate transaminase
BMI   
   Body Mass Index 
β-TCP    
    β- Tri Calcium Phosphate 
CDC  
    Center for Disease Control 
CKD 
   Chronic Kidney Disease 
Cm 
 Centimetres 
eCRF 
Electronic Case Report Form 
CVA     
    Cerebro Vascular Accident 
DSSI 
    Deep incisional Surgical Site Infection 
EC/IRB 
Ethics Committee/Independent Review Board 
ECG   
    Electrocardiogram 
ESRD 
End Stage Renal Failure 
EU
European Union
G
Gram
GCP
Good Clinical Practice
GI  
Gastrointestinal 
GMP 
Good Manufacturing Practice  
GRAS    
    Generally Recognized As Safe 
IB
Investigator’s Brochure
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IFU
Instructions for Use

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CONFIDENTIAL 
IP
Investigational Product
ISO
International Organization for Standardization 
IV
Intravenous
LDH
Lactate Dehydrogenase
MG
Milligram
MOH 
Ministry of Health 
MRSA
Methicillin-resistant Staphylococcus aureus
MSSA
Methicillin-sensitive Staphylococcus aureus
NHSN 
National Healthcare Safety Network 
PI
Principal Investigator
PK 
    Pharmacokinetics   
PLGA 
    Poly (DL-lactide-co-glycolide) 
PLEX  
   Polymer- Lipid Encapsulation matrix 
PVD    
    Peripheral Vascular Disease 
QA
Quality Assurance
QC
Quality Control
SAR
Serious Adverse Reaction
SAE
Serious Adverse Event
SDV
Source Document Verification
SOC 
Standard of Care 
SOP
Standard Operating Procedure
SSI
Surgical Site Infection
SSSI 
    Superficial incisional Surgical Site Infection 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment emergent adverse event 
TIA    
    Transient Ischemic Attack 
USP  
United States Pharmacopeia 

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CONFIDENTIAL 
TRIAL PERSONNEL 
 
Sponsor’s Representatives 
 
 
 
1. 
 
VP Clinical 
PolyPid Ltd.  
18 HaSivim Street, Petach Tikva. Israel 4917002 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 SUMMARY 
Study Number: 
Study D-PLEX-310 

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CONFIDENTIAL 
Study Title: 
Phase II, Prospective, Multicentre, Randomized, Controlled, Two 
arm, Single Blind, Study to assess Safety and Efficacy of D-PLEX 
Administered Concomitantly with the Standard of Care (SOC), 
compared to a SOC treated control arm, in prevention of post 
abdominal surgery incisional infection. 
Phase: 
Phase II 
Objectives: 
The primary objectives are as follows: 
x 
To assess the anti-infective efficacy of D-PLEX over a period of 
30 days post operation, by preventing surgical site infection 
(SSI), defined as superficial and deep infection, in the target 
incision(s), compared to the SOC treated control arm. 
x 
To assess the safety of D-PLEX 
Number of Centers: 
 centers in Israel will participate in this study. 
 
Subject Population: 
Male and female, 18 years old and above at screening, undergoing 
elective abdominal colorectal surgery.  
Number of Subjects: 
About 
 subjects: A blinded non-comparative sample size re-
assessment to evaluate the infection rate precision assumptions 
will be conducted: after about 
 subjects, and about 
 
subjects, have been assessed for primary efficacy endpoint. The 
maximal sample size allowed to upsize is about 
 subjects.  
Test Product: 
D-PLEX is a new formulation of extended release of Doxycycline. 
Each 
 
 
D-PLEX is supplied as a sterile powder to be reconstituted to paste 
in the operating room, using standard aseptic techniques and is 
intended for single administration.  
The non-active components of the extended release antibiotic 
formulation are β Tri-Calcium Phosphate (β-TCP), poly (DL-lactide-
co-glycolide acid) or PLGA, and a lipid matrix.  
All formulation components are biodegradable. 
Indication: 
D-PLEX is indicated for prevention of post abdominal surgery 
incisional infection. 
Other Drugs Required for 
the Study: 
NA 

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CONFIDENTIAL 
Standard of Care (SOC): 
The SOC prophylactic antibiotic treatment which will be used in this 
study is based on the MOH's (Berlowitz 2001) and international 
(Ongom & Kijjambu 2013, Bratzler 2013) guidelines. It will be 
consistence and standardized for all sites in the clinical study and is 
composed of antibiotic treatment from the 1st or 2nd generation of 
Cephalosporine family, plus Metronidazole.    
Bowel preparation (mechanical only) and post-surgery treatment 
will be at the discretion of the PI as well as the SOC per each site's 
SOP, as applicable.   
Dose Administration: 
D-PLEX dose is individualized, pending length of the surgical 
incision; up to a total max of 
) may be administered in a 
single application.  
Duration of Dosing: 
D-PLEX is administered as a single application.  
The active material (Doxycycline) is continuously released for 
approximately 3-4 weeks. 
Study Design:  
This is a phase II, prospective, multicenter, randomized, controlled, 
two arm, single blind study. The study population includes male 
and female, 18 years old and above at screening, undergoing 
elective abdominal colon surgery involving resection and including 
at least 1 incision that is > 5cm. 
Subjects who meet the inclusion criteria and none of the exclusion 
criteria and provide signed informed consent will be enrolled in the 
study.  
Subjects will be randomized to either the investigational arm (SOC 
+ D-PLEX) or to the control arm (SOC only) in a 1:1 ratio.  
Subjects will be blinded to the study arm. 
For subjects randomized to the investigational arm, D-PLEX 
treatment will be applied during the abdominal surgery at the 
stage of closure of the abdominal wall surgical target incision 
(index procedure), as an adjunct to the SOC treatment.  
For subjects randomized to the control arm, the surgical treatment 
will be as per SOC as outline in this protocol. 
For both arms the pre-operative prophylactic antibiotic care will be 
consistence and standardized for all sites in the clinical study. Post-
operative care will be performed per site SOC.  Post-operative 
resumption of activity is at the discretion of investigator based on 
subject medical condition. 

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CONFIDENTIAL 
Doxycycline pharmacokinetic sampling will be collected from three 
subsets administered with different entire dose of D-PLEX 
 
) in at least 
patients (i.e.,  patients per subset, pending 
subset recruitment).  
 
The occurrence of any adverse events (AE/SAE) will be recorded 
throughout the study.  
The planned clinical study will evaluate the safety and efficacy of 
the controlled release antibiotic (Doxycycline) in the prevention of 
post abdominal surgery incisional infection over a period of 30 
days for the primary outcomes. All patients will be followed for an 
overall of 60 days for safety. 
Primary Efficacy Endpoint: 
x 
Infection rate as measured by the proportion of subjects with 
abdominal incisional infection event, as determined by a 
blinded and independent adjudication committee, within 
30 days post abdominal surgery.  
[abdominal incisional infection is composed of Deep Incisional 
Surgical Site Infection (DSSI) and Superficial Incisional Surgical 
Site Infection (SSSI)]. 
Mortality from any reason within 30 days post index surgery, will 
be analyzed as treatment failure. 
An independent and blinded adjudication committee will review 
each case suspected for SSI and will adjudicate if meets an 
endpoint.   
Secondary Efficacy Endpoints: 
Key endpoints: 
x 
Number of hospitalization days post colorectal surgery due to 
SSI 
x 
Average ASEPSIS assessment score during 30 days post-surgery. 
x 
Number of Surgical Intervention due to SSI's 
Additional endpoints: 
x 
Incidence of SSSI during 30 days post-surgery.  
x 
Incidence of DSSI during 30 days post-surgery 
x 
Mortality rate within 60 days post abdominal surgery  

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CONFIDENTIAL 
x 
Determination of susceptibility to Doxycycline of any organisms 
recovered from an abdominal surgery incisional Infection Site. 
x 
Number of overall hospitalization days within 60 days post-
surgery (including days of readmission due to surgical site 
infection). Primary hospitalization for surgery and, if occurred, 
readmission due to abdominal incisional surgical site infection. 
Hospitalization days will be counted as aggregated overall 
hospitalization days per subject. 
x 
Number of re-admissions due to surgical site infection. 
x 
Number of antibiotic treatment days (all routes of 
administration) due to abdominal incisional surgical site 
infection (data will be aggregated and presented both for 
overall days of antibiotic treatment all routes of administration 
and IV administration treatment days). 
x 
Time to surgical site infection post-surgery 
  
Identification of a Surgical site infection will be based on CDC/NHSN 
Patient Safety Component Manual criteria (January 2018, chapter 9)  
Safety Evaluation: 
The following safety parameters will be evaluated in this trial: 
x 
Adverse events, physical examinations & vital signs.  
x 
Incisional wound healing will be assessed by a blinded 
investigator, using a visual examination as well as wound 
assessment questionnaires. 
x 
Safety laboratory parameters: 
hematology, chemistry, urinalysis. 
It is expected that each subject will be in the study for 
approximately 60 days.  
Inclusion Criteria: 
Subjects who meet all of the following criteria will be eligible to 
participate in the study: 
1. Subjects undergoing elective abdominal colon surgery 
involving resection and ileocolonic, ileorectal, colocolonic or 
colorectal anastomosis or with a stoma, who are preoperative 
stable hemodynamically. In a laparoscopic surgery an 
abdominal wall incision of at least ≥ 5 cm should be involved.  
2. Male or non-pregnant female. 

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CONFIDENTIAL 
3. Female of childbearing potential should have a negative serum 
pregnancy test prior to index procedure. 
 Note: All female of childbearing potential must agree to use a highly 
effective method of contraception (such as double barrier, oral or 
parenteral hormonal, intrauterine device and spermicide) 
consistently and correctly for the duration of the study. 
4. Subjects' age 18 years old and above at screening. 
5. Subjects who sign a written informed consent. 
6. Subjects who are willing and able to participate and meet all 
study requirements.  
7. Survival expectancy of at least 60 days post randomization 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria are 
prohibited from participating in the study: 
1. Subjects scheduled for abdominal surgery which is classified as 
emergency. 
2. Subjects with any preoperative active infection that is currently 
being treated with antibiotics. 
3. Subjects receiving any antibiotic therapy in the past 4 weeks 
prior to enrolment besides prophylaxis or antibiotic for the 
treatment of the disease that consists the indication for 
surgery. 
4. Patients undergoing concomitant additional procedures 
besides colon resection surgery, e.g. Hyper-thermic 
Intraperitoneal Chemotherapy, liver resection etc.             
Female sterilization surgery (i.e. salpingo-oophorectomy, 
hysterectomy etc.), involvement of a small bowel procedure or 
Cholecystectomy may be allowed, pending an advanced 
consultation and approval from the sponsor.   
5. Subject received chemotherapy within the last 4 weeks of 
surgery, or radiation for colorectal cancer to the abdomen area, 
prior to the planned abdominal surgery (neo-adjuvant 
treatment). 
6. Subjects that received oral or IV Doxycycline during the past 4 
weeks prior to screening. 
7.  Subjects with known sensitivity to Doxycycline and/or to the 
tetracycline family of drugs or to the D-PLEX's excipients. 

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8. Subjects with known allergies to more than 3 substances (an 
allergy questionnaire will be filled in during the screening 
process). 
9. Subjects with history of allergic/hypersensitivity reaction to any 
substance having required hospitalization and/or treatment 
with intravenous steroids/intramuscular epinephrine or in the 
opinion of the investigator the patient is at high risk of 
developing severe allergic/hypersensitivity reactions. 
10. Subjects with uncontrolled Asthma (GINA III-IV). 
11. Subjects with End Stage Renal Disease (ESRD/ CKD stage 5). 
12. Subjects with chronic urticaria. 
13. Subjects diagnosed with TIA/CVA/ACS within the past 1 year 
prior to randomization.  
14. Subjects that undergone any abdominal surgery and current 
planned surgery involves re-opening the scar of prior 
abdominal surgery.  
15. Any subject with active malignancy or with malignancy that has 
not been in complete remission for at least 5 years.       
Excluding: 
* subjects with potentially resectable non-metastatic colorectal 
cancer which consists the indication for surgery.  
* Subjects who have had carcinoma in situ of the cervix, 
squamous cell carcinoma of the skin and basal cell carcinoma of 
the skin  
* Subjects with non-violent cancer that does not require 
treatment 4 weeks prior to, and throughout the entire study 
duration. 
 
16. Subjects with other concurrent severe and/or uncontrolled 
medical condition that could compromise participation in the 
study (e.g. non-GI active infection, uncontrolled diabetes, 
uncontrolled hypertension, congestive heart failure, unstable 
angina, ventricular arrhythmias, active ischemic heart disease, 
uncompensated cirrhosis, active upper gastrointestinal (GI) 
tract ulceration). 
17. Psychiatric, addictive, or any other disorder that compromises 
ability to provide informed consent for participation in this 
study. 
18. Chronic alcoholic or drug abuse subjects. 

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19. Pregnant or breast-feeding women or women of childbearing 
age who refuse or prohibited of using an effective 
contraceptive method of birth control (such as double barrier, 
oral or parenteral hormonal, intrauterine device and 
spermicide) throughout study participation including safety 
follow-up period. 
20. Subjects that received any investigational drug within 30 days 
or 5½ half-lives of enrollment to the study (whichever is 
longer). 
21. Subjects participating in any other interventional studies. 
22. In the opinion of investigator, subject is not eligible to 
participate in the study and/or to comply with protocol 
requirements (e.g. due to a cognitive or medical condition). 
Sample Size: 
About 
subjects with potential increase to 
 subjects 
following sample size re-assessment 
Statistical Methods: 
The study will enrol about 
 subjects, with about 
 subjects 
allocated to each treatment group.  This sample size was chosen by 
the Sponsor to collect adequate data for evaluating the primary 
study objectives.  This study is not powered to test formal 
statistical hypotheses.  However, exploratory sample size 
calculations show that a sample of 
 subjects provides 
 
power to detect an 
 decrease in the SSI rate (
 versus 
) at 
a two-sided α=0.10 level of significance. A blinded sample size re-
assessment to evaluate the infection rate precision assumptions 
will be conducted after about 
 subjects have been 
assessed for primary efficacy endpoint. The maximal sample size 
allowed to upsize the study will not exceed about 
 subjects. 
Primary Endpoint Analysis: The number and proportion of subjects 
with at least one SSI, as determined by a blinded and independent 
adjudication committee, within 30 days post abdominal surgery will 
be tabulated per treatment group.  A 95% confidence interval using 
exact binomial methods will be constructed for each proportion. 
Missing data for the primary efficacy endpoint will be imputed 
according to the methods described in Section 14.3.5 
Secondary endpoints & safety evaluation analysis are detailed in 
sections 14.3.3 and 14.3.4 
 

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Dosing regimen: The product is to be administered on a single occasion prior to surgical wound 
closure following abdominal surgical procedures. The total dose applied at the surgical site will be 
determined based on surgical incision length. A maximum of three vials (
) may be 
administered. Therefore, the total amount of Doxycycline free base for a single surgical procedure 
with D-PLEX can reach up to 
 mg.  
 
The individualized dose will follow the following scheme: 
 
Surgical incision length (cm) 
Max number of vials to apply* 
5 – 10 
1 
11-20 
2 
>21 
3 
* Used D-PLEX paste will be measured and documented in the eCRF.   
2.1.1.5 
  D-PLEX Product 
D-PLEX is a biodegradable formulation of Beta-Tri Calcium Phosphate (β-TCP), Poly (DL-lactide-co-
glycolide) (PLGA) and a lipid matrix.  incorporating Doxycycline hyclate.  D-PLEX is supplied in a glass 
vial (
) as a sterile powder to be reconstituted to paste and is intended for a single 
administration. 
2.1.1.6 
    Antibacterial Activity of the Drug Substance 
Doxycycline is a well-known antibacterial drug substance that inhibits bacterial protein synthesis by 
binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against most isolates 
of a broad range of Gram-positive and Gram-negative bacteria. Doxycycline is effective for 
eradication of most of the bacteria known to cause surgical site infection.   
 
2.1.2 
Unmet medical need for prevention of post abdominal surgery incisional 
infection   
Surgical site infection (SSI) are one of the most frequent complications in open abdominal surgeries, 
and they represent a significant cause of mortality and morbidity.  SSIs rate has varied from 
approximately 5.0% to 30.0% of abdominal soft tissue surgeries, such as up to 4.0% of 
hysterectomies (Bratzler et al. 2013) and 30.0% (Mihaljevic et al. 2015) of colorectal surgeries and 
approximately 6.8% in urological procedures (Alonso-Isa et al. 2017) . Chemotherapy and other 
immunosuppressive medications affect the function of the immune system and as a result the SSI 
rate increases (Aga et al. 2015).   
Approximately 10M abdominal surgeries are performed annually in US; of these 7.1M general 
(Gastroenterological) surgeries including 575,000 colorectal resection surgeries (Carney et al. 2017; 
Fingar et al. 2014), 2.9M Gynecological Surgeries and 608,000 urological surgeries.  
SSIs may be classified as superficial incisional if limited to the skin and subcutaneous tissue, or deep 
incisional when involving the fascia and muscle.  It is classified as organ space when involving an 
organ within the body cavity i.e. below the fascia. Such infections are usually manifested as abscess 
(Azoury et al. 2015; Fry 2013). Deep tissue and organ space SSIs are less frequently encountered 

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than superficial SSIs, but are associated with greater morbidity/mortality, more readmission rates, 
longer hospital stay, and increased overall hospital-associated costs when compared to superficial 
SSIs. Although the majority of SSIs are uncomplicated, others may be severe and more challenging 
to manage, such as necrotizing deep soft tissue infections. The latter often requires extensive 
surgical debridement, multiple reoperations, and can be life-threatening (Azoury et al. 2015).   
Colorectal surgeries are performed for diseases such as colorectal cancer, ulcerative colitis, Crohn’s 
disease, mechanical bowel obstruction and recurrent diverticulitis, often resulting in major 
reconstruction of the gastrointestinal tract. Trauma, or Intestinal injuries, ischemia, rectal prolapse 
and proctological disorders may also require large or small bowel resection (Kirchhoff et al. 2010). 
Patients undergoing colorectal surgeries are at higher risk of developing abdominal wall SSIs 
because the colon and rectal tracts contain a large number of bacteria which become exposed 
during surgery. For most colon procedures, E. coli, Staphylococcus spp. (including community-
associated, methicillin-resistant strain) and Bacteroides fragilis are the most likely organisms to be 
encountered. Other gram-negative species include Klebsiella pneumoniae and Enterobacter spp 
(Fry 2013, Fa-Si-Oen 2005).  
Traditionally, the cancer organ (colon, uterus etc.) were removed through large abdominal incisions. 
In recent years, there has been a widespread shift toward the minimally invasive surgery (Lee et al. 
2017). However, in 2013 open abdominal surgery is still the most common (>60%) surgical 
treatment for all abdominal surgeries especially for general abdominal, abdominal colon cancer, 
urology and obstetric surgeries (Carney et al. 2017, Lee et al. 2017). In addition, in most abdominal 
laparoscopic surgeries one incision of about 5 cm is still needed to remove the resected organ 
(Bennett-Guerrero et al, 2010). 
In gynecologic surgery, SSIs generally fit into these categories, including superficial incisional 
cellulitis, deep incisional abscesses, and pelvic or vaginal cuff abscess formation. During a 
hysterectomy, the surgical site is in risk to be exposed to a unique variety of endogenous flora, 
including common bacteria of the skin, gastrointestinal tract and vaginal tract (Steiner and Strand 
2017). Selection of prophylactic antibiotics must consider the need to cover a variety of gram-
positive bacteria (i.e Staph. aureus, MRSA, Staph. Epidermitis and Entrococcus faecalis), gram-
negative (e.g. E. coli and Klebsiella sp) and anaerobic organisms (i.e Clostridum) (Hemsell 1997).  
The high incidence of SSI in cystectomies could be explained by the manipulation of the urinary and 
digestive tracts, the use of drains and catheters, and because these surgeries are usually performed 
in elderly patients with comorbidities. (Alonso-Isa et al. 2017). The most frequently isolated 
microorganisms reported in Spain from SSI in patients after undergoing laparotomy for urology 
indications were Enterococcus spp. (27.1%), E. coli (22.9%), S. aureus (14.6%) and P. aeruginosa 
(12.5%) (Alonso-Isa et al. 2017). According to a retrospective database of radical cystectomy 
patients from Boston, the most common pathogens in patients diagnosed with cystectomy SSI were 
Coagulase-negative staphylococci, E. coli and Klebsiella (Goldberg 2017). 
Despite the routine use of prophylactic systemic antibiotics, the incidence of abdominal surgical-
site infection does not entirely negate the risk. Therefore, the prevention of post abdominal surgery 
infection represents an unmet medical need. 
 

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2.1.3 
Justification for the use of D-PLEX for prevention post abdominal surgery 
incisional infection 
D-PLEX represents a novel formulation of Doxycycline which has the potential to be superior in 
prevention of post-surgical incisional infections following abdominal surgery over current standard 
of care preventive measures.  Common practices that have been shown to reduce the incidence 
of SSIs include administering prophylactic antibiotics prior to incision, clipping rather than shaving 
the operative site, maintaining normal body temperature and oxygen supplementation 
perioperatively, and achieving adequate glycemic control (Azoury et al. 2015, Avkan-Oğuz et al. 
2016, Pellegrini et al. 2017, Steiner and Strand 2017). Despite high compliance to guidelines, 
these interventions alone have not been proven to lower surgical site infection rates, which 
suggests that additional interventions are needed (Johnson et al. 2016).  
While these measures have reduced the rate of infection, they have not eliminated it.  Part of the 
reason for the persistence of these types of infections (despite the above procedures) is because 
a local hematoma forms at the surgical site following surgery.  This is a wet environment suitable 
for bacterial growth.  To reduce the hematoma, strict homeostasis and drainage are used.  
However, drains also constitute a risk for bacterial introduction.  In addition, the blood supply and 
lymphatic fluid at the surgical site are disrupted.  Therefore, systemic antibiotics and immune 
defences have impaired ability to reach the affected areas, causing them to be more susceptible 
to bacterial proliferation and to the development of infection. Low local prophylactic antibiotic 
concentrations, at the surgical site raises the risk of developing antibiotic resistant bacteria. 
However, raising the systemic antibiotic dose may cause systemic toxicity. In an attempt to 
overcome these problems, some surgeons dispense antibiotics locally before closing the incision.  
Such antibiotic treatment results only in a very short release duration of 1-2 hours and does not 
succeed in preventing the development of bacterial infection (Huiras et al. 2012, Bennett-Guerrero 
et al. 2010, Bennett-Guerrero et al. 2017, McHugh et al. 2011).  In addition, the American Society 
of Health-System Pharmacists, SIS, IDSA, and SHEA have all stated that lacking sufficient 
evidence, the use of currently available topical antibiotics cannot be recommended (Edmiston et 
al. 2017). A product such as D-PLEX that provides sustained local high levels of Doxycycline has 
the potential of achieving a reduction in infection not achievable with present available products 
or procedures. 
Doxycycline is effective for eradication of most of the bacteria known to cause abdominal surgery 
site infection.  
As indicated above, D-PLEX is a new formulation of extended-release of Doxycycline for 
administration during surgery at the stage of closure of the surgical incision of the abdominal wall, 
and as an adjunct to the SOC treatment. D-PLEX releases Doxycycline immediately upon 
administration into the surgical site and continues to release Doxycycline for approximately 3-4 
weeks following administration, which is the time period in which most of the laparotomy colon 
surgical site infection occur (Fry 2013). 
During this period, the expected local Doxycycline concentration is well above the minimal 
inhibitory concentration (MIC) of sensitive organisms. By preventing growth of bacteria via high 
local concentration of Doxycycline at the surgical site during the 3-4 weeks post its administration, 
D-PLEX is intended to be effective for prevention of post-abdominal surgery incisional infection.  
 

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2.2 NON-CLINICAL DATA  
Non-clinical pharmacology studies, performed to demonstrate Doxycycline antimicrobial activity, 
include the following: 
x 
Six Studies in rabbit sternal wound infection model (each with a different clinically relevant 
bacteria1) showed that D-PLEX at an applied dose comparable to 7.5 g administered to a 70 
kg adult on a mg/kg basis, demonstrates reduction of infection [as reflected in the 
maintenance of overall health, the limited changes in hematologic parameters and the 
reduction in bacteria count isolated from the sternum wound (i.e. bone defect and 
surrounding soft tissue)] and infection-related toxicities. 
x 
Intramuscular surgical site infection model in rat demonstrated the ability of D-PLEX to 
reduce S. aureus proliferation and infection (as shown in the reduced signs of 
inflammation). 
x 
In vitro anti-microbial studies demonstrated D-PLEX ability to reduce the load of clinically 
relevant bacteria. In vitro anti-microbial study for extended period further demonstrated 
that D-PLEX is effective against Staphylococcus aureus (which is a common bacterium in 
human sternal and colorectal surgical wound infections) over 5 weeks period in which it is 
subject to release in vitro. This supports the claim that D-PLEX has anti-microbial activity 
against Doxycycline sensitive bacteria for approximately 30 days.  
These findings support the claim of anti-bacterial activity of D-PLEX in prevention of infections in 
bone and soft tissue environment in human.  
Non-clinical pharmacokinetic studies were performed to demonstrate Doxycycline local and 
systemic concentration after its administration.  
x 
According to local PK study in rabbit sternal model, the expected unbound Doxycycline 
concentrations at the administration site are maintained above the MIC value of clinically 
relevant sensitive bacterial species (e.g., Staphylococcus aureus: MIC of 1 μg/mL; 
Vibramycin, NDA 050007) for up to 30 days. 
x 
D-PLEX ability to release Doxycycline for a period of at least 29 days in vivo was shown in 
rabbits after local administration of D-PLEX in the sternum and in rats after SC administration 
of D-PLEX.   
Non-clinical safety and toxicity studies, include the following: 
x 
A safety and toxicity pivotal study in which D-PLEX was administered into a sternal defect 
in rabbits, shows that D-PLEX comparable on a mg/kg basis to twice the maximum D-PLEX 
applied dose to a 70-kg adult (i.e. 30 gr D-PLEX), demonstrates no systemic effects, no 
deleterious effects on healing of the sternal site, and no effect on the sternal bone's 
strength according to the 15-months available results.  
                                                 
1 i.e. Methicillin Resistant Staphylococcus Aureus (MRSA), Staphylococcus epidermitis coagulase negative 
(CoN), Enterococcus faecalis, Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae. 

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x 
A safety study in which D-PLEX was administered onto the top of the sternum of rats (i.e. in 
between the muscles and the sternal bone) showed that D-PLEX comparable on mg/kg basis 
to 
 D-PLEX in a 70-kg adult, does not cause any systemic toxic effects nor local cytotoxic 
effects up to 3 months.  
x 
Two safety studies performed to evaluate the peritoneum reaction to D-PLEX after 24 hours 
and 28 days from D-PLEX administration in case of intra-abdominal leakage in rat abdominal 
model showed that D-PLEX exposure (comparable on mg/kg basis to 
 D-PLEX in a 70-
kg adult) to abdominal cavity is safe exposure. 
Hence, 
D-PLEX 
can 
be 
considered 
safe 
and 
suitable 
for 
its 
intended 
use.  
For detailed non-clinical studies summary of the D-PLEX, see D-PLEX Investigator’s Brochure, 
#DV-0079. 
 
2.3 CLINICAL DATA 
A Phase Ib/II clinical trial, conducted in Israel.  The study included two parts; part 1 open label 
single arm, and part 2 randomized, controlled, single-blinded to assess the safety and efficacy of 
D-PLEX concomitantly with Standard of Care (SOC) vs. SOC alone, in the prevention of sternal 
wound infection post cardiac surgery for up to 24 weeks (6 months) following surgery. The 
recruitment to this study was completed with a total of 
 enrolled subjects: 
subjects in part 
1 & 
 subjects in part 2 of the study (
 patients in the SOC arm and 
 patients in the treatment 
arm). 
A total of 
 subjects were allocated to D- PLEX with SOC group, however, one subject withdrew 
consent before study treatment. 
In a statistical report for the study the following were shown: 
x 
A single patient in the SOC arm 
) had superficial sternal wound infection (SSWI), on day 6 
post-surgery. No surgical re-intervention was required due to sternal infection.  
x 
No subjects in the treatment group experienced any sternal wound infection ( %). 
x 
No hospitalizations, re admissions or surgical reintervention due to Sternal Surgical Site 
infection were reported in the study.  
x 
No safety issues were indicated and no AE/SAE related to D- PLEX has been reported. 
x 
 of the 
 subjects in the SOC group (
) and 
 of the 
 subjects (
) in the D-PLEX 
with SOC group experienced adverse events 
x 
One subject in the D-PLEX plus SOC group died due to cardiogenic shock on day 6 post surgery, 
not related to the investigational product or study procedure. 
Intense PK sampling was used to evaluate the plasma pharmacokinetic characteristics of the drug 
in a sub set of subjects in that study.   
x 
Release of antibiotics from D-PLEX start upon administration 
x 
Cmax of Doxycycline released from D-PLEX in sternal treated patients is at least 18 times lower 
than a systemic treatment of a comparable known oral drug 
x 
Detectable plasma levels for three to four weeks from patients treated with the D-PLEX 
formulation. 

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x 
Based on the AUC (inf) parameters vs. the comparable known oral drug, most of the D-PLEX 
entrapped Doxycycline was released  
 
2.3.1 
Safety profile of Doxycycline 
The antibiotic drug Doxycycline has been on the market for over 5 decades and its side effects are 
well established. 
Information on adverse reactions of Doxycycline capsules USP are provided in the IB.  
Furthermore, given the total dose of Doxycycline present in D-PLEX (i.e. maximum 
), 
which is lower than the overall daily dose of systemically administered Doxycycline 
), and 
given it is being gradually released over a period of approximately 3-4 weeks, it is unlikely that 
clinically significant systemic levels will be present to give significant side effects. This is further 
supported by pharmacokinetic data derived from a phase Ib/II clinical study which was recently 
completed. It shows detectable plasma levels of Doxycycline for well into three to four weeks 
following administration of the D-PLEX formulation. 
 
2.4   POTENTIAL BENEFITS OF D-PLEX FOR PREVENTION OF POST 
ABDOMINAL SURGERY INCISIONAL INFECTION  
x 
Prevention of surgical site infection, which may occur within 30 days post-surgery. 
x 
Significant improvement in prevention of surgical site infection when used in surgical 
procedures that hold high risk of infection such as: laparotomy and laparoscopy. 
x 
Induces faster recovery and early return to normal activity as compared to SOC due to lower 
surgical site infection rate. 
x 
Reduction in the number of surgical re-interventions due to surgical site infections. 
x 
Reduction in the number of hospitalizations and/or shortening hospitalization, thus providing 
financial savings and reducing hospital load. 
x 
Used concomitantly with SOC. 
x 
Ease of administration, no special training is required. 
x 
Local administration of effective dose of Doxycycline during surgery (which result in local 
concentration above the minimal inhibitory concentration for Doxycycline sensitive bacteria), 
which cannot be achieved by systemic or current local solutions.  
x 
Administration of low total dose of Doxycycline compared to the dose in oral administered 
Doxycycline capsules.  
x 
Broad spectrum activity of Doxycycline. 
x 
Low potential risk for development of bacterial resistance. 
x 
D-PLEX excipients are widely used in the medicinal or medical device industry, have an 
established history of safety and acceptable clinical use in contact with bone/ soft tissue and/or 
blood circulation and are biodegradable.   
2.5 POTENTIAL RISKS OF D-PLEX FOR PREVENTION OF POST ABDOMINAL 
SURGERY INCISIONAL INFECTIONS AND THEIR MITIGATIONS 
a) 
Potential contamination of microorganisms and pyrogens by the aseptic product. 

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Mitigation:  
x Clear and detailed instructions on how to store, administer and use. 
b) 
Potential for local toxicity by the drug product, including irritation of the tissues. 
Mitigations: 
x At subject level: 
In case of serious local toxicity induced by D-PLEX, removal and washing out the product 
will be done by the surgeon.  
x At population level: 
o Close follow up of patients 
o Safety Monitoring 
c) 
Hypersensitivity to Doxycycline and to the Tetracycline family of antibiotics  
Mitigation: 
x Exclude susceptible subjects with known allergy to Doxycycline / Tetracycline family and/or 
three different allergens. 
x In case of allergic reaction to Doxycycline, the administered D-PLEX can be removed by re-
exploring the surgical incision and washing out the D-PLEX. 
 
d) 
Potential of bacteria resistant to Doxycycline-treatment failure. 
Mitigation: 
x SOC concomitantly administered with D-PLEX provides systemic antibacterial coverage. 
e) 
Administration outside of the target surgery site. 
Mitigations: 
x 
Training of the surgeons participating in the clinical trials, as part of the study initiation and 
the protocol training.  
x 
Clear instructions how to apply, detailed in section 9.1.3.    
f) 
Inadequate anti-bacterial activity of the product 
Mitigations: 
x 
SOC concomitantly administered with D-PLEX provides systemic antibacterial coverage. 
g) 
Re-use of D-PLEX between different patients, can lead to cross contamination. 
Mitigations: 
x 
D-PLEX vial will be re-allocated to a different patient only if (i) package carton was never 
opened (ii) storage conditions were kept and (iii) with the permission of the site's head 
of pharmacy.  If, for some reason, it was not used also after the 2nd allocation - any 
remaining drug not applied should be discarded.  
x 
Training of site clinical staff. 

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h) 
Potential for permanent tooth discoloration or enamel hypoplasia - Tetracycline form 
stable complex in any bone formation tissue; Reversible decrease in fibula growth rate 
has occurred in premature infants receiving oral tetracyclines. 
Mitigations: 
x Exclusion of patients less than 18 years old from the clinical study. 
x Exclusion of pregnant or lactating woman from the clinical study. 
i) 
Photosensitivity reaction: exaggerated sun burn reaction. 
Mitigations: 
x 
Close follow up of patients 
 
j) 
Transient hypercalcemia 
Mitigation: 
x Close follow up of patients. 
x Blood levels of calcium are tested at screening and every visit after the procedure during 
the clinical study. 
 
k) 
 D-PLEX removed from the target organ following re-operation  
Mitigation: 
x 
D-PLEX should be re-applied during re-operation, if occurs within 72 hours of initial 
surgery, pending incision debridement. The amount to be re-used is pending size of the 
current incision. 
 
2.6 SAFETY & EFFICACY SUMMARY 
Based on the current data available from the one study with D-PLEX, in which 
 cardiac patients 
were treated with D-PLEX, no safety concern was observed. Overall, based on risk/benefit 
assessment, the expected benefits outweigh the expected risks associated with the use of D-PLEX.  
Therefore, a clinical trial with D-PLEX in patients undergoing abdominal surgery procedures, may 
be beneficial. 
 
3 OBJECTIVES 
x 
To assess the anti-infective efficacy of D-PLEX (in addition to SOC) over a period of 30 days 
post operation, by preventing surgical site infection (SSI) defined as superficial and deep 
abdominal wall surgical incision infection, compared to the SOC treated control arm. 
x 
To assess the safety of D-PLEX.  
 

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4 STUDY ENDPOINTS 
4.1 PRIMARY EFFICACY ENDPOINT  
The following will be evaluated in this trial: 
Infection rate as measured by the proportion of subjects with an SSI event, as determined by a 
blinded and independent adjudication committee, within 30 days post abdominal surgery.  
Mortality from any reason within 30 days post index surgery, will be analyzed as treatment failure. 
SSI is composed of Deep Incisional Surgical Site Infection (DSSI) and Superficial Incisional Surgical 
Site Infection (SSSI). 
Superficial incisional SSI - Infection involves only skin and subcutaneous tissue of the incision and 
does not includes diagnosis/treatment of cellulitis, a stich abscess alone or a localized stab wound 
or pin site infection. 
Deep incisional SSI - Infection involves deep tissues, such as fascia and muscle layers; this also 
includes infection involving both superficial and deep incision sites.   
An organ/space Surgical Site Infection (e.g. infection/abscess in the operated organ or peritoneal 
cavity) will not be accounted as an endpoint event.  
Anastomosis leak will not be accounted as an endpoint event.  
 
4.2 SECONDARY EFFICACY ENDPOINTS: 
Key endpoints: 
x 
Number of hospitalization days post colorectal surgery due to SSI 
x 
Average ASEPSIS assessment score during 30 days post-surgery. 
x 
Number of Surgical Intervention due to SSI's 
Additional endpoints: 
x 
Incidence of SSSI rates during 30 days post-surgery.  
x 
Incidence of DSSI rates during 30 days post-surgery 
x 
Mortality rate within 60 days post abdominal surgery  
x 
Determination of susceptibility to Doxycycline of any organisms recovered from an 
abdominal surgery incisional Infection Site. 
x 
Number of overall hospitalization days within 60 days post-surgery (including days of 
readmission due to surgical site infection). Primary hospitalization for surgery and, if 
occurred, readmission due to abdominal incisional surgical site infection. Hospitalization 
days will be counted as aggregated overall hospitalization days per subject. 
x 
Number of re-admissions due to surgical site infection. 

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x 
Number of antibiotic treatment days (all routes of administration) due to abdominal 
incisional surgical site infection (data will be aggregated and presented both for overall 
days of antibiotic treatment all routes of administration and IV administration treatment 
days). 
x 
Time to surgical site infection post-surgery.    
Identification of a Surgical site infection will be based on CDC/NHSN Patient Safety Component 
Manual criteria (January 2018, chapter 9).  
4.3 END-POINTS ADJUDICATION COMMITTEE (EPAC) 
A blinded and independent End-Point Adjudication Committee will be established to review and 
adjudicate study’s primary efficacy end-point. 
This committee is an independent clinical events classification committee, composed of 3 experts 
in the fields of surgeries and infectious disease who will remain blinded to the treatment 
assignments.  
All information collected regarding efficacy (suspected SSI's, as per blinded investigator’s 
assessments, as well as occurrences of deaths) will be reviewed by the End-Point Adjudication 
Committee.  It is within their scope to make an independent decision whether a subject has met 
the primary endpoint or to assess, in case of a death, for its relationship to infection or to the 
study drug.  
Vote followed by decision will be made based on an agreement of at least 2 out of 3.  
In case of dispute between investigator and the committee’s assessment, End-Point Adjudication 
Committee’s adjudication will prevail. 
Summaries of the committee meetings will be provided periodically to the sponsor. 
5     TRIAL DESIGN 
5.1  OVERALL DESIGN 
This is a phase II, prospective, multicentre, randomized, controlled, two arm, single blind study. 
The study population includes male and female, 18 years old and above at screening, undergoing 
elective abdominal colon surgery which involves resection and including at least 1 incision that is > 
5cm. 
Subjects who meet the inclusion criteria and none of the exclusion criteria and provide a signed 
informed consent will be enrolled in the study.  
Subjects will be randomized to either the investigational arm (SOC + D-PLEX) or to the control arm 
(SOC only) in a 1:1 ratio.  
Subjects will be blinded to the study arm. 
For subjects randomized to the investigational arm, D-PLEX treatment will be applied during the 
abdominal surgery at the stage of closure of the abdominal wall surgical target incision (index 
procedure), as an adjunct to the SOC treatment.  
For subjects randomized to the control arm, the surgical treatment will be as per SOC as outline in 
this protocol. 

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Pre-operative care will be given to the study participants within 30-60 minutes prior to surgery 
and will include an antibiotic treatment from the 1st or 2nd generation of Cephalosporine family, 
plus Metronidazole. 
Bowel preparation (mechanical only) and post-operative care for both arms will be performed per 
PI discretion and site SOC.  Post-operative resumption of activity is at the discretion of investigator 
based on the subject's medical condition. 
The occurrence of any adverse events (AE/SAE) including death will be recorded throughout the 
study. 
The planned clinical study will evaluate the efficacy of the controlled release antibiotic 
(Doxycycline) in the prevention of SSIs over a period of 30 days for the primary and secondary 
outcomes. All patients will be followed for an overall of 60 days for safety.  
5.2 DESCRIPTION & JUSTIFICATION OF THE DURATION OF TREATMENT, SUBJECT 
PARTICIPATION AND TRIAL FOLLOW-UP 
The infection rate is measured within 30 days of index surgery, based on the literature that this is 
the time period in which most of the abdominal surgery surgical wound infections occur. 
The 60 days follow up period was determined to allow a sufficient follow up period to demonstrate 
the initial and sustainability safety endpoints of D-PLEX.  
 
6 SELECTION OF SUBJECTS 
About 
 eligible subjects will be enrolled and randomized 1:1 (D-PLEX therapy concomitant with 
SOC vs. SOC alone) 
 
6.1 INCLUSION CRITERIA 
Deviations from any inclusion criteria are not allowed because it can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Subjects undergoing elective abdominal colon surgery involving resection and ileocolonic, 
ileorectal, colocolonic or colorectal anastomosis or with a stoma, who are preoperative 
stable hemodynamically. In a laparoscopic surgery, an abdominal wall incision of at least 
≥ 5 cm should be involved.  
2. Male or non-pregnant female. 
3. Female of childbearing potential should have a negative serum pregnancy test prior to 
index procedure. 
     Note: All female of childbearing potential must agree to use a highly effective method of 
contraception (such as double barrier, oral or parenteral hormonal, intrauterine device and 
spermicide) consistently and correctly for the duration of the study. 

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4. Subjects age 18years old and above at screening. 
5. Subjects who sign a written informed consent. 
6. Subjects who are willing and able to participate and meet all study requirements. 
7. Survival expectancy of at least 60 days post randomization. 
 
6.2 EXCLUSION CRITERIA 
Deviations from any exclusion criteria are not allowed because it can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 
Subjects who meet any of the exclusion criteria are prohibited from participating in the study: 
1. Subjects scheduled for abdominal surgery which is classified as emergency. 
2. Subjects with any preoperative infection that is currently being treated with antibiotics.  
3. Subjects receiving any antibiotic therapy in the past 4 weeks prior to enrolment besides 
prophylaxis or antibiotic for the treatment of the disease that consists the indication for 
surgery. 
4. Patients undergoing concomitant additional procedures besides colon resection surgery, 
e.g. Hyper-thermic Intraperitoneal Chemotherapy, liver resection etc.  Female sterilization 
surgery (i.e. salpingo-oophorectomy, hysterectomy etc.), involvement of a small bowel 
procedure or Cholecystectomy may be allowed, pending an advanced consultation and 
approval from the sponsor.   
5. Subject received chemotherapy within the last 4 weeks of surgery, or radiation for 
colorectal cancer to the abdomen area, prior to the planned abdominal surgery (neo-
adjuvant treatment). 
6. Subjects that received oral or IV Doxycycline during the past 4 weeks prior to screening. 
7. Subjects with known sensitivity to Doxycycline and/or to the tetracycline family of drugs or 
to the D-PLEX's excipients. 
8. Subjects with known allergies to more than 3 substances.  (an allergy questionnaire will be 
filled in during the screening process). 
9. Subjects with history of allergic/hypersensitivity reaction to any substance having required 
hospitalization and/or treatment with intravenous steroids/intramuscular epinephrine or 
in the opinion of the investigator the patient is at high risk of developing severe 
allergic/hypersensitivity reactions. 
10. Subjects with uncontrolled Asthma (GINA III-IV). 
11. Subjects with End Stage Renal Disease (ESRD/CKD stage 5). 
12. Subjects with chronic urticaria. 
13. Subjects diagnosed with TIA/CVA/ACS within the past 1 year prior to randomization.  
14. Subjects that undergone any abdominal surgery and current planned surgery involves re-
opening the scar of prior abdominal surgery.  

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15. Any subject with active malignancy or with malignancy that has not been in complete 
remission for at least 5 years. Excluding:  
* Subjects with potentially resectable non-metastatic colorectal cancer which consists the 
indication for surgery.  
* Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma of the 
skin and basal cell carcinoma of the skin 
* Subjects with a Non-violent cancer that does not require treatment 4 weeks prior to, and 
throughout the entire study duration.  
16. Subjects with other concurrent severe and/or uncontrolled medical condition that could 
compromise participation in the study (e.g. non-GI active infection, uncontrolled diabetes, 
uncontrolled hypertension, congestive heart failure, unstable angina, ventricular 
arrhythmias, active ischemic heart disease, uncompensated cirrhosis, active upper 
gastrointestinal (GI) tract ulceration). 
17. Psychiatric, addictive, or any other disorder that compromises ability to provide informed 
consent for participation in this study. 
18. Chronic alcoholic or drug abuse subjects. 
19. Pregnant or breast-feeding women or women of childbearing age who refuse or prohibited 
of using an effective contraceptive method of birth control (such as double barrier, oral or 
parenteral hormonal, intrauterine device and spermicide) throughout study participation 
including safety follow-up period. 
20. Subjects that received any investigational drug within 30 days or 5½ half-lives of 
enrollment to the study (whichever is longer). 
21. Subjects participating in any other interventional studies. 
22. In the opinion of investigator, subject is not eligible to participate in the study and/or to 
comply with protocol requirements (e.g. due to a cognitive or medical condition). 
 
7 RECRUITMENT 
Patient recruitment will be conducted in general surgery departments at sites in Israel. 
Recruitment period is expected to take approximately 6 months. 
 
8 STUDY PROCEDURES & SCHEDULE OF ASSESSMENTS 
8.1 STUDY PROCEDURES 
8.1.1 
Informed consent procedure 
An Informed Consent Form (ICF) will be prepared in accordance with the study protocol, ICH-GCP 
and any applicable global and national regulations/requirements. The consent will include the 
information that data will be recorded, collected, processed and may be transferred to Competent 
Authorities.  In accordance with the applicable global and national regulations, the data will not 
identify any persons taking part in the study. 

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The final EC/IRB approved ICF and a copy of the approval must be submitted to PolyPid prior to the 
initiation of patient enrolment at each investigational site. 
Prior to any study-specific procedures or assessments, all subjects must document their consent, in 
writing, for study participation and authorization for use and disclosure of health information by 
signing the ICF.  As part of the consent process, the subject will have the opportunity to ask 
questions and receive answers from the personnel conducting the study and will have ample time 
to consider and consult prior to providing his consent to participate in the study.   
An original signed copy will be retained at the study site and copy of the signed consent form will 
be provided to the subject. 
Procedures conducted as part of the subject’s routine clinical management (e.g., imaging) and 
obtained prior to signing of informed consent may be used for screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed within the 
timeframe specified in the protocol. 
If during the study new information becomes available that can significantly affect the subject’s 
future health and medical care that information shall be provided to the respective affected subject 
in written form.  If relevant, all affected subjects shall be asked to confirm their continuing informed 
consent in writing.   
8.1.2 
Screen failure 
Subjects who sign the informed consent but do not meet the eligibility criteria and were not 
randomized will be considered screen failures.  
 For such subjects, the reason for screen failure will be recorded in the screening log, the CRF and 
in the source documents. 
8.1.3 
Randomization / enrollment 
Upon confirmation that the subject fulfils all inclusion criteria and none of the exclusion criterion 
is met, subjects will be randomized through an interactive web randomization system (IWRS) 
integrated with the eCRF, based on subject’s information collected during the screening period and 
details of the planned surgery. 
The following information for maintaining balance between the 2 arms must be entered into the 
system to obtain the treatment assignment: 
x 
Gender 
x 
Age (18-40, 41-65, 66and above) 
x 
Open laparotomy surgery or laparoscopic surgery  
x 
Surgery includes Colostomy - yes/no  
Randomization will be done centrally using a randomization schedule generated by the study 
statistician, which will assign subjects in a 1:1 ratio to: 
x 
Treatment Arm – Standard of Care (SOC) concurrently with D-PLEX application. 
x 
Control Arm – SOC treatment alone. 

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Instructions and training for randomization and stratification process will be provided during site 
initiation visit. 
8.1.4 
Blinding 
This is a single blind clinical trial. Subjects will be blinded to the treatment arm assignment. The 
study site personnel present at the baseline procedure as well as the physician performing the 
procedure will be trained not to disclose the treatment arm to the subject, his/her family, to other 
health care providers not present during the surgery or to the study sponsor representatives. 
Wound assessment throughout the study follow-up visits will be done by a blinded investigator. 
An emergency card containing the Study Name, NIH number, Center Name/number, PI’s name 
and contact details will be provided to the subjects. Subjects will be instructed to keep this card 
with them at all times and present it to medical staff in case of a medical urgency.  
8.1.4.1 
Emergency un-blinding 
As a general rule, code breaks should occur only in exceptional circumstances when knowledge of 
the actual treatment is absolutely essential for further management of the patient. This is a single 
blinded study and as such, the investigator performing the procedure and study coordinator are 
expected to know the treatment arm of the subject and have access to this information through 
the eCRF, while all other medical staff should be kept blinded. If un-blinding is deemed necessary, 
the investigator can access information regarding the treatment arm information in the eCRF or 
the patient file.  
In the rare case in which the investigator and study coordinator are unattainable or unable to 
access the eCRF, unblinding could be done by the study site personnel through a toll-free help line 
or through the local emergency number as the back-up system. 
The Investigator is requested to maintain the blind as much as possible. Investigators are 
encouraged to discuss with a sponsor's representative if he/she believes that unblinding is 
necessary. The actual allocation must NOT be disclosed to the patient and/or other study 
personnel including other site personnel, monitors, corporate sponsors or project office staff. 
The Investigator must report all code breaks (with reason) as they occur to the study CRA and on 
the corresponding CRF [case report form] page. 
8.1.5 
End point - assessment of infection rate 
Primary Efficacy Endpoint: 
Infection rate as measured by the proportion of subjects with an SSI event, as determined by the 
blinded and independent adjudication committee, within 30 days post abdominal surgery.  
Mortality from any reason within 30 days post index surgery, will be analyzed as treatment failure. 

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Surgical site infection will be identified by the predefined criteria based on CDC/NHSN Patient Safety 
Component Manual (January 2018, chapter 9). 
SSI is composed of Deep Incisional Surgical Site Infection (DSSI) and Superficial Incisional Surgical 
Site Infection (SSSI). 
 Superficial incisional SSI - Infection involves only skin and subcutaneous tissue of the incision and 
does not includes diagnosis/treatment of cellulitis, a stich abscess alone or a localized stab wound 
or pin site infection. 
Deep incisional SSI - Infection involves deep tissues, such as fascia and muscle layers; this also 
includes infection involving both superficial and deep incision sites.  
An organ/space Surgical Site Infection (e.g. infection/abscess in the operated organ or peritoneal 
cavity) is excluded and will not be accounted as an endpoint event.  
Anastomosis leak is excluded and will not be accounted as an endpoint event.  
 
8.1.5.1 
SSI criteria (based on CDC/NHSN January 2018, chapter 9,): 
 
Superficial incisional SSI definition 
Must meet the following criteria:  
Date of event for infection occurs within 30 days after any NHSN operative procedure (where day 
1 = the procedure date)  
  AND 
Involves only skin and subcutaneous tissue of the incision  
  AND 
 Patient has at least one of the followings:  
a) Purulent drainage from the superficial incision  
b)  Organisms identified from an aseptically-obtained specimen from the superficial incision 
or subcutaneous tissue by a culture based microbiologic testing method 
c)   Superficial incision that is deliberately opened  
       AND 
Patient has at least one of the following signs or symptoms: (1) pain or tenderness,          
(2) localized swelling, (3) erythema or (4) heat.   
d) Diagnosis of a superficial incisional SSI by the surgeon or attending physician or another 
designee. 
 
Deep incisional SSI Definition 
Must meet the following criteria:  

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The date of event for infection occurs within 30 days after he operative procedure (where day 1 = 
the procedure date)  
  AND  
Involves deep soft tissues of the incision (e.g., fascia and muscle layers)  
  AND  
Patient has at least one of the followings:  
a)     Purulent drainage from the deep incision.   
b)     A deep incision that spontaneously dehisces, or is deliberately opened or aspirated by a       
physician and organism is identified by a microbiologic testing method 
               AND 
              Patient has at least one of the following signs or symptoms: (1) fever (>38°C);                           
(2) localized pain or (3) tenderness.  
  c)     An abscess or other evidence of infection involving the deep incision that is detected        
on gross anatomical or histopathologic exam, or imaging test  
 
8.1.6 
Management of suspected SSI  
In case of a suspected SSI, the following procedures should be followed: 
Action 
Time Line 
Collect Bacteriological Sample – BEFORE 
antibiotic treatment initiation and arrange for 
shipment into AML central lab for testing 
Once suspicion arises 
Collect Hematology/Chemistry Blood Samples  
Immediately 
Perform a clinical assessment of surgical incision 
area. 
Immediately 
Report infection suspicion through eCRF page  
within 24h of knowledge 
Send a detailed email to medical monitor/study 
group email. 
Within 5 working days 
 
8.1.7 
 Safety evaluation 
The following safety parameters will be evaluated in this trial: 
x 
Adverse events, physical examinations & vital signs.  
x 
Incisional wound healing will be assessed by visual examination by investigators. A 
questionnaire will be provided to investigators to prompt meticulous evaluation of 
surgical wound for any suspicion of infection as well as evaluation of wound healing.   
x 
Safety laboratory parameters: hematology, chemistry, urinalysis  

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8.1.8 
Adverse events  
The investigator and site staff are responsible for detecting, documenting, and reporting events 
that meet the definition of an AE, SAE or Event of Special Interest (i.e. SSI).  Adverse events (AEs) 
will be collected once the abdominal wall incision closure process started, during the follow-up 
visits and until study termination at visit 7 (60 days after surgery).  
Details on AE definition, assessment and reporting can be found in Section 10 “RECORDING & 
REPORTING OF ADVERSE EVENTS & REACTIONS”.   
8.1.9 
Laboratory examinations 
The following laboratory tests will be performed and then analyzed by the respective local 
laboratories: 
a. 
Complete blood count (CBC) with differential white blood cell (WBC) count and 
platelet count; (all visits, except visit 2). 
b. 
Urinalysis at screening and as per investigator discretion pH, Specific Gravity, 
Protein, Glucose, Bilirubin, Ketones, Nitrites, Leukocytes. 
c. 
Blood chemistry: Glucose, Urea (BUN), AST (SGOT), ALT (SGPT), Total Bilirubin, 
Alkaline Phosphatase, Calcium, Potassium, Phosphorus, Sodium, Chloride, Total 
Proteins, Albumin, Serum Creatinine, Creatinine phosphokinase (CPK), C-reactive 
protein (CRP) & LDH.  
Coagulation (at screening only): INR, PT & (a)PTT. 
d. 
Pregnancy test by serum at screening only, performed in females of child-bearing 
potential only. All females of child bearing potential must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the 
study.  
e. 
Rectal swab, at screening and at day 30. Kits will be provided. Samples will be 
forwarded to AML central lab for testing and results reported back to the referring 
investigator.  
Any abnormal finding with respect to baseline, assessed by the investigator as clinically significant, 
should be recorded as adverse events in the relevant CRF form. 
 
8.1.10 
Bacteriological testing - (Should be taken in any case of suspected 
infection before starting Antibiotic treatment)   
Bacteriological tests (from surgical site and/or surrounding soft tissue and/or drainage) will be 
performed in order to assess infection at the abdomen surgical target incision site.  
Bacteriological tests from the wound will be taken if there is a wound discharge.  
The bacteriological specimen source should be indicated on source documents and CRF.  
The test kit will be forwarded to AML central lab where bacterial growth, identification and 
sensitivity to Doxycycline and other common practice antibiotics, will be assessed.  
Results will be reported back to the referring investigator.  

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Any abnormal finding, assessed by the investigator as clinically significant, should be recorded as AE 
in the relevant CRF section. 
8.1.11 
Physical examination  
The investigator will perform a complete physical examination of the major body systems and will 
assess whether the subject experiences Doxycycline reactions or other allergies.  
Any abnormal finding with respect to baseline, assessed by the investigator as clinically significant, 
should be recorded as an adverse event in the relevant CRF section. 
8.1.12 
Vital signs  
Systolic/diastolic blood pressure, Heart rate, & temperature will be recorded at each visit after 5 
minutes of rest. 
Weight and height will be taken from the subject, or the subject will be asked for this information 
at screening/admission.  
All measurements and the time performed will be recorded in the eCRF.  
   Any abnormal finding, assessed by the investigator as clinically significant, should be recorded as 
an AE in the relevant eCRF section. 
8.1.13 
Electrocardiogram (ECG)  
A standard 12-lead electrocardiogram (ECG) will be performed at screening, to identify subjects 
who have undiagnosed clinically significant anomalies that the investigator believes would 
preclude study participation. 
The investigator may choose to use a copy of an ECG print-out/results done up to 90 days prior to 
the planned surgery. 
The ECG review is under the investigator's responsibility. 
Any abnormal finding, assessed by the investigator as clinically significant, should be recorded in 
the relevant eCRF form and source documents. 
8.1.14 
Medical history and prior concomitant medications  
Demographic data and a complete medical history of past, present illnesses and surgeries as well 
as medications currently being taken to treat current illnesses will be recorded by the investigator. 
The medical history will include alcohol consumption, tobacco use, concurrent diseases, detailed 
allergy status (an allergy questionnaire will be completed) and assessment of possible infection.  
Subjects with known hypersensitivity to Doxycycline and/or tetracycline family of drugs, or to D-
PLEX's excipients should be excluded. 
Subjects will be permitted to receive concomitant therapy as medically required, except for 
systemic Doxycycline or steroids use that in the opinion of the investigator puts the patient is at 
high risk of developing severe allergic/hypersensitivity reactions.  
A record of all concomitant prescription medications will be maintained. 

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8.1.15 
Allergy questionnaire  
An allergy questionnaire will be filled in at screening as part of subject’s medical history. 
8.1.16 
Assessment of surgical site  
A blinded investigator will inspect the surgical site and asses the healing of the surgical wound. 
Special attention is to be paid for signs of infection. The Investigator should follow the protocol 
guidelines for assessment of SSI (see above section 8.1.5). 
Two questionnaires will be completed: SSI assessment questionnaire per CDC criteria, and an 
ASEPSIS scoring.  
Every effort must be made to assess the incisional surgical site at every visit. In case a subject is un 
willing or un able to attend a scheduled visit, a phone conversation should be held with him, his 1st 
degree relative or community physician and assessment of the wound per CDC should be done.   
8.1.16.1 
ASEPSIS: (Additional treatment, Serous discharge, Erythema, 
Purulent exudate, Separation of deep tissue, Isolation of 
bacteria, Stay duration as inpatient) scoring method. 
ASEPSIS is acronym of wound assessment and treatment parameters, which provides numerically 
score during an inspection of the surgical site. The final score is being interpreted to severity of 
wound appearance and the clinical consequences of the infection. 
Parameters are: serous exudate, erythema, purulent exudate, separation of deep tissue and also 
antibiotic therapy, drainage of pus under local/general anesthesia, isolation od pathogenic 
bacteria and stay as inpatient. 
8.1.17 
Pharmacokinetics 
Doxycycline pharmacokinetic sampling will be collected from three subsets administered with 
different dose of D-PLEX (whole 1, 2 or 3 vials) in at least 24 patients (i.e., 8 patients per subset, 
pending subset recruitment).  
Pharmacokinetic samples of 4ml blood will be collected at each PK time point, prepared and 
shipped to a central laboratory. 
 

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• 
Record demographics (including age, gender, etc.) 
• 
Record medical history 
• 
Complete allergy questionnaire 
• 
Record concomitant medications  
• 
Measure vital signs (Height, weight, Temp., heart rate & blood pressure) 
• 
Perform physical examination  
• 
Perform blood laboratory tests * 
• 
Perform 12-lead ECG**  
• 
Perform Urine analysis * 
• 
Perform a rectal swab for bacteriology 
• 
Record baseline safety (any future planned elective procedure should be recorded so it will 
not be counted later on as an AE or SAE as applicable)  
• 
Eligibility determination according to inclusion and exclusion criteria  
*      Blood tests and Urinalysis done at the medical center's lab within 21 days prior to surgery may be used       
         for eligibility determination. 
**   ECG done within the last 90 days prior to surgery can be used for eligibility determination. 
8.2.2 
Visit 2: Surgery – index procedure (day 0) 
Subjects will be enrolled into the study and will be treated with D-PLEX concomitantly with SOC or 
SOC alone.  
The SOC prophylactic antibiotic treatment used in this study is consistence and standardized for all 
sites in the clinical study and is composed of antibiotic treatment from the 1st or 2nd generation of 
Cephalosporine family, plus Metronidazole.  
Bowel preparation (mechanical only) and post-surgery treatment will be done as per each site's 
SOPs.   
The following will be performed during visit 2: 
x 
Randomization***  
x 
Vital signs 
x 
Pre-application Doxycycline PK sampling (for applicable subjects) 
x 
Abdominal Surgery 
x 
D-PLEX administration at the stage of closure of the abdominal wall surgical incision 
x 
Post-application Doxycycline PK sampling (at 2h, 4h, 6h, 8h & 12h) – selected subjects 
x 
Adverse Events assessment and recording 
x 
Concomitant Medication Review  
*** for surgery planned for early morning time, randomization via the eCRF could be done a day in 
advance.  
8.2.3 
Visits 3 – 6: follow up visits (Days 1, 5 ,14 & 30 post-surgery) 
Post-operative care will be performed per SOC. Post-operative resumption of activity are at the 
discretion of investigator based on subject medical condition. 
The subsequent follow up visits (visits 3-5) will take place at 1 day, 5 days and 14 days post-surgery. 
These visits are usually performed after this type of surgery.  

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The additional follow up visit (visit 6) will take place 30 days post-surgery and is required by the 
study, i.e. in addition to the routine visits usually performed after this kind of surgery. 
During all the above-mentioned visits, the following procedures will be performed:  
x 
Vital signs 
x 
Assessment of surgical site wound healing – Including visual examination and wound 
assessment questionnaires.   
x 
Laboratory examinations  
x 
Post-application Doxycycline PK sampling – selected subjects 
x 
Adverse Events assessment and recording 
x 
Concomitant Medication Review  
x 
Physical examination [at visit 6 (D30)] 
x 
Rectal swab for comparable bacteriology [at visit 6 (D30)] 
Urinalysis will be performed only at the discretion of the investigator. 
Bacteriology cultures will be taken if there is wound discharge.   
8.2.4 
Unscheduled visit(s) 
An unscheduled visit may be performed at any time during the study at the subject's request or as 
deemed necessary by the Investigator. The date and reason for the unscheduled visit will be 
recorded. Vital signs, adverse events and concomitant medications will be assessed. In addition, any 
procedures and evaluations may be performed as deemed necessary by the investigator for the 
subject's safety. 
This visit should be recorded in the eCRF, including all related procedure. 
8.2.5 
Visit 7 - end of study (60 days post-surgery) 
x 
Vital signs 
x 
Assessment of surgical site  
x 
Laboratory examinations  
x 
Adverse Events assessment and recording.  
x 
Concomitant Medication Review  
x 
Physical examination 
   
Table 1 details all scheduled/planned assessment at these visits. 

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8.4 
 DEFINITION OF END OF TRIAL 
Total duration of the study is expected to be approximately 8 months from first subject enrolled until 
last subject completed. The end of the trial will be the 60 days final follow up visit for the last enrolled 
patient.  
 
8.5 
DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS & ‘STOPPING 
RULES’ 
While study withdrawal is not encouraged, subjects may choose to withdraw from the study at any 
time, with or without reason and without prejudice to further treatment. Moreover, subject’s 
participation in any clinical trial is voluntary and the subject has the right to withdraw at any time 
without penalty or loss of benefit.  
In the event that a subject withdraws from the study, every effort should be made to have the subject 
return for a final study follow-up assessment and the information identified for collection at the 60 
days follow-up visit will be obtained to the extent possible.  Withdrawn subjects will not be replaced 
(the justified sample size considers an estimated allowance for attrition).  
The reason for withdrawal (if given) will be recorded on the appropriate eCRF and subject’s medical 
records in all cases of withdrawal.  If more than one reason is cited for withdrawal, study personnel 
should identify the most significant reason.   
The Investigator may discontinue a subject from participation in the study if the Investigator feels that 
the subject can no longer fully comply with the requirements of the study or if any of the study 
procedures are deemed potentially harmful to the subject.  
The sponsor may suspend or prematurely terminate this study either in an individual investigational 
site, or the entire study. Reasons for suspending or early terminating the study by sponsor should be 
justified, documented and reported as applicable.  
EC or regulatory authority may suspend or prematurely terminate participation in the study at the 
investigational sites for which they are responsible. 
If suspicion of an unacceptable risk to subjects arises during the study, or when so instructed by the EC 
or regulatory authorities, the sponsor shall suspend the clinical trial while the risk is assessed. The 
sponsor shall terminate the study if an unacceptable risk is confirmed. 
Data that has already been collected on withdrawn subjects will be retained and used for analysis but 
no new data will be collected after withdrawal.  
 
9 
NAME & DESCRIPTION OF ALL DRUGS USED IN THE TRIAL 
D-PLEX is the investigational medicinal product to be administered in this study. A comprehensive 
description is provided below. No additional drugs will be administered as part of the requirements of 
this clinical study. 

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• 
Remove the vial cap by flipping the cap up and tearing it counter clockwise, according to the 
arrows stamped on the cap. 
• 
Open the vial slowly close to a sterile mixing surgical bowl, using standard aseptic 
techniques.  
• 
Pour the entire content of the vial (
) into the sterile mixing bowl using standard aseptic 
techniques.  
              Make sure that only the vial neck is found above the sterile mixing bowl. 
x 
Repeat steps 1-10 above for the second vial, if two vials are needed for administration, and 
also for the third vial, if a total of three vials are needed for administration. The content of 
all the vials intended to be administered should be poured into the same bowl. 
 
Step 2: 
NOTE: This preparation step should commence upon surgeon confirmation. It should be done by a 
sterile team member. 
• 
Slowly hydrate the D-PLEX powder in the bowl with the following volume of sterile saline:    
D-PLEX powder from 1 vial should be hydrated with 2ml of sterile saline. 
D-PLEX powder from 2 vials should be hydrated with 3.5ml of sterile saline. 
D-PLEX powder from 3 vials should be hydrated with 5ml of sterile saline. 
Do not over hydrate.  
• 
Mix D-PLEX powder, with the sterile saline using sterile spatula, for approximately 1 minute, 
until uniform paste appearance is reached. 
Step 3:   
Should be done by the operating surgeon. 
x 
Administer the whole quantity of the paste directly within the surgical site: between 
the two halves of the surgical incision immediately after hydration and mixing, using the 
same spatula. 
x 
Discard the remaining of D-PLEX per local environmental standards. 
x 
Packages (vial and box) should be kept for inventory documentation purposes. 
 
9.1.4 
Product Usage and Dosage 
The product is to be administered on a single occasion prior to surgical wound closure following 
abdominal surgical procedures, as an adjunct to the SOC treatment. The total dose applied at the 
surgical site will be determined based on surgical incision length. A maximum of three vials 
 
may be administered. Therefore, the total amount of Doxycycline free base for a single surgical 
procedure with D-PLEX can reach up to 
 mg.  
 
 
The individualized dose will follow the following scheme: 

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Surgical incision length (cm) 
Max number of vials 
to apply* 
5-10 
1 
11-20 
2 
>21 
3 
* Used D-PLEX paste will be measured and documented in the eCRF. 
D-PLEX will be applied directly within the surgical site immediately after hydration and mixing, using 
the same spatula. 
Following closure of the fascia, D-PLEX reconstituted paste will be applied on the fascia suture line 
followed by soft tissues of the abdominal wall along the whole length of the surgical wound (including 
muscle, fat and dermis). Application is to be done at the time of initial closure of the abdominal wall 
incision, a thin layer of paste will be spread on the entire surface of each side of the abdominal 
incisional wall, except for the top of the skin (suture line), as an adjunct to the SOC treatment.   
9.1.5 
 Contra-Indications  
Please refer to the exclusion criteria (section 7.2).  
9.1.6 
Use in Specific Populations 
Please refer to the inclusion criteria in D-PLEX (section 7.1).  
9.1.7 
Warnings and Precautions   
9.1.7.1 
Clinical warning and precautions  
x 
Proper surgical procedures are the responsibility of the surgeon. 
x 
Each certified surgeon must evaluate the appropriateness of the procedure 
used, based on his/her medical training. 
x 
  Use sterile technique and equipment only. 
9.1.7.2 
Product related warnings and precautions 
x 
Keep the vial in its original package. 
x 
Do not use vials which were not properly stored. 
x 
Do not use vials which were not stored at 2-8°C. 
x 
Use D-PLEX before the expiration date specified on the package. 
x 
Do not use damaged vial or damaged package. 
x 
Never use D-PLEX vial that was previously used, not even on the same patient. 
x 
Avoid extended exposure to extreme heat, or humidity. 

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9.1.8 
Overdose  
Guidance on the recognition and treatment of possible overdose and adverse drug reactions 
Overdose of D-PLEX is defined as using more than 3 vials of D-PLEX per patient (i.e. more than 
 
per patient) in a single application. It is not expected to occur during the study as no more than 
maximum of 3 vials will be dispensed per patient.  
Overdose of D-PLEX will be recognized by the report of number of vials used as documented by the 
operation room (OR) team. 
In case of an overdose or adverse drug reaction, treat symptomatically and institute supportive 
measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of 
over dosage. Per surgeon decision, the administered D-PLEX can be removed by re-exploring the 
surgical incision and washing out the D-PLEX. 
All overdoses should be recorded and notified to the sponsor.  
If an SAE is associated with the overdose the PI should ensure the overdose if fully described in the 
SAE report form. 
Information on adverse drug reactions of D-PLEX are provided in the IB. 
9.1.9 
Packaging  
D-PLEX is aseptically packed in sterile, de-pyrogenated amber (brown) glass vial and closed with a 
sterile and de-pyrogenated rubber stopper and aluminium flip off cap.  
Please note that the outer surface of the vial is not sterile. Only the vial content is sterile. 
 
9.2 
CONCOMITANT MEDICATION 
9.2.1 
Medication(s)/Treatment(s) Permitted 
• 
Concomitant Medications 
All currently used concomitant medications, as well as all medication taken/prescribed 
to the patient throughout the study will be recorded in the case report form (eCRF). 
• 
Antibiotics Treatment per SOC Allowed in this Protocol: 
Subjects will receive prophylactic IV antibiotics per protocol. Additional antibiotics 
(excluding Doxycycline) can be administered (per need), according to investigator 
discretion. 
Any additional concomitant medication for the treatment of concurrent illnesses are 
allowed at the discretion of the treating physicians. 
9.2.2 
Medication(s) prohibited during the trial 
x 
Additional antibiotics (including antimicrobial sutures), except those used as part of 
the post-operative SOC or approved by the study investigator. 

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x 
High steroids dose that in the opinion of the investigator puts the patient at high 
risk of developing severe allergic/hypersensitivity reactions 
x 
Doxycycline IV/PO administration is not allowed in this protocol during the entire 
trial period. 
 
9.3 
PREPARATION & LABELING OF INVESTIGATIONAL PRODUCT (IP) 
The investigational product is manufactured aseptically at Nextar, at a Grade A (ISO 5) clean room. The 
investigational product will be provided to the investigational site by PolyPid Ltd. via IMP Ltd. depot, 
once Ethics Committee approval of the protocol and the Informed Consent Form, Investigator 
Agreement is signed and all key documents required by GCP and local regulation have been collected. 
D-PLEX is provided as a sterile and primarily packaged in a depyrogenated inert glass amber vial (
 
), and each product vial contains 
 of D-PLEX.  The sterile vial is packaged in a carton box. 
Preparation and labelling of the investigational medicinal products will be completed in accordance 
with the relevant GMP guidelines.  
Information on the Storage and Handling of the IP can be found in section 10.1.3 of this protocol.  
 
9.4 
DRUG ACCOUNTABILITY 
The Investigator or designee (i.e., SC, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of study 
product (quantity and condition) and recoding of subject dispensing, returned or destroyed study 
product. Dispensing records will document quantities received from PolyPid and quantities dispensed 
to subjects, including lot number, date dispensed, subject identifier number, and the name of the 
person dispensing the medication.  
All drug supplies and associated documentation will be periodically reviewed and verified by the study 
monitor over the course of the study.  
Investigators will be notified in writing of enrolment completion. All unused D-PLEX vials must be 
returned to the Sponsor when enrolment is complete according to sponsor instructions. 
 
10 
RECORDING & REPORTING OF ADVERSE EVENTS & REACTIONS 
The investigator or site staff will be responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE.  
10.1 
DEFINITIONS 
10.1.1 
Adverse event (AE) 
Any untoward medical occurrence in a subject participating a clinical trial, temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 

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NOTE: An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product.  
Examples of events meeting the definition of an AE include: 
x 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition. 
x 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
x 
Signs, symptoms, or the clinical sequelae of a suspected interaction of study 
medication with any other treatment provided to the subject. 
x 
Signs, symptoms, or the clinical sequela of suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE).  
“Lack of efficacy” or “failure of expected pharmacology action” per se will not be reported as an AE or 
SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfil the definition of an AE or SAE. 
Events that do not meet the definition of an AE include: 
x 
Medical or surgery procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
x 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
x 
The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 
10.1.2 
Adverse drug reaction (ADR) 
Any untoward and unintended response in a subject to an investigational medicinal product which is 
related to any dose administered to that subject.  
This includes medication errors, uses outside of protocol (including misuse and abuse of product) 
10.1.3 
Serious adverse event (SAE) 
A serious adverse event is any untoward medical occurrence that, at any dose: 
x 
Results in death 
x 
Is life-threatening 

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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. 
x 
Requires hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AE’s. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE.  
x 
Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions 
but do not constitute a substantial disruption. 
x 
Is a congenital anomaly/birth defect.  
x 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasia or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
10.1.4 
 Unexpected adverse event 
An adverse reaction which the nature and/or severity of which is not consistent with the information 
about the medicinal product in question set out in the investigator's brochure relating to the trial in 
question. 
 
10.2 
ASSESSMENT OF ADVERSE EVENT 
Adverse event and serious adverse events will be reported in accordance  
 
10.2.1 
Severity 
  

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10.3 
DOCUMENTATION AND REPORTING OF SAE 
All serious adverse events will need to be reported to the sponsor within 24 hours of knowledge, 
according to local regulations. 
SAEs will be reported through the study eCRF. In case the eCRF is not available, the Principal 
Investigator will complete the sponsor’s serious adverse event form and the form will be emailed to 
the sponsor to the following email: safety@polypid.com within 24 hours of knowledge.  
It is the Principal Investigator's responsibility to respond to any SAE queries raised by the sponsor as 
soon as possible.  
The information should be completed as fully as possible and contain: 
1. 
SAE event description 
2. 
SAE onset date  
Report the start date the event became SAE. If signs and symptoms started prior to 
event turning into SAE, record them as an AE.  
3. 
SAE end date   
Report the date the subject’s medical condition resolved or stabilised, or the date of 
discharge from hospital. Should signs and symptoms continued following discharge, 
report them as an AE.   
4. 
Seriousness criteria 
5. 
Severity (mild, moderate, severe) 
6. 
Relatedness to the surgical procedure 
7. 
Relatedness to the IP (Not Related, Possibly Related, unlikely related or Related) 
8. 
Action taken to resolve the SAE (Treatment, Other Action) 
9. 
Outcome (Ongoing, Resolved with Sequelae, Resolved, Death, Lost to Follow Up) 
10. 
Narrative of the event 
 
10.4 
TIME PERIOD AND FREQUENCY FOR DETECTING AEs, SAEs AND EVENTs 
OF SPECIAL INTEREST  
The investigator and site staff are responsible for detecting, documenting, and reporting events that 
meet the definition of an AE, SAE or Event of Special Interest (i.e SSI).  
Adverse events (AEs) will be collected from the time of randomization and during follow-up visit until 
study termination at visit 7 (60 days after surgery).  
Serious adverse events (SAEs) will be collected over the same time period as stated above for AEs.  In 
addition, any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests etc.), will be recorded from the time subject consents to participate in the study. 

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10.6 
DEVELOPMENT OF SAFETY UPDATE REPORTS 
The sponsor will provide all ECs/IRBs and the Ministry of Health/Regulatory Authority with a Safety 
Report which will be written in conjunction with the trial team and the Sponsor’s office and which will 
be updated yearly on the anniversary of receipt of hospital's approval to conduct the study (Form # 7).  
 
10.7 
THE TYPE & DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER 
ADVERSE EVENTS 
All AE/ SAEs not related to the study product should be followed up until resolution, permanent 
outcome or study termination, whichever is earliest.  
All AE/SAEs suspected to be related to the study product should be followed up until resolution or 
permanent outcome. 
SAE- If information is not available at the time when the first report becomes available, the investigator 
should fill out a follow-up SAE report at a later date and send to the Sponsor. (Per the instructions of 
EDC completion). 
It is the responsibility of investigators to inform their Ethics Committee of SAEs (whether IP related or 
not) as required by their Ethics Committee procedure. 
Any AE related to the IP (D-PLEX) will need to be reported to the Sponsor irrespective of how long after 
IP administration the event has occurred. 
 
11 
 NOTIFICATION OF SERIOUS GCP BREACHES AND/OR PROTOCOL   
VIOLATION 
The Investigator is responsible for ensuring the study is conducted in accordance with the procedures 
and evaluations described in this protocol.  
A “serious breach” is a breach which is likely to effect to a significant degree – 
(a) The safety or physical or mental integrity of the subjects of the trial; or 
(b)  The scientific value of the trial. 
It is within the site's PI to notify the regulatory authority in writing of any serious breach of (i) The 
conditions and principles of GCP in connection with that trial; or (ii) The protocol relating to that trial, 
as amended from time to time, within 7 days of becoming aware of that breach. 
The sponsor will be notified immediately of any case where the above definition applies during the 
trial.   
 

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12 
DATA MANAGEMENT & QUALITY ASSURANCE 
CONFIDENTIALITY 
The Electronic Case Report Form (eCRF) will not bear the subject’s name or other personal identifiable 
data.  The subject’s date of birth and trial unique identification number, will be used for identification. 
DATA COLLECTION TOOLS & SOURCE DOCUMENT IDENTIFICATION 
Primary data collection based on source-documented hospital and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the clinical trial protocol and eCRF 
completion. The Sponsor or designee will provide clinical monitoring throughout the study. 
It will be the responsibility of the investigator to ensure the accuracy of all data entered in the eCRFs.  
DATA HANDLING & ANALYSIS 
The procedures for data review and query management are described in the Data Management Plan 
and the Edit Checks Specification Table. Data will be reviewed throughout the study, in a blinded 
manor, according to these documents. 
Data will be collected using eCRFs that are specifically designed for this study. The data collected on 
the eCRFs will be captured in a clinical data management system (CDMS) that meets the technical 
requirements described in 21 CFR Part 11 and EU regulations. The CDMS will be fully validated to 
ensure that it meets the scientific, regulatory, and logistical requirements of the study before it is used 
to capture data from this study. Before using the CDMS, all users will receive training on the system 
and study-specific training. After they are trained, users will be provided with individual system access 
rights.  
Data will be collected at the investigational center by appropriately designated and trained personnel, 
and eCRFs must be completed for each screened subject according to their source documents. In no 
case can the eCRF be considered as source data for this trial. 
Subject identity should not be discernible from the data provided on the eCRF.  
A comprehensive validation check program will verify the data and automatically generate 
discrepancies for resolution by the investigator. 
Data will be verified using the source data by the study monitor and reviewed for consistency by Data 
Management using both automated logical checks and manual review.   
All data collected will be approved by the investigator at the investigational center. This approval 
acknowledges the investigator’s review and acceptance of the data as being complete and accurate. 
 
13 
RECORD KEEPING & ARCHIVING 
The Investigator shall arrange for the retention of all study records for at least 15 years after 
completion of the study.  
The investigator should ensure that the following records are maintained: 

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Modified intention to treat (mITT) set - The mITT analysis set is a subset of the ITT set and will consist 
of all patients randomized and treated with D-PLEX or SOC, for whom there is at least one valid post-
surgical observation on the primary endpoint and meet all inclusion/exclusion criteria. 
 
The analysis of primary and secondary efficacy endpoints will be performed on the ITT and mITT 
populations.  Analyses of safety will be performed on the safety analysis set.  Baseline subject 
characteristics and demographics will be summarized for the ITT population 
 
14.3 
STATISTICAL AND ANALYTICAL PLANS 
14.3.1 
Analysis of Demographics and Baseline Subject Characteristics 
Baseline and demographic characteristics will be summarized for all subjects in the ITT population by 
treatment group and overall.  Continuous variables will be displayed via summary statistics (mean, 
median, sample size, standard deviation, minimum, and maximum).  Categorical variables will be 
summarized via counts and percentages. 
 
14.3.2 
Primary Endpoint Analysis 
The number and proportion of subjects with at least one SSI, as determined by a blinded and 
independent adjudication committee, within 30 days post abdominal surgery will be tabulated per 
treatment group.  A 95% confidence interval using exact binomial methods will be constructed for 
each proportion. 
Missing data for the primary efficacy endpoint will be imputed according to the methods described in 
Section 14.3.5. 
 
14.3.3 
Secondary Endpoint Analysis 
Secondary endpoints analyses will be defined in the Statistical Analysis Plan (SAP) for the study.  The 
SAP will be written and finalized prior to database lock. 
  
14.3.4 Safety Evaluations 
Prior to analysis, all AEs will be coded using the MedDRA coding dictionary.  The number and 
percentage of subjects with at least one AE will be summarized by system organ class (SOC) and by 
preferred term (PT) within SOC for each treatment group.  A similar summary will be provided 
related to subjects with at least one serious AE (SAE).  In addition, tables will be constructed to 
summarize the Treatment Emergent Adverse Events (TEAEs) by relation to study treatment and by 
severity.   
Summary statistics on the raw and change from baseline data will be computed for each vital sign 
parameter and continuous laboratory parameter by time point for each treatment group.  Shift 

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tables will be constructed to show the changes in laboratory findings from pre-treatment to each 
post-treatment time point. 
A physical exam (PE) shift table will be constructed for each treatment group to identify the 
changes in body system findings from pre-treatment to each post-treatment time point where 
PE is performed (visits 6 and 7).   
Further analyses of safety variables for this study will be described in the SAP. 
 
14.3.5 Handling of Missing Data 
Missing data for the primary efficacy endpoint will be imputed for the ITT analysis set.  Deaths 
occurring within the first 30 days post abdominal surgery will be counted as treatment failures in the 
calculation of the primary efficacy endpoint for each treatment group.  Subjects who have missing 
primary efficacy endpoint data due to other reasons will also be counted as treatment failures in the 
calculation of the primary efficacy endpoint for each treatment group. 
  
There will be no imputation of missing data for the mITT analysis of the primary endpoint, and there 
will be no imputation of missing data for all other study endpoints (i.e., a complete case analysis will 
be used).  
 
14.3.6 
Interim Analyses 
No formal interim analyses are planned for this study.   
 
A complete statistical report including safety and efficacy endpoints will be prepared when all the 
subjects complete their follow-up period and all safety and efficacy evaluations are completed. 
 
15 
DIRECT ACCESS TO SOURCE DATA DOCUMENTS 
As required, the principal investigator shall obtain permission for direct access to source documents 
from the subject, hospital administration and national regulatory authorities before starting the clinical 
trial. 
The investigator will permit trial-related monitoring, audits, EC/IRB review, and regulatory 
inspection(s), providing direct access to source data/documents.  Trial participants are informed of this 
during the informed consent discussion.  Participants will consent to provide access to their medical 
notes. 
 

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16 
ETHICS & REGULATORY REQUIREMENTS 
The protocol, informed consent form and Authorization for the Use and Disclosure of Health 
Information or country specific confidentiality requirements must be reviewed and approved by the 
respective EC/IRB and the Sponsor before subject enrolment.  Changes to the protocol must be 
approved in writing by the Sponsor and the EC/IRB (as applicable) before the change is implemented.  
Prior to subject enrolment, a signed copy of the EC/IRB approval letter addressed to the investigator 
must be submitted to the Sponsor, certifying study approval.  Investigators are responsible for 
submitting and obtaining initial approval and continuing approval from the EC/IRB and forwarding 
copies of the approval letters to the Sponsor.  The original letters are to be kept in the investigational 
centres' Regulatory Binder designated for this study.   
The investigator will notify the Sponsor immediately of withdrawal of EC/IRB approval.   
 
17 
QUALITY CONTROL (STUDY MONITORING) 
In accordance with applicable regulations, GCP, and PolyPid procedures, the site will be contacted prior 
to the start of the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and PolyPid requirements.  When reviewing data 
collection procedures, the discussion will include identification, agreement and documentation of data 
items for which the CRF will serve as the source document. 
The investigator and the head of the medical institution (where applicable) agree to allow the 
monitor direct access to all relevant documents and to allocate their time and the time of their staff 
to monitor to discuss findings and any issues. 
Monitoring visits will be conducted in a manner to ensure that the: 
x Data are authentic, accurate, and complete. 
x Safety and rights of subjects are being protected. 
x Study is conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
A trial specific monitoring plan will be established for the study. The trial will be monitored according 
to the agreed plan. 
 
18 
QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, PolyPid may conduct a 
quality assurance assessment and/or audit of the site records. Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study.  
In the event of an assessment, audit or inspection, the investigator (and institution) must agree to 
grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate 
their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues 
and to implement any corrective and/or preventative actions to address any findings/issues identified. 

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19 
INSURANCE 
The Sponsor will provide insurance or indemnify (legal and financial coverage), the 
Investigatory/Institution against claims arising from the study, insurance covering the cost of 
treatment of the subjects in the event of clinical-trial-related injuries, in accordance with national 
regulations, except for claims that arise from malpractice, negligence, or non-compliance with the 
protocol.  The certificate of insurance and coverage will be provided upon request. 
20 
PUBLICATION POLICY 
All data generated from this study are the property of PolyPid and shall be held in strict confidence 
along with all information furnished by PolyPid, subject to the right of the Investigator or any member 
of his/her staff to publish the results in accordance with the publication procedure to be defined in the 
clinical trial agreement.  
Independent analysis and/or publication of this data by the Investigator or any member of his/her staff 
are permitted subject to obtaining the prior written consent of PolyPid.  
Written permission to the Investigator will be contingent on the review by PolyPid of the statistical 
analysis and manuscript and will provide for nondisclosure of PolyPid confidential or proprietary 
information. In all cases, the parties agree to submit all manuscripts or abstracts to all other parties 30 
days prior to submission. This will enable all parties to protect proprietary information and to provide 
comments based on information that may not yet be available to other parties. 
21 
STATEMENT OF COMPLIANCE 
The trial will be conducted in compliance with the approved protocol, Declaration of Helsinki, ICH GCP 
and local applicable regulatory requirement(s). 
The clinical trial shall not begin until the required approval or favorable opinion from the EC/IRB has 
been obtained and, if applicable, any local or national regulatory authority approvals or notifications 
have been obtained.  
The Sponsor has obtained clinical trial insurance that will cover expenses in the event of any physical 
injury resulting from research procedures. 
 
 

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22 
REFERENCES 
1. 
Emil Aga, Lital Keinan-Boker, Arieh Eithan, Tamar Mais, Alia Rabinovich & Faris Nassar (2015) 
Surgical site infections after abdominal surgery: incidence and risk factors. A prospective 
cohort study, Infectious Diseases, 47:11, 761-767, DOI: 10.3109/23744235.2015.1055587 
2. 
Alonso-Isa M., Medina-Polo J., Lara Isla A., Pérez-Cadavid S., Arrébola-Pajares A., Sopena-Sutil 
R., Benítez-Sala R., Justo-Quintas J., Gil-Moradillo J., Passas-Martínez J.B., Tejido-Sánchez A. 
2017. Surgical wound infection in urology. Analysis of risk factors and associated 
microorganisms. Actas Urol Esp. 41(2):109-116 
3. 
Avkan-Oğuz V, Baykam N, Sökmen S, Güner R, Agalar F, Alp E, Doğrul A, Turhan O, Ağalar C, 
Kurtaran B, Geçim IE, Özaras R, Yılmaz G, Akbulut A, Koksa I. 2016. Recommendations for 
intra-abdominal infections consensus report. Ulus Cerrahi Derg; 32: 306-321 
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Appendix 1: PK instructions for Collection and Processing 
 
The following instructions must be followed for the collection of plasma PK samples. 
 
1. At the allotted time points, draw at least 4 mL of venous blood into a polypropylene 
K2 EDTA lavender top tube.  Record time and date of collection for each sample. 
2. Gently invert tube at least 8 times to allow the specimen to mix with the 
anticoagulant in the tube to avoid clotting. 
3. Store vacutainer at ambient temperature prior to centrifugation.  Proceed to 
centrifugation within 18 hours of blood draw. 
4. Centrifuge the tube(s) at 2000 rpm (equivalent to 3000 g) for 15 minutes. 
5. Using a disposable pipette, transfer the supernatant (plasma) layer into 2 pre-
labelled polypropylene 2ml Eppendorf tubes. Try to keep equal amounts of plasma 
with the 2 tubes.   
x Mark these 2 tubes as:  A (primary) and B (back-up), complete the appropriate 
label and place them onto the 2ml tubes.  
6. Plasma samples must be stored at or below -20qC or below 
 
PK Sample Specimen Handling 
1. Two cryotubes (A and B) are obtained for each sample time point.  Shipments must 
be split (e.g. Set ‘A’ is sent first, followed by Set ‘B’, dispatched 24h to 72h later). 
2. It is important that SHIPMENTS MUST NOT CONTAIN BOTH CRYOTUBES A and B for 
the same time point, in the same shipment.  
3. Specimen collection times must be documented in the source records.  These must 
be kept up to date. 
4. Cryotubes should be packed in groups with samples A and B packed separately, 
according to subject number and stored at -20qC prior to shipment to: XenoBiotic 
Laboratories, Inc. 
Back-up Sample Shipment  
Back-up samples are to be shipped once XenoBiotic Laboratory confirms the 
primary samples have been received. XenoBiotic Laboratory will send an e-mail 
alert to the site confirming receipt of the primary samples. Back-up samples should 
be handled and shipped in the same manner as the primary samples.