A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate Humoral Immunogenicity of Various Schedules of Intramuscular Full-Dose and Intradermal Fractional Dose of Inactivated Polio Vaccine in Latin American Infants
Phase: PHASE3
Conditions: Poliomyelitis
Sponsor: Fidec Corporation

 
Final Version 1.0. Clinical Study Protocol  
09-Aug- 2017 
Administrative change 
 
Confidential 
Page 1 
 
A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate Humoral 
Immunogenicity of Various Schedules of Intramuscular Full Dose and 
Intradermal Fractional Dose of Inactivated Polio Vaccine in Latin 
American Infants  
 
Product IPV and f-IPV 
Protocol Number IPV-004 ABMG 
ClinicalTrials.gov Number NCT03239496 
Clinical Phase Phase 3 
Clinical Indication Injectable Polio Vaccine immunization  
Version Final 1.0 
                              Issue Date 
Date of the administrative 
change 
09-Aug-2017 
12-Apr-2018 
 
Sponsor FIDEC – Fighting Infectious Diseases in Emerging 
Countries  
2050 Coral Way, Suite 407 
Miami, FL 33145 USA 
Sponsor Representative  Ricardo Rüttimann, MD 
Tel + 1 305 854 0075, Fax + 1 305 856 7847  

 
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SIGNATURES 
Signature of Sponsor Representative 
 
Title: A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate Humoral 
Immunogenicity of Various Schedules of Intramuscular Full-Dose and 
Intradermal Fractional Dose of Inactivated Polio Vaccine in Latin 
American Infants 
 
Name: 
Ricardo Rüttimann, MD 
Tel + 1 305 854 0075, Fax + 1 305 856 7847  
 
 
This Clinical Study Protocol and Amendments (if any) have been reviewed and 
approved by the Sponsor in order to ensure compliance with Good Clinical Practice. 
 
 
Signature: 
Date: 
 
 
 
 
 

 
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Signature of Statistician  
 
Title: A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate Humoral 
Immunogenicity of Various Schedules of Intramuscular Full Dose and 
Intradermal Fractional Doses of Inactivated Polio Vaccine in Latin 
American Infants 
 
Name:  
Chris Gast 
Affiliation:  
Gast Statistical Consulting, LLC 
Address: 
Woodinville, WA, USA 
 
 
This Clinical Study Protocol and Amendments (if any) have been reviewed and 
approved by the study statistician in order to ensure that the protocol and any 
amendments cover all relevant statistical matters clearly and accurately, using technical 
terminology as appropriate. 
 
 
Signature: 
 
Date: 
 
 

 
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Signature of Investigator 
 
Title: 
A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate 
Humoral Immunogenicity of Various Schedules of Intramuscular Full 
Dose and Intradermal Fractional Doses of Inactivated Polio Vaccine in 
Latin American Infants 
 
Name: 
Luis Rivera, MD 
Affiliation: 
Hospital Maternidad Nuestra Señora de la Altagracia 
 
Address: 
Calle Pedro Henríquez Ureña #49,  
Santo Domingo, Dominican Republic 
 
 
 
I have read this Clinical Study Protocol and Amendments (if any) and agree that it 
contains all information necessary for the proper conduct of the study. I will carry out 
the study as outlined herein, will complete the study within the designated time and in 
accordance with Good Clinical Practice. 
 
 
Signature: 
 
Date: 
 
 
 
 
 

 
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Signature of Investigator 
 
Title: 
A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate 
Humoral Immunogenicity of Various Schedules of Intramuscular Full 
Dose and Intradermal Fractional Doses of Inactivated Polio Vaccine in 
Latin American Infants 
 
Name: 
 Xavier Sáez-Llorens, MD 
Affiliation: 
Cevaxin,  
Address: 
Panama City and Chiriquí, Republic of Panama  
 
 
I have read this Clinical Study Protocol and Amendments (if any) and agree that it 
contains all information necessary for the proper conduct of the study. I will carry out 
the study as outlined herein, will complete the study within the designated time and in 
accordance with Good Clinical Practice. 
 
 
Signature: 
 
Date: 
 
 

 
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PROTOCOL HISTORY 
Protocol History 
FIDEC  
Document  
Issue Date 
Amendment Type 
Comments/Rationale for the changes 
Final version 1.0 
09-August-2017 
-NA 
 
Final version with administrative 
changes 
09-April-2018 
Administrative change 
Section 6.3, Other 
medications administered in 
the study, Page 32 
 
“All details from 
concomitants vaccines 
administered will be recorded 
in the corresponding forms. 
 
Only medications to treat 
SAEs, IMEs and severe local 
reactions will be documented 
in the corresponding forms” 
 
 
 
 
 
The statement that concomitant medications will be recorded in the CRF 
was deleted, since the study centers will use specific forms for this. 
 
 
 
Administrative change 
Section 7 Prior and 
concomitant therapy, Page 35 
 
“Infants in Panama will 
receive 2 doses of influenza at 
6 and 7 months old, according 
to the National Immunization 
Schedule.  
 
This procedure will not be 
part of the study visits.” 
  
 
 
 
As per study centers request, it is clarified that participants in Panama will 
receive other vaccines part of the EPI. 
 
 
Administrative change 
Section 8.1 Table 2 Time and 
 
 
 

 
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Event Schedule, page 36 and 
37 
 
- “Serious Adverse (SAEs), 
Important Medical Events 
(IMEs) and severe local 
reactions: To be reported and 
followed up at any moment 
throughout the study, upon 
signature of the Informed 
Consent until the week 40. 
 
- +  Concomitant vaccines at 
weeks 6 and 14 are 
Pneumococcal Rotavirus and 
DTPw-HB-Hib and at week 
10 only DTPw-HB-Hib. 
Infants in Panama will receive 
2 doses of influenza at 6 and 7 
months old, according to the 
National Immunization 
Schedule. This procedure will 
not be part of the study visits. 
 
- µ Measurement will be 
performed with a standard 
millimeter ruler and will 
include 2 photos to be taken: 1 
at 0 minutes, and a second 
photo at 30 minutes after 
vaccination. 
 
- The period between 
vaccination visits will be of at 
least 28 days. The period 
between visits for blood 
 
 
 
For greater clarity at study centers, the moment in which SAEs and IMEs 
must be reported is specified, as well as the week until they will be 
reported 
 
 
 
 
 
 
As per study centers request, it is clarified that participants in Panama will 
receive other vaccines part of the EPI. 
 
 
 
 
 
 
 
 
 
The photo was added to document the measurements  
 
 
 
 
 
 
For greater clarity at study centers, the minimum period between visits and 
samples collection is specified 

 
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collection will be of at least 
28 days.” 
 
 
 
Administrative change  
Section 8.1.1 Collection and 
handling of blood samples, 
page 37 
 
“A total of four vein or 
arterial blood samples will be 
collected from each infant, 
prior to vaccination and 
according to their scheduled 
visits. Blood will be collected 
using butterfly needle or 
hypodermic needles and 
syringe. The location of the 
puncture will vary, depending 
on the subject” 
 
 
 
 
 
For greater clarity at study centers, details of the blood sample are added: 
vein or arterial blood, and information about the location of the puncture, 
depending on the subjects. 
 
 
Administrative change  
Section 11.1.1 Serious 
Adverse Events Page 46 
 
“The Investigator(s) will be 
responsible for recording and 
reporting within 24 hours and 
according to regulatory 
timelines all SAEs observed 
during the study period (upon 
signature of the Informed 
Consent)” 
 
 
 
 
For greater clarity at study centers, the moment in which SAEs must be 
reported is specified 
 
 
Administrative change  
Section 11.1.2 Important 
Medical Event Page 46 
 
 
 
 
 

 
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“The Investigator(s) will be 
responsible for recording and 
reporting within 24 hours and 
according to regulatory 
timelines all IMEs observed 
during the study period (upon 
signature of the Informed 
Consent)”  
 
For greater clarity at study centers, the moment in which IMEs must be 
reported is specified 
 
 
Administrative change 
Section 11.6 Reporting of 
serious adverse events and 
important medical events to 
the sponsor, page 48 
 
“The form will be sent 
encrypted, and the password 
to open it will be sent in a 
separate email.   
 
The SAE form should include 
a clearly written narrative 
describing signs, symptoms, 
and treatment of the event, 
diagnostic procedures, 
concomitant medication, as 
well as any relevant 
laboratory data” 
 
 
 
 
 
 
 
Information about SAE and IME form encrypting and the means to send 
the report via email, instead of fax, is added, as well as information about 
the password to open the document 
 
 
Concomitant medications is added to the SAEs narrative 
 
 
Administrative change 
Section 11.7 Reporting of 
Serious Adverse Events to 
Competent Authority/Ethics 
Committees Page 49 
 
 
 
 
 
 
 
 

 
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“The investigators assume 
responsibility for appropriate 
reporting of SAEs to the 
regulatory authorities- The 
investigators will also report 
all SAEs…” 
The responsible for reporting adverse events before authorities is clarified 
It is specified that the report is of SAEs 
In Uruguay is deleted since it was an error 
 
 
 
 
 
 
 
 
 
 
Administrative change  
Section 13.3 Source 
Documentation Page 54 
 
“At a minimum, source 
documentation must be 
available to confirm the 
following data collected in the 
eCRF: subject identification, 
eligibility, and study 
identification; study 
discussion and date of 
informed consent, dates of 
visits, results of safety and 
immunogenicity parameters as 
required by the protocol, 
record of all AEs, follow-up 
of AEs,”  
 
 
 
 
Concomitant medications is eliminated since they will not be recorded on 
the eCRF, but on specific forms in the event of SAEs, IMEs and severe 
local reactions. 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
Title Page ........................................................................................................................... 1 
Signatures .......................................................................................................................... 2 
Protocol History ................................................................................................................ 6 
Table of Contents ............................................................................................................ 11 
Protocol Synopsis ............................................................................................................ 14 
List of Abbreviations and Definitions of Terms .......................................................... 19 
Study Administrative Structure .................................................................................... 21 
1. 
Introduction ............................................................................................................ 22 
 
Background Information .................................................................................... 22 
 
Risk Benefit Analysis ......................................................................................... 23 
1.2.1 
Potential Risks ...................................................................................... 23 
1.2.2 
Potential Benefits ................................................................................. 24 
2. 
Study Objectives ..................................................................................................... 25 
 
Primary Objectives ............................................................................................. 25 
 
Secondary objectives .......................................................................................... 25 
 
Exploratory Objectives ....................................................................................... 26 
3. 
Study Endpoints ...................................................................................................... 27 
 
Primary Endpoints .............................................................................................. 27 
 
Secondary Endpoints .......................................................................................... 27 
 
Exploratory Endpoints ........................................................................................ 27 
4. 
Study Design ............................................................................................................ 29 
 
Overview of Study Design ................................................................................. 29 
 
Discussion of Study Design................................................................................ 29 
5. 
Selection of Study Population ................................................................................ 30 
 
Inclusion Criteria ................................................................................................ 30 
 
Exclusion Criteria ............................................................................................... 30 
 
Criteria for Elimination from the Per-Protocol Population ................................ 30 
 
Contraindications to Further Vaccination .......................................................... 30 
6. 
Vaccines ................................................................................................................... 32 
 
Physical Description of the Study Vaccine ........................................................ 32 
 
Dose and Administration .................................................................................... 32 
 
Other Medication Administered in the Study ..................................................... 32 
 
Packaging and Labeling ..................................................................................... 32 
 
Storage and Vaccine Accountability .................................................................. 33 
 
Randomization .................................................................................................... 33 
 
Compliance ......................................................................................................... 34 
7. 
Prior and Concomitant Therapy ........................................................................... 35 
8. 
Assessments ............................................................................................................. 36 
 
Timing of Assessments....................................................................................... 36 
8.1.1 
Collection and handling of blood samples ........................................... 37 
 
Immunogenicity .................................................................................................. 37 

 
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8.2.1 
Immunogenicity Variables ................................................................... 37 
 
Safety Evaluations .............................................................................................. 38 
8.3.1 
Serious Adverse Events ........................................................................ 38 
8.3.2 
Important medical events (IMEs) ......................................................... 38 
9. 
Study Termination/Completion ............................................................................. 40 
 
Study Completion ............................................................................................... 40 
 
Removal of Subjects From Study or Investigational Product ............................ 40 
9.2.1 
Removal from Study ............................................................................ 40 
10. Statistical Methods.................................................................................................. 42 
 
Statistical Analysis ............................................................................................. 42 
10.1.1 
Study Populations ................................................................................. 42 
10.1.2 
Initial Characteristics of the Subject Sample ....................................... 42 
10.1.3 
Immunogenicity Data ........................................................................... 42 
10.1.4 
Safety Data ........................................................................................... 43 
10.1.5 
Missing Data ........................................................................................ 43 
 
Determination of Sample Size ............................................................................ 43 
 
Immunogenicity Analysis ................................................................................... 45 
11. Serious Adverse Event Reporting ......................................................................... 46 
 
Definitions .......................................................................................................... 46 
11.1.1 
Serious Adverse Events ........................................................................ 46 
11.1.2 
Important Medical Event ...................................................................... 46 
 
Causality Assessment ......................................................................................... 47 
 
Action Taken Regarding the Study Vaccine ...................................................... 48 
 
Outcome ............................................................................................................. 48 
 
Recording of serious adverse events .................................................................. 48 
 
Reporting of serious adverse events and important medical events to the sponsor
 48 
 
Reporting of Serious Adverse Events to Competent Authority/Ethics 
Committees ......................................................................................................... 49 
12. Ethical Aspects ........................................................................................................ 50 
 
Study-Specific Design Considerations ............................................................... 50 
 
Regulatory Ethics Compliance ........................................................................... 50 
12.2.1 
Investigator Responsibilities ................................................................ 50 
12.2.2 
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) ............................................................................................. 50 
12.2.3 
Informed Consent ................................................................................. 52 
12.2.4 
Privacy of Personal Data ...................................................................... 53 
13. Administrative Requirements ............................................................................... 54 
 
Protocol Amendments/Notifications .................................................................. 54 
 
Subject Identification and Enrollment Logs ....................................................... 54 
 
Source Documentation ....................................................................................... 54 
 
Case Report Form Completion ........................................................................... 55 
 
Monitoring .......................................................................................................... 55 
 
Data Management ............................................................................................... 55 
 
Data Quality Assurance ...................................................................................... 56 

 
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On-Site Audits .................................................................................................... 56 
 
Study Termination .............................................................................................. 57 
 
Record Retention ................................................................................................ 57 
 
Use of Information and Publication ................................................................... 57 
 
Registration of Clinical Studies and Disclosure of Results ................................ 58 
 
Investigator Indemnity........................................................................................ 59 
 
Confidentiality .................................................................................................... 59 
14. References ................................................................................................................ 60 

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PROTOCOL SYNOPSIS 
Study Title A Phase 3, Open-label, Multicenter Randomized Trial to Evaluate Humoral Immunogenicity 
of Various Schedules of Intramuscular Full Dose and Intradermal Fractional Doses of Inactivated Polio 
Vaccine in Latin American Infants  
Product  
IPV and f-IPV 
Clinical Phase 
Phase 3 
Protocol Number 
IPV-004 ABMG 
Indication   
Injectable Polio Vaccine 
immunization 
ClinicalTrials.gov Number   
NCT03239496 
 
Sponsor 
FIDEC  
Sponsor Representative 
Ricardo Rüttimann, MD 
 Investigational Sites: Hospital Maternidad Nuestra Señora de la Altagracia in Dominican Republic, and 
Cevaxin in Panamá City and Chiriquí 
 
Primary Objective:  
1. To determine if the seroconversion rate of a 2-dose intradermally administered fractional-dose 
inactivated poliovirus vaccine (f-IPV) regimen administered at 14 and 36 weeks of age is non-
inferior to that of a 2-dose intramuscularly administered inactivated poliovirus vaccine (IPV) 
regimen administered at 14 and 36 weeks of age 4 weeks after the last dose, for poliovirus serotypes 
1 and 2. 
2. To determine if the seroconversion rate of a 2-dose IPV regimen administered at 14 and 36 weeks 
of age is non-inferior to that of a 3-dose IPV regimen administered at 10, 14, and 36 weeks of age 
4 weeks after the last dose, for poliovirus serotypes 1 and 2. 
3. To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks 
of age is non-inferior to that of a 3-dose f-IPV regimen administered at 10, 14, and 36 weeks of 
age 4 weeks after the last dose, for poliovirus serotypes 1 and 2. 
Secondary Objectives:  
1. To determine if the seroconversion rate of a 2-dose IPV regimen administered at 14 and 36 weeks 
of age is superior to that of a 2-dose IPV regimen administered at 10 and 14 weeks of age, 4 weeks 
after the second dose for poliovirus serotypes 1 and 2. 
2. To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks 
of age is superior to that of a 2-dose f-IPV regimen administered at 10 and 14 weeks of age 4 weeks 
after the second dose, for poliovirus serotypes 1 and 2. 
3. To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks 
of age is non-inferior to that of a 3-dose IPV regimen administered at 10, 14, and 36 weeks of age, 
4 weeks after the last dose, for poliovirus serotypes 1 and 2. 
4. To determine if the seroconversion rate of a 3-dose f-IPV regimen administered at 10, 14, and 36 
weeks of age is non-inferior to that of a 3-dose IPV regimen also administered at 10, 14, and 36 
weeks of age, 4 weeks after the last dose, for poliovirus serotypes 1 and 2. 
5. To determine if the seroconversion rate to a 3-dose regimen of f-IPV administered at 10, 14, and 
36 weeks of age is non-inferior to that of a 2-dose IPV regimen administered at 14 and 36 weeks 
of age, 4 weeks after the last dose for poliovirus serotypes 1 and 2.  
6. To assess the safety of each vaccine (IPV and f-IPV) as measured by the incidence of serious 
adverse events (SAEs), important medical events (IMEs) and severe local reactions. 
7. To assess all primary and secondary immunogenicity objectives through comparison of 
neutralizing antibody (NAb) titers. 
Exploratory Objectives:  
1. To assess immune responses to poliovirus type 3 analogous to the primary and secondary 
immunological objectives. 
2. To determine if an additional dose of IPV at 36 weeks of age provides a superior humoral immune 
response when added to a 2-dose IPV regimen at 10 and 14 weeks of age, as compared to the 2-

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dose regimen alone, for all three poliovirus serotypes, as measured by seroconversion rate, 
geometric mean and median NAb titers, 4 weeks after the last dose. 
3. To determine if an additional dose of f-IPV at 36 weeks of age provides a superior humoral immune 
response when added to a 2-dose f-IPV regimen at 10 and 14 weeks of age, as compared to the 2-
dose regimen alone, for all three poliovirus serotypes, as measured by seroconversion rate, 
geometric mean and median NAb titers, 4 weeks after the last dose. 
4. To determine if the humoral immune response to a single dose of f-IPV administered at 10 weeks 
of age is non-inferior to that of a single dose of IPV administered at 10 weeks of age, for all three 
poliovirus serotypes, 4 weeks following vaccination, as measured by seroconversion rate, 
geometric mean and median NAb titers. 
5. To determine if the humoral immune response to a 2-dose regimen of f-IPV administered at 10 and 
14 weeks of age is non-inferior to that of a 2-dose regimen of IPV administered at 10 and 14 weeks 
of age, for all three poliovirus serotypes, as measured by seroconversion rate, geometric mean and 
median NAb titers, 4 weeks after the second dose. 
6. To determine if the humoral immune response to a single dose of f-IPV administered at 14 weeks 
of age is non-inferior to that of a single dose of IPV administered at 14 weeks of age, for all three 
poliovirus serotypes, 4 weeks following vaccination, as measured by seroconversion rate, 
geometric mean and median NAb titers. 
7. To determine if the humoral immune response to a single dose of f-IPV administered at 14 weeks 
of age is non-inferior to that of a single dose of IPV administered at 14 weeks of age, for all three 
poliovirus serotypes, 22 weeks following vaccination, as measured by seroconversion rate, 
geometric mean and median NAb titers. 
8. To assess the response to an additional f-IPV dose administered at 36 weeks of age to infants 
receiving a single dose of f-IPV at 14 weeks of age, for all three poliovirus serotypes, as measured 
by seroconversion rate, geometric mean and median NAb titers, 4 weeks after the final dose. 
9. To assess the response to an additional IPV dose administered at 36 weeks of age to infants 
receiving a single dose of IPV at 14 weeks of age, for all three poliovirus serotypes, as measured 
by seroconversion rate, geometric mean and median NAb titers, 4 weeks after the final dose. 
10. 
To describe the relationship between the humoral immune response to vaccination, as measured 
by seroconversion rate and median NAb titers at weeks 18, 36 and 40, and each post-vaccination 
fluid bleb diameter in the group receiving two doses of ID f-IPV at weeks 14 and 36, for serotypes 
1 and 2.  
Primary Endpoints:  
1. Serotypes 1 and 2 seroconversion four weeks after the second vaccination for the groups receiving 
2 doses of f-IPV or 2 doses of IPV  
2. Serotypes 1 and 2 seroconversion four weeks after the last vaccination for the group receiving 2 
doses of IPV and for the group receiving 3 doses of IPV 
3. Serotypes 1 and 2 seroconversion four weeks after the last vaccination for the group receiving 2 
doses of f-IPV and for the group receiving 3 doses of f-IPV 
 
Seroconversion will be defined as a change from seronegative to seropositive (antibody titers of ≥1:8), and 
in infants seropositive at baseline (assumed to be from maternally-derived antibody titers), as a ≥4-fold rise 
in antibody titers post-vaccination, computed by assuming an exponential decay model with a half-life of 
24 days. 
 
Secondary Endpoints: 
In addition to primary endpoints: 
1. Serotypes 1 and 2 seroconversion at week 40 for the groups receiving 2 doses of IPV at weeks 14 
and 36 and at week 18 for the groups receiving 2 doses of IPV at weeks 10 and 14. 
2. Serotypes 1 and 2 seroconversion at week 40 for the groups receiving 2 doses of f-IPV at weeks 
14 and 36 and at week 18 for the groups receiving 2 doses of f-IPV at weeks 10 and 14. 
3. Serotypes 1 and 2 seroconversion at week 40 for the group receiving 2 doses of f-IPV and the 
group receiving 3 doses of IPV.  
4. Serotypes 1 and 2 seroconversion at week 40 for the groups receiving 3 doses of f-IPV or 3 doses 
of IPV.  

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5. Serotype 1 and 2 seroconversion at week 40, for the group receiving 3 doses of f-IPV, compared 
to the group receiving 2 doses of IPV at weeks 14 and 36 
6. Safety Endpoints: SAEs, IMEs and severe local reactions throughout the study period. 
7. Serotype 1 and 2 geometric mean and median NAb titers through all immunogenicity endpoints. 
 
Exploratory Endpoints: 
Humoral immune response defined as seroconversion to serotypes 1, 2 and 3, geometric mean and median 
NAb titers for the following endpoints, in addition to primary and secondary endpoints.  
1. Humoral immune response to serotype 3, four weeks after each vaccination for all groups receiving 
IPV and f-IPV, and 22 weeks after receiving a single dose of IPV or f-IPV for the group receiving 
doses at weeks 14 and 36. 
2. Humoral immune response at weeks 18 and 40, for the group receiving 3 doses of IPV 
3. Humoral immune response at weeks 18 and 40, for the group receiving 3 doses of f-IPV 
4. Humoral immune response at week 14, for the groups receiving 1 dose of f-IPV or 1 dose of IPV 
at week 10 
5. Humoral immune response at week 18, for the groups receiving 2 doses of f-IPV or 2 doses of IPV 
at weeks 10 and 14  
6. Humoral immune response at week 18, after receiving 1 dose of f-IPV or 1 dose of IPV at week 
14  
7. Humoral immune response at week 36, for the groups receiving 1 dose of f-IPV or 1 dose of IPV 
at week 14  
8. Humoral immune response at week 40 for infants receiving 2 doses of f-IPV  
9. Humoral immune response at week 40 for infants receiving 2 doses of IPV  
10. Humoral immune response to serotypes 1 and 2, measured at weeks 18, 36 and 40 according to the 
diameter of fluid blebs (measured in millimeters) resulting from ID f-IPV vaccination at weeks 14 
and 36, in the group receiving two doses of f-IPV  
 
Overview of Study Design: 
This will be an open-label, multicenter, randomized trial to be conducted in various pediatric centers in 
Dominican Republic and Panama. The subjects will be allocated to 4 study groups, in which an IPV vaccine 
with two different indications will be used:  
- 
IPV full dose via intramuscular injection, or 
- 
f-IPV fractional dose via intradermal administration 
The vaccines will be administered in different immunization schedules to 773 healthy infants at different 
weeks of age, as shown in Table 1.  
Table 1. Summary of study vaccine group assignments, administration of study vaccine and blood 
samples 
Vaccine 
Group* 
Vaccination weeks** 
Blood samples*** 
Subjects 
 
IM IPV 
A 
10, 14, 36 
10, 14, 18, 40 
200 
B 
14, 36 
14, 18, 36, 40 
178 
  
ID f-IPV§ 
C 
10, 14, 36 
10, 14, 18, 40 
178 
D 
14, 36 
14, 18, 36, 40 
217 
Total 
773 
*Groups A and C (3 doses), will also serve as 2-dose arms for 10 and 14 weeks regimens.  
** Allowed windows: First and second dose administered at weeks 10 and/or 14 : +7 days  
                                     Second and third dose administered at week 36: -7+7 days 
*** Allowed window for the blood samples: +7 days 
       Allowed window for blood samples at week 36: -7+7 days 
§ Fractional-dose IPV Intradermal 
 
Study Population: 
The study will be conducted in various pediatric centers in Dominican Republic and Panama. The sites 
belong to both public and private health care providers. Parents or legal representatives of the infants will 
be invited to participate in the study at the earliest possible age. Infants will be considered eligible according 
to the following criteria:  

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Eligibility Criteria: 
 
Inclusion Criteria 
1. Infants of 6 weeks of age (-7 to + 7 days) on date of enrollment. 
2. Healthy, as assessed from medical history and physical examination by a study physician, 
3. Written informed consent obtained from parents or legal representatives who have been properly 
informed about the study and are able to comply with planned study procedures. 
Exclusion Criteria  
1. Vaccinated with any poliovirus vaccine prior to inclusion,  
2. A household contact with OPV vaccination history in the past 4 weeks, 
3. HIV infection or pharmacologic or clinical immunosuppression,  
4. Known allergy to any component of the study vaccines (phenoxyethanol, formaldehyde), 
5. Uncontrolled coagulopathy or blood disorder contraindicating intramuscular and intradermal 
injections, 
6. Acute severe febrile illness on day of vaccination deemed by the Investigator(s) to be a 
contraindication for vaccination, 
7. Not suitable for inclusion or is unlikely to comply with the protocol in the opinion of the 
investigator(s).  
Study Procedures  
An overview of the timing of vaccine administration and assessments is given in Table 2. Time and Events 
Schedule. SAEs, IMEs and severe local reactions will be assessed throughout the study participation, upon 
signature of the Informed Consent.  
 
Table 2. Time and Events Schedule 
Age of infants (weeks) 
6 W 
10 W 
14 W 
18 W 
36 W 
 
40 W 
 
Visit * 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Allowed visit window 
for vaccination and 
blood samples 
-7+7 days 
+7 days 
+7 days 
 
+ 7 days 
-7+7 days  
+ 7 days 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
X 
 
 
 
Medical history 
X 
X 
X 
 
 
 
Physical examination 
X 
X 
X 
 
X 
 
Randomization and 
allocation 
X 
 
 
 
 
 
Concomitant vaccines 
administration 
X+ 
X+ 
X+ 
 
 
 
Vaccination Groups A/C 
 
IPV/f-IPV 
IPV/f-IPV 
 
IPV/f-IPV 
 
Blood sample Groups 
A/C 
 
X 
Xβ 
X 
 
Xβ 
Vaccination Groups B/D 
 
 
IPV/f-IPV 
 
IPV/f-IPV 
 
Blood sample Groups 
B/D  
 
 
X 
Xβ 
X 
Xβ 
Check contraindications 
 
X@  
X@  
 
X@  
 
Immediate surveillance 
(30 mins) after 
vaccination 
 
X@ 
X@ 
 
X@ 
 
Measurement of fluid 
bleb after ID 
vaccination for Group D 
µ 
 
X 
X 
 
 
 

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* Not all groups will attend the same visits. Infants’ attendance depends on their vaccination regimen 
+  Concomitant vaccines at weeks 6 and 14 are Pneumococcal, Rotavirus and DTPw-HB-Hib and at week 10 only 
DTPw-HB-Hib. Infants in Panama will receive 2 doses of influenza at 6 and 7 months old, according to the National 
Immunization Schedule.  This procedure will not be part of the study visits 
β  Determination of hematocrit, hemoglobin and RBC morphology in the second and in the last blood sample 
@ For study groups receiving vaccination  
µ Measurement will be performed with a standard millimeter ruler and will include 2 photos to be taken: 1 at 0 
minutes, and a second photo at 30 minutes after vaccination. 
 
Infants from study groups B, C and D will receive 1 or 2 additional doses of full IPV intramuscularly after 
the end of the study. Thus, by 12 months of age, all children should be considered protected against all 
polioviruses.   
The period between vaccination visits will be of at least 28 days. The period between visits for blood 
collection will be of at least 28 days. 
 
Statistical Methods: 
Sample size 
 
It is assumed that almost all participants enrolled will provide data for safety analysis and at least 90 percent 
of enrolled subjects will be evaluable for immunogenicity assessments.  
This study utilizes superiority tests (Fisher’s exact test) and non-inferiority tests (score-based confidence 
intervals, non-inferiority margin = 10%) of seroconversion rates. Sample size calculations are based on 
assumed seroconversion rates that apply to all three serotypes. The seroconversion rates for all types after 
two doses of f-IPV are assumed to be 64% (10/14 regimen) or 94% (14/36 regimen) and after two doses of 
IPV are assumed to be 80% (10/14 regimen) or 96% (14/36 regimen).  
There are two different power computations: the power of the comparison (either superiority or non-
inferiority) to be successful for any individual serotype and the power to be successful for both serotypes 1 
and 2 simultaneously, assuming independence of responses for each serotype. 
The group sizes are chosen to provide ≥80% power for each of the primary objectives for the individual 
statistical tests of each serotype, as well for the test of both serotypes simultaneously. Power of 
approximately ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV 
regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power for 62% for 
individual serotypes, and 39% for the combined serotypes. Given the much larger sample size necessary to 
boost the sample size to meet 80% power for this objective, this was considered an acceptable compromise 
for a feasible study designed mainly to assess primary objectives. 
Based on the above, 773 infants will be included in the trial in order to account for an estimated ~10% drop-
outs/withdrawals, for a total of 695 evaluable subjects. 
Comparisons of geometric mean and median NAb titers between regimens will be conducted using 
geometric mean titer (GMT) ratios, facilitated by an analysis of covariance (ANCOVA) model of the log2 
titer, which adjusts for the baseline level and study site as fixed effects. Non-inferiority of regimen 1 to 
regimen 2 will be declared if the lower 95% bound of the two-sided confidence interval for the GMT ratio 
(regimen 1 relative to regimen 2) is greater than 0.67. If an excessive amount of censoring at LLOQ or 
ULOQ occurs in either group, a one-sided randomization test for the median titer ratio, with resampling 
conducted within study site and using alpha level 0.025, will be applied instead. Details will be described 
in a statistical analysis plan, prepared prior to database lock and unblinding. 
Serious Adverse 
(SAEs), Important 
Medical Events (IMEs) 
and severe local 
reactions 
To be reported and followed up at any moment throughout the study, upon signature of 
the Informed Consent until the Week 40 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
List of Abbreviations 
AE 
Adverse event 
bOPV 
Bivalent oral polio vaccine 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CRF 
Case Report Form 
EPI 
WHO Expanded Programme on Immunization 
f-IPV 
Fractional-dose Inactivated polio vaccine 
GCP 
Good Clinical Practice 
 
GMT 
Geometric Mean Titers 
GPEI 
Global Polio Eradication Initiative 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements 
for Pharmaceuticals for Human Use 
ID 
Intradermal administration 
 
 
IEC 
Independent Ethics Committee 
IM 
Intramuscular administration  
IME  
Important medical event  
IPV 
Inactivated polio vaccine 
IRB 
Independent Review Board 
ITT 
Intention to treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
NIP 
National Immunization Program 
OPV 
Oral polio vaccine 
PAHO 
Pan American Health Organization 
PI 
Principal Investigator 
PP  
Per protocol 
SAE 
Serious adverse event 

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SAGE  
Strategic Advisory Group of Experts on Immunization 
SAP 
Statistical Analysis Plan 
SC 
 
SII  
Seroconversion 
 
Serum Institute of India 
TAG 
Technical Advisory Group on Vaccine-preventable Diseases 
tOPV 
Trivalent oral polio vaccine 
TVP 
Total vaccinated population 
WHO 
World Health Organization 
 
 
 
 
 
 
 

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STUDY ADMINISTRATIVE STRUCTURE  
SPONSOR 
FIDEC – Fighting Infectious Diseases in 
Emerging Countries (with grant support from 
the Bill and Melinda Gates Foundation) 
 
2050 Coral Way, Suite 407 
Miami, FL 33145 USA 
 
 
Medical Expert: Ricardo Rüttimann, MD 
 
 
Biostatistician: Christopher Gast, PhD 
 
  
MONITORING 
VAXTRIALS 
Calle 50, FyF Tower, 12B, Panama City, 
Panama 
Project Manager: Jose Jimeno, MD 
 
 
 
 
 

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1. INTRODUCTION  
 
BACKGROUND INFORMATION 
In 2013, the Global Polio Eradication Initiative (GPEI) launched the Polio Eradication and 
Endgame Strategic Plan with the aim to end all polio disease globally. The four main 
objectives of the Polio Eradication and Endgame Strategic Plan are to detect and interrupt 
all poliovirus transmission, to strengthen immunization systems and withdraw the oral 
polio vaccine (OPV), to contain poliovirus and certify interruption of transmission, and 
transition planning.1  
The global effort to eradicate polio has made significant progress so that only 3 countries 
remain where wild-type poliovirus transmission has never been interrupted —Afghanistan, 
Pakistan and Nigeria. 2  
For decades, trivalent oral polio vaccine (tOPV, with poliovirus types 1, 2, and 3) was the 
preferred vaccine for polio control and eradication. Global use of this vaccine has enabled 
the elimination of wild poliovirus type 2 and also contributed to the progress made in 
reducing the incidence of type 1 and 3 disease in most geographies.3 However, in many 
developing countries, a reduced per dose immune response to poliovirus types 1 and 3 has 
been observed with tOPV4. The bivalent oral polio vaccine (bOPV), which does not 
contain type 2, is more effective against the types 1 and 3 wild poliovirus 5.  
With the successful, globally synchronized switch from tOPV to bOPV in April 2016, IPV 
is currently the only source of type-2 immunity for polio.6 Several clinical trials in recent 
years in the Latin America region, and elsewhere, have contributed to the clinical evidence 
base around such new b OPV – IPV mixed and sequential schedules that have been adopted 
globally.7, 8, 9 Except for approximately 40 countries where IPV introduction had to be 
delayed due to supply constraints, most of the developing countries have included one dose 
of IPV in their bOPV primary series. The WHO, through the Strategic Advisory Group of 
Experts on Immunization (SAGE), and the PAHO, through the Technical Advisory Group 
(TAG), has stressed on the need to use alternative IPV vaccination schemes to cope with 
the constraints in the supply and has recommended intradermal application of fractional 
doses of IPV, instead of a single full dose of IPV, if needed10,11, 12. Also, it has become 
urgent to generate scientific evidence that allows to establish which reduced-dose or 
fractional dose IPV schemes would work optimally.  
IPV is made from Salk (wild) strains or, less frequently, from Sabin (attenuated) strains 
and grown in Vero cell culture, or in human diploid cells (MRC-5). Manufacture of all 
current vaccines relies on inactivation of cell culture-derived polioviruses with 
formaldehyde in a final formulation containing standardized antigen units for each 
serotype. According to manufacturer specifications, IPV can be administered by 
subcutaneous or intramuscular injection. A fractional dose of stand-alone IPV can be 
administered intradermally.13 
IPV is considered very safe, whether administered alone or in combination with other 
vaccines. There is no proven causal relationship with any adverse events other than 
temporary minor local symptoms such as erythema (<1%), induration (3%–11%) and 
tenderness (14%–29%).14,15 
Studies have generally demonstrated that a single fractional dose of IPV (f-IPV 1/5 of the 
full dose) gives lower seroconversion rates than a full dose, but after 2 fractional doses, the 

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rates are similar to those achieved after 2 full doses. Studies in Cuba and in Bangladesh 
have shown 2 doses of f-IPV inducing seroconversion rates of 98% to poliovirus type 2 in 
Cuba at 4 and 8 months of age, and 81% to poliovirus type 2 in Bangladesh at 6 and 14 
weeks of age. The results indicate that 2 fractional doses of IPV provide higher 
seroconversion rates than the achieved with a single full dose, being 63% at 4 months of 
age in Cuba16 and 39% at 6 weeks of age in Bangladesh17. However, seroconversion is still 
inferior to that of 2 full doses of IPV18. This approach (2 fractional doses instead of 1 full 
dose), might increase the immune response as compared to a single dose and could extend 
coverage if supplies are limited. Moreover, intradermal administration of fractional doses 
of IPV (0.1 mL or 1/5 of a full dose) offers potential moderate cost reduction18,19; yet the 
cost and logistics of using this method still need to be considered20.  
Study Rationale 
The rationale for this study (IPV-004 ABMG) is to assess and compare the immune 
response to full-dose inactivated polio vaccines (IPV) via intramuscular (IM) 
administration and of the fractional dose of inactivated poliovirus vaccine (f-IPV) via 
intradermal (ID) administration, in different schedule combinations in the EPI primary 
series.  
This study prioritizes comparisons involving two-dose regimens recently recommended 
by the WHO Strategic Advisory Group of Experts on immunization (SAGE) and PAHO11 
in response to global IPV supply shortages 21. Furthermore, the study will provide data on 
the comparative humoral immunogenicity of various schedules to inform polio 
immunization policy for the post-eradication era.  
The study population will include infants in Dominican Republic and in Panama. Absence 
of wild and circulating vaccine derived polioviruses along with the lack of regular 
Supplementary Immunization Activities (SIAs) in the Latin America region provide an 
ideal epidemiologic setting to study polio vaccine immunogenicity.   
Infants will receive two or three doses of full-dose IPV IM or f-IPV ID, in two schedules 
(10, 14 and 36 weeks and 14 and 36 weeks). Immunological and safety assessments will 
be made after one dose, two doses and three doses. 
A total of 773 infants will be enrolled and distributed into 4 groups, according to a 
randomization scheme. During the study period, infants will be administered other 
concomitant vaccines according to the national schedules of the participating countries, 
but the effect, if any, of the concomitant administration on IPV immunogenicity will not 
be assessed.  
Optimum immunogenicity expected from the dose(s) of IPV in the post-eradication era 
will have to be balanced with the cost and supply constraints of IPV.  This study will be 
critical to determine how many doses of IPV and which schedule are optimal for the post-
eradication era after the global cessation of OPV use.  
 
RISK BENEFIT ANALYSIS 
1.2.1 Potential Risks 
The anticipated risks associated with the participation in the study are expected to be very 
low. The IPV vaccines to be studied are safe, effective, are licensed in Latin America, and 
have been used since the 1950s. All children would receive IPV as part of the NIP schedule. 

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As with all vaccines, allergic reactions of various severity may occur within a few minutes 
to a few hours after vaccination if the recipient is sensitive to components or excipients 
present in the vaccine product. As with all injectable vaccines, local injection site reactions 
of various severities may occur. Potential risks of venipuncture such as mild pain or 
hematoma are also expected to be low.  
ID administration is being considered by the WHO and the PAHO as a recommendation 
to be evaluated in countries in situations of outbreaks or scarce vaccine supply. With 
intradermal vaccination, possible local reactions as redness, induration and infiltration may 
occur 22.  Depending on group assignment, some infants participating in the study will 
receive IPV or f-IPV vaccine just a few weeks later than they would otherwise receive 
them in the national immunization schedule of each country. Children which have received 
less than the recommended 3 full doses of IPV in the primary schedule will receive 
additional full IPV doses after the end of the study Thus, by 12 months of age, all children 
should be considered protected against all polioviruses.    
Infants will be monitored at the study centers after vaccinations, and SAEs, IMEs and 
severe local reactions observed will be recorded in the infant’s CRF.  Furthermore, SAEs, 
IMEs and severe local reactions will be followed during the whole study period. Also, for 
the group receiving intradermal vaccination at weeks 14 and 36, the diameter of the bleb 
(if it occurs) will be measured in millimeters.  
1.2.2 Potential Benefits 
The outcome of this trial will provide the participating countries and the Latin American 
Region, as well as WHO SAGE, with information on vaccination policy development for 
the current setting of scarce IPV supply and for the OPV cessation era. It will also provide 
information on optimal number of doses and route of administration of IPV in the context 
of the post-eradication era, balancing immune response, risk of infection, supply 
constraints and cost. It will also help middle-and low-income countries to determine the 
best way to sustain polio eradication with the use of IPV. By strengthening the post-
eradication immunization policy formulation, the study is expected to enhance the prospect 
of sustaining a polio-free world for long-term, and thereby protect each and every children 
globally from the paralytic disease. 
 

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2. STUDY OBJECTIVES 
 
PRIMARY OBJECTIVES 
1. To determine if the seroconversion rate of a 2-dose intradermally administered 
fractional-dose inactivated poliovirus vaccine (f-IPV) regimen administered at 14 
and 36 weeks of age is non-inferior to that of a 2-dose intramuscularly administered 
inactivated poliovirus vaccine (IPV) regimen administered at 14 and 36 weeks of 
age 4 weeks after the last dose, for poliovirus serotypes 1 and 2. 
2. To determine if the seroconversion rate of a 2-dose IPV regimen administered at 
14 and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen administered 
at 10, 14, and 36 weeks of age 4 weeks after the last dose, for poliovirus serotypes 
1 and 2. 
3. To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 
14 and 36 weeks of age is non-inferior to that of a 3-dose f-IPV regimen 
administered at 10, 14, and 36 weeks of age 4 weeks after the last dose, for 
poliovirus serotypes 1 and 2. 
 
SECONDARY OBJECTIVES 
1. To determine if the seroconversion rate of a 2-dose IPV regimen administered at 
14 and 36 weeks of age is superior to that of a 2-dose IPV regimen administered at 
10 and 14 weeks of age, 4 weeks after the second dose for poliovirus serotypes 1 
and 2. 
2. To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 
14 and 36 weeks of age is superior to that of a 2-dose f-IPV regimen administered 
at 10 and 14 weeks of age 4 weeks after the second dose, for poliovirus serotypes 
1 and 2. 
3. To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 
14 and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen administered 
at 10, 14, and 36 weeks of age, 4 weeks after the last dose, for poliovirus serotypes 
1 and 2. 
4. To determine if the seroconversion rate of a 3-dose f-IPV regimen administered at 
10, 14, and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen also 
administered at 10, 14, and 36 weeks of age, 4 weeks after the last dose, for 
poliovirus serotypes 1 and 2. 
5. To determine if the seroconversion rate of a 3-dose regimen of f-IPV administered 
at 10, 14, and 36 weeks of age is non-inferior to that of a 2-dose IPV regimen 
administered at 14 and 36 weeks of age, 4 weeks after the last dose for poliovirus 
serotypes 1 and 2.  
6. To assess the safety of each vaccine (IPV and f-IPV) as measured by the incidence 
of serious adverse events (SAEs), important medical events (IMEs) and severe 
local reactions. 
7. To assess all primary and secondary immunogenicity objectives through 
comparison of neutralizing antibody (NAb) titers. 
 

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EXPLORATORY OBJECTIVES 
1. To assess immune responses to poliovirus type 3 analogous to the primary and 
secondary immunological objectives. 
2. To determine if an additional dose of IPV at 36 weeks of age provides a superior 
humoral immune response when added to a 2-dose IPV regimen at 10 and 14 weeks 
of age, as compared to the 2-dose regimen alone, for all three poliovirus serotypes, 
as measured by seroconversion rate, geometric mean and median NAb titers, 4 
weeks after the last dose. 
3. To determine if an additional dose of f-IPV at 36 weeks of age provides a superior 
humoral immune response when added to a 2-dose f-IPV regimen at 10 and 14 
weeks of age, as compared to the 2-dose regimen alone, for all three poliovirus 
serotypes, as measured by seroconversion rate, geometric mean and median NAb 
titers, 4 weeks after the last dose. 
4. To determine if the humoral immune response to a single dose of f-IPV 
administered at 10 weeks of age is non-inferior to that of a single dose of IPV 
administered at 10 weeks of age, for all three poliovirus serotypes, 4 weeks 
following vaccination, as measured by seroconversion rate, geometric mean and 
median NAb titers. 
5. To determine if the humoral immune response to a 2-dose regimen of f-IPV 
administered at 10 and 14 weeks of age is non-inferior to that of a 2-dose regimen 
of IPV administered at 10 and 14 weeks of age, for all three poliovirus serotypes, 
as measured by seroconversion rate, geometric mean and median NAb titers, 4 
weeks after the second dose. 
6. To determine if the humoral immune response to a single dose of f-IPV 
administered at 14 weeks of age is non-inferior to that of a single dose of IPV 
administered at 14 weeks of age, for all three poliovirus serotypes, 4 weeks 
following vaccination, as measured by seroconversion rate, geometric mean and 
median NAb titers. 
7. To determine if the humoral immune response to a single dose of f-IPV 
administered at 14 weeks of age is non-inferior to that of a single dose of IPV 
administered at 14 weeks of age, for all three poliovirus serotypes, 22 weeks 
following vaccination, as measured by seroconversion rate, geometric mean and 
median NAb titers. 
8. To assess the response to an additional f-IPV dose administered at 36 weeks of age 
to infants receiving a single dose of f-IPV at 14 weeks of age, for all three 
poliovirus serotypes, as measured by seroconversion rate, geometric mean and 
median NAb titers, 4 weeks after the final dose. 
9. To assess the response to an additional IPV dose administered at 36 weeks of age 
to infants receiving a single dose of IPV at 14 weeks of age, for all three poliovirus 
serotypes, as measured by seroconversion rate, geometric mean and median NAb 
titers, 4 weeks after the final dose. 
10. To describe the relationship between the humoral immune response to vaccination, 
as measured by seroconversion rate and median NAb titers at weeks 18, 36 and 40, 
and each post-vaccination fluid bleb diameter in the group receiving two doses of 
ID f-IPV at weeks 14 and 36, for serotypes 1 and 2.  

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3. STUDY ENDPOINTS 
 
PRIMARY ENDPOINTS 
1. Serotypes 1 and 2 seroconversion four weeks after the second vaccination for the 
groups receiving 2 doses of f-IPV or 2 doses of IPV  
2. Serotypes 1 and 2 seroconversion four weeks after the last vaccination for the group 
receiving 2 doses of IPV and for the group receiving 3 doses of IPV 
3. Serotypes 1 and 2 seroconversion four weeks after the last vaccination for the group 
receiving 2 doses of f-IPV and for the group receiving 3 doses of f-IPV 
 
Seroconversion will be defined as a change from seronegative to seropositive (antibody 
titers of ≥1:8), and, in infants seropositive at baseline (assumed to be from maternally-
derived antibody titers), as a ≥4-fold rise in antibody titers post-vaccination, computed by 
assuming an exponential decay model with a half-life of 24 days. 
 
SECONDARY ENDPOINTS 
In addition to primary endpoints: 
1. Serotypes 1 and 2 seroconversion at week 40 for the groups receiving 2 doses of 
IPV at weeks 14 and 36 and at week 18 for the groups receiving 2 doses of IPV at 
weeks 10 and 14. 
2. Serotypes 1 and 2 seroconversion at week 40 for the groups receiving 2 doses of f-
IPV at weeks 14 and 36 and at week 18 for the groups receiving 2 doses of f-IPV 
at weeks 10 and 14. 
3. Serotypes 1 and 2 seroconversion at week 40 for the group receiving 2 doses of f-
IPV and the group receiving 3 doses of IPV.  
4. Serotypes 1 and 2 seroconversion at week 40 for the groups receiving 3 doses of f-
IPV or 3 doses of IPV.  
5. Serotype 1 and 2 seroconversion at week 40, for the group receiving 3 doses of f-
IPV, compared to the group receiving 2 doses of IPV at weeks 14 and 36 
6. Safety Endpoints: SAEs, IMEs and severe local reactions throughout the study 
period. 
7. Serotype 1 and 2 geometric mean and median NAb titers through all 
immunogenicity endpoint 
 
EXPLORATORY ENDPOINTS 
Humoral immune response defined as seroconversion to serotypes 1, 2 and 3, geometric 
mean and median Nab titers for the following endpoints, in addition to primary and 
secondary endpoints.  
1. Humoral immune response to serotype 3, four weeks after each vaccination for all 
groups receiving IPV and f-IPV, and 22 weeks after receiving a single dose of IPV 
or f-IPV for the group receiving doses at weeks 14 and 36. 
2. Humoral immune response at weeks 18 and 40, for the group receiving 3 doses of 
IPV 
3. Humoral immune response at weeks 18 and 40, for the group receiving 3 doses of 
f-IPV 
4. Humoral immune response at week 14, for the groups receiving 1 dose of f-IPV or 
1 dose of IPV at week 10 

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5. Humoral immune response at week 18, for the groups receiving 2 doses of f-IPV 
or 2 doses of IPV at weeks 10 and 14  
6. Humoral immune response at week 18, after receiving 1 dose of f-IPV or 1 dose of 
IPV at week 14  
7. Humoral immune response at week 36, for the groups receiving 1 dose of f-IPV or 
1 dose of IPV at week 14  
8. Humoral immune response at week 40 for infants receiving 2 doses of f-IPV  
9. Humoral immune response at week 40 for infants receiving 2 doses of IPV  
10. Humoral immune response to serotypes 1 and 2, measured at weeks 18, 36 and 40 
according to the diameter of fluid blebs (measured in millimeters) resulting from 
ID f-IPV vaccination at weeks 14 and 36, in the group receiving two doses of f-
IPV  
 
 

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4. STUDY DESIGN 
 
OVERVIEW OF STUDY DESIGN 
Overview of Study Design: 
This will be an open-label, multicenter, randomized trial to be conducted in various 
pediatric centers in Dominican Republic and Panama. The subjects will be allocated to 4 
study groups, in which an IPV vaccine with two different indications will be used:  
- 
IPV using full dose via intramuscular injection 
- 
f-IPV using fractional dose via intradermal administration 
The vaccines will be administered in different immunization schedules to 773 healthy 
infants at different weeks of age, as shown in Table 1. 
Table 1 Summary of study vaccine group assignments, administration of study 
vaccine and blood samples 
Vaccine 
Group 
Vaccination weeks** 
Blood samples*** 
Subjects 
 
IM IPV 
A 
10, 14, 36 
10, 14, 18, 40 
200 
B 
14, 36 
14, 18, 36, 40 
178 
 
ID f-IPV§ 
C 
10, 14, 36 
10, 14, 18, 40 
178 
D 
14, 36 
14, 18, 36, 40 
217 
Total 
773 
*Groups A and C (3 doses), will also serve as 2-dose arms for 10 and 14 weeks.   
** Allowed windows: First and second dose administered at weeks 10 and/or 14: +7 days 
                                     Second and third dose administered at week 36: -7+7 days 
*** Allowed window for the blood samples: +7 days 
       Allowed window for blood samples at week 36: -7+7 days 
§ Fractional-dose IPV Intradermal 
 
DISCUSSION OF STUDY DESIGN 
This will be an open-label study. The study staff, including the one performing vaccination 
at the investigational site and the participants will know which vaccine and indication will 
be administered. However, the identity of the vaccine and indication administered will 
remain unknown to the staff performing the polio antibody analysis. Participants will be 
assigned to 4 different groups which will receive an IPV vaccine in a two- or three-dose 
regimen and two different indications: via intramuscular injection or via intradermal 
administration.  
This design will allow use of data collected after the first, second and third doses from 
infants allocated to the two or three-dose regimens of the vaccines evaluated, to perform 
comparisons among the different study schedules.  
 

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5. SELECTION OF STUDY POPULATION 
 
INCLUSION CRITERIA 
The study will be conducted in outpatient pediatric centers and at private and public 
vaccination centers, depending on each country. Parents or legal representatives of the 
infants will be invited to participate in the study at the earliest possible age. Infants will be 
considered eligible according to the following criteria:  
1. Infants of 6 weeks of age (-7 to + 7 days) on date of enrollment. 
2. Healthy, as assessed from medical history and physical examination by a study 
physician. 
3. Written informed consent obtained from parents or legal representatives that they 
have been properly informed about the study and are able to comply with planned 
study procedures. 
 
EXCLUSION CRITERIA 
1. Vaccinated with any poliovirus vaccine prior to inclusion.  
2. A household contact with OPV vaccination history in the past 4 weeks.  
3. HIV infection or pharmacologic immunosuppression.  
4. Known allergy to any component of the study vaccines (phenoxyethanol, 
formaldehyde). 
5. Uncontrolled coagulopathy or blood disorder contraindicating intramuscular and 
intradermal injections. 
6. Acute severe febrile illness on day of vaccination deemed by the Investigator(s) to 
be a contraindication for vaccination. 
7. Not suitable for inclusion or is unlikely to comply with the protocol in the opinion 
of the investigator(s). 
 
CRITERIA FOR ELIMINATION FROM THE PER-PROTOCOL 
POPULATION 
• Infant did not receive all vaccinations per protocol schedule,  
• Violation of any inclusion /exclusion criteria 
• A household contact with OPV vaccination history 
 
CONTRAINDICATIONS TO FURTHER VACCINATION 
Before administration of each dose of the study vaccine, permanent contraindications must 
be checked. The following adverse events (AEs) constitute absolute contraindications to 
further administration of the study vaccines:  
• SAE, IME and severe local reactions, considered to be consistent with a causal 
association to the study vaccine (after first or second dose) 
• Known hypersensitivity to any component of the vaccine or severe reaction 
following administration of the vaccine (after first or second dose) 
• Acute severe febrile illness on day of vaccination deemed by the Investigator(s) to 
be a temporal contraindication for vaccination. 
• Any intercurrent medical condition that in the judgment of the study physician will 
interfere with scheduled vaccinations and/or possibly impair the immune response 
to polio vaccination including those listed in Section 5.2 

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If any of these AEs occur during the study, the infant should not receive additional doses 
of the vaccine but may continue other study procedures at the discretion of the 
Investigator(s), including blood sampling. The infant will be followed until resolution of 
the event and to determine the immune response. Since vaccines to prevent these diseases 
are recommended for all infants, subsequent vaccination will be conducted after 
consultation with an appropriate sub-specialist to determine the most appropriate vaccines 
to administer.  
 

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6. VACCINES 
 
PHYSICAL DESCRIPTION OF THE STUDY VACCINE 
Inactivated Polio Vaccine  
Poliomyelitis Vaccine (Inactivated), produced by Serum Institute of India (SII) Pvt. Ltd., 
and prequalified by WHO, is a sterile suspension of three types of inactivated poliovirus: 
Type 1 (Mahoney), Type 2 (MEF-1), and Type 3 (Saukett). Each of the three strains of 
poliovirus is individually grown in Vero cells, a continuous line of monkey kidney cells 
cultivated on microcarriers. Polio vaccine is manufactured from the bulk imported from 
Bilthoven Biologicals B.V., Bilthoven, The Netherlands. The vaccine meets the 
requirements of WHO when tested by the methods outlined in the current WHO 
requirements. 
Each dose of vaccine (0.5 mL) contains 40 D antigen units of Mahoney strain (Type 1); 8 
D antigen units of MEF-1 strain (Type 2); and 32 D antigen units of Saukett strain (Type 
3). It also contains 2.5 mg of 2-phenoxyethanol and a maximum of 12.5 mcg of 
formaldehyde as preservatives 
 
DOSE AND ADMINISTRATION 
The dose of IPV vaccine should be 0.5 mL administered strictly intramuscularly in the 
anterolateral aspect of the thigh, using a standard needle and syringe.  
The fractional IPV (f-IPV) dose should be 0.1 mL or 1/5 of the full IPV dose, and the 
administration site is strictly the upper arm, using a 0.1 mL AD (auto disable) syringe 23. 
Care should be taken to avoid administering the injection into or near blood vessels and 
nerves. 
 
IPV and f-IPV vaccines will be administered according to the study groups described in 
Table 1.  
After administration of the study vaccines, the infant will be observed for at least 30 
minutes for signs of any reaction, including measurement of the fluid bleb, if any, in infants 
receiving the intradermal vaccination at weeks 14 and 36. 
 
 
OTHER MEDICATION ADMINISTERED IN THE STUDY  
The following concomitant vaccines DTPw-HB-Hib, Pneumococcal and Rotavirus will be 
administered in the opposite thigh to which IPV will be applied, according to the schedule 
presented in Table 2. All details from concomitants vaccines administered will be recorded 
in the corresponding forms.  
 
There will be no restrictions in using medications/treatments. Only medications to treat 
SAEs, IMEs and severe local reactions will be documented in the corresponding forms. 
All other medications will only be captured in the source documentation at the 
investigational site. 
 
PACKAGING AND LABELING 
The Poliomyelitis Vaccine (Inactivated) is manufactured by Serum Institute of India and 
filled into multi-dose vials of up to 1mL (2-dose vial) or 2.5 mL (5-dose vial). The label 

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and packaging will be according to WHO standards. The expiry date of the vaccine is 
indicated on the label and packaging.   
Vaccine Vial Monitor (VVMs) are part of the label on Poliomyelitis Vaccine (Inactivated) 
supplied through Serum Institute of India Pvt. Ltd. The color dot which appears on the 
label of the vial is a VVM. This is a time-temperature sensitive dot that provides an 
indication of the cumulative heat to which the vial has been exposed. It warns the end user 
when exposure to heat is likely to have degraded the vaccine beyond an acceptable level 
 
STORAGE AND VACCINE ACCOUNTABILITY 
The Investigator(s) (or their designee) is responsible for the safe storage of all study 
vaccine assigned to the clinical site, in a locked, secure storage facility with access limited 
to those individuals authorized to dispense the study vaccine, and maintained within the 
appropriate ranges of temperature.  In case the country does not have an IPV stand alone 
vaccine available, the Sponsor will supply it. All study vaccines must be stored as specified 
at delivery and in the original packaging. The IPV vaccine is stable if stored in the 
refrigerator at 2°C to 8°C. The vaccine must not be frozen. 
Regular temperature logging of the refrigerator where the study vaccine will be stored at 
the clinical site should be performed. In case a deviation in storage conditions should 
occur, the clinical site must not further dispense the affected study vaccine and should 
notify the Sponsor. 
The Investigator(s) will be responsible for ensuring that all study vaccines received at the 
clinical site are inventoried and accounted for throughout the study. 
Study vaccine should be dispensed under the supervision of the Investigator(s), a qualified 
member of the clinical staff, or by a hospital/clinic pharmacist. The Investigator(s) must 
maintain accurate records demonstrating date and amount of vaccine administered to 
whom and by whom. Study vaccine will be supplied only to subjects participating in the 
study. 
The Sponsor’s designated site monitor will periodically check the supplies of study vaccine 
held by the Investigator(s) or pharmacist to ensure accountability and appropriate storage 
conditions of all study vaccine used. 
Unused study vaccine must be available for verification by the site monitor during on-site 
monitoring visits.  
After the last visit of the last subject in the study (LSLV), any remaining study vaccine 
will be returned to the Sponsor, or destroyed at the clinical site with the Sponsor’s written 
permission (in this case a certificate of destruction will be provided and filed in the Trial 
Master File [TMF]). 
 
RANDOMIZATION  
Eligible infants will be randomized into one of the 4 study groups using computer-
generated block randomization to balance allocation across sites.  The allocations will be 
provided to the study Investigator(s) by a central location after informed consent has been 
obtained.  

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COMPLIANCE 
Adequate and sufficient procedures will be established to ensure that the development of 
the clinical study is carried out in compliance with the global recommendations on Good 
Clinical Practices and local regulations for clinical trials, ensuring adherence to the ethical 
principles of biomedical research and protection of the study population. 
 
Subject compliance will be addressed by evaluating the vaccine administration data 
recorded by the staff in the study documents. During the clinical study, the monitor will 
check that vaccine administration data is recorded correctly. 

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7. PRIOR AND CONCOMITANT THERAPY 
In addition to the study vaccines (IPV or f-IPV), participating infants will receive the 
DTPw-HB-Hib, Pneumococcal and Rotavirus concomitant vaccines according to the 
schedule presented in Table 2. Infants in Panama will receive 2 doses of influenza at 6 
and 7 months old, according to the National Immunization Schedule.  
This procedure will not be part of the study visits. 
All concomitant intramuscular vaccines will be administered in the thigh or arm opposite 
to which IPV and f-IPV will be applied.  

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8. 
ASSESSMENTS 
 
TIMING OF ASSESSMENTS 
An overview of the timing of vaccine administration and assessments is given in Table 2.  
Parent(s)/legal representatives will be given a full explanation of the nature of the study 
and written informed consent (approved by the local ethics committee) will be obtained 
from parent(s)/legal representatives according to local requirements before any study-
related assessment will be carried out.  
Serious Adverse Events (SAEs) and Important Medical Events (IMEs), severe local 
reactions and the diameter of the fluid bleb, if any, in infants who will receive intradermal 
administration at weeks 14 and 36, will be monitored after the first vaccination and until 
the last study-related activity.  
A blood sample will be taken from infants according to their study group visit schedule. 
When it is a vaccination visit, blood sample will be taken before vaccination. Infants will 
receive the first dose of study vaccine according to the procedure described in Section 6.6, 
followed by further assessments as outlined in Table 2. A measurement of the fluid bleb 
after intradermal vaccination will be performed with a millimeter ruler. Infants will be kept 
under medical supervision for at least 30 minutes after each IPV and f-IPV vaccination. 
Unscheduled visits can be planned; for instance: 
- 
To obtain additional information to ensure safety to the infant. Additional blood 
and urine samples may be taken at the discretion of the Investigator(s). 
Findings made during unscheduled visits should be reported in the source documents and 
in the designated sections of the eCRF. 
Table 2 Time and Events Schedule 
Age of infants (weeks) 
6 W 
10 W 
14 W 
18 W 
36 W 
 
40 W 
 
Visit * 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Allowed visit window 
for vaccination and 
blood samples 
-7+7 days 
+7 days 
+7 days 
 
+ 7 days 
-7+7 days  
+ 7 days 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
X 
 
 
 
Medical history 
X 
X 
X 
 
 
 
Physical examination 
X 
X 
X 
 
X 
 
Randomization and 
allocation 
X 
 
 
 
 
 
Concomitant vaccines 
administration 
X+ 
X+ 
X+ 
 
 
 
Vaccination Groups A/C 
 
IPV/f-IPV 
IPV/f-IPV 
 
IPV/f-IPV 
 
Blood sample Groups 
A/C 
 
X 
Xβ 
X 
 
Xβ 
Vaccination Groups B/D 
 
 
IPV/f-IPV 
 
IPV/f-IPV 
 
Blood sample Groups 
B/D  
 
 
X 
Xβ 
X 
Xβ 
Check contraindications 
 
X@  
X@  
 
X@  
 

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* Not all groups will attend the same visits. Infants’ attendance depends on their vaccination regimen 
+  Concomitant vaccines at weeks 6 and 14 are Pneumococcal Rotavirus and DTPw-HB-Hib and at week 10 only 
DTPw-HB-Hib, Infants in Panama will receive 2 doses of influenza at 6 and 7 months old, according to the National 
Immunization Schedule.  
This procedure will not be part of the study visits. 
 
β  Determination of hematocrit, hemoglobin and RBC morphology in the second and in the last blood sample 
@ For study groups receiving vaccination  
µ Measurement will be performed with a standard millimeter ruler and will include 2 photos to be taken: 1 at 0 
minutes, and a second photo at 30 minutes after vaccination. 
 
 
Infants from study groups B, C and D will receive 1 or 2 additional doses of full IPV 
intramuscularly after the end of the study. Thus, by 12 months of age, all children should 
be considered protected against all polioviruses.   
The period between vaccination visits will be of at least 28 days. The period between 
visits for blood collection will be of at least 28 days. 
 
Immediate surveillance 
(30 mins) after 
vaccination 
 
X@ 
X@ 
 
X@ 
 
Measurement of fluid 
bleb after ID 
vaccination forGroup D 
µ 
 
 
X 
 
X 
 
Serious Adverse 
(SAEs), Important 
Medical Events (IMEs) 
and severe local 
reactions 
To be reported and followed up at any moment throughout the study, upon 
signature of the Informed Consent until the Week 40 
 
8.1.1 Collection and handling of blood samples 
A total of four vein or arterial blood samples will be collected from each infant, prior to 
vaccination and according to their scheduled visits. Blood will be collected using butterfly 
needle or hypodermic needles and syringe. The location of the puncture will vary, 
depending on the subject. A minimum of 3.5 mL and a maximum of 4 mL will be collected 
in each visit, for a total of approximately 16mL over the entire study period. Blood will be 
collected into blood tubes in the vaccination sites and then centrifuged to separate serum. 
Serum will be transferred to cryotubes suitable for serum collection and will be stored at -
20°C until its transportation to the CDC designated laboratory. The shipping courier will 
be International Air Transport Association certified and arranged locally at each site. 
Procedures for processing blood samples will be conducted following internal standard 
operating procedures (SOPs) and laboratory manuals approved by the sponsor.    
 
IMMUNOGENICITY 
8.2.1 Immunogenicity Variables 
Immunogenicity endpoints will be determined by assessment of neutralizing antibody 
titers against polioviruses 1, 2 and 3. The level of neutralizing antibody present on serum 
samples will be expressed as a titer. A serum -neutralization assay will be used for antibody 
determinations24  
Type-specific neutralizing antibody titers will be summarized descriptively on the 
logarithmic (base 2) scale. 

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Seroprotection will be tabulated at each pre- and post-vaccination serology collection time 
point. 
Seroconversion will be defined as a change from seronegative to seropositive (antibody 
titers of ≥1:8) and in infants seropositive at baseline (assumed to be from maternally-
derived antibody titers), as a ≥4-fold rise in antibody titers post-vaccination, computed by 
assuming an exponential decay model with a half-life of 24 days. 
 
SAFETY EVALUATIONS 
Safety will be evaluated using the following parameters: 
• SAEs as defined in the protocol throughout the study period. 
• IMEs and severe local reactions, as defined in the protocol throughout the study 
period. 
8.3.1 Serious Adverse Events 
The Investigator(s) will be responsible for recording and reporting to the 
pharmacovigilance reporting system and regulatory authorities in the participating 
countries, within 24 hours and according to regulatory timelines, all SAEs observed during 
the study (treatment and follow-up) period. 
A SAE, experience or reaction, is any untoward medical occurrence (whether considered 
to be related to study vaccine or not) that at any dose: 
- 
Results in death. 
- 
Is life-threatening (the infant is at a 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). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization: 
Hospital admissions and/or surgical operations planned before or during a study 
are not considered SAEs if the illness or disease existed before the infant was 
enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
- 
Results in persistent or significant disability/incapacity. 
- 
Is a congenital abnormality/birth defect detected only after study inclusion. 
8.3.2 Important medical events (IMEs)  
IMEs are medically significant events that do not meet any of the SAE criteria above, but 
require medical or surgical consultation or intervention to prevent this event from 
becoming one of the serious outcomes listed in the SAE definition above.  
Examples of important medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias (e.g., neutropenia or anemia 
requiring blood transfusion, etc.).  

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To avoid judgement bias, IMEs will be reported separately and not as a subgroup of SAEs. 
They will be processed in the same way as SAEs. Every aspect described for SAEs 
(including trial objectives and endpoints) also applies to an IME. 
The term "severe" is often used to describe the intensity (severity) of a specific event. The 
event itself, however, may be of relatively minor medical significance (such as severe 
headache). This is not the same as "serious," which is based on patient/event outcome or 
action criteria usually associated with events that pose a threat to a patient's life or 
functioning. 
Severe local reactions can include severe pain, inflammation, induration and edema in the 
injection area25. Very rarely, abscess at injection site within 7 days of vaccine 
administration26. Nodules at the injection site with more than 2.5 centimeters in diameter 
and cellulitis27. 

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9. STUDY TERMINATION/COMPLETION 
 
STUDY COMPLETION 
9.1.1 Subject Completion 
Infants will complete the study four weeks after the last study vaccination, which is at week 
40 for all study groups. 
9.1.2 Study Completion Date 
The study completion date is considered to be the date on which the final serologic analysis 
is available for the purpose of assessing the primary immunogenicity objective.  
 
REMOVAL OF SUBJECTS FROM STUDY OR INVESTIGATIONAL 
PRODUCT 
9.2.1 
Removal from Study 
Parents(s)/legal representatives have the right to withdraw their infants from the study at 
any time for any reason, including personal reasons. An infant can be withdrawn without 
giving a reason. The Investigator(s) should however try to find out why an infant is 
withdrawn from the study and document the reason for withdrawal in the source documents 
and on the eCRF. 
Withdrawal will not affect in any way the treatment of the infant by the health care system.  
If the child is withdrawn, investigators will ensure that the child continues with their 
vaccination schedule according to the NIP in the participant countries. 
Infants may be withdrawn from the study in the event of: 
- 
A SAE, an IME or severe local reactions 
- 
Difficulties in obtaining blood  
- 
Failure of the subject and/or subject’s parent(s)/legal representative to comply with 
the protocol requirements or to cooperate with the Investigator(s). 
Infants must be withdrawn from the study in the event of: 
- 
Administration of any poliovirus vaccines outside the study protocol  
- 
Withdrawal of consent by parent(s)/legal representative; 
- 
For safety reasons, if, in the Investigator’s opinion, in the best interest of the infant. 
In the event of an infant being withdrawn from the study, the monitor and Sponsor should 
be informed: in the event of withdrawal due to an SAE (for details on SAE reporting see 
Section 11), the Sponsor should be notified within 24 hours; in the event of withdrawal for 
other reasons, the Sponsor should be notified within 2 days from the event. 
If there is a medical reason for withdrawal, the infant will remain under the supervision of 
the Investigator(s) until satisfactory health has returned. 
Infants who are withdrawn from the study prior to completion of the scheduled study 
procedures for any reason (e.g. AE, withdrawal of consent) should be invited to complete 
the assessments as much as possible: as long as the infants’ parent(s)/legal representative 
consents, all relevant assessments of the day on which the infant withdrew from the study 

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should be completed, at least those related to safety. In case of a SAE, the appropriate 
follow-up will be done. 
Infants who are withdrawn from the study will not be replaced. 

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10. 
STATISTICAL METHODS 
 
STATISTICAL ANALYSIS 
All statistical methods shall be detailed in the Statistical Analysis Plan (SAP) that will be 
finalized before database lock. 
Unless otherwise specified, descriptive statistics include mean, standard deviation (SD), 
median, maximum, minimum and range for continuous variables and the number and 
percentage in each group for categorical variables. 
Unless specified otherwise in the SAP, statistical tests and confidence intervals (CIs) will 
be computed using a two-sided 5% significance level. P-values will be presented with 4 
decimal places; p-values < 0.0001 will be presented as “< 0.0001”. 
Prior and concomitant medications will be coded using the WHO_DRUG Dictionary, and 
serious adverse events will be coded into system organ class and preferred term using 
MedDRA.  
10.1.1 Study Populations 
The following populations will be considered for analysis: 
- 
Intention-to-treat (ITT) population, defined as all enrolled infants scheduled to 
receive study vaccine, regardless of whether a study vaccine was administered. 
- 
Total Vaccinated population (TVP), defined as all infants who are in the ITT 
population who received at least one dose of study vaccine. Dropout from ITT to 
TVP will be described. 
- 
Per-protocol (PP) population, consisting of all eligible study participants who are 
in the Total Vaccinated population who receive all of the immunizations scheduled 
for the group to which they are allocated and who do not meet any of the criteria in 
Section 5.3 
Unless specified otherwise, the Total Vaccinated population will be used for safety 
analysis, and the PP population will be used for immunogenicity analysis. All 
immunogenicity analyses (primary and secondary) will be repeated in the TVP. 
Descriptive summaries of demographics will be computed in both the TV and PP 
populations. 
10.1.2 
Initial Characteristics of the Subject Sample 
Unless otherwise specified, descriptive statistics will be provided per group for 
demographics (e.g., age, weight, race, gender), baseline seroprotection rates for each of the 
polioviruses, and other initial subject characteristics (e.g., medical and surgical history, 
concomitant diseases). Descriptive statistics include mean, standard deviation (SD), 
median, maximum, minimum and range for continuous variables, and the number and 
percentage in each group for categorical variables. 
10.1.3 
Immunogenicity Data 
For an overview of primary, secondary and exploratory endpoints, see Section 3. 
Poliovirus Antibody Titers 

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At each pre-and post-vaccination time point where neutralizing antibody titers are 
obtained: 
- 
Seroprotection rates with 95% score-based confidence intervals (CIs) will be 
tabulated. 
- 
Seroconversion rates with 95% score-based confidence intervals (CIs) will be 
computed at post-vaccination time points. 
- 
Continuous summaries of log2 antibody titers will be computed along with 95% CIs 
for the median and geometric mean. CIs for the median will be obtained via the 
bootstrap method, and normal-based methods will be used for the geometric mean. 
- 
Plots of the reverse cumulative distribution of antibody titers will be generated. 
10.1.4 Safety Data 
Safety will be assessed through collection and tabulation by study arm of Adverse Events. 
Adverse events will be classified into standardized terminology from the verbatim 
description according to the most recent version of the MedDRA adverse event coding 
dictionary available. Adverse events will be presented by preferred term nested within 
system organ class. Verbatim description and all MedDRA-coded terms for all AEs will 
be contained in listings. 
Adverse Events will be summarized by the incidence of AEs by body system and preferred 
term. The incidence of AEs will be based on the number and percent of subjects with AEs. 
Although a term may be reported more than once for a subject, that subject will be counted 
only once in the incidence count for that MedDRA term. The severity of the AEs and the 
causal association to study vaccine will be summarized for each body system and preferred 
term by group. Withdrawals due to AEs will be summarized for each body system and 
preferred term. Concomitant vaccines will be tabulated by study groups. 
10.1.5 Missing Data 
The reasons for any missing data will be ascertained and appropriate statistical methods 
will be used to accommodate these absences in the analyses of trial data, to minimize 
potential biases and maximize efficiency conditional on the causes for data being missing. 
Data values that are identified to be spurious by quality control procedures will not be used 
in final analyses of trial data. If an excessive amount of missing immunogenicity is present, 
additional sensitivity analyses may be computed to determine its influence on important 
analyses. 
 
DETERMINATION OF SAMPLE SIZE 
A total of 773 infants will be enrolled in the study. For sample size calculations, the 
assumed seroconversion rates applying to all three serotypes are presented in Table 3. 
 
 

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Table 3  Assumed SC rates at 4 weeks post last dose for poliovirus types 1, 2 and 3 
after two doses of IPV, two doses of f-IPV, three doses of IPV and three doses of f-
IPV 
Group 
Assumed SC rates 
at 4 weeks, post 2 
doses 
Assumed SC rates 
at 4 weeks, post 3 
doses 
Min N 
evaluable 
sample size 
N for 
enrollment* 
Group A 
80% 
99% 
180 
200 
Group B 
96% 
NA 
160 
178 
Group C 
64% 
96% 
160 
178 
Group D 
94% 
NA 
195 
217 
Total 
695 
773 
* Assumes 10% dropout rate from enrolled population to PP population, for immunogenicity objectives 
Power is computed for the primary and secondary seroconversion objectives. There are 
two different power estimates for the study: (Table 4) 
 
1. The power of the comparison (either superiority or non-inferiority) to be 
successful for any individual serotype. 
2. The power of the comparison (either superiority or non-inferiority) to be 
successful for serotypes 1 and 2 simultaneously 
 
Table 4 Power estimation 
Comparison* 
Comparison 
Type 
Superiority vs. 
Non-Inferiority 
Objective 
Power for Any 
Individual 
Serotype 
Power for both 
Serotypes 
Simultaneously 
D vs B (2 f-IPV vs IPV at 14, 36) 
NI 
Primary 
90% 
80% 
B vs A (IPV at 14/36 vs 10, 14, 36) 
NI 
Primary 
90% 
81% 
D vs C (f-IPV at 14, 36 vs 10, 14, 36) 
NI 
Primary 
90% 
81% 
Superiority of 14, 36 to 10, 14 (IPV) 
S 
Secondary 
100% 
99% 
Superiority of 14, 36 to 10, 14 (f-IPV) 
S 
Secondary 
100% 
100% 
D vs A (f-IPV at 14, 36 vs IPV at 10, 14, 36) 
NI 
Secondary 
62% 
39% 
A vs C (3 f-IPV vs 3 IPV) 
NI 
Secondary 
90% 
80% 
C vs B (3 f-IPV vs 2 IPV at 14, 36) 
NI 
Secondary 
98% 
96% 
* Comparisons to be made with study data. In general, groups A and C (3 doses) serve as 2 dose 
arms for 10 and 14 weeks represents  
The group sizes, selected via simulation of the study using the assumed seroconversion 
rates and the efficacy analysis methods described below, are chosen to provide ≥ 80% 
power for each of the primary objectives, for the individual statistical tests of each 
serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available 
for all secondary objectives, except for the comparison of the f-IPV regimen administered 
at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual 
serotypes, and 39% for the combined serotypes. Given the much larger sample size 
necessary to boost the sample size to meet 80% power for this objective, this was 
considered an acceptable compromise for a feasible study designed mainly to assess 
primary objectives. In order to conclude a vaccination schedule is completely 

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superior/non-inferior to another across both serotypes, the conclusion must be met for each 
serotype individually. 
 
IMMUNOGENICITY ANALYSIS 
A number of comparisons of seroconversion rates between vaccine regimens and vaccine 
types are intended to be made. All non-inferiority comparisons of seroconversion rates will 
be made utilizing the lower bound of two-sided score-based confidence intervals (α = 0.05) 
with non-inferiority margin 10%, and superiority comparisons of seroconversion rates will 
be made using one-sided Fisher’s exact test (α = 0.025). 
For all comparisons, type-specific superiority or non-inferiority of seroconversion rates 
will be presented; uniform superiority/non-inferiority will be declared if the superiority or 
non-inferiority conclusion can be made for both serotypes 1 and 2 simultaneously. 
Comparisons of NAb titers between regimens will be conducted using geometric mean 
titer (GMT) ratios, facilitated by an analysis of covariance (ANCOVA) model of the log2 
titer, which adjusts for the baseline level and study site as fixed effects. Non-inferiority of 
regimen 1 to regimen 2 will be declared if the lower 95% bound of the two-sided 
confidence interval for the GMT ratio (regimen 1 relative to regimen 2) is greater than 
0.67. If an excessive amount of censoring at LLOQ or ULOQ occurs in either group, a 
one-sided randomization test for the median titer ratio, with resampling conducted within 
study site and using alpha level 0.025, will be applied instead. 
Detailed specification of statistical methods and exploratory analyses will be fully-
described in the Statistical Analysis Plan. 

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11. 
SERIOUS ADVERSE EVENT REPORTING 
 
DEFINITIONS 
11.1.1 Serious Adverse Events 
The Investigator(s) will be responsible for recording and reporting within 24 hours and 
according to regulatory timelines all SAEs observed during the study period (upon 
signature of the Informed Consent). 
A SAE, experience or reaction, is any untoward medical occurrence (whether considered 
to be related to study drug or not) that at any dose: 
- 
Results in death. 
- 
Is life-threatening (the infant is at a 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). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization: 
Hospital admissions and/or surgical operations planned before or during a study 
are not considered AEs if the illness or disease existed before the infant was 
enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
- 
Results in persistent or significant disability/incapacity. 
- 
A congenital abnormality/birth defect will be considered only if it is detected after 
the inclusion of the infant in the study.  
11.1.2 Important Medical Event 
The Investigator(s) will be responsible for recording and reporting within 24 hours and 
according to regulatory timelines all IMEs observed during the study period (upon 
signature of the Informed Consent). 
Important medical events (IMEs) are medically significant events that do not meet any of 
the SAE criteria above, but require medical or surgical consultation or intervention to 
prevent this event to become one of the serious outcomes listed in the SAE definition 
above. Examples of important medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias (e.g., neutropenia 
or anemia requiring blood transfusion, etc.) or convulsions that do not result in 
hospitalization. To avoid judgement bias, IMEs will be reported separately and not as a 
subgroup of SAEs. They will be processed in the same way as SAEs. Every aspect 
described for SAEs (including trial objectives and endpoints) also applies to an IME. 
Severe local reactions can include severe pain, inflammation, induration and edema in the 
injection area25. Very rarely, abscess at injection site within 7 days of vaccine 
administration26. Nodules at the injection site with more than 2.5 centimeters in diameter 
and cellulitis27.  

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CAUSALITY ASSESSMENT 
The investigator(s) are obligated to assess the causal association between investigational 
vaccine and the occurrence of each SAE and IME and severe local reactions. The 
investigator(s) will use clinical judgement to determine the causal association. Alternative 
plausible causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal causal association of the event to the investigational 
vaccine will be considered and investigated. The investigator(s) will also consult the 
Investigator’s Brochure to determine their assessment. 
Causality should be assessed by the investigator(s) using AEFI causality algorithm 
developed by WHO for individual AEFI evaluation. When appropriate information is 
available the investigator(s) should arrive to the following possible conclusions: 
 
 
If an event meets the criteria to be determined as ‘serious’ (see Section 11.1.1), additional 
examinations/tests will be performed by the investigator(s) in order to determine ALL 
possible contributing factors for each SAE. 
Possible contributing factors include: 
- 
Medical history. 
- 
Other medication. 
- 
Protocol required procedure. 
- 
Other procedure not required by the protocol. 
- 
Lack of efficacy of the vaccine, if applicable. 
- 
Erroneous administration. 
- 
Other cause (specify). 

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ACTION TAKEN REGARDING THE STUDY VACCINE 
The action taken towards the study vaccine must be described as follows: 
- 
Permanently discontinued. 
- 
Stopped temporarily. 
- 
No action taken. 
- 
Not applicable. 
 
OUTCOME 
The outcome of each SAE/IME must be rated as follows: 
- 
Recovered/resolved. 
- 
Recovering/resolving. 
- 
Not recovered/not resolved. 
- 
Recovered with sequelae/resolved with sequelae. 
- 
Fatal (SAEs only). 
 
RECORDING OF SERIOUS ADVERSE EVENTS 
All SAEs, IMEs and severe local reactions occurring during the clinical investigation must 
be documented in the source documents and on the SAE forms of the eCRF. The 
Investigator(s) will inquire about the occurrence of SAEs at every visit/contact during the 
study. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as “upper respiratory infection”). Investigators must record their 
opinion concerning the possible causality of the SAE to the study vaccine in the source 
documents and on the eCRF. All measures required for SAEs management must be 
recorded in the source documents and reported according to Sponsor’s instructions. 
All SAEs occurring at any time during the study will be followed by the Investigator(s) 
until satisfactory resolution (e.g., value back to baseline value) or stabilization or until final 
database lock. If necessary, in order to obtain additional information to ensure safety to the 
infant, additional blood and urine samples may be taken at the discretion of the 
Investigator(s). Certain long-term SAEs related to therapy cannot be followed until 
resolution within the setting of this study. In these cases, follow-up will be the 
responsibility of the treating physician. 
 
REPORTING OF SERIOUS ADVERSE EVENTS AND IMPORTANT 
MEDICAL EVENTS TO THE SPONSOR 
All SAEs, IMEs and severe local reactions, independent of the circumstances or suspected 
cause must be reported on a SAE Form by the Investigator(s) to the Sponsor within 24 h 
of their knowledge of the event, preferably by email. The form will be sent encrypted, and 
the password to open it will be sent in a separate email.   
The SAE form should include a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, concomitant medication, as well as any 

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relevant laboratory data and any sequelae, in order to allow a complete medical assessment 
of the case and independent determination of the possible causality.  
Follow-up and outcomes should be reported for all infants who experience an SAE. 
It is critical that the information provided on the SAE Form matches the information 
recorded in the source documents and on the eCRF for the same event. 
Copies of additional laboratory test results, consultation reports, postmortem reports, 
hospital case reports, autopsy reports and other documents should be sent when requested 
and applicable. Follow-up reports relative to the infant’s subsequent course must be 
submitted to the Sponsor until the event has subsided or, in the event of permanent 
impairment, until the condition stabilizes. 
 
REPORTING OF SERIOUS ADVERSE EVENTS TO COMPETENT 
AUTHORITY/ETHICS COMMITTEES 
The investigators assume responsibility for appropriate reporting of SAEs to the regulatory 
authorities. The investigators will also report all SAEs that are unlisted (unexpected) and 
associated with the use of the vaccine. The Investigator(s) must report these events to the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that 
approved the protocol, unless otherwise required and documented by the IEC/IRB. 
Adverse event reporting, including suspected unexpected serious adverse reactions 
(SUSARs), will be carried out in accordance with applicable local regulations. 
After termination of the clinical study (determined as the last subject’s last visit [LSLV]), 
any unexpected safety issue that changes the risk-benefit analysis and is likely to have an 
impact on the infants who have participated in the study, together with proposed actions, 
will be reported by the Sponsor to the competent authorities concerned as soon as possible. 

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12. 
ETHICAL ASPECTS 
 
STUDY-SPECIFIC DESIGN CONSIDERATIONS 
The parent(s)/legal representative of potential subjects will be fully informed of the nature 
of the study and of the risks and requirements of the study before any study-related 
assessment will be carried out. During the study, parent(s)/legal representative of the infant 
will be given any new information that may affect their decision to continue their child 
participating. They will be informed that their child’s participation in the study is voluntary 
and that they may withdraw their child from the study at any time with no reason given, 
and without penalty or loss of benefits to which they or their child would otherwise be 
entitled. Only infants whose parent(s)/legal representative are fully able to understand the 
risks, benefits, and potential AEs of the study and who provide their consent voluntarily 
will be enrolled in the study. 
 
REGULATORY ETHICS COMPLIANCE 
12.2.1 Investigator Responsibilities 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications 
specified by the applicable regulatory requirements, and should provide evidence of such 
qualifications through up-to-date curriculum vitae or other relevant documentation 
requested by the Sponsor, the IRB/IEC, or the regulatory authorities. 
The Investigator(s) are responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of study subjects are protected, consistent with the principles 
originating from the Declaration of Helsinki (1964 and revisions), and that the clinical 
study data are credible. 
12.2.2 Independent Ethics Committee or Institutional Review Board 
(IEC/IRB) 
An IRB/IEC should safeguard the rights, safety, and well-being of all study subjects in 
each country. Special attention should be paid to studies that may include vulnerable 
infants. 
Before the start of the study, the Investigator(s) (or Sponsor where required) will provide 
the IEC/IRB with current and complete copies of the following documents: 
- 
Final protocol and, if applicable, amendments. 
- 
Sponsor-approved ICF (and any updates or any other written materials to be 
provided to the subjects). 
- 
Sponsor-approved subject recruiting materials. 
- 
Prescribing information of the licensed vaccine. 

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- 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable. 
- 
Investigator’s current curriculum vitae or other documentation evidencing 
qualifications (unless not required, as documented by the IEC/IRB). 
- 
Information regarding funding, name of the Sponsor, institutional affiliations, 
other potential conflicts of interest, and incentives for subjects. 
- 
Any other documents that the IEC/IRB may require to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full written approval of the 
final protocol and amendments (if any), the ICF(s) and updates (if any), applicable 
recruiting materials, and any other written information to be provided to the subjects, and 
the Sponsor has received a copy of this approval. This approval letter must be dated and 
must clearly identify the IEC/IRB and the documents being approved. 
During the study, the Investigator(s) (or Sponsor where required) will send the following 
documents and updates to the IEC/IRB for its review and approval, where appropriate:  
- 
Protocol amendments. 
- 
Revisions to the ICF and any other written materials to be provided to the infants’ 
parents. 
- 
New or revised subject recruiting materials approved by the Sponsor. 
- 
Revisions to compensation for study-related injuries or payment to subjects or their 
parent(s)/legal representative for participation in the study. 
- 
Prescribing information of the licensed vaccine. 
- 
Summaries of the status of the study at intervals stipulated in guidelines of the 
IEC/IRB (at least annually). 
- 
Reports of AEs that are serious, unlisted, and associated with the investigational 
product (SUSARs). 
- 
New information that may adversely affect the safety of the infants or the conduct 
of the study. 
- 
Deviations from or changes to the protocol to eliminate immediate hazards to the 
infants. 
- 
Report of death of any infants under the Investigators’ care. 
- 
Notification if a new Investigator is responsible for the study at the clinical site. 
- 
Development Safety Update Report, Short-Term Study Specific Safety Summary 
and Line Listings, where applicable. 
- 
Any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s), except when necessary to eliminate immediate hazard to 
the study subjects. If a deviation from or a change to the protocol was implemented to 
eliminate an immediate hazard to study subjects, then the implemented deviation or 

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change, the reasons for it, and, if appropriate, the protocol amendment should be submitted 
to the IEC/IRB as soon as possible. 
The Investigator(s) (or Sponsor where required) will notify the IEC/IRB about the study 
completion within 90 days after the end of the study (defined as LSLV). 
12.2.3 Informed Consent 
The parent(s)/legal representative of each infant must give written consent according to 
local requirements after the nature of the study has been fully explained. The consent form 
must be signed before performance of any study-related activity. The consent form that is 
used must be approved by both the Sponsor and the reviewing IEC/IRB. The informed 
consent should be in accordance with the principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and 
Sponsor policy. 
Before enrollment in the study, the Investigator(s) or an authorized member of the clinical 
staff must explain to the parent(s)/legal representative of potential subjects the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. Infants’ parent(s)/legal representative will 
be informed that the infant’s participation is voluntary and that they may refuse to allow 
the infant to participate or withdraw consent for the infant to participate at any time, 
without penalty or loss of benefits to which the parent(s)/legal representative and/or infant 
was entitled. Finally, they will be told that the Investigator(s) will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that the 
infant’s records may be accessed by health authorities and authorized Sponsor staff without 
violating the confidentiality of the infant, to the extent permitted by the applicable law(s) 
or regulations. By signing the ICF the infant’s parent(s)/legal representative is authorizing 
such access, and agrees to allow the infant’s study physician to re-contact the infant’s 
parent(s)/legal representative for the purpose of obtaining consent for additional safety 
evaluations, if needed. 
The ICF will include a paragraph whereby the infant’s parent(s)/legal representative allow 
or not the use of the infant’s biological samples for additional polio related research, if 
needed. 
The language about the study used in the oral and written information, including the ICF, 
should be non-technical and practical and should be understandable to the infants’ 
parent(s)/legal representative. The infants’ parent(s)/legal representative will be given 
sufficient time to read the ICF and the opportunity to ask questions. After this explanation 
and before entry of the infant into the study, consent should be appropriately recorded by 
means of the infant's parent(s)/legal representative personally dated signature. After having 
obtained consent, a copy of the ICF must be given to the infant’s parent(s)/legal 
representative. 
If a parent(s)/legal representative of an infant is unable to read or write, an impartial 
witness should be present for the entire informed consent process (which includes reading 
and explaining all written information) and should personally date and sign the ICF after 
their oral consent is obtained, if permitted by local law. 

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12.2.4 Privacy of Personal Data 
The collection and processing of personal data from infants enrolled in the study will be 
limited to those data that are necessary to investigate the safety, quality and 
immunogenicity of the vaccine used in the study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations. Appropriate technical and organizational measures to protect the personal data 
against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration must be put in place. Sponsor personnel whose responsibilities 
require access to personal data need to agree to keep the identity of the study subjects 
confidential. 
The informed consent obtained from the infants’ parent(s)/legal representative includes 
explicit consent for the processing of personal data and for the Investigator(s) to allow 
direct access to infants’ original medical records for study-related monitoring, audit, 
IEC/IRB review, and regulatory inspection. This consent also addresses the transfer of the 
data to other entities and to other countries. 

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13. 
ADMINISTRATIVE REQUIREMENTS 
 
PROTOCOL AMENDMENTS/NOTIFICATIONS 
Neither the Investigator(s) nor the Sponsor will modify this protocol without a formal 
amendment (except modifications that do not alter the benefit/risk-see next paragraph). All 
protocol amendments must be issued by the Sponsor and signed and dated by the 
Investigator(s). Protocol amendments must not be implemented without prior IEC/IRB 
approval nor when the relevant competent authority has raised any grounds for non-
acceptance, except when necessary to eliminate immediate hazard to the infants, in which 
case an amendment must be promptly submitted to the IEC/IRB and relevant competent 
authority. Documentation of amendment approval by the Investigator(s) and IEC/IRB 
must be provided to the Sponsor or its designee. 
When the change(s) involves only logistic or administrative aspects of the study, the IRB 
(and IEC where required) only needs to be notified. 
 
SUBJECT IDENTIFICATION AND ENROLLMENT LOGS 
The Investigator(s) agree to complete a subject identification and enrollment log to permit 
easy identification of each infant during and after the study. This document will be 
reviewed by the monitor for completeness. 
The subject identification and enrollment log will be treated as confidential and will be 
filed by the Investigator(s) in the study file. To ensure subject confidentiality, no copies 
will be made. All reports and communications related to the study will identify infants by 
initials and/or assigned number only. 
 
SOURCE DOCUMENTATION 
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent, dates of visits, results of safety and 
immunogenicity parameters as required by the protocol, record of all AEs, follow-up of 
AEs, study vaccine receipt/dispensing/return records, study vaccine administration 
information, laboratory printouts, date of study completion, and reason for early 
discontinuation of study vaccine or withdrawal from the study, if applicable. 
Direct access to source documentation (medical records) must be allowed for the purpose 
of verifying that the data recorded on the eCRF are consistent with the original source data. 
It is recommended that the author of an entry in the source documents be identifiable. 
At a minimum, the type and level of detail of source data available for a study subject 
should be consistent with that commonly recorded at the clinical site as a basis for standard 
medical care. Specific details required as source data for the study will be reviewed with 
the Investigator(s) before the study and will be described in the monitoring guidelines (or 
other equivalent document). The nature and location of all source documents will be 
identified in the Source Document Identification Form. Data that will be recorded directly 
into the eCRF.  

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CASE REPORT FORM COMPLETION 
Electronic Data Capture (EDC) will be used for this study. The study data will be 
transcribed by study personnel from the source documents into an eCRF, and transmitted 
in a secure manner to the Sponsor. The electronic file will be considered to be the eCRF. 
All eCRF entries, corrections, and alterations must be made by the Investigator(s) or other 
authorized study-site personnel. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. 
Any such worksheet will become part of the infant’s source documentation. Such 
worksheet should not resemble an eCRF. All data related to the study must be recorded on 
the eCRFs prepared by the Sponsor. Data must be entered into the eCRFs in English. 
Designated site personnel must complete the eCRF as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit. 
The Investigator(s) must verify that all data entries on the eCRFs are accurate and correct. 
 
MONITORING 
The monitoring of the study will be done under the responsibility of the Sponsor by 
VaxTrials. 
The monitor will perform sites evaluations, study initiation, during study and study closure 
on-site visits as frequently as necessary. The monitor will record the dates of the visits in 
a study site visit log that will be kept at the clinical site. The first post-initiation visit will 
be made as soon as possible after enrollment has begun. At these visits, the monitor will 
compare the data entered into the eCRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the eCRF are known to the Sponsor 
and clinical staff and are accessible for verification by the Sponsor site contact. If 
electronic records are maintained at the investigational site, the method of verification must 
be discussed with the clinical staff. 
Direct access to source documentation (medical records) must be allowed at all times for 
the purpose of verifying that the data recorded in the eCRF are consistent with the original 
source data. Findings from this review of eCRFs and source documents will be discussed 
with the clinical staff. During on-site monitoring visits (notified and agreed upfront with 
the clinical staff), the relevant clinical staff will be available, the source documentation 
will be accessible, and a suitable environment for review of study-related documents will 
be provided. The monitor will meet with the Investigator(s) on a regular basis during the 
study to provide feedback on the study conduct. 
 
DATA MANAGEMENT 
Data management of the study will be performed under the responsibility of the Sponsor 
by VaxTrials, who will subcontract this service and the eCRF management.  
After the monitor reviews the data entered into the eCRFs for completeness and accuracy 
and the data are released by the Investigator(s), data will be uploaded into the clinical 
database to perform cleaning activities. Computerized data cleaning checks will be used in 
addition to manual review, including listings review, to check for discrepancies and to 
ensure consistency and completeness of the data. 

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If necessary, queries will be generated in the EDC tool. The Investigator(s) or an authorized 
member of the clinical staff must adjust the eCRF (if applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done 
in 3 different ways: 1- site personnel can make corrections in the EDC tool at their own 
initiative or as a response to an auto query (generated by the EDC tool), 2- the site manager 
can generate a query (field data correction form [DCF]) for resolution by the clinical staff, 
and 3- the clinical data manager can generate a query for resolution by the clinical staff. 
The clinical database will be locked as soon as it is considered clean. Only authorized and 
well-documented updates to the study data are possible after database lock. The locked 
database is used in the final statistical analysis for study reporting. Measures will be 
undertaken to protect subject data handed over by the Investigator(s) to the data 
management department and during inspections against disclosure to unauthorized third 
parties. Subject confidentiality will be maintained at all times. 
 
DATA QUALITY ASSURANCE 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the 
Investigator(s) and associated personnel prior to the study, and by periodic monitoring 
visits by the Sponsor or designate. 
The Sponsor or his designee will review the eCRF system for accuracy and completeness 
during (on-site) monitoring visits and after transmission to the Sponsor; any discrepancies 
will be resolved with the Investigator(s) or designee, as appropriate. After upload of the 
data into the clinical study database, their accuracy verified using appropriate validation 
programs. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, 
the Sponsor will be entitled to audit the facilities used in the clinical and laboratory parts 
of the study, as well as to access all the data files pertaining to the study. Similar procedures 
may also be conducted by agents of any regulatory body, either as part of a national GCP 
compliance program or to review the results of this study in support of a regulatory 
submission. The Investigator(s) should immediately notify the Sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection. 
 
ON-SITE AUDITS 
Representatives of the Sponsor’s clinical quality assurance department or any other 
qualified auditor appointed by the Sponsor may visit the clinical site at any time during or 
after completion of the study to conduct an audit of the study in compliance with regulatory 
guidelines and company policy. These audits will require access to all study records, 
including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The Investigator(s) and clinical staff are to be present 
and available for consultation during routinely scheduled site audit visits conducted by the 
Sponsor or its designees. 
Similar procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of 
a regulatory submission. The Investigator(s) should immediately notify the Sponsor if they 
have been contacted by a regulatory agency concerning an upcoming inspection. 

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STUDY TERMINATION 
The Sponsor has the right to terminate the study at any time. In the event of early 
termination of the study or temporary halt by the Sponsor, the IEC/IRB and the regulatory 
authorities should be notified within 15 calendar days and should be provided with a 
detailed written explanation of the reasons for the termination/halt. 
An end-of-study declaration will be submitted to the regulatory authorities and IEC/IRB 
after the complete study has ended. This notification will be submitted within 90 days after 
the end of the study. 
 RECORD RETENTION 
In compliance with the ICH/GCP guidelines, the Investigator(s)/Institution will maintain 
all eCRFs and all source documents that support the data collected from each infant, as 
well as all study documents as specified in ICH/GCP Section 8, Essential Documents for 
the Conduct of a Clinical Trial, and all study documents as specified by the applicable 
regulatory requirement(s). The Investigator(s)/Institution will take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents must be retained until at least 15 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 5 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents will be 
retained for a longer period if required according to the applicable regulatory requirements 
or per agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator(s)/Institution as to when these documents no longer need to be retained.  
If the responsible Investigator(s) retires, relocates, or for any other reasons withdraws from 
his responsibility of keeping the study records, custody must be transferred to a person 
who will accept the responsibility. The Sponsor must be notified in writing of the name 
and address of the new custodian. Under no circumstance shall the Investigator(s) relocate 
or dispose of any study documents without having obtained written approval from the 
Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review 
any documentation related to the study, the Investigator(s) must permit access to such 
reports. 
 USE OF INFORMATION AND PUBLICATION 
All information, including but not limited to, information regarding the study vaccine or 
the Sponsor’s operations (e.g., patent application, formulas, manufacturing processes, 
basic scientific data, prior clinical data, formulation information) supplied by the Sponsor 
to the Investigator(s) and not previously published, and any data generated as a result of 
this study are considered confidential and remain the sole property of the Sponsor. The 
Investigator(s) agrees to maintain this information in confidence, to use this information 
only to accomplish this study, and not to use it for other purposes without the Sponsor’s 
prior written consent. 
The Investigator(s) understands that the information generated in this clinical study will 
be used by the Sponsor in connection with the continued development of the study vaccine, 
and thus may be disclosed as required to other clinical Investigators or regulatory agencies. 

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To permit information derived from the clinical studies to be used, the Investigator(s) is 
obliged to provide the Sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated under the 
responsibility of the Sponsor and will contain eCRF data from all clinical sites that 
participated in the study. Recruitment performance or specific expertise related to the 
nature and the key assessment parameters of the study will be used to determine a 
coordinating Investigator. 
Clinical narratives will be written for the following events (for example): 
- 
All deaths (irrespective of causal association to vaccine). 
- 
All other SAEs and IMEs after vaccination. 
- 
All discontinuations of the study vaccine due to AEs (irrespective of causal 
association to vaccine). 
- 
At the discretion of the team and after statistical analysis of the data, certain 
discontinuations not related to AEs or treatment failure, i.e., related to lost to 
follow-up or withdrawal of consent (irrespective of treatment group). 
- 
Any events of special interest explicitly requested by the regulatory agencies. 
The coordinating Investigator(s) will sign off the final version of the Clinical Study Report. 
A summary of this final version will be provided to the Investigators, the applicable 
regulatory authorities, and the IECs/IRBs, if required by the applicable regulatory 
requirements, within 1 year after the end of the study (LSLV). 
The Sponsor shall have the right to publish study data and information without approval 
from the Investigator(s). If an Investigator wishes to publish information from the study, a 
copy of the manuscript must be provided to the Sponsor for review at least 30 days before 
submission for publication or presentation. Expedited reviews will be arranged for 
abstracts, poster presentations, or other materials. If requested by the Sponsor in writing, 
the Investigator(s) will withhold such publication for up to an additional 30 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity 
or regulatory compliance, the Sponsor will review these issues with the Investigator(s). 
The Sponsor will not mandate modifications to scientific content and does not have the 
right to suppress information. Authorship of publications resulting from this study will be 
based on the guidelines on authorship, such as those described in the Recommendations 
for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, which state that the named authors must have made a significant contribution to 
the design of the study or analysis and interpretation of the data, provided critical review 
of the paper, and given final approval of the final version. 
 REGISTRATION OF CLINICAL STUDIES AND DISCLOSURE OF 
RESULTS 
The Sponsor will register the existence and disclose the results of this clinical study as 
required by law, on Clinicaltrials.gov and the WHO International Clinical Trials Registry 
Platform (ICTRP). 
For the public disclosure of clinical study documentation or data, e.g., the study protocol 
or clinical study report, appropriate measures will be taken to redact such material so as to 

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protect the privacy and confidentiality of the data as applicable to the study subjects in 
agreement with the legislative authority requiring such disclosure. 
 INVESTIGATOR INDEMNITY 
The Sponsor holds and will maintain an adequate insurance policy covering damages 
arising out of FIDEC-sponsored clinical research studies. 
The Sponsor will indemnify the Investigator(s) and hold them harmless for claims related 
to damages arising from the investigation, provided that the study vaccine was 
administered under the Investigator(s) or deputy’s supervision and in strict accordance 
with accepted medical practice and the study protocol. 
The Investigator(s) must notify the Sponsor immediately upon notice of any claims or 
lawsuits. 
 CONFIDENTIALITY 
All study documents are provided by the Sponsor to the Investigator(s) and appointed 
clinical staff in confidence. None of this material may be disclosed to any party not directly 
involved in the study without the Sponsor’s written permission. 
The Investigator(s) must assure that infants’ anonymity will be maintained. The 
Investigator(s) will keep a separate list with at least the initials, the subjects’ study 
numbers, names, addresses, and telephone numbers. The Investigator(s) will maintain this 
for the longest period of time allowed by his/her own institution and, in any case, until 
further communication from the Sponsor. 

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14. 
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