A Phase Ib/II Prospective, Multicenter, Two Part Study; Part 1 - Open Label, Single Arm & Part 2 Randomized, Single-blinded Study to Assess Safety and Efficacy of D-PLEX Concomitantly With Standard of Care vs. Standard of Care Alone in the Prevention of Sternal Infection Post Cardiac Surgery.
Phase: PHASE1
Conditions: Postoperative Wound Infection Superficial Incisional, Postoperative Wound Infection Deep Incisional Surgical Site
Sponsor: PolyPid Ltd.



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PROTOCOL AGREEMENT SIGNATURES 
 
The Principal Investigator and the Sponsor have discussed this protocol. The investigator/s agree to 
perform the investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, current ICH GCP, 
Declaration of Helsinki and Israel Ministry of Health (Pharmaceutical Administration), Guidelines for 
Clinical Trials in Human Subjects 2016, and other regulatory requirements as amended. 
 
Protocol Title:                                       A Phase Ib/II Prospective, Multicenter, Two part study; Part 1 - 
Open Label, Single Arm & Part 2 Randomized, Single-blinded Study 
to Assess Safety and Efficacy of D-PLEX Concomitantly with 
Standard of Care vs. Standard of Care Alone in the Prevention of 
Sternal Infection Post Cardiac Surgery. 
 
 Protocol version and date:                Version: 05,  
Date: 13 August 2017 
Study Principal Investigator 
, MD 
 
 
 
Signature 
Date 
 
Sponsor Representative 
 
Clinical Project Manager 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
 

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Update of study duration  
Section: 3.3.1, 3.3.3 
Updated status & number of enrolled 
subjects in active studies (103 & 301)  
Updated information 
 
Section: 3.5 
Rephrasing 
Clarification 
Version 04 
Sections: Protocol Title, Summary, 6.1, 14.1.1 
Change of the study phase to Ib/II according 
to Israel MOH approval 
 
The study is comparative (D-
PLEX concomitantly with 
standard of care versus 
standard of care alone). 
 
Total number of patients was 
raised to 
. 
 
Safe use of D-PLEX in humans 
was demonstrated in 
 
patients administered with D-
PLEX in part 1 of the study (no 
AE related to D-PLEX were 
reported until now).  
 
Sections: Summary, 3, 4, 5.1, 6, 9.2.8 
Change of “primary sternal infection” to 
“sternal infection” 
 
D-PLEX indication is for 
prevention of sternal infection. 
 
Sections: Summary, 5.1 
Efficacy parameters were revised to primary 
and secondary efficacy endpoints.   
Change of the study phase to Ib/II.  
The primary endpoint provides the 
most clinically relevant evidence 
regarding efficacy of D-PLEX. 
Sections: Summary, 5.2 
Safety parameters were revised to safety 
endpoints 
Change of the study phase to Ib/II. 
 
Section: 9.4.2 
Added clarification of time point for PK 
sample collection “day 5 or discharge, 
whichever comes first” 
Clarification of time point  
Section: 9.5 
To avoid unnecessary duplication 
of test.  

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TABLE OF CONTENTS 
PROTOCOL AGREEMENT SIGNATURES……………………….…………………………….…….…….….3 
DOCUMENT HISTORY…………………………………………………………………………………………4 
TABLE OF CONTENTS…………………………………………………………………….………………..….7 
LIST OF ABBREVIATIONS…………………………………………………………….………………..……10 
1. TRIAL PERSONNEL……………………………………………………..……………..………………12 
2. SUMMARY………………………………………………………………………………….……..……13 
3. INTRODUCTION………………………………………………………………………………….……17 
3.1 
BACKGROUND………………………………………………………………………………………17 
3.1.1 
NAME & DESCRIPTION OF THE INVESTIGATIONAL MEDICINAL PRODUCT………..…17 
3.1.2 
RATIONAL FOR PERFORMING RESEARCH WITH THE INVESTIGATIONAL MEDICINAL 
PRODUCT & THE ANTICIPATED PROPHYLACTIC INDICATION…………………….…….18 
3.2 
NON-CLINICAL STUDIES…………………………………………………………………………...20 
3.3 
CLINICAL DATA…………………………………………………………..…………………………21 
3.3.1 
BONYPID – 1000 TM - 101 STUDY – FIRST IN MAN..………………………………………….21 
3.3.2 
BONYPID – 1000 TM - 102 STUDY……………………………………………………………….22 
3.3.3 
BONYPID -1000 TM - 103 STUDY…………………………………………………………….…..23 
3.3.4 
SAFETY PROFILE OF DOXYCYCLINE…………………………………………………………23 
3.4 
RATIONALE & RISKS/BENEFITS…………………………………………………………………..23 
3.4.1 
POTENTIAL BENEFITS OF D-PLEX FOR PREVENTION OF POST CARDIAC SURGERY 
STERNAL INFECTION…………………………………………………………………………….24 
3.4.2 
POTENTIAL RISKS OF D-PLEX FOR PREVENTION OF POST CARDIAC SURGERY 
STERNAL INFECTION……………………………………………………………………………25 
3.4.3 
ASSESSMENT & MANAGEMENT OF RISK………………………………………….………...25 
3.5 
SAFETY & EFFICACY SUMMARY…………………………………………………………………27 
4. OBJECTIVES…………………………………………………………………………………………….27 
5. EFFICACY & SAFETY ENDPOINTS………………………………………………..……………...….27 
5.1 
EFFICACY ENDPOINTS………………………………………………………………………….…..27 
5.1.1 
CDC/NHSN SURVEILLANCE DEFINITIONS FOR SPECIFIC TYPES OF INFECTIONSs)…..28 
5.1.2 
SUPERFICIAL INCISIONAL PRIMARY (SIP) SSI :……………………………………………..28 
5.2 
SAFETY ENDPOINTS…………………………………………………………………………….….29 
6. TRIAL DESIGN…………………………………………………………………………………………29 
6.1 
OVERALL DESIGN……………………………………………………………………………….….29 

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6.2 
DESCRIPTION & JUSTIFICATION OF THE DURATION OF TREATMENT, SUBJECT 
PARTICIPATION AND        TRIAL FOLLOW-UP………………………………………………….30 
7. SELECTION OF SUBJECTS…………………………………………………………………………….31 
7.1 
INCLUSION CRITERIA………………………………………………………………………….……31 
7.2 
EXCLUSION CRITERIA………………………………………………………………………………31 
8. RECRUITMENT………………………………………………………………………………………….32 
9. STUDY PROCEDURES & SCHEDULE OF ASSESSMENTS…………………………………………32 
9.1 
INFORMED CONSENT PROCEDURE...……………………………………….………….………....32 
9.2 
SCREENING PERIOD- VISIT 1…………………………...………………………………………….33 
9.2.1 
CARDIAC & MEDICAL HISTORY (ONLY AT SCREENING)…………………………………..33 
9.2.2 
VITAL SIGNS (ALL VISITS)……………………………………………………………………….33 
9.2.3 
PHYSICAL EXAMINATION (SCREENING & VISITS 6,8 & 10)…………………….……….…33 
9.2.4 
LABORATORY EXAMINATIONS………………………………………………………...………34 
9.2.5 
BACTERIOLOGICAL TESTING……………………………………………………………...……34 
9.2.6 
ELECTROCARDIOGRAM (ECG)- (Only at screening)………………………………………...….35 
9.2.7 
CHEST X-RAYS (at Screening & VISIT 8)……………….…………………………………..……35 
9.2.8 
ASSESSMENT of STERNAL INFECTION (at all visits)…………………………………….…/…35 
9.2.9 
ALLERGY QUESTIONNAIRE (at screening only)……………………………………………..….35 
9.2.10 
ADVERSE EVENTS (All visits)………………………………………………………………….…35 
9.2.11     MEDICAL RESOURCE UTILIZATION (MRU)…………………………………………………..36  
9.2.12 
STERNUM STABILITY ASSESSMENT…………………………………………………….…….36 
9.3 
SURGERY – INDEX PROCEDURE -VISIT 2………………………………………………..………36 
9.4 
SUBSEQUENT VISITS AND ASSESSMENTS – VISITS 3-9……………………………….………37 
9.4.12 
SAFETY ENDPOINTS TO BE ASSESSED DURING ASSESSMENTS………………………….37 
9.4.13 
DOXYCLINE PHARMACOKINETICS…………………………………………………………….38 
9.5 
TABLE OF STUDY ASSESSMENTS………………………………………………………………...39 
9.6 
METHODS………………………………………………………………………………………….….42 
9.6.12 
LABORATORY PROCEDURES…………………………………………………………………...42 
9.7 
DEFINITION OF END OF TRIAL…………………………………………………………………….42 
9.8 
DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS &  ‘STOPPING RULES’……….…..42 
10. NAME & DESCRIPTION OF ALL DRUGS USED IN THE TRIAL…………………………………...43 
10.2 TREATMENT OF SUBJECTS………………………………………………………………………...43 
10.3 CONCOMITANT MEDICATION…………………………………………………………………….43 
10.4 PREPARATION, HANDLING, & LABELING OF INVESTIGATIONAL MEDICINAL……….….44 

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10.5 DRUG ACCOUNTABILITY………………………………………………………………………….44 
11. RECORDING & REPORTING OF ADVERSE EVENTS & REACTIONS…………………………….45 
11.2 DEFINITIONS…………………………………………………………………………………………45 
11.3 RECORDING ADVERSE EVENTS…………………………………………………………………..46 
11.4 ASSESSMENT OF ADVERSE EVENTS………………………………………………………….….47 
11.4.12 SEVERITY……………………………………………………………………………………….….47 
11.4.13 CAUSALITY…………………………………………………………………………………………47 
11.4.14 EXPECTEDNESS…………………………………………………………………………………..48 
11.4.15 SERIOSNESS………………………………………………………………………………………48 
11.5 PROCEDURES FOR RECORDING & REPORTING SERIOUS ADVERSE EVENTS……..…..…48 
11.5.12 NOTIFICATION OF DEATHS……………………………………………………………....…….49 
11.5.13 REPORTING OF SUSARs………………………………………………………………….……...49 
11.5.14 DEVELOPMENT OF SAFETY UPDATE REPORTS………………………………….………....49 
11.5.15 OVERDOSE……………………………………………………………………………….………..49 
11.5.16 REPORTING URGENT SAFETY MEASURES………………………………………….……….49 
11.5.17 THE TYPE & DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER  
ADVERSE EVENTS………………………………………………………………………………………..50 
11.5.18 NOTIFICATION OF SERIOUS BREACHES TO GCP AND/OR PROTOCOL VIOLATION….50 
12. DATA MANAGEMENT & QUALITY ASSURANCE……………………….……………………..….51 
12.2 CONFIDENTIALITY…………………………………………………………………………….…...51 
12.3 DATA COLLECTION TOOLS & SOURCE DOCUMENT IDENTIFICATION…………..……….51 
12.4 DATA HANDLING & ANALYSIS…………………………………………………………….….…51 
13. RECORD KEEPING & ARCHIVING………………………………………………………….…..….52 
14. STATISTICAL CONSIDERATIONS…………………………………………………………..…..….52 
14.2 SAMPLE SIZE & RECRUITMENT……………………………………………………………...….52 
14.2.12 PLANNED RECRUIMENT RATE…………………………………………………………..….…52 
15. EFFICACY AND SAFETY ASSESSMENT……………………………………………………………52 
16. NAMES OF COMMITTEES INVOLVED IN TRIAL………………………………………………...53 
17. DIRECT ACESS TO SOURCE DATA DOCUMENTS…………………………………………….…53 
18. ETHICS & REGULATORY REQUIRMENTS………………………………………………………..53 
19. MONITORING REQUIRMENTS FOR THE TRIAL……………………………………………….....54 
20. INSURANCE…………………………………………………………………………………………....54 
21. PUBLICATION POLICY…………………………………………………………………………….…54 

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22. STATEMENT OF COMPLIANCE………………………………………………………………….….55 
23. REFERENCES…………………………………………………………………………………….…….56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
ASC/AST                                                             Active Surveillance Culture/Testing 
BMI                                                                     Body Mass Index 
β-TCP                                                                 β- Tri Calcium Phosphate 
CABG  
 
 
 
   Coronary Artery Bypass Grafting 
CDC                                                                    Center for Disease Control 
COPD                                                                 Chronic Obstructive Pulmonary Disease 
 
eCRF 
Electronic Case Report Form 
CVA                                                                     Cerebro Vascular Accident 
DPPC                                                                  Dipalmitoylphosphatidylcholine 
DSPC                                                                   Distearoyl Phosphatidylcholine  
DSWI 
 
 
 
 
    Deep sternal wound infections 
EC 
Ethics Committee 
ECG                                                                     Electrocardiogram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GRAS                                                                  Generally Recognized As Safe 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
MED 
Mediastinitis 
MRI                                                                     Magnetic Resonance Imaging 
PI 
Principal Investigator 
PK                                                                       Pharmacokinetics   
PLGA                                                                  Poly (DL-lactide-co-glycolide) 
PLEX  
 
 
 
        
   Polymer- Lipid Encapsulation matrix 
PVD                                                                    Peripheral Vascular Disease 

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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 
SSWI 
 
 
 
 
    Superficial Sternal Wound Infection  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TIA                                                                      Transient Ischemic Attack 
TX                                                                        Treatment 
USP             
United States Pharmacopeia 
VADs 
 
 
 
 
    Ventricular Assist Devices 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Indication 
D-PLEX is indicated for prevention of post cardiac surgery sternal 
infection. 
Standard Of Care (SOC) 
The SOC is based on The Society of Thoracic Surgeons Practice 
Guideline Series:  Antibiotic prophylaxis in cardiac surgery, Part II:  
antibiotic choice. 
The SOC will be consistent for all sites that will participate in the 
clinical program. 
Dose Administration 
The D-PLEX dose is dependent on the length of the sternum 
incision. For subjects with sternum length up to 22cm, two vials of 
D-PLEX will be used. For subjects with sternum length of 22cm or 
more, three vials of D-PLEX will be used. 
Duration Of Dosing 
D-PLEX is administered as a single application.  The active material 
(i.e., doxycycline) is being constantly released for approximately 4 
weeks. 
Phase of Trial  
Phase Ib/II 
Objectives 
 
To assess the safety of D-PLEX. 
 
To assess the anti-infective efficacy of D-PLEX over a 
period of 3 months (90 days) post operation by preventing 
sternal infection post cardiac surgery in patients above the 
age of 18, including high risk patients for infection 
Type of Trial 
Phase Ib/II, Prospective, Multicenter, Two part study; Part 1 Open 
Label, Single arm & Part 2 Randomized, single-blinded. 
Trial Design & Methods 
Phase Ib/II, Prospective, Multicenter, Two part study; Part 1 Open 
Label, Single arm & Part 2 Randomized, Single-blinded, D-PLEX 
Concomitantly with Standard Of Care vs. Standard of Care alone. 
Study population include subjects above the age of 18 years, that 
undergoing cardiac surgery through mid-sternotomy, including 
patients with high risk of infection, such as diabetes (Insulin and/or 
non-insulin dependent), patients with Peripheral Vascular Disease 
(PVD), Chronic Obstructive Pulmonary Disease (COPD), heavy 
smokers, Bilateral  Mammary artery  harvesting, and subjects 
administered chronic steroid treatment.   
Subjects who meet the eligibility criteria and provide signed 
informed consent, will be enrolled into the study and will be 
treated with D-PLEX concomitantly with standard of care (part 1) 
or randomized 2:1 to D-PLEX concomitantly with standard of care 
vs. standard of care only (part 2).  

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Subjects eligible for enrollment in the study must meet all of the 
following criteria; 
1. 
Male or non-pregnant female above 18 years old 
2. 
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. 
3. 
Subjects undergoing elective or urgent cardiac 
surgery, who are preoperative stable 
hemodynamically 
4. 
Subjects with (20≤BMI≤40) 
5. 
Subjects who sign a written informed consent 
Exclusion criteria (part 1 & 2): 
Subjects meeting any of the following criteria, are ineligible and 
must not be enrolled in the study; 
1. Subject received any investigational drug within 30 days of 
start of the study or within 5½ half-lives (pharmacokinetic 
or pharmacodynamics) prior to enrollment (whichever is 
longer)  
2. Subject that meet any of the following, are ineligible;  
a. Any preoperative active significant infection 
b. Antibiotic sensitivity to Doxycycline and/or  
tetracycline family of drugs 
c. Known allergies to more than 3 substances.(Allergy 
questionnaires should be filled during the enrolment 
process) 
d. History of allergic/hypersensitivity reaction to any 
substance having required hospitalization and/or 
treatment with intra-venous steroids/epinephrine or 
in the opinion of the investigator the patient is at high 
risk of developing severe allergic / hypersensitivity 
reactions. 
e. History of uncontrolled Asthma (GINA ≥ III) 
f. History of chronic urticaria 
3. Pregnant or breastfeeding women 

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4. Subjects who have taken oral or IV doxycycline during the 
last 4 weeks prior to screening  
5. Subjects who undergo cardiac/open chest surgeries, which 
are classified as emergency 
6. Immunocompromised subjects from any reason, at 
screening 
7. Subjects undergone TIA/CVA within the last 3 months prior 
to enrollment 
8. Subjects undergone previously any cardiac surgery through 
mid-sternotomy 
9. In the opinion of investigator, subject is not eligible to 
participate in the study due to a cognitive status, medical 
condition or medication status (other than items listed 
above) 
Efficacy Endpoints 
Primary Efficacy Endpoint: 
 
Decrease of infection rate as measured by the proportion of 
subjects with at least 1 identified sternal infection within 
90 days post-cardiac surgery. 
Sternal infection is composed from Deep Sternal Infection 
(DSWI) and Superficial Sternal Wound Infection (SSWI). 
Secondary Efficacy Endpoints: 
 
Reduction in Number of readmissions due to Sternal Surgical 
Site infection. 
 
Reduction in Number of surgical re-interventions due to Sternal 
Surgical Site infection. 
 
Time to sternal infection post-cardiac surgery. 
 
Decrease of Sternal Infection rate (DSWI and SSWI) during the 
first 30 days post operation. 
 
Decrease of Sternal infection rate (DSWI and SSWI) between 
day 30 and 3 months. 
 
Decrease in The total number of sternal infections (DSWI and 
SSWI) (including several in the same patient) between day 30 
and 3 months. 
 
Reduction of Number of hospitalization days due to Sternal 
Surgical Site infection. 
Sternal infection will be identified and assessed by the investigator 
based on predefined criteria in the CDC’s Criteria for Surgical Site 

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For a detailed technical summary of the D-PLEX formulation composition, see Section 5.2 in the D-PLEX 
Investigator’s Brochure, #DV-0079.  
 
3.1.2 
RATIONAL FOR PERFORMING RESEARCH WITH THE INVESTIGATIONAL MEDICINAL 
PRODUCT & THE ANTICIPATED PROPHYLACTIC INDICATION 
3.1.2.1 UNMET NEED FOR PREVENTION OF SURGERY STERNAL INFECTION FOLLOWING 
CARDIAC PROCEDURES 
 
Sternal infections post cardiac surgery are a major cause of post-operative illnesses resulting in 
increased morbidity and mortality, and hold a major impact on the cost of health.  
In North America and Europe two million cardiac surgeries are performed a year, whereas circa 5,000 
are conducted in Israel. Cardiac procedures include Coronary Artery Bypass Grafting (CABG) procedures, 
valve replacement and repair, placement of temporary or permanent implantable cardiac devices, 
including ventricular assist devices (VADs) and ascending aorta surgeries associated with cardiac 
procedures. Deep and superficial sternal wound Infection, are rare (0.23 to 5.67 per 100 operations) but 
the consequences of infection are severe2.  
One of the most dangerous complication following cardiac surgery is Deep Sternal Wound Infection 
(Mediastinitis). The incidence of deep sternal wound infections ranges between 0.3-3.2% 3,4,5,6,7,8  with 
mortality rate reaching 40%3. In high-risk patients undergoing cardiac surgery, complications are even 
higher reaching 5-7% 9 , 10. Prolonged hospitalization last weeks or months, with repeated surgical 
interventions and long-term antibiotic treatment, in cases of Osteomyelitis. DSWI affects quality of life, 
and causes suffering to the patient and family. The financial burden in these patients to the health 
systems is estimated to be 3-time-fold compared to patients undergoing open cardiac surgery, without 
any infection11,12,13 . 
One of the causes for infection are any bacteria (of local natural flora and/or nosocomial) present at 
multiple body sites and on the skin surface. Almost two thirds of organisms isolated in patients 
undergoing cardiac procedures are gram-positive Staphylococci, including S. aureus, coagulase-negative 
staphylococcus. Gram-negative organisms are less commonly isolated in these patients and include 
Enterobacter species, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Proteus 
mirabilis, and Acinetobacter species14,15,16,17,18,19,20,21. 
Multiple studies have found that antimicrobial prophylaxis in cardiac procedures lowers the occurrence 
of postoperative Sternal Site Infection (SSI) up to fivefold22. 
The American Society of Health System Pharmacists (ASHP) has developed guidelines of antimicrobial 
prophylaxis in surgery. The antibacterial prophylaxis for patients undergoing cardiac procedures, is a 
single pre-incision dose of cefazolin or cefuroxime with appropriate intraoperative re-dosing if needed.  
Currently, there is no evidence to support continuing I.V. prophylaxis until all drains or catheters are 
removed. The currently accepted duration of prophylaxis for cardiac procedures is less than 24 hours, 
but prophylaxis should be continued for the duration of the procedure23,24,25,26.  

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Topical antimicrobials, mainly gentamicin or vancomycin, applied to the sternum during cardiac 
procedures in combination with I.V. antibiotics to prevent mediastinitis has been evaluated. In the 
literature, the safety and efficacy of topical antimicrobials have not been clearly established and 
therefore cannot be recommended for routine use in cardiac procedures15,27,28. Randomized control 
studies in US, of gentamicin collagen sponges failed to show any efficacy in a large prospective study of 
cardiac surgery in US10.  
In recent years, despite the development of new surgical techniques, new technologies for diagnosing 
postoperative infection, and wound care technologies, there is no decrease in the occurrence of sternal 
infections following cardiac surgeries. This is mainly due to the growing number of older patients 
undergoing cardiac surgery, suffering from other diseases with co-morbidities necessitating longer 
postoperative hospitalization, caused by postoperative complications 4,7. 
 
3.1.2.2 JUSTIFICATION FOR THE USE OF D-PLEX FOR PREVENTION OF SSI FOLLOWING 
CARDIAC PROCEDURES 
Following cardiac surgery the blood supply to the sternal bone is disrupted. Therefore, systemic 
antibiotics and immune defence cannot sufficiently reach the designated areas, causing these areas to 
be more susceptible to proliferation of bacteria and subsequent development of infection. In addition, 
there is a risk of developing antibiotic resistant bacteria in the presence of low local prophylactic 
antibiotic concentrations, while an increased systemic antibiotic dose may cause systemic toxicity. In an 
attempt to overcome these problems, some surgeons locally dispense antibiotics before closing the 
incision. This antibiotic treatment presents a very short release durations of 1-2 hours, and does not 
prevent development of bacterial infection15,27,28. D-PLEX is a new formulation of extended controlled 
release of Doxycycline, intended to be administered in the sternal surgical site post sternotomy 
performed in cardiac surgery.  
Doxycycline is effective for eradication of most of the bacteria known to cause, sternal infection mainly 
cocci bacteria which cause at least 80% of the infections29. In addition, Doxycycline-PLEX based product 
(BonyPid-500TM), demonstrated efficacy in prevention of infections caused by S. aureus30. 
D-PLEX is administered directly at the surgical site and releases doxycycline immediately upon product 
administration and during approximately 4 weeks following administration, which is the time period in 
which most of the sternal infections occur31.   
During this period, the expected local Doxycycline concentration is well above the minimal inhibitory 
concentration (MIC) of sensitive organisms (e.g. S. aureus).  
By preventing growth of bacteria via high local concentration of doxycycline at the sternal surgical site 
during the 4 weeks post its administration, D-PLEX is intended to be effective for prevention of post 
cardiac surgery sternal infection. 
 

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3.2 
NON-CLINICAL STUDIES  
Non-clinical pharmacology and pharmacokinetic studies were performed with D-PLEX in order to 
demonstrate its relevance to the investigated therapeutic and the possible unfavourable and 
unintended effects in humans. These studies included:  
 
A number of in vitro development studies with D-PLEX (See IB, section 6.2.1) that demonstrated 
doxycycline antimicrobial activity post hydration. The studies showed that antibacterial 
effectiveness of the doxycycline, as incorporated in D-PLEX, and released, is maintained for up 
to 35 days. The doxycycline release is a high short term initial release (25-30% in the first 24 
hours) followed by daily release of 1-3% of the rest of the Doxy reservoir from day 5 up to day 
32. Between days 33 and 35 the daily release is below 1% (See IB, section 6.3.2).  
 
In vivo, rat model, study that demonstrated the ability of D-PLEX to significantly reduce bacterial 
proliferation following induction of a surgical site infection (SSI) attained by intramuscular 
administration of the test product combined with Staphylococcus aureus (ATCC 25923). 
 
In vivo pharmacokinetic study that demonstrated that after administration of high dose of D-
PLEX (more than 100 times higher than the maximum amount allowed to be administered in 
human) doxycycline was detected in the plasma up to 35 days. This proves the ability of the D-
PLEX product to release doxycycline for a period of 35 days in vivo (which is also supportive by 
the in vitro data). Furthermore, it was observed that after subcutaneously (SC) administration 
of low dose of D-PLEX (equivalent to twice the maximum amount allowed to be administered 
in human), doxycycline was detected in the plasma for up to 24 hours only. This indicates that 
the systemic exposure to doxycycline as consequences of local administration is negligible. In 
vivo, safety study, rabbit model demonstrated that was no gross pathological findings after 
administration of D-PLEX in clinically-relevant model (Deep sternal administration).  
 
In vivo, safety study, rabbit model (PLP-002-EF, see IB, section 6.4.1) demonstrated no gross 
pathological findings after administration of D-PLEX in clinically-relevant sternal model.   
 
Toxicology studies were not performed on D-PLEX. However, the following is regarded as supportive of 
the non-clinical toxicity of the D-PLEX product: 
 
The systemic Doxycycline label, which is incorporated in D-PLEX IFU, #L01002ENG, is referred to 
as supportive of the non-clinical toxicity of doxycycline. 
 
Two of PolyPid's products (BonyPid-1000™ and BonyPid-500TM) toxicology program is referred 
to as supportive of the non-clinical toxicity of doxycycline and the other constituents used in the 
D-PLEX product (see IB, section 6.4.2). This support is based on: 
o The amount of doxycycline and polymer-lipid encapsulation matrix (PLEX) components 
administered in D-PLEX and BonyPid-1000™ are comparable. 
o The amount of β Tri-calcium phosphate (β-TCP) is lower in D-PLEX as compared to 
BonyPid-1000™.  
 
The BonyPid-1000™ toxicology program consists of GLP and International Organization for 

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Standardization (ISO) 10993-1:2009-compliant biocompatibility studies conducted to evaluate 
BonyPid-1000™-equivalent coated granules without doxycycline, the BonyPid-1000™ product, 
and BonyPid-1000™ impurities, including 4-epidoxycycline. 
 
The biocompatibility studies indicate the following:  
o BonyPid-1000™ is not associated with clinically relevant local irritation or sensitization; 
o The slight irritant result obtained was not considered to be biologically relevant; 
o Extracts of BonyPid-1000™ were not acutely toxic, pyrogenic, or genotoxic in a standard 
battery of assays; and 
o A 13-week subcutaneous implantation study also indicated that there was no evidence 
of systemic toxicity induced by BonyPid-1000™. 
For detailed non clinical studies summary of the D-PLEX, see Section 6 in the D-PLEX Investigator’s 
Brochure, #DV-0079. 
  
3.3 
CLINICAL DATA 
D-PLEX is indicated for the prevention of sternal wound infection post cardiac surgery. 
 As of today
 subjects were enrolled to this protocol No AE or SAE were considered to be related to D-
PLEX by the investigators.  Nevertheless, clinical experience from BonyPid-1000TM can contribute to the 
understanding of the safety and efficacy of D-PLEX, under the following considerations: 
Both products include identical components, except for beta-TCP which differs in its shape, size and 
function and manufacturer as described: 
a) BonyPid-1000™ includes 
, which have CE mark approval 
(CE-0459) and FDA 510(k) clearance (K042340) as a bone void filler. 
b) D-PLEX includes 
, which is not an approved medical device and 
does not have any bone healing properties of a bone filler. 
c) Both products are tested according to ASTM F1088-04a. 
The maximum amount of each component allowed to be administered in both products per patient is 
the same.  
Although they differ in their indications for use1, both products are administered in the same tissue 
environment i.e. in bone. Hereinafter is a brief summary of the clinical experience from BonyPid-
1000TM:  
                                                 
1
 D-PLEX 
is 
indicated 
for 
prevention 
of 
post 
cardiac 
surgery 
sternal 
wound 
infection. 
BonyPid-1000™ is a bone graft substitute intended for filling bone voids or defects that are not intrinsic to the stability of the 
bony structure. These defects may be surgically created osseous defects or osseous defects created from traumatic injury to 
the bone. BonyPid-1000™ is resorbed and replaced with bone during the healing process. BonyPid-1000™ contains doxycycline 
to reduce microbial colonization on the bone void filler of microorganisms sensitive to doxycycline. 
 

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Clinical Investigation: Study # BonyPid-1000TM -101  
Clinical Investigation: Study # BonyPid-1000TM -102  
Clinical Investigation: Study # BonyPid-1000TM -103 
 
3.3.1 
BONYPID-1000TM- 101 STUDY - FIRST-IN-MAN 
BonyPid-101 study was a First in Man Clinical Study to evaluate the safety and the effectiveness of 
BonyPid-1000TM concomitantly to Standard of Care (SOC) in the treatment of contaminated or infected 
open fractures and was conducted in Manila, the Philippines. This was a single arm, open label, 
investigator initiated study using BonyPid-1000™ in open tibia fractures.  
Sixteen (16) patients with Gustilo IIIA and IIIB tibia fractures were enrolled. All were treated with 
standard of care treatment defined as: irrigation and debridement (I&D) of the soft tissues and the target 
fracture, IV antibiotics and fracture stabilization. BonyPid-1000™ was implanted immediately during the 
first surgical intervention.  
Study Effectiveness Results: 
In 15/16 subjects callus formation was demonstrated at week 16 and in 16/16 subjects at week 20. 
Study Safety Results: 
All clinical adverse events were related to initial injury and complications. No adverse events were 
assessed as being related to the study device – BonyPid-1000TM.  No deep infection at the target fracture 
was reported during the study. 
 
3.3.2 
BONYPID-1000TM-102 STUDY 
BonyPid-102 study was a multicenter study to confirm the safety and the effectiveness of BonyPid- 1000TM 
concomitantly to Standard of Care (SOC) in the treatment in contaminated or infected open fractures 
conducted in two sites in Romania. This was a single arm, open label, study using BonyPid-1000TM in long 
bone fractures. 
Three (3) subjects with Gustilo II, IIIA and IIIB tibia and femur fractures were enrolled.  
Similarly to study BonyPid-1000TM-101, no adverse events related to BonyPid-1000™, were reported. 
Study Effectiveness results: 
In this study 2/3 subjects have met the efficacy end-point of wound closure and bone union at 24 weeks.  
Study Safety results: 
No serious adverse events were reported. No adverse events were assessed as being related to BonyPid-
1000TM.  No deep infection at the target fracture was reported during the study. 
 

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o. All PLEX components are widely used in the medicinal or medical device industry, have an 
established history of safety and acceptable clinical use in contact with bone and/or blood 
circulation and are biodegradable.  
 
3.4.2 
POTENTIAL RISKS OF D-PLEX FOR PREVENTION OF POST CARDIAC SURGERY 
STERNAL INFECTION 
  
Potential risks associated with addition of new antimicrobial coating as well as repositioning 
the method of administration from oral/systemic into local administration during sternal 
cardiac surgery are:   
a) Potential contamination of microorganisms and pyrogens by the aseptic product. 
b) Potential for local toxicity caused by the drug products, including irritation of the 
tissues. 
c) Individual susceptibility to Doxycycline, leading to allergic reaction. 
d) Potential of bacteria resistant to doxycycline (treatment failure) - causing 
exacerbation of infection. 
e) Administration outside of the target organ- sternal surgery site. 
f) D-PLEX will be removed from the target organ following repeated I&Ds. 
g) Inadequate antibacterial activity of the product. 
h) Re-use of D-PLEX, can lead to cross contamination. 
i) 
Potential for permanent tooth discoloration or enamel hypoplasia during tooth          
development. 
j) 
Tetracycline form stable complex in any bone formation tissue. Reversible 
decrease in fibula growth rate has occurred in premature infants receiving oral 
tetracycline. 
k) Photosensitivity reaction: exaggerated sun burn reaction. 
 
3.4.3 
ASSESSMENT & MANAGEMENT OF RISK 
Risks Mitigation process of D-PLEX for prevention of post cardiac surgery sternal 
infection 
a) Potential contamination of microorganisms and pyrogens by the aseptic product. 
Mitigation:  
o IFU- instruction how to store, administer and use. 
 

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b) Potential for local toxicity by the drug product, including irritation of the tissues. 
Mitigations: 
o At subject level: 
In case of serious of local allergic reaction induced by D-PLEX, removal and 
irrigation of the product will be done by the surgeon.  
o At population level: 
- 
Close follow up of patients. 
- 
Safety Monitoring Committee. 
c) Individual susceptibility to doxycycline, leading to allergic reaction. 
Mitigation: 
o Exclude susceptible subjects with known allergy to doxycycline / tetracycline family 
and/or three different allergens. 
d) Potential of bacteria resistant to doxycycline-treatment failure/exacerbation of infection. 
Mitigation: 
o SOC concomitantly administered with D-PLEX provides systemic antibacterial 
coverage. 
e) Administration outside of the target organ- sternal surgery site. 
Mitigations: 
o Training of professional surgeons during development phase. 
o IFU, clear instructions how to apply.    
   
f) D-PLEX will be removed from the target organ following repeated I&Ds. 
Mitigation: 
o Apply D-PLEX following I&D procedure as instructed in the IFU. 
g) Inadequate anti-bacterial activity of the product 
Mitigations: 
o Doxycycline assay is tested per batch in release and stability.  
o SOC concomitantly administered with D-PLEX provides systemic antibacterial coverage. 
h) Re-use of D-PLEX between different patients, can lead to cross contamination. 
Mitigations: 
o D-PLEX is intended as a single use administration. 
o Training of site clinical staff during clinical trials and IFU during marketing. 
i) 
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. 
 

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Mitigations: 
o Exclusion of patients less than 18 years old from the clinical study. 
o Exclusion of pregnant or lactating woman from the clinical study. 
j) 
Photosensitivity reaction: exaggerated sun burn reaction. 
Mitigations: 
o D-PLEX is administered locally at very low dose once in the surgical site. 
o Blood levels of doxycycline are negligible, if any. Therefore no potential for photo 
toxicity is expected. 
 
3.5 
SAFETY & EFFICACY SUMMARY 
Based on the current data available from the ongoing clinical study with D-PLEX and the 3 Clinical studies 
with BonyPid-1000TM, no major safety concern was observed. Overall, based on risk: benefit assessment, 
the expected benefits are outweigh the expected risks associated with the use of D-PLEX.  
Therefore, clinical trial with D-PLEX in patient undergoing cardiac sternal surgery is warranted. 
 
4 
OBJECTIVES 
 
To assess the safety of D-PLEX.  
 
To assess the anti-infective efficacy of D-PLEX over a period of 3 months post operation by 
preventing sternal infection post cardiac surgery in patients above the age of 18, including 
high risk patients for infection. 
 
5 
EFFICACY & SAFETY ENDPOINTS 
5.1 
EFFICACY ENDPOINTS  
The following will be evaluated in this trial: 
Primary Efficacy Endpoint 
 
Decrease of infection rate as measured by the proportion of subjects with at least 1 identified 
sternal infection within 90 days post-cardiac surgery.  
Sternal infection is composed from Deep Sternal Infection (DSWI) and Superficial Sternal 
Wound Infection (SSWI). 
Secondary Efficacy Endpoints 
 
Reduction in Number of readmissions due to Sternal Surgical Site infection. 
 
Reduction in Number of surgical re-interventions due to Sternal Surgical Site infection. 
 
Time to sternal infection post-cardiac surgery. 

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 
Decrease in Sternal infection rate (DSWI and SSWI) during the first 30 days post operation. 
 
Decrease in Sternal infection rate (DSWI and SSWI) between day 30 and 3 months. 
 
Decrease in The total number of sternal infections (DSWI and SSWI) (including several in the 
same patient) between day 30 and 3 months. 
 
Reduction in Number of hospitalization days due to Sternal Surgical Site infection. 
 
Sternal infection will be identified by the following predefined criteria as assessed by the 
investigator: 
5.1.1 
CDC/NHSN SURVEILLANCE DEFINITIONS FOR SPECIFIC TYPES OF INFECTIONS 
(JANUARY 2016, p. 17-12) 
The patient has at least one of the following: 
a. Patient has organisms identified from mediastinal tissue or fluid by a culture or 
non-culture based microbiologic testing method, which is performed for purposes 
of clinical diagnosis or treatment [e.g., not Active Surveillance Culture/Testing 
(ASC/AST)].  
b. Patient has evidence of mediastinitis on gross anatomic or histopathologic exam. 
c. Patient has at least one of the following signs or symptoms:  fever (>38.0°C), chest 
pain*, or sternal instability*; and at least one of the following: 
i. 
Purulent drainage from mediastinal area 
ii. 
Mediastinal widening on imaging test 
     * with no other recognized cause 
 
and/or 
 
5.1.2 SUPERFICIAL INCISIONAL PRIMARY (SIP) SSI (Based on PROCEDURE- ASSOCIATED 
MODULE SSI, JANUARY 2016, p. 9-7): 
 
Infection occurs within 90 days after any NHSN operative procedure (where day 1 = the 
procedure date)  
 
AND  
the patient has at least one of the following:  
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 or non-culture based microbiologic testing 

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method which is performed for purposes of clinical diagnosis or treatment (e.g., not 
Active Surveillance Culture/Testing (ASC/AST).  
c. Superficial incision that is deliberately opened by a surgeon, attending physician** or 
other designee and culture or non-culture based testing is not performed.  
AND  
the patient has at least one of the following signs or symptoms: pain or tenderness; 
localized swelling; erythema; or heat. A culture or non-culture based test that has a 
negative finding does not meet this criterion.  
 
d. Diagnosis of a superficial incisional SSI by the surgeon or attending physician or other 
        designee.  
 
** The term attending physician for the purposes of application of the NHSN SSI criteria may be interpreted to mean the 
surgeon(s), infectious disease specialist, other physician on the case, emergency physician or physician’s designee (nurse 
practitioner or physician’s assistant). 
 
5.2 
SAFETY ENDPOINTS 
The following safety endpoints will be evaluated in this trial: 
 
Adverse events, physical examinations & vital signs.  
 
Bone non-union will be assessed by sternum stability, which will be clinically evaluated by 
investigators. In case of suspected bone non-union further evaluation will be done according 
to standard clinical practice (CT imaging). 
 
Sternum  mechanical dehiscence will be evaluated by X-Ray at visit 8 (90 days) and at 
investigator’s discretion  
 
Fibrosis/Scarring will be assessed by visual wound examination by investigators as an 
evaluation of wound healing. 
 
Safety laboratory parameters;  
Routine hematology, chemistry and urinalysis. 
 
Bacterial growth, identification and sensitivity to antibiotics (especially to tetracycline) 
 
6 
TRIAL DESIGN 
6.1 
 OVERALL DESIGN 
This is a Phase Ib/II Prospective, Multicentre, Two parts Study; Part 1 Open Label, Single Arm & 
Part 2 Randomized, Single-Blind, of the Initial Safety and Efficacy of D-PLEX Concomitantly to 
Standard of Care Study vs. Standard Of Care alone in the Prevention of Sternal Infection Post 
Operatively Following Cardiac Surgery.  

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The study population includes any subject above the age of 18 years, who undergoes cardiac 
surgery post mid-sternotomy, including patients with high risk for infection, such as Diabetes 
(Insulin and/or non-insulin dependent), Peripheral Vascular Disease (PVD), Chronic Obstructive 
Pulmonary Disease (COPD), Heavy smokers, Bilateral Mammary artery Harvesting, Chronic Steroid 
Treatment.  
Subjects who meet the eligibility criteria and provide signed informed consent will be enrolled in 
the study. 
Subjects will be enrolled into the study and will be treated with D-PLEX concomitantly with SOC 
(part 1) or randomized 2:1 to D-PLEX concomitantly with standard of care vs. to standard of care 
only (part 2).  
The D-PLEX will be applied during the cardiac surgery (index procedure), as an adjunct to the 
standard care, immediately prior to sternal closure. Sternum and chest closure will be performed 
per investigator discretion.  
Post-operative care will be performed per SOC that will be consistent for all sites. Post-operative 
resumption of activity are at the discretion of investigator based on subject medical condition. 
Spontaneous adverse events (AEs) will be recorded throughout the study. 
The study will assess the efficacy and safety of the controlled release antibiotic (doxycycline) by 
the reduction in the number of sternal infections observed during the study period in any subject 
above the age of 18 years, including patients with high risk for infection. 
Additional follow up for prolonged safety assessments only, will be done until 6 months. 
D-PLEX is a sterile powder, primarily packaged in sterile, depyrogenated inert glass amber vial 
(6ml vial), with each product vial containing 5g of D-PLEX. 
 
6.2 DESCRIPTION & JUSTIFICATION OF THE DURATION OF TREATMENT, SUBJECT 
PARTICIPATION AND TRIAL FOLLOW-UP 
 
A number of factors have been considered for determining the 6 months follow up period. Primarily, 
allowing a sufficient follow up period to demonstrate the initial and sustainability safety and efficacy 
endpoints of D-PLEX including the safety and efficacy of doxycycline incorporated into D-PLEX.  
The anti-infective effect of D-PLEX by preventing sternal infection post cardiac surgery over a period 
of 1 and 3 months post operation. The prevention of Infection rate is measured by the reduction in 
the number of sternal infections. 6 months period is a sufficient time to demonstrate the prolonged 
effect32.  
 

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7 
SELECTION OF SUBJECTS 
7.1 INCLUSION CRITERIA 
Subjects eligible for enrollment in the study must meet all of the following criteria; 
a) 
Male and non-pregnant female subjects above 18 years old. 
b) 
Females of childbearing potential should have a negative serum pregnancy test prior to 
index procedure. 
Note: All females of child bearing age 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. 
c) Subjects eligible and undergoing elective or urgent cardiac surgery, who are preoperative 
stable hemodynamically. 
d) 
Subjects with (20≤BMI≤40). 
e) 
Subjects who sign a written consent form. 
 
7.2 
EXCLUSION CRITERIA 
Subjects who meet any of the exclusion criteria are prohibited from participating in the 
study. 
a) 
Received any investigational drug within 30 days of start of study or within 5½ half-lives 
(pharmacokinetic or pharmacodynamics) prior to enrolment (whichever is longer). 
b) 
Are ineligible to receive treatment with: 
i. Any preoperative active significant infection.  
ii. Antibiotic sensitivity to Doxycycline and/or tetracycline family of drugs. 
iii. Known allergies to more than 3 substances. (Allergy questionnaire should be 
filled during the enrolment process). 
iv. History of allergic/hypersensitivity reaction to any substance having required 
hospitalization and/or treatment with intra-venous steroids/epinephrine or in 
the opinion of the investigator the patient is at high risk of developing severe 
allergic / hypersensitivity reactions. 
v. History of uncontrolled Asthma (GINA ≥ III). 
vi. History of chronic urticarial. 

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c) 
Pregnant or breastfeeding women. 
d) 
Subjects who have taken oral or IV doxycycline during the last 4 weeks prior to 
screening. 
e) 
Subjects who undergo cardiac/open chest surgeries which are classified as 
emergencies. 
f) 
Immunocompromised subjects for any reason at screening. 
g) 
Subjects that undergo TIA/CVA within the last 3 months prior to enrolment. 
h) 
Subjects that previously underwent any cardiac surgery through mid-sternum. 
i) 
In the opinion of investigator, subject is not eligible to participate in the study due to a 
cognitive status, medical condition or medication status (other than items listed above. 
 
8 
RECRUITMENT 
Patient recruitment will be via cardiac surgical admission units at 
 Israeli sites: 
Medical Centers. 
 
9 
STUDY PROCEDURES & SCHEDULE OF ASSESSMENTS 
9.1 INFORMED CONSENT PROCEDURE 
The Investigator will prepare an informed consent form (ICF) in accordance with this study 
protocol and all local and national regulatory requirements. The informed consent form must 
be submitted to the EC and a copy of the final EC-approved consent form must be submitted 
to the Sponsor prior to the start of the study at that investigational site. 
Prior to any study procedures, all subjects must document their consent, in writing, for study 
participation and authorization for use and disclosure of health information by signing the 
Ethics Committee (EC)-approved informed consent form.  As part of the consent process, the 
subject will have the opportunity to ask questions of, and receive answers from, the personnel 
conducting the study.   
It is the responsibility of the Investigator, or a person delegated by the Investigator to obtain 
written informed consent from each subject prior to participation in the trial, following 
adequate explanation of the aims, methods, anticipated benefits and potential hazards of the 
study.  
“Adequate time” must be given for consideration by the patient before taking part. The PI 
must record when the patient information sheet has been given to the patient.  
The Investigator or designee will explain the patients are under no obligation to enter the trial 
and that they can withdraw at any time during the trial, without having to give a reason. 

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No clinical trial procedures will be conducted prior to taking consent from the participant. 
Consent will not denote enrolment into trial.  
A copy of the signed Informed Consent form will be given to the participant.  The original 
signed form will be retained at the study site and a copy placed in the medical notes. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form will be reviewed and updated if necessary and subjects will be re-consented as 
appropriate. 
 
9.2 SCREENING PERIOD - VISIT 1 
Patient will be screened for study eligibility at the clinic within 7 days prior to surgery at Day 0 
following ICF process and signature. The following screening assessments will be performed: 
 
9.2.1  CARDIAC & MEDICAL HISTORY (ONLY AT SCREENING) 
Demographic data and complete cardiac and medical history of past, present illnesses and 
surgeries as well as medications currently being taken to address current illnesses will be 
recorded by the investigator. The medical history will include alcohol consumption, tobacco 
use, diabetic status, and concurrent disease/allergy status. 
Subjects with known hypersensitivity to doxycycline and/ or tetracycline family of drugs should 
be excluded. 
Subjects will be permitted to receive concomitant therapy as medically required, except for 
long term high steroids dose (defined as steroid use for over 3 consecutive months during a 6 
month period), immunosuppressive agents and systemic doxycycline (IV/PO).  
A record of all concomitant medications will be maintained. 
9.2.2  VITAL SIGNS (ALL VISITS) 
Systolic/diastolic blood pressure, pulse, temperature will be recorded after 5 minutes of rest. 
Weight and height (taken at visit 1 and termination only) will be taken from the subject, or the 
subject will be asked for this information at screening/admission.  
All measurements and the time will be recorded in CRF.  
   Any abnormal finding, assessed by the investigator as clinically significant, should be recorded 
as AE in the relevant CRF section. 
9.2.3 PHYSICAL EXAMINATION (SCREENING & VISITS 6, 8 & 10) 
The investigator will perform a complete physical examination of the major body systems 
(Eyes, Ears, Nose and Throat; Cardiovascular; Respiratory; Gastrointestinal; 

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Musculoskeletal/Connective Tissue; Neurological; Endocrine/Metabolic; 
Hematopoietic/Lymphatic; Dermatologic; Genitourinary) 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. 
 
9.2.4 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 visits 1 and as per investigator discretion at visits 5 – 10 and termination 
visit: pH, Specific Gravity, Protein, Glucose, Bilirubin, Ketones, Nitrites, Leukocytes, [At 
screening & on visits 5-10 (at the discretion of the investigator)]. 
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 & Triglyceride. At screening only; PT, PTT & Blood typing. 
d. 
Pregnancy test by serum at screening only, performed by female of child-bearing 
potential only. All female of child bearing potential must agree to use of a highly 
effective method of contraception consistently and correctly for the duration of the 
study.  
Doxycycline pharmacokinetic sampling will be collected from a subgroup of up to 
eligible 
subjects and will be shipped to a central laboratory. 
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. 
 
9.2.5 
BACTERIOLOGICAL TESTING - (Should be taken in any case of infection before 
starting Antibiotic TX)   
Bacteriological tests (from sternal bone and/or surrounding soft tissue) will be performed in 
order to assess infection at the sternum surgical site.  
Bacteriological tests from the wound will be taken if there is a wound discharge, at the 
discretion of the investigator. 
The bacteriological swab specimen source (sternal bone or soft tissue) should be indicated on 
source documents and CRF. 

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Bacterial growth, identification and bacteria sensitivity to antibiotics (specifically to 
tetracycline) will be assessed by the respective local laboratories.  
Any abnormal finding, assessed by the investigator as clinically significant, should be recorded 
as AE in the relevant CRF section. 
 
9.2.6 ELECTROCARDIOGRAM (ECG) - (Only at screening)  
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 ECG review is under the investigator's responsibility. 
Any abnormal finding, assessed by the investigator as clinically significant, should be recorded 
under the medical history section in the relevant CRF form and source documents. 
9.2.7  CHEST X-RAYS (at Screening and at visit 8) 
Routine chest X-Ray will be performed to all subjects at screening visit or on surgery day (pre-
operative), at visit 8 and at investigator’s discretion.  
9.2.8     ASSESSMENT of STERNAL INFECTION (at all visits) 
Sternal infection will be identified as assessed by investigator by the following predefined 
criteria in the CDC’s Criteria for Surgical Site Infection (SSI) & Surveillance Definition for Specific 
Types of Infections Chapters, January 2016 (see 5.1.1 & 5.1.2). 
 
9.2.9  ALLERGY QUESTIONNAIRE (at screening only) 
An allergy questionnaire will be filled at screening as part of subject’s medical history. 
 
9.2.10 ADVERSE EVENTS (All visits) 
Adverse events will be recorded starting from visit 1 and throughout the study. Pre-existing 
conditions (present before start of the AE collection period) are considered “concurrent 
medical conditions” and should NOT be recorded as AEs. However, if the subject experiences a 
worsening or complication of such a concurrent condition, the worsening or complication 
should be recorded as an AE. Investigators should ensure that the AE term recorded captures 
the change in the condition (e.g. “worsening of….”). 
 

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9.2.11 MEDICAL RESOURCE UTILIZATION (MRU)  
All MRU information pertaining to unscheduled (not scheduled per protocol) hospitalizations 
(i.e. total hospitalization days), unscheduled clinic visits, unscheduled laboratory tests, and 
unscheduled procedures will be collected during the follow-up period. 
9.2.12 STERNUM STABILITY ASSESSMENT 
Bone non-union will be assessed by sternum stability, which will be clinically evaluated by 
investigators. In case of suspected bone non-union further evaluation will be done according 
to standard clinical practice (CT imaging). 
 
9.3 
SURGERY – INDEX PROCEDURE - VISIT 2 
Subjects will be enrolled into the study and will be treated with D-PLEX concomitantly with SOC 
or SOC alone.  
 
The SOC is based on: 
The Society of Thoracic Surgeons practice guideline series: antibiotic prophylaxis in cardiac surgery, 
part II: antibiotic choice; 
1. In patients for whom cefazolin is the appropriate prophylactic antibiotic for cardiac 
surgery, administration within 60 minutes of the skin incision is indicated. The pre-
operative prophylactic dose of cefazolin for a patient of greater than 60 kg body weight 
is recommended to be 2g. 
2. When surgical incision remains open in the operating room, to patients with normal renal 
function, a second dose of 1g should be administered every 3 to 4 hours. If it is apparent 
that cardiopulmonary bypass will be discontinued within 4 hours, it is appropriate to 
delay until perfusion is complete to maximize effective blood levels. 
3. In patients for whom vancomycin is an appropriate antibiotic for cardiac surgery, a dose 
of 1 to 1.5 g or a weight adjusted dose of 15 mg/kg administered intravenously slowly 
over 1 hour, with completion with 1 hour of the skin incision, is recommended. A second 
dose of vancomycin of 7.5 mg/kg may be considered during cardiopulmonary bypass, 
although its usefulness is not well established. 
4. For patients who receive an aminoglycoside (usually gentamycin, 4 mg/kg) in addition to 
vancomycin before cardiac surgery, the initial dose should be administered within 1 hour 
of the skin incision. Re-dosing an aminoglycoside during cardiopulmonary bypass is not 
indicated and may be harmful.  
The standard of care will be consistent for all sites that will participate in the clinical study. 
The D-PLEX will be applied during the cardiac surgery (index procedure), as an adjunct to the 
standard care, immediately prior to sternal closure.  

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D-PLEX is supplied as sterile powder to be reconstituted to paste in the operating room, using 
standard aseptic techniques and is intended for single administration. 
The D-PLEX dose is dependent on the length of the sternum incision.  For subjects with sternum 
length up to 22cm, two vials of D-PLEX will be used. For subjects with sternum length of 22cm or 
more, three vials of D-PLEX will be used. 
D-PLEX will be applied directly within the surgical site: between the two halves of the sternum bone 
and over its surface before wound closure (sewing) 
For more details, please refer to the IFU- D-PLEX IFU. 
  
9.4 
SUBSEQUENT VISITS AND ASSESSMENTS – VISITS 3 - 10 
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 index 
procedure. These visits are usually performed after this kind of surgery.  
The additional follow up visits (visits 6-10) will take place at 1 month, 2 months, 3 months, 4 
months and 6 months post index procedure and are required by the study, i.e. in addition to the 
routine visits usually performed after this kind of surgery. 
During these visits the following procedures will be performed: Vital signs, Assessment of infection, 
Laboratory examinations (Haematology & Chemistry) and Adverse Events. Urinalysis will be 
performed only at the discretion of the investigator. Bacteriology cultures will be taken at the 
discretion on the investigator if there is a wound discharge.  AB initiation will continue from 
screening to V3. Physical examination will be performed only at visits 6, 8 and 10. 
Follow up assessments will be done over a total of 6 clinic visits until final assessment at 6 months 
±14 days.  Table 1 details all scheduled/ planned assessment at these visits. 
 
9.4.1 
    SAFETY ENDPOINTS TO BE ASSESSED DURING THE STUDY 
Collection of adverse events  
Physical examinations, vital signs 
Bone non-union will be assessed by sternum stability, which will be clinically evaluated by 
investigators. In case of suspected bone non-union further evaluation will be done according to 
standard clinical practice (CT imaging). 
X-Ray: to assess sternum mechanical dehiscence  
Fibrosis/Scarring will be assessed by visual wound examination by investigator  
Safety laboratory parameters: Routine hematology, chemistry 

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4. 
Bacteriology test – growth, identification and sensitivity to antibiotics  (specifically to tetracycline) will be done at the discretion of the investigator if there is a suspected sternum 
infection 
5. 
Sternum stability will be clinically evaluated by investigators  
6. 
Chest X-Rays will be performed at screening and at visit 8 for sternum mechanical dehiscence assessment and at investigator’s discretion. In case other chest imaging (i.e. CT/MRI) was 
performed, X-Ray may not be performed. 
7. 
In case X-Ray (or CT/MRI) scan was performed within 3 months before surgery, and there was no significant change in subject’s medical profile, this X-Ray (or CT/MRI) can be used for 
screening process. 
8. 
Investigator will confirm eligibility before surgery, including bacteriologic tests if needed 
9. 
Fibrosis/Scarring will be assessed by visual wound examination by investigator 
10. Doxycycline pharmacokinetic sampling will be collected from a subgroup of up to 
eligible subjects 
11. Only weight should be measured at study termination 
 
 

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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 investigation 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.  
Subjects who withdraw from the study will not be replaced. 
Stopping Rules: 
Not applicable at this stage of development. 
 
10 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 in Section 3.1.1. No additional drugs will be administered 
as part of the requirements of this clinical study. 
 
10.1 TREATMENT OF SUBJECTS 
  
Investigational Medicinal Product – D-PLEX. 
The D-PLEX will be applied during the cardiac surgery (index procedure), as an adjunct to the 
standard care, immediately prior to sternal closure.  
D-PLEX is supplied as sterile powder to be reconstituted to paste in the operating room, using 
standard aseptic techniques and is intended for single administration. 
The D-PLEX dose is dependent on the length of the sternum incision. For subjects with sternum 
length up to 22cm, two vials of D-PLEX will be used. For subjects with sternum length of 22cm 
or more, three vials of D-PLEX will be used. 
D-PLEX will be applied directly within the surgical site: between the two halves of the sternum 
bone and over its surface before wound closure (sewing). 
For more details, please refer to the IFU- D-PLEX IFU. 
 
10.2 CONCOMITANT MEDICATION 
Medication(s)/Treatment(s) Permitted  
• 
Concomitant Medications 
- All concomitant medications will be recorded in the case report form (eCRF). 
• 
Antibiotics Treatment per SOC Allowed in this Protocol 

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- Subjects will receive IV antibiotics, followed by oral antibiotics (as needed), according 
to the SOC. 
- Any additional concomitant medication for the treatment of concurrent illnesses are 
allowed at the discretion of the treating physicians. 
 
Medications prohibited during the trial   
 
Additional antibiotics, except those listed as part of the SOC post sternotomy, or 
approved by the study investigator. 
 
Long term high steroids dose (defined as steroid use for over 3 consecutive months 
during a 6 month period). 
 
Immunosuppressive agents.  
 
Doxycycline IV/PO administration is not allowed in this protocol during the entire 
trial period. 
 
10.3 
PREPARATION, HANDLING, & LABELING OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP) 
The investigational medicinal product is manufactured aseptically at Nextar, at a Grade A (ISO 
5) clean room. The investigational medicinal product will be provided to the investigational 
site by PolyPid Ltd., once a signed Investigator Agreement and documentation of Ministry of 
Health and Ethics Committee approval of the protocol and consent forms have been received. 
D-PLEX is provided sterile and primarily packaged in sterile, depyrogenated inert glass amber 
vial 
 and each product vial contains g of D-PLEX. The sterile vial is packaged in an 
aluminium packaging. All packaging will bear the following statement per Israel Ministry of 
Health regulations:  
 “For Clinical Trial Use Only” in Hebrew and/or in English. 
Preparation and labelling of the investigational medicinal products are completed in 
accordance with the relevant GMP guidelines.  
Information on the Storage and Handling of the IMP can be found in D-PLEX IFU. 
 
10.4 
DRUG ACCOUNTABILITY 
The Investigator or designee (i.e., 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 subject dispensing records and 
returned or destroyed study product. Dispensing records will document quantities received 

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11.4.1 
NOTIFICATION OF DEATHS 
All deaths will be reported to the sponsor irrespective of whether the death is related to 
disease progression, the IMP, or an unrelated event. Deaths should be reported within 24 
hours of knowledge to the sponsor. 
 
11.4.2 
REPORTING OF SUSARs 
The sponsor will notify the Investigator of all SUSARs.  SUSARs that are fatal or life-
threatening must be notified to the Investigator within 7 days after the sponsor has learned 
of them.  Other SUSARs must be reported to the Investigator within 15 days after the sponsor 
has learned of them.   
Investigator will forward SUSARs that occurred at his centre to the EC in a timely manner. All 
other SUSARs will be forwarded to EC periodically (at least every 6 months). 
 
11.4.3 
DEVELOPMENT OF SAFETY UPDATE REPORTS 
The sponsor will provide the main EC and the Ministry of Health with a Safety Report which 
will be written in conjunction with the trial team and the Sponsor’s office.  
 
11.4.4 
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 
 gr per patient). Overdose of D-PLEX will be recognized by the report of number of 
vials used as documented by the operation room (O.R.) team. 
Information on adverse drug reactions of D-PLEX are provided in the D-PLEX IFU. 
In case of an overdose or adverse drug reactions and per surgeon decision, the implanted 
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. 
 
11.4.5 
REPORTING URGENT SAFETY MEASURES  
If any urgent safety measures are taken the PI/Sponsor shall immediately and in any event 
no later than 3 days from the date the measures are taken, give written notice to the Israel 

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Ministry of Health and the relevant EC of the measures taken and the circumstances giving 
rise to those measures. 
 
11.4.6 
THE TYPE & DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER ADVERSE 
EVENTS 
All AE/ SAEs should be followed up until resolution or permanent outcome of the event. 
 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 IMP 
related or not) as required by their Ethics Committee procedure. 
Any SUSAR related to the IMP (D-PLEX) will need to be reported to the Sponsor irrespective 
of how long after IMP administration the reaction has occurred. 
 
11.4.7 NOTIFICATION OF SERIOUS BREACHES TO GCP 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. 
The sponsor of a clinical trial shall notify the licensing 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 conduct phase.  The sponsor’s SOP on the ‘Notification of violations, urgent 
safety measures and serious breaches’ will be followed.  
 

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12 
DATA MANAGEMENT & QUALITY ASSURANCE 
12.1 CONFIDENTIALITY 
The Electronic Case Report Form (eCRF) will not bear the subject’s name or other personal 
identifiable data.  The subject’s initials, date of birth and trial identification number, will be 
used for identification. 
12.2 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 investigation 
plan 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.  
 
12.3 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 according to this document. 
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 EMA 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 the eCRF could be considered as data source 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 data source 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. 

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13 
RECORD KEEPING & ARCHIVING 
The Investigator shall arrange for the retention of study records for at least 15 years after 
completion or discontinuation of the study. Subject files and other source data shall be kept 
for the maximum period of time permitted by the hospital or institution. 
The investigator should ensure that the following records are maintained: 
a) Subject files containing copies of completed case reports and supporting 
documentation and a copy of the signed, Informed Consent form. 
b) Investigator files containing copies of the documents required for the initiation of the 
study (signed Investigator’s Agreement, Curricula Vitae for the principal and all sub-
investigators, copy of the EC approval of the protocol and Informed Consent form), 
copies of correspondence received from and sent to CRO/Sponsor. In addition to these 
records required by regulations, CRO/Sponsor requests that the investigator keep a 
copy of the Financial Agreement between CRO/Sponsor and the investigator. 
c) Files containing copies of the Investigational Medicinal Product Accountability Log 
(IPAL) or an equivalent form approved by CRO/Sponsor, instructions for the use of the 
IPAL and instructions for use (IFU) inserts and/or the Investigator’s Brochure.  
These documents should be retained for a longer period, if required by local or national 
regulations. No records will be destroyed without the written consent of the Sponsor. It is 
the responsibility of the Sponsor to inform the investigator when these documents no 
longer need to be retained. 
 
14 
STATISTICAL CONSIDERATIONS  
No formal statistical analysis will be performed. Only descriptive statistics (mean values, 
standard deviation will be presented). 
 
14.1 
SAMPLE SIZE & RECRUITMENT 
14.1.1 PLANNED RECRUITMENT RATE 
Total duration of the study is expected to be approximately 9-12 months from first subject 
enrolled until last subject completed.  
It is expected that each subject will be in the study for approximately 6 months 
Initial enrolment anticipated: Q4 2016 
Final enrollment anticipated: Q3 2017 
Last 6 months follow up: Q1 2018 

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This is a phase Ib/II clinical study, a total of up to 
 subjects, will be enrolled across 
 
Israeli sites. 
15 
EFFICACY AND SAFETY ASSESSMENT 
Efficacy assessment will be applied when all the subjects complete 3 months in the study. 
The primary efficacy endpoint (the reduction in the number of sternal infections observed) 
will be evaluated and summarized in appropriate tables. 
The data will be locked before the statistical analysis will be performed. Sponsor will remain 
blinded to individual patient treatment and all data will be presented as aggregated per 
treatment arm, as long as the last patient has not completed the safety follow up period. No 
listings will be issued in order to maintain safety evaluation by Sponsor throughout safety 
follow-up period. 
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 additional data 
was completed. 
 
16 
NAME OF COMMITTEES INVOLVED IN TRIAL 
The Executive Committee including PolyPid Safety Officer will review and adjudicate any AE 
and SAE considered as related to investigational medicinal product or SAE leading to death 
or life threatening.  
Executive Committee: A committee responsible for overseeing the conduct of the study from 
various aspects: 
a) Review, classification and adjudication of Adverse Events and Serious Adverse 
Events, as defined in the clinical protocol. 
b) Recommending on study specific needs such as special training to site staff. 
c) Reviewing the study results. 
It comprises of physician members from disciplines relevant to the study, who are not 
participating in the study and will not have any conflict interest with the study sponsor. The 
Executive Committee is responsible to schedule periodic meetings and ad hoc meeting upon 
PolyPid request and study needs. 
This committee adjudicates AE/SAE as defined in the protocol and classifies the adjudicated 
AEs as to their relation to the IMP/procedure. 
 

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17 
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 investigation. 
The investigator will permit trial-related monitoring, audits, EC 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. 
 
18 
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 and the Sponsor before subject enrolment.  Changes to the protocol 
must be approved in writing by the Sponsor and the EC (as applicable) before the change is 
implemented.  
Prior to subject enrolment, a signed copy of the EC 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 and forwarding copies of the approval letters to the Sponsor.  The original letters are to 
be kept in the investigational center’s Regulatory Binder designated for this study.   
The investigator will notify the Sponsor within five (5) working days of withdrawal of EC 
approval.   
 
19 
MONITORING REQUIREMENT FOR THE TRIAL 
A trial specific monitoring plan will be established for the study. The trial will be monitored 
with the agreed plan. 
The Sponsor and/or designee will monitor the study over its duration according to the pre-
specified monitoring plan. The study monitor will visit each site at appropriate intervals to 
review investigational data for accuracy and completeness and ensure compliance with the 
clinical investigation plan. The study monitor may inspect all documents and required records 
that are maintained by the Investigator/Site, including medical records (office, clinic, or 
hospital) for the subjects in this study. Source documentation must be available to 
substantiate proper informed consent procedures, adherence to clinical investigation plan 
procedures, adequate reporting and follow-up of adverse events, accuracy of data collected 
on case report forms, and device information. A monitoring visit sign-in log will be maintained 
at the site. The Investigator and/or research coordinator will be available for monitoring 

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visits. It is expected that the Investigator/Site will provide the study monitor with a suitable 
working environment for review of study-related documents. 
 
20 
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-investigation-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. 
 
21 
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 these 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. 
 
22 
STATEMENT OF COMPLIANCE 
The trial will be conducted in compliance with the approved protocol, Declaration of Helsinki, 
ICH GCP and the applicable Israel Ministry of Health regulatory requirement(s). 
The clinical investigation shall not begin until the required approval or favorable opinion from 
the EC has been obtained and, if applicable, any local or national regulatory authority 
approvals or notifications have been obtained.  
The Sponsor has obtained clinical investigation insurance that will cover expenses in the 
event of any physical injury resulting from research procedures. 
 
 

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23 
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