A Phase 2, Observer-blind, Randomized, Controlled Study to Evaluate the Safety and Immunogenicity of Two Formulations of Investigational Meningococcal Groups ACYWX Conjugate Vaccine, Administered to Healthy Malian Children 12-16 Months of Age
Phase: PHASE2
Conditions: Meningitis, Meningococcal
Sponsor: Serum Institute of India Pvt. Ltd.

 
 
 
 
A Phase 2, Observer-blind, Randomized, Controlled Study to Evaluate the 
Safety and Immunogenicity of Two Formulations of Investigational 
Meningococcal Groups ACYWX Conjugate Vaccine, Administered to 
Healthy Malian Children 12-16 Months of Age 
 
 
Sponsored by: 
Serum Institute of India Private Limited (SIIPL) 
PATH 
 
 
 
 
 
 
Confidential 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable Independent Ethics 
Committees or Institutional Review Boards. The contents of this document shall not be 
disclosed to others without written authorization from PATH and SIIPL, unless it is 
necessary to obtain informed consent from potential study volunteers. 
Protocol number 
: ACYWX-02 / CVIA058 
Version 
: Final Version 2.0 
 
Date 
: 11 August 2017 
Amendment 
: 1 
Investigational 
Product 
 
:Meningococcal Groups ACYWX Conjugate Vaccine (NmCV-5) 
CLINICAL TRIAL PROTOCOL 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
LIST OF ABBREVIATIONS ........................................................................................... 5 
PROTOCOL SIGNATURE PAGE .................................................................................. 6 
PARTICIPATING INSTITUTIONS ............................................................................... 7 
STUDY SYNOSPIS ........................................................................................................... 9 
1  INTRODUCTION& BACKGROUND INFORMATION ..................................... 20 
1.1 
PATHOGEN ....................................................................................................................................... 20 
1.2 
BURDEN OF DISEASE ........................................................................................................................ 20 
1.3 
MENINGOCOCCAL VACCINES ........................................................................................................... 21 
1.4 
STUDY VACCINE ............................................................................................................................... 22 
1.5 
RATIONALE FOR STUDY DESIGN ...................................................................................................... 24 
2  HYPOTHESIS, OBJECTIVES AND ENDPOINTS .............................................. 26 
2.1 
STUDY HYPOTHESES ........................................................................................................................ 26 
2.2 
STUDY OBJECTIVES ......................................................................................................................... 26 
2.3 
STUDY ENDPOINTS ........................................................................................................................... 27 
3  STUDY DESIGN ........................................................................................................ 28 
3.1 
METHODOLOGY ............................................................................................................................... 28 
4  STUDY POPULATION ............................................................................................ 32 
4.1 
INCLUSION CRITERIA ....................................................................................................................... 32 
4.2 
EXCLUSION CRITERIA ....................................................................................................................... 32 
4.3 
CRITERIA FOR ADMINISTRATION OF SECOND STUDY VACCINATION ................................................ 33 
4.4 
CRITERIA FOR DELAY OF VACCINATION AND/OR BLOOD SAMPLING ............................................... 34 
5  TREATMENT OF SUBJECTS ................................................................................ 34 
5.1 
DESCRIPTION OF STUDY VACCINES .................................................................................................. 34 
5.2 
PRECAUTIONS TO BE OBSERVED IN ADMINISTRATING STUDY VACCINES .......................................... 36 
5.3 
PREPARATION AND ADMINISTRATION OF THE STUDY VACCINE ........................................................ 36 
5.4 
VACCINE SUPPLY, LABELLING, STORAGE, ACCOUNTABILITY AND DISPOSAL .................................... 37 
6  STUDY PROCEDURES ........................................................................................... 39 
6.1 
GENERAL CONSIDERATIONS ............................................................................................................. 39 
6.2 
COMMUNITY PERMISSION ................................................................................................................ 39 
6.3 
RECRUITMENT ................................................................................................................................. 39 
6.4 
INFORMED CONSENT ........................................................................................................................ 40 
6.5 
RANDOMIZATION AND BLINDING PROCEDURES ............................................................................... 41 
6.6 
DELAY OF MENA VACCINATION ...................................................................................................... 41 
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6.7 
STUDY VISITS ................................................................................................................................... 42 
6.8 
SUBJECT WITHDRAWAL CRITERIA ................................................................................................... 48 
6.9 
PRIOR AND CONCOMITANT THERAPY ............................................................................................... 50 
7  ASSESSMENTS OF IMMUNOGENICITY ........................................................... 51 
7.1 
SPECIFICATION OF THE IMMUNOGENICITY PARAMETERS .................................................................. 51 
7.2 
METHODS FOR PROCESSING, LABELLING AND STORAGE OF SERUM SAMPLES ................................... 52 
7.3 
BIOHAZARD CONTAINMENT ............................................................................................................. 53 
8  ASSESSMENT OF SAFETY .................................................................................... 53 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ......................................................................................... 53 
8.2 
SOLICITED ADVERSE EVENTS ........................................................................................................... 53 
8.3 
UNSOLICITED SAFETY MEASUREMENTS .......................................................................................... 54 
8.4 
SAFETY LABORATORY MEASUREMENTS .......................................................................................... 58 
8.5 
DATA AND SAFETY MONITORING BOARD ........................................................................................ 58 
8.6 
STUDY PAUSE ................................................................................................................................... 58 
9  STATISTICAL CONSIDERATIONS ..................................................................... 59 
9.1 
OVERVIEW AND GENERAL CONSIDERATIONS .................................................................................. 59 
9.2 
RANDOMIZATION SCHEME ............................................................................................................... 59 
9.3 
SAMPLE SIZE AND POWER................................................................................................................. 60 
9.4 
ANALYSIS POPULATIONS ................................................................................................................. 61 
9.5 
ANALYSIS PLAN ............................................................................................................................... 62 
9.6 
ANALYSES SEQUENCE ...................................................................................................................... 66 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 67 
10.1 
PRE-STUDY DOCUMENTATION .................................................................................................... 67 
10.2 
MONITORING ............................................................................................................................... 67 
10.3 
DATA MANAGEMENT AND PROCESSING ...................................................................................... 68 
10.4 
STUDY AND SITE CLOSURE ......................................................................................................... 69 
10.5 
AUDITS AND INSPECTIONS ........................................................................................................... 69 
11 
REGULATORY AND ETHICAL REQUIREMENTS .................................... 71 
11.1 
ETHICS COMMITTEE REVIEW AND COMMUNICATION ................................................................... 71 
11.2 
PROTOCOL AMENDMENTS ........................................................................................................... 71 
11.3 
SUBJECT INFORMATION AND INFORMED CONSENT ..................................................................... 71 
11.4 
SUBJECT CONFIDENTIALITY ........................................................................................................ 72 
11.5 
ETHICAL CONDUCT OF THE STUDY .............................................................................................. 72 
11.6 
MINIMIZING RISK ........................................................................................................................ 73 
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12 
DATA HANDLING AND RECORD KEEPING .............................................. 74 
13 
INSURANCE OF STUDY SUBJECTS ............................................................. 76 
14 
PUBLICATION POLICY & CONFIDENTIALITY ....................................... 77 
15 
REFERENCES ..................................................................................................... 78 
16 
APPENDIX I: WORLD MEDICAL ASSOCIATION. DECLARATION OF 
HELSINKI: ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS (FORTALEZA, 2013) ................................................................ 82 
17 
APPENDIX II: DIVISION OF AIDS (DAIDS) TABLE FOR GRADING 
THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS, VERSION 
2.1. [MARCH 2017]. ........................................................................................................ 88 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE  
Adverse event 
CDC  
Centers for Disease Control and Prevention (US) 
CI 
Confidence interval 
CPPT  
1-cyano-4 pyrrolidinopyridiniumtetrafluoroborate 
CRF 
Case report form 
CRM 
Cross reactive material 
CRO 
Contract research organization 
CVD 
Centre for Vaccine Development, University of Maryland  
CVD-Mali 
Centre pour le Développement des Vaccins du Mali 
DSMB  
Data Safety Monitoring Board 
EPI 
FDA  
Expanded Program on Immunization 
Food and Drug Administration (US) 
FIH  
First in human 
GCP 
Good Clinical Practices 
GLP  
Good Laboratory Practices 
GMTs  
Geometric mean titers 
ICF 
Informed consent form 
IM  
Intramuscular 
IMD 
Invasive meningococcal disease 
IRB 
Institutional review board 
hSBA 
Human complement serum bactericidal activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
NmCV-5 
Neisseria meningitidis Groups ACYWX Conjugate Vaccine 
PHE 
Public Health England 
PI 
Principal Investigator 
PT 
Preferred term 
q.s. 
Quantum satis 
rSBA 
Rabbit complement serum bactericidal activity 
SAE  
Serious adverse event 
SBA  
Serum bactericidal activity 
SIIPL  
Serum Institute of India Private Limited. 
SOC 
System organ class 
SOP  
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TT  
Tetanus toxoid 
WHO  
World Health Organization 
WHO DD 
World Health Organization Drug Dictionary 
 
 
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PARTICIPATING INSTITUTIONS 
Regulatory Sponsor 
Serum Institute of India Private Limited (SIIPL) 
212/2 Hadapsaar, Pune – 411028, India 
Phone: +91 206 993 900 ext. 2384  
Fax: +91 206 993 945 
Collaborating Sponsor 
PATH 
2201 Westlake Avenue, Suite 200 
Seattle, WA 98121 USA 
Clinical Trial Site 
Centre pour le Développement des Vaccins du Mali (CVD-
Mali) 
CNAM, Ex-Institut Marchoux, Ministère de la Santé et de 
l’Hygiène Publique, BP251 Bamako, Mali 
Principal Investigator 
and Sub-Investigators 
Samba Sow, MD, MSc 
Centre pour le Développement des Vaccins du Mali (CVD-Mali) 
 
Milagritos D. Tapia, MD 
Associate Professor Department of Pediatrics, Division of 
Pediatric Infectious Diseases Center for Vaccine Development 
Institute for Global Health 
University of Maryland School of Medicine 685 W. Baltimore St, 
Rm 480 Baltimore, MD 21201  
phone: (410) 706-5328  
fax: (410) 706-6205 
email: mtapia@som.umaryland.edu 
 
Fadima Cheick Haidara, MD 
Fatoumata Diallo, MD 
Flanon Coulibaly, MD 
Awa Traoré, PharmD 
Mamoudou Kodio, PharmD 
Moussa Doumbia, MD 
Centre pour le Développement des Vaccins du Mali (CVD-Mali) 
Ethics Committee(s) 
Research Ethics Committee of the Faculté de Médecine, de 
Pharmacie et d’Odonto-Stomatologie (FMPOS), Bamako, Mali. 
University of Maryland Institutional Review Board, Baltimore, 
USA. 
Research Laboratory 
(Primary 
immunogenicity) 
Vaccine Evaluation Unit, 
National Infection Service 
Public Health England, 
Public Health Laboratory, Manchester, 
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Manchester Medical Microbiology Partnership, 
2nd Floor, Clinical Sciences Building II, 
Manchester Royal Infirmary, 
Oxford Road, 
Manchester, 
M13 9WL, 
UK. 
Medical Monitoring 
Prasad Kulkarni, MD 
SIIPL Medical Director 
Amol Chaudhari, MD 
SIIPL Medical Officer 
Medical Advice 
Simonetta Viviani, MD 
PATH Medical Consultant 
Abdi Naficy, MD 
PATH Medical Officer 
Biostatistics 
Yuxiao Tang, PhD 
PATH Biostatistician 
Clinical Operations 
Lionel Martellet, MA 
PATH Clinical Operations Manager 
Contract Research 
Organization 
PAREXEL International (India) Private Limited 
11th Floor, Bldg No. 20 
Sundew Properties SEZ Pvt Ltd Mindspace 
Madhapur 
Hyderabad, AP 
India - 500081 
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STUDY SYNOSPIS 
Title of the Study: 
A Phase 2, Observer-blind, Randomized, Controlled Study to Evaluate the Safety and 
Immunogenicity of Two Formulations of Serum Institute of India Private Limited 
Investigational Meningococcal Groups ACYWX Conjugate Vaccine, Administered  to 
Healthy Malian Children 12-16 Months of Age 
Phase of Development: Phase 2 
Name of the Study Vaccine: 
Meningococcal Groups ACYWX Conjugate Vaccine (NmCV-5; Serum Institute of India 
Private Limited) 
Indication: 
Prophylaxis against Neisseria meningitidis infection caused by serogroups A,C,Y, W, & X. 
Protocol No.: ACYWX-002 / CVIA058 
Study Rationale: 
Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis worldwide, 
capable of causing outbreaks and epidemics of invasive disease. Meningococcal disease
causes high rates of morbidity and mortality even among patients who receive early antibiotic 
treatment. 
Based on antigenic differences in their capsular polysaccharide, 13 serogroups of N. 
meningitidis have been identified. Virtually all disease-associated isolates are encapsulated, 
with six serogroups (A, B, C, W, Y and X) being responsible for the large majority of invasive 
meningococcal infections worldwide. 
The best option for the control of meningococcal disease is the use of effective vaccines that 
would include all six of the most common serogroups responsible for invasive disease.  
Several combined meningococcal conjugate vaccines against serogroups A, C, W and Y 
(Menactra®, Menveo® and Nimenrix®) containing capsular oligosaccharides conjugated to a 
protein carrier have been developed and successfully licensed. They are immunogenic across 
all age groups, including young children, confer long lasting protection and are able to prime 
for immunological memory. 
 
Recently, two meningococcal vaccines against invasive meningococcal disease caused by 
Neisseria meningitidis group B (Bexsero® and Trumenba®) were licensed and recommended 
in some countries; however, information about their effectiveness against diverse serogroup 
B strains and the duration of protection are limited. 
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Currently, there is no licensed vaccine that is protective against Neisseria meningitidis group 
X, which has caused multiple recent outbreaks in Africa and suggests a hyperendemicity and 
high capacity for localised epidemics.  
Following the successful development of a meningococcal group A conjugate vaccine 
(MenAfriVac®) and its introduction via mass vaccination campaigns in 15 African countries 
with the highest burden of disease, Serum Institute of India Private Limited (SIIPL) has 
developed a candidate pentavalent conjugate vaccine composed of Neisseria meningitidis 
groups A, C, Y, W and X capsular polysaccharides (NmCV-5). The individual 
polysaccharides are  conjugated to protein carriers, CRM197 or tetanus toxoid, and formulated 
with or without aluminum phosphate as an adjuvant.  
The vaccine is intended for the prevention of invasive meningococcal diseases caused by 
vaccine serogroups in countries with high incidence of the disease, such as the countries in 
the African meningitis belt. The target population includes children and adults covering an 
age group of 9 months and above. 
The first-in-human Phase 1 study was initiated among 60 healthy adults in the USA to 
evaluate safety and immunogenicity of both the adjuvanted and non-adjuvanted formulations 
of the NmCV-5 with respect to Menactra, a quadrivalent meningococcal conjugate vaccine 
(n=20 in each group). Following analysis of interim safety data at 28 days after vaccination, 
no safety issues were identified. The pattern of solicited reactions and adverse events among 
adjuvanted and non-adjuvanted NmCV-5 recipients were similar to the control group 
receiving Menactra. Immunogenicity responses in the first 20 subjects receiving NmCV-5 
were also found promising with rising titers for all five serogroups in both adjuvanted and 
non-adjuvanted formulations (n=10 in each group). This satisfactory safety and 
immunogenicity profile paves the way to the Phase 2 study in Malian toddlers. 
This study is designed to evaluate safety and immunogenicity of the non-adjuvanted and 
adjuvanted formulations of the investigational NmCV-5 vaccine in healthy children 12-16 
months of age, in comparison with the licensed quadrivalent meningococcal conjugate 
vaccine (MenACWY-D; Menactra®). Menactra has been selected as an active control given 
the large safety database accumulated since the vaccine was introduced in the US in 2005, 
prequalified by WHO and progressively introduced in other countries. Both vaccines will be 
administered according to a 0, 3 month schedule to meningococcal vaccine-naïve healthy 
subjects.  
The ability of NmCV-5 to elicit functional bactericidal antibodies against each serogroup will 
be measured with the serum bactericidal activity assay using rabbit complement as the 
exogenous complement source (rSBA). 
Additional assays to further characterize the immune response to NmCV-5 or MenACWY-D 
vaccines (e.g. serum bactericidal activity assay with human complement [hSBA]) may be 
performed. 
Study Hypothesis: 
The non-adjuvanted and adjuvanted formulations of the investigational NmCV-5 vaccine are 
safe and well tolerated and induce robust immune responses against all of the five vaccine 
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serogroups at 1 month after a 2-dose vaccination series in healthy children 12-16 months of 
age. 
Primary Objective: 
1. To assess the reactogenicity of non-adjuvanted and adjuvanted formulations of NmCV-5
vaccine in comparison with the licensed MenACWY-D vaccine, as measured by the 
percentage of subjects with at least one severe solicited AE reported within 7 days after 
any study vaccination. 
Secondary Immunogenicity Objectives: 
1. To assess immunogenicity of non-adjuvanted formulation of NmCV-5 vaccine in 
comparison with MenACWY-D vaccine, as measured by rSBA against serogroups A, C, 
W, Y and X at 1 month after the second vaccination. 
2. To assess immunogenicity of adjuvanted formulation of NmCV-5 vaccine in comparison 
with non-adjuvanted formulation of NmCV-5 vaccine, as measured by rSBA against 
serogroups A, C, W, Y and X, at 1 month after the second vaccination. 
3. To assess immune response elicited by non-adjuvanted and adjuvanted formulations of 
NmCV-5 vaccine and MenACWY-D vaccine at 1 and 3 months after the first vaccination.
Secondary Safety Objective: 
1. To evaluate the safety and reactogenicity of adjuvanted and non-adjuvanted formulations 
of NmCV-5 vaccine in healthy children, when compared to MenACWY-D. 
Exploratory objective: 
1. To assess immunogenicity of adjuvanted and non-adjuvanted formulations of NmCV-5
vaccine and MenACWY-D vaccine, as measured by hSBA against serogroups A, C, W, 
Y and X at baseline, 1 month after the first vaccination and 1 month after the second 
vaccination (in a subset of subjects) 
2. To further assess immunogenicity of adjuvanted and non-adjuvanted formulations of 
NmCV-5 vaccine and MenACWY-D vaccine, as measured by rSBA against serogroups 
A, C, W, Y, and X at baseline, 1 month and 3 months after the first vaccination and 1 
month after the second vaccination. 
Study Design and Methodology: 
Design: Phase 2, randomized (2:2:1), controlled, observer-blind, single-center study in 
healthy children 12 to 16 months of age with three study groups. 
Duration of the study: The study duration is approximately 6 months for each subject. 
Vaccination schedule: 0, 3 months. 
Study groups: 
- 
NmCV-5_non-adjuvanted group: approximately 150 subjects receiving the non-
adjuvanted formulation of NmCV-5 vaccine at Visit Day 0 and Visit Day 84. 
- 
NmCV-5_adjuvanted group: approximately 150 subjects receiving the adjuvanted 
formulation of NmCV-5 vaccine at Visit Day 0 and Visit Day 84. 
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- 
ACWY-D group: approximately 75 subjects receiving the licensed MenACWY-D 
(Menactra®) vaccine at Visit Day 0 and Visit Day 84. 
Randomization: At Visit Day 0, prior to the study vaccination, subjects will be randomized 
into the three study groups according to a 2:2:1 ratio.  
Blinding: Observer-blind study. 
Data collection: Electronic Case Reporting Form (eCRF). 
 
Table A:  Study design 
Note: BS – blood sample; ACWY-D - Menactra®. 
Blood sample schedule: Four blood samples (approximately 5 mL each) at Visit 1 (Day 0, 
first vaccination), Visit 3 (Day 28), Visit 4 (Day 84, second vaccination) and Visit 6 (28 days 
after second vaccination). 
Study visits: Seven visits at Day 0, Day 7, Day 28, Day 84, Day 91 (7 days post Dose 2), Day 
112 (28 days post Dose 2) and Day 168 (84 days post Dose 2). 
Solicited AEs: occurring during 7 days following each study vaccination will be assessed 
daily by site staff and recorded in the home visit worksheets and the CRF at Visit 2 and Visit 
5. 
Unsolicited AEs: occurring within 28 days after each study vaccination will be collected 
weekly by site staff during home and site visits. 
AEs leading to study withdrawal and SAEs: will be collected during the entire study period. 
These data will be captured through the home visit worksheets, by interviewing the subjects’ 
parents / guardians during the home visits, the planned and unplanned site visits, and by 
review of available medical records. 
Written agreement to delay the EPI MenAfriVac dose scheduled at 9 months of age: Prior to 
written informed consent, subject’s parents/guardians may be asked to sign a pre-screening 
agreement as early as 9 months of age in order to delay the EPI MenAfriVac dose until they 
can be considered for enrolment in the trial (trial subjects must be at least 12 months of age, 
have not received any meningococcal vaccines and have not received any vaccinations in the 
past 28 days). 
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Written informed consent will be obtained from the subject’s parents / guardians before 
conducting any study-specific procedures. 
After 
signing 
informed 
consent, 
a 
review 
of 
medical 
history 
and 
prior 
medications/vaccination, a physical examination, and confirmation of subject eligibility, 
subjects will be enrolled into the study. 
Number of Subjects: 
A total of approximately 375 subjects are planned for enrolment into this study. This would 
yield 150 subjects for each of the NmCV-5 groups (non-adjuvanted and adjuvanted) and 75 
subjects for the MenACWY-D group. Assuming a 10% drop-out rate, this should provide 
approximately 135 or 67 evaluable subjects per respective study group. 
Study Population and Subject Characteristics: Subjects will be included in the study if 
they meet all specified eligibility criteria. 
Inclusion Criteria: In order to participate in this study, all subjects must meet ALL of the
inclusion criteria described. 
1. Male and female children between 12 months and 16 months old inclusive (minimum 365 
days of age and maximum 16 months plus 29 days of age);  
2. For whom parent(s)/legal guardian(s) have given written informed consent after the nature 
of the study has been explained according to local regulatory requirements; 
3. Who the investigator believes that their parent(s)/ guardian(s) will be available for all the 
subject visits and would comply with the requirements of the protocol (e.g., timely 
reporting of adverse events, availability for study site visits and home visits); 
4. Individuals in good health as determined by the outcome of medical history, physical 
examination and clinical judgment of the investigator. 
5. Individuals who completed their local infant EPI schedule through 9 months of age 
(except MenAfriVac dose). A birth dose of OPV is not required. 
Exclusion Criteria: In order to participate in this study, all subjects must meet NONE of the 
exclusion criteria described. 
1. History of any meningococcal vaccine administration. 
2. Current or previous, confirmed or suspected disease caused by N. meningitidis.   
3. Household contact with and/or intimate exposure to an individual with any laboratory 
confirmed N. meningitidis infection within 60 days of enrolment. 
4. History of severe allergic reactions after previous vaccinations or hypersensitivity to any 
study vaccine component including tetanus, diphtheria and diphtheria toxoid (CRM197). 
5. Acute or chronic, clinically significant pulmonary, cardiovascular, metabolic, 
neurological, hepatic, or renal functional abnormality, as determined by medical history 
or physical examination.  
6. Any confirmed or suspected condition with impaired/altered function of immune system 
(immunodeficient or autoimmune conditions). 
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7. Have any bleeding disorder which is considered as a contraindication to intramuscular 
injection or blood draw. 
8. Severe acute malnutrition. 
9. A family history of congenital or hereditary immunodeficiency. 
10. History of either hepatitis B or hepatitis C virus infection or human immunodeficiency 
virus infection.  
11. Major congenital defects.  
12. Chronic administration (defined as more than 14 days) of immunosuppressants or other 
immune-modifying drugs within three months prior to the study vaccination or planned 
use throughout the study period. (For corticosteroids, this means prednisone, or 
equivalent, ≥ 0.5 mg/kg per day. Inhaled, intranasal and topical steroids are allowed). 
13. Administration of blood, blood products and/or plasma derivatives or any parenteral 
immunoglobulin preparation in the past 3 months or planned use throughout the study 
period. 
14. Administration of any vaccine within 28 days prior to enrolment in the study or planned 
administration of any vaccine within 14 days before or after any study vaccination. 
15. Use of any investigational or non-registered drug or vaccine within 30 days prior to the 
administration of study vaccines or planned during the study. 
16. Malaria infection as confirmed by a Rapid Diagnostic Test. 
Note: Subjects positive at screening may be treated for malaria as per national guidelines,
and if subject remains eligible, vaccinated no earlier than five days after completing 
treatment.  
17. Individuals who are close family members of individuals conducting this study. 
18. Have experienced a moderate or severe acute infection and/or fever (defined as 
temperature ≥ 37.5°C) within 3 days prior to enrolment. 
19. Have received systemic antibiotic treatment within 3 days prior to enrolment. 
20. Non-residence in the study area or intent to move out within six months. 
21. Any condition which, in the opinion of the investigator, might pose additional risk to the 
subject due to participation in the study. 
Study Vaccines and Control Vaccine Composition: 
The NmCV-5 investigational vaccine is a fixed-combination available as the lyophilized 
powder containing meningococcal groups A and X polysaccharides conjugated to tetanus 
toxoid and meningococcal groups C, W and Y polysaccharides conjugated to CRM197 protein. 
The vaccine will be reconstituted with either saline alone (non-adjuvanted formulation) or 
saline containing aluminum phosphate at 125 mcg Al3+ /dose (adjuvanted formulation) just 
prior to administration. After reconstitution, the NmCV-5 vaccine formulations to be used 
will have the following composition per 0.5 mL of injectable solution 
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Table B: 
Composition 
of 
reconstituted 
non-adjuvanted 
and 
adjuvanted 
formulations of NmCV-5 vaccine (per 0.5 mL dose) 
Vaccine component 
Non-adjuvanted 
NmCV-5 (per 0.5 mL 
dose) 
Adjuvanted NmCV-5
(per 0.5 mL dose) 
Meningococcal A polysaccharide1 
5 g 
5 g 
Meningococcal C polysaccharide2 
5 g 
5 g 
Meningococcal Y polysaccharide2 
5 g 
5 g 
Meningococcal W polysaccharide2
5 g 
5 g 
Meningococcal X polysaccharide1 
5 g 
5 g 
Sucrose 
2.42 mg 
2.42 mg 
Sodium Citrate 
0.40 mg 
0.40 mg 
TRIS (Trometamol) 
0.098 mg 
0.098 mg 
Aluminum phosphate Al3+ 
 
125 g /dose 
0.9% Sodium Chloride 
q. s.  
q. s.  
Tetanus Toxoid 
7.8 to 33.4 µg 
7.8 to 33.4 µg. 
CRM197 
11.7 to 50.1 µg 
11.7 to 50.1 µg 
Note: 1 each polysaccharide conjugated to Tetanus Toxoid; 2 each polysaccharide conjugated to CRM197; q.s. -Quantum satis
The licensed MenACWY-D polysaccharide conjugate vaccine (Menactra®, manufactured by 
Sanofi Pasteur Inc.) is supplied as a single 0.5 mL dose formulated in sodium phosphate 
buffered isotonic sodium chloride solution to contain 4 μg each of meningococcal A, C, Y, 
and W polysaccharides conjugated to approximately 48 μg of diphtheria toxoid protein carrier 
(Table C). No preservative or adjuvant is added during manufacture. Each 0.5 mL dose may 
contain residual amounts of formaldehyde of less than 2.66 µg. 
Table C: 
Composition of Menactra® (per 0.5 mL dose) 
Vaccine component 
Per Dose of 0.5 mL 
Meningococcal group A polysaccharide 
4 g 
Meningococcal group C polysaccharide 
4 g 
Meningococcal group Y polysaccharide 
4 g 
Meningococcal group W polysaccharide 
4 g 
Diphtheria toxoid protein total 
48 g 
Sodium phosphate 
0.7 mg 
Sodium chloride 
4.35 mg 
 
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Endpoints: 
Primary reactogenicity endpoint: 
 Percentage of subjects with at least one severe solicited AE* within 7 days after any study 
vaccination (Days 0-6 and Days 84-90) 
*Solicited AEs include tenderness, swelling/induration, irritability, drowsiness, decrease eating, vomiting, 
and fever. 
Secondary immunogenicity endpoints: 
 Percentage of subjects with rSBA titer ≥ 8 against serogroups A, C, W, Y and X at Visits 
Day 0, Day 28, Day 84 and Day 112. 
 Percentage of subjects with rSBA titer ≥ 128 against serogroups A, C, W, Y and X at 
Visits Day 0, Day 28, Day 84 and Day 112. 
 Percentage of subjects with fourfold rise in rSBA titers against serogroups A, C, W, Y 
and X at Visits Day 28 and Day 112. 
o For subjects with a pre-vaccination rSBA titer < 8, a post-vaccination titer of ≥
32; 
o For subjects with a pre-vaccination rSBA titer ≥ 8, an increase in rSBA titer of at 
least 4 times the pre-vaccination titer. 
 rSBA GMT for serogroups A, C, W, Y and X at Visits Day 0, Day 28, Day 84 and Day 
112. 
Secondary safety endpoints: 
 Solicited local and systemic AEs reported during the 7 days after each vaccination (Days 
0-6 and Days 84-90); 
 Unsolicited AEs reported during 28 days after each vaccination (Days 0-27 and Days 84-
111);  
 AEs leading to premature withdrawal during the entire study period; 
 SAEs reported during the entire study period. 
Exploratory immunogenicity endpoints: 
 Percentage of subjects with hSBA titer ≥ 8 against serogroups A, C, W, Y and X at Visits 
Day 0, Day 28 and Day 112 (in a subset of subjects). 
 Percentage of subjects with hSBA seroresponse against serogroups A, C, W, Y and X at 
Visits Day 28 and Day 112 (in a subset of subjects), defined as: 
o for subjects with baseline hSBA titer < 4, post vaccination hSBA titer ≥ 8;  
o for subjects with baseline hSBA titer ≥ 4, an increase of at least four times the pre-
vaccination hSBA. 
 hSBA GMTs for serogroups A, C, W, Y and X at Visits Day 0, Day 28 and Day 112 (in 
a subset of subjects). 
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 Percentage of subjects with rSBA titer ≥4, ≥16, ≥ 32, and ≥ 64 against serogroups A, C, 
W, Y and X at Visits Day 0, Day 28, Day 84 and Day 112 
 Percentage of subjects with a fourfold increase in rSBA titers against serogroups A, C, 
W, Y and X at Visits Day 28 and Day 112 with the following criteria: 
o For subjects with a pre-vaccination rSBA titer < 4, a post-vaccination titer of ≥
16; 
o For subjects with a pre-vaccination rSBA titer ≥ 4, a post-vaccination titer of at 
least 4 times the pre-vaccination titer. 
 Among subjects with a pre-vaccination rSBA titer ≥4, ≥8, ≥16, ≥ 32, ≥ 64, and ≥ 128, 
percentage of subjects with a post-vaccination titer of at least 4 times the pre-vaccination 
titer at Visits Day 28 and Day 112 
Statistical Consideration: 
With 150 enrolled subjects per NmCV-5 arm and 75 subjects in the MenACWY-D arm, the 
study has a power of 80% to detect a 15.4% difference in proportion of subjects with severe 
solicited AEs reported within 7 days after any study vaccination between each NmCV-5
group and the MenACWY-D group, assuming a rate of severe reactions in the MenACWY-
D group of 5%, a drop-out rate of 10%, and alpha of 0.05.  
Power to show comparability of immune response in terms of the percentage of subjects with 
antibody titer greater than or equal to the cut-off level, based on various group sizes and equal 
underlying expected underlying percentages, was done using one-sided Miettinen and 
Nurminen test [21] and is provided in Table D.  
Assuming the expected proportion of subjects with antibody response greater than or equal 
to the cut-off (e.g. rSBA titer ≥ 8) is at least 95% for each of the vaccine serogroups in the 
NmCV-5 non-adjuvanted and MenACWY-D groups, then with 135 / 67 evaluable subjects 
per group, the study has power of 86% to demonstrate that the lower limit (LL) of 95% 
confidence interval (CI) for difference between the non-adjuvanted NmCV-5 group and 
MenACWY-D group is above -10% (commonly accepted non-inferiority margin)  for each 
serogroup. With the same assumptions, the overall power to demonstrate that the lower limit 
(LL) of 95% confidence interval (CI) for difference between the non-adjuvanted NmCV-5 
group and MenACWY-D group is above -10% for all serogroups would be at 46%. 
 
Table D: Power to show comparability of immune response in terms of the percentage 
of subjects with antibody titer greater than or equal to the cut-off level, based 
on various group sizes and equal true underlying percentages 
Expected percentage 
of subjects who 
achieve titers ≥ cut-
off 
Number of 
evaluable 
subjects per 
group 
Power to demonstrate 
that the LL of 95% CI 
of the difference 
between groups is > -
10%  for an individual 
serogroup 
Overall Power to 
demonstrate that the LL of 
95% CI of the difference 
between groups is > -10%  
for all serogroups 
85% 
120 vs. 60 
47% 
2% 
135 vs. 67 
52% 
4% 
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150 vs. 75 
56% 
5% 
90% 
120 vs. 60 
61% 
8% 
135 vs. 67 
65% 
12% 
150 vs. 75 
70% 
17% 
95% 
120 vs. 60 
81% 
36% 
135 vs. 67 
86% 
46% 
150 vs. 75 
89% 
56% 
Power to show that the ratio of rSBA GMT in the adjuvanted NmCV-5 group to that in the 
non-adjuvanted NmCV-5 group is at least 2 was calculated using a two-sample t-test 
according to different expected rSBA GMTs in the non-adjuvanted NmCV-5 group and 
assumed standard deviations (SD) of log2-transferred rSBA titers and is provided in Table E.
Table E: Power to detect at least a 2-fold increase of rSBA GMTs after a 2-dose series 
with the adjuvanted NmCV-5 vs. non-adjuvanted NmCV-5, based on various 
group sizes and different assumed SD of log 2 rSBA titers 
Expected rSBA 
GMTs in non-
adjuvanted NmCV-5 
group at 1 month 
post-Dose 2 
Assumed 
SD of 
log2 
rSBA 
titers 
Number of 
evaluable 
subjects per 
group 
Power to detect at 
least a 2-fold rSBA 
GMTs in adjuvanted 
NmCV-5 vs non-
adjuvanted NmCV-5  
for an individual 
serogroup 
Overall power to 
detect at least a 2-
fold rSBA GMTs in 
adjuvanted NmCV-5 
vs non-adjuvanted 
NmCV-5  for all 
serogroups 
500 to 1500 for 
various 
serogroups 
1.5 
150 vs. 150 
>99% 
> 99% 
135 vs. 135 
>99% 
> 99% 
120 vs. 120 
>99% 
> 99% 
2.0 
150 vs. 150 
99% 
95% 
135 vs. 135 
98% 
92% 
120 vs. 120 
97% 
86% 
2.5 
150 vs. 150 
93% 
70% 
135 vs. 135 
91% 
61% 
120 vs. 120 
87% 
50% 
3.0 
150 vs. 150 
82% 
37% 
135 vs. 135 
78% 
29% 
120 vs. 120 
73% 
21% 
3.5 
150 vs. 150 
69% 
16% 
135 vs. 135 
65% 
11% 
120 vs. 120 
60% 
8% 
Assuming the true standard deviation of log2 rSBA titers is below than or equal to 2.5 for 
each of the five vaccine serogroups, with 135 evaluable subjects per group, the study has a 
power of 91% to detect a 2-fold rSBA GMT increase in the adjuvanted NmCV-5 vs non-
adjuvanted NmCV-5 for each serogroup. With the same assumptions, the overall power to 
detect a 2-fold rSBA GMT increase in the adjuvanted NmCV-5 vs non-adjuvanted NmCV-5
for all serogroups would be at least 61%.   
Due to the hypothesis generating nature of this study, all statistical comparisons for 
reactogenicity, safety, and immunogenicity endpoints will be carried out without an 
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adjustment for multiple comparisons. All statistical tests except for non-inferiority will be 
two-sided with a type I error rate of 5%. The 95% confidence interval will be presented for 
estimations, as appropriate.   
Analyses Sequence: 
 An interim analysis including safety, reactogenicity and immunogenicity results 
(rSBA) at 1 month after the first vaccination will be performed. Individual listings 
will not be generated at this point and any access to subject-level information 
about study groups will be masked. 
 The final safety, reactogenicity and immunogenicity analysis (rSBA) will be 
performed at 3 months after the second vaccination. 
 
Data and Safety Monitoring Board: 
An independent Data and Safety Monitoring Board (DSMB) will be set up for periodic review 
of safety data during the study conduct. The composition and responsibilities of DSMB 
members are presented in the DSMB charter. 
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1 
INTRODUCTION& BACKGROUND INFORMATION 
1.1 
Pathogen 
Among several different bacteria that can cause meningitis, Neisseria meningitidis (a gram-
negative aerobic capsular bacterium, also referred as meningococcus), is known to cause 
large epidemics. Neisseria meningitidis otherwise a harmless commensal of human 
nasopharynx, under appropriate conditions is responsible for invasive meningococcal 
disease (IMD)–a spectrum of diseases that includes most commonly meningitis and 
fulminant septicaemia. Pneumonia, myocarditis, or pericarditis may also occur in IMD, 
albeit less commonly.1, 2 
Meningococci are classified into serogroups based on their capsular polysaccharides. Six 
of these serogroups viz. A, B, C, W, X, and Y are known to cause the majority of IMD 
cases.1 
These serogroups have the potential to cause large epidemics but this potential varies in 
each serogroup with respect to time and geographic location.3 Serogroup A for example 
has been the most important cause of meningitis in sub-Saharan Africa and its outbreaks 
are commonest during December to June. On the other hand, most IMD cases in Europe 
and USA are caused by serogroup B, followed by C and Y (Figure 2). Most recently, cases 
of serogroup X are on the rise, especially in Africa.1, 4 
 
Figure 1: Global serogroup distribution of invasive meningococcal disease.1 
Apart from serogroup variability, IMD also shows variation with respect to age groups, 
with peak incidence occuring among children less than 2 years of age and adolescents 
between 16 and 21 years. During epidemics, disease rates show a shift towards older age 
groups.1 
1.2 
Burden of Disease 
Meningococcal disease commonly alternates between an endemic situation of few isolated 
cases and fatal unpredictable epidemics in the African meningitis belt (a large area that 
spans sub-Saharan Africa from Senegal in the west to Ethiopia in the east).5 This region 
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has the highest annual incidence of IMD and is plagued with problem of recuring epidemics 
of large proportions. The incidence has been known to reach rates of up to 1000 cases per 
100,000 people or 1% of the entire population.3 This was seen during the large epidemics 
of 1996 and 2000 through 2001. In 1996 and 1997 there were > 250,000 cases, an estimated 
25,000 deaths, and disability in 50,000 people. It is believed to be the largest epidemic in 
history. Similarly in the 2006 to 2007 epidemic season, there were 53,438 suspected cases 
and 3,816 deaths were reported to WHO from 15 African countries.4 
Outside of the African meningitis belt, the incidence of IMD is significantly low, although 
there have been reports of outbreaks. In such areas any substantial increase in IMD cases 
above that which is expected at that place and time is considered as outbreak.3, 4 
Respiratory droplets are the main source of meningococcal transmission and occurs most 
commonly due to close contact with an asymptomatic carrier.6 Symptoms of IMD mainly 
include fever, loss of appetite, lethargy, vomiting, diarrhoea, photophobia and convulsions, 
and usually manifest 1 to 14 days after acquiring the pathogen.2 
Meningococcal meningitis and fulminant septicemia—the two most serious presentations 
of IMD—may prove fatal in 50% of cases if untreated within 24 to 48 hours. Even when 
adequately treated, the mortality is close to 10%. Among the survivors of meningitis, it may 
cause in 10 to 20% of cases, severe permanent brain damage and sequelae such as mental 
retardation, deafness, epilepsy, or other neurological disorders.1, 4 
1.3 
Meningococcal vaccines 
The majority of the meningococcal epidemics in the African meningitis belt over the years 
have been caused by serogroup A with incidence rates as high as 500 cases per 100,000 
population. In an effort to overcome this problem in a cost-effective way, the Meningitis 
Vaccine Project (MVP), a partnership between the WHO and PATH, was established with 
funding from the Bill and Melinda Gates Foundation.7 The resultant product was a 
monovalent vaccine against serogroup A, MenAfriVac®, manufactured by the Serum 
Institute of India Private Limited and developed specifically to tackle the meningitis A 
(MenA) epidemics in the African meningtis belt.8 
MenAfriVac® is a lyophilized vaccine containing purified meningococcal A polysaccharide 
conjugated to tetanus toxoid.1 The vaccine underwent an elaborate clinical development 
process that included a Phase 1 study in India, followed by seven Phase 2 and 3 studies 
conducted in India and the African meningitis belt.9, 10 
The vaccine was subsequently licensed in 2009 and was prequlaified by WHO in 2010. 
Since then it has been widely used in over 294 million individuals of 1 to 29 years of age 
and has been found to be highly effective and safe.3, 8, 11-14 
Use of MenAfriVac® has been highly effective at preventing IMD of serogroup A, reducing 
it by nearly 100%, eliminating outbreaks as well as decreasing carrier states.11, 15 It also 
reduced the incidence in those too young or too old to have been vaccinated, demonstrating 
an additional indirect herd effect. In the data generated for two years since its use started in 
three African countries viz. Burkina Faso, Mali and Niger, there have been no cases of 
MenA disease reported in the vaccinated population.8 As MenAfriVac has continued to be 
rolled out across the meningitis belt until 2017, Men A cases have continued to remain 
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extremely low with a handful of breakthrough cases reported in recent years (2015-2017).16, 
17 
The best option for the control of meningococcal disease globally is the use of effective 
vaccines that would include all six of the most common serogroups responsible for invasive 
disease.  
Several combined meningococcal conjugate vaccines against serogroups A, C, W and Y 
(Menactra®, Menveo® and Nimenrix®) containing capsular oligosaccharides conjugated to 
a protein carrier have been developed and successfully licensed.18-20 They are immunogenic 
across all age groups, including young children, confer long lasting protection and are able 
to prime for immunological memory. 
Recently, two meningococcal vaccines against invasive meningococcal disease caused by 
Neisseria meningitidis group B (Bexsero® and Trumenba®) were licensed and 
recommended in some countries; however, information about their effectiveness against 
diverse serogroup B strains and the duration of protection are limited. 
The widespread use of conjugate meningococcal vaccines, especially in higly endemic 
settings and at a population level has reduced the burden of IMD drastically since the pre-
vaccination era. In spite of this, the use of conjugate vaccines is still a big hurdle in the 
developing world due to its high cost. Unlike the Men A vaccine, which was specifically 
developed for the meningitis belt in Sub-Saharan Africa and hence was very cost effective, 
the tetravalent vaccine still remains elusive for that kind of application in this region.21, 22 
1.4 
Study vaccine 
Currently, there is no vaccine available against serogroup X of N. meningitidis. This 
bacterium has caused many outbreaks in Africa and Europe in recent past. The serogroup 
X has been responsible for outbreaks between 2006 and 2010 in Kenya, Niger, Togo, 
Uganda, and Burkina Faso, the latter with at least 1,300 cases of serogroup X meningitis 
among the 6,732 reported annual cases.23 
As a result, SIIPL has developed the candidate vaccine NmCV-5, which is a polyvalent 
conjugate vaccine composed of serogroups A, C, Y, W, and X of Neisseria meningitidis 
capsular polysaccharides, conjugated to protein carriers, CRM and tetanus toxoid, with 
aluminum phosphate as an adjuvant. It is intended for the prevention of meningitis and/or 
septicemia caused by serogroups A, C, Y, W, and X N. meningitidis in countries where the 
disease is endemic and causes large epidemics such as the countries in the African 
meningitis belt. The target population consists of infants and children and adults aged 9 
months and above. 
1.4.1 Summary of Nonclinical Studies 
The summary of completed non-clinical studies is presented in Table 1.4.1-1. The 
detailed description of the toxicology and immunogenicity results are included in the 
latest version of the Investigator Brochure. 
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Table 1.4.1-1:  
Summary of non-clinical studies 
There are no toxicological or other findings indicating any significant safety issues for the 
NmCV-5 vaccine formulations. The completed studies showed that the NmCV-5 
pentavalent vaccine formulation produced a strong immune response against all five 
serogroups. The addition of adjuvant resulted in an increase in immune response for all five 
serogroups with a statistically significant increase for three serogroups.  
The toxicology data with NmCV-5 formulations, and the nonclinical experience with the 
component vaccines, support the clinical testing of the proposed formulations. 
1.4.2 Clinical Studies 
A first-in-human (FIH) Phase 1 clinical study was designed and initiated in healthy US 
adults to evaluate the safety and immunogenicity of the study vaccine. Two formulations 
Study Title 
Study Site 
Study Type & 
Compliance 
Animal 
Model 
A 5-week subcutaneous dose-ranging 
immunogenicity study of monovalent 
meningococcal serogroup X polysaccharide 
conjugate (MenX-TT) with and without 
aluminum phosphate adjuvant in mice 
SIIPL 
Immunogenicity 
Non-GLP 
Swiss albino 
mice 
A 7-week subcutaneous immunogenicity 
study of the MenX-TT component in the 
NmCV-5 presentation with and without 
aluminum phosphate adjuvant in mice. 
National Institute 
for Biological 
Standards and 
Control, London 
(NIBSC), United 
Kingdom 
Immunogenicity 
Non-GLP 
BALB/c 
mice 
A 5-week intramuscular immunogenicity 
study of candidate SIIPL NmCV-5 vaccine 
formulations in comparison to commercial 
vaccine in rabbits 
SIIPL 
Immunogenicity 
Non-GLP 
New Zealand 
white rabbits 
A 5-week intramuscular dose-ranging 
immunogenicity study of pentavalent SIIPL 
NmCV-5 vaccine (tox formulation) with and 
without aluminum phosphate adjuvant in 
rabbits 
SIIPL 
Immunogenicity 
Non-GLP 
New Zealand 
white rabbits  
A 7-week intramuscular toxicity study of 
[pentavalent] meningococcal (A,C,Y,W,X) 
polysaccharide conjugate vaccine (freeze-
dried) in New Zealand white rabbits with a 
6-week recovery 
MPI Research, Inc, 
54943 North Main 
Street Mattawan, 
MI49071-8353, 
U.S.A.  
Toxicity & 
immunogenicity 
study. 
GLP  
New Zealand 
white rabbits  
Series of toxicology studies of 4-
Pyrrolidinopyridine (4-PP, a byproduct of 
CPPT conjugation chemistry)  
MPI Research, Inc, 
54943 North Main 
Street Mattawan, 
MI49071-8353, 
U.S.A. and 
BioReliance, 
Rockville, MD 
Byproduct 
toxicology. 
Mutagenicity 
GLP  
Rats, guinea 
pigs, 
prokaryotic 
& eukaryotic 
cells 
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of NmCV-5 vaccine (adjuvanted and non-adjuvanted) were tested in comparison with the 
licensed quadrivalent serogroups A, C, W and Y vaccine (Menactra®) in 60 volunteers aged 
18 to 45 years. 
The subjects were followed up for 6 months post vaccination which involved visits to study 
site at day 7, 28 & 84 and a phone call at six months. All 60 subjects had completed their 
day 28 follow up. An interim analysis with Day 28 safety data of the first 58 subjects and 
immunogenicity data of the first 30 subjects was performed. 
All study vaccines were well-tolerated, and the rate of solicited local as well systemic 
reactions reported till day 7 post vaccination with NmCV-5 was comparable to Menactra. 
There were no NmCV-5 vaccine related unsolicited adverse events (AEs) during 28 day 
follow up. No serious AEs were reported during the study. Overall, no safety concerns 
around the use of NmCV-5 were raised from this study.  
Immunogenicity was analysed via serum bactericidal activity assay using baby rabbit 
complement. The results for each 10 subjects receiving adjuvanted and non adjuvanted 
formulation of NmCV-5 showed that both the vaccines are immunogenic. The GMTs were 
comparable to those seen among subjects receiving Menactra. 
More details of interim results can be found in the investigator’s brochure. 
There is no clinical data of NmCV-5 available in children 1-2 years of age, although it is 
anticipated that the vaccine will have a safety profile similar to that of currently licensed 
vaccines against meningococci including Menactra® (reference vaccine in present study) 
and MenAfriVac®. 
Apart from local solicited reactions such as tenderness, erythema and swelling, other 
common (≥10%) solicited systemic reactions in children 9 to 12 months of age who 
received Menactra® included irritability, abnormal crying, drowsiness, appetite loss, 
vomiting, and fever.18, 24 Solicited reactions were considered those occurring within seven 
days of vaccination. 
 
1.5 
Rationale for Study Design 
Substantial safety data are available for currently licensed monovalent and polyvalent 
meningococcal conjugate vaccines (Menactra®, Menveo®, Nimenrix® and MenAfrivac®) 
across all age groups, including infants and toddlers.3, 18-20 Safety data indicate a favorable 
risk/benefit profile with low rates of solicited and unsolicited AEs following vaccination. 
After completion of the Phase 1 clinical study in adults and following a positive outcome 
of safety data assessment by the Safety Review Team, clinical development of NmCV-5 
vaccine will be continued in children 12-16 months of age (the target group for routine 
meningococcal vaccination in Africa). 
The immunogenicity data of licensed polyvalent meningococcal vaccines indicate that a 2-
dose vaccination series is required to induce a robust immune response against all vaccine 
serogroups in children 9 to 23 months of age. As such, a 2-dose vaccination schedule will 
be tested in this study. Immune responses will be evaluated at one month after each study 
vaccination and prior to administration of the second vaccine dose, to assess possible 
waning of antibody titers.  
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Immunogenicity of adjuvanted and non-adjuvanted formulations of NmCV-5 will be 
compared with the licensed quadrivalent meningococcal conjugate vaccine (MenACWY-
D; Menactra®). Menactra® has been selected as an active control given the large safety 
database accumulated since the vaccine was introduced in the US in 2005, prequalified by 
WHO and progressively introduced into other countries.  
Both vaccines will be administered to meningococcal vaccine-naïve healthy subjects to 
avoid possible enhancement of immune response due to a previous meningococcal vaccine 
administration. 
Mali introduced MenAfriVac during a national campaign in 2010 and 2011 for the 
prevention of Group A N.meningitidis in the 1 to 29 years of age. This campaign was part 
of a broader effort to eliminate Group A meningococcal meningitis in Sub-Saharan Africa, 
with all countries located in the meningitis belt introducing the Men A conjugate vaccine 
between 2010 and 2016. In the same period, epidemic meningococcal disease caused by 
serogroup A has been observed to practically disappear from the immunized regions 
following a herd immunity effect. Mali’s first Men A case since 2010 was reported in 
Kieneba district in March 2016. This case occurred in a 15 year old who had not been 
vaccinated as part of the campaign that took place in that district in 2011. Neighboring 
Guinea experienced an epidemic in 2014-15 secondary to disruptions in health care due to 
the Ebola outbreak and a MenAfriVac campaign that was started only in 2015.  To maintain 
effort in the protection against Men A in Mali, an introduction into the EPI schedule for 
MenAfriVac-5 (MenAfriVac with a 5 µg concentration in Men A polysaccharide) at 9 
months of age was completed in February 2017 and a national catch-up campaign to 
immunize the 1 to 5 years of age (born after the initial campaign) was implemented on 5-
14 June, 2017.16, 17, 25-29 
Because of the need for vaccine-naïve healthy subjects aged 12-16 months for this study, 
recruitment efforts will need to start as early as 9 months to identify potential subjects and 
postpone the administration of meningococcal vaccine. 
Subjects will be enrolled as soon as possible once they meet all eligibility criteria. If found 
not eligible, they will be followed to receive the MenAfriVac. 
Given the almost complete absence of invasive meningococcal disease caused by serogroup 
A in Mali following the national preventive vaccination campaign in 2010-11, the 
introduction of MenAfriVac in the EPI in February 2017 and the MenAfriVac National 
Catch-up Campaign completed in 2017 in the 1 to 5 years of age with reported coverage 
rates of 112% in the study area and 104.7% nationally, the herd immunity effect is expected 
to be reinforced for several years, preventing any new circulation of Men A in the study 
area.30, 31 Under this context, the deferral of Men A vaccination constitutes an acceptable 
risk / benefit ratio as subjects would receive either two doses of polyvalent meningococcal 
vaccine during the clinical study or, alternatively, a dose of meningococcal group A vaccine 
by a delay of 3 months.  
 
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2 
HYPOTHESIS, OBJECTIVES AND ENDPOINTS 
2.1 
Study Hypotheses 
Both formulations of investigational NmCV-5 vaccine (adjuvanted and non-adjuvanted) 
administered intramuscularly to healthy children 12-16 months of age will be safe and well 
tolerated. 
NmCV-5 (adjuvanted and non-adjuvanted formulations) administered according to a 0,3 
month schedule to healthy children will elicit a measurable functional immune response 
against all vaccine serogroups at 1 month after the second vaccination. 
2.2 
Study Objectives 
2.2.1 Primary objective 
1. To assess the reactogenicity of non-adjuvanted and adjuvanted formulations of 
NmCV-5 vaccine in comparison with the licensed MenACWY-D vaccine, as 
measured by the percentage of subjects with at least one severe solicited AE 
reported within 7 days after any vaccination. 
2.2.2 Secondary Immunogenicity Objectives 
1. To assess immunogenicity of non-adjuvanted formulation of NmCV-5 vaccine in 
comparison with MenACWY-D vaccine, as measured by rSBA against serogroups 
A, C, W, Y and X at 1 month after the second vaccination. 
2. To assess immunogenicity of adjuvanted formulation of NmCV-5 vaccine in 
comparison with non-adjuvanted formulation of NmCV-5 vaccine, as measured by 
rSBA against serogroups A, C, W, Y and X, at 1 month after the second vaccination. 
3. To assess immune responses elicited by non-adjuvanted and adjuvanted 
formulations of NmCV-5 vaccine and MenACWY-D vaccine at 1 and 3 months 
after the first vaccination. 
2.2.3 Secondary Safety Objective 
1. To evaluate the safety and reactogenicity of adjuvanted and non-adjuvanted 
formulations of NmCV-5 vaccine in healthy children, when compared to 
MenACWY-D. 
2.2.4 Exploratory Objective 
1. To assess immunogenicity of adjuvanted and non-adjuvanted formulations of 
NmCV-5 vaccine and MenACWY-D vaccine, as measured by hSBA against 
serogroups A, C, W, Y and X at baseline, 1 month after the first vaccination and 1 
month after the second vaccination (in a subset of subjects). 
2. To further assess immunogenicity of adjuvanted and non-adjuvanted formulations 
of NmCV-5 vaccine and MenACWY-D vaccine, as measured by rSBA against 
serogroups A, C, W, Y, and X at baseline, 1, month and 3 months after the first 
vaccination and 1 month after the second vaccination. 
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2.3 
Study Endpoints 
2.3.1 Primary reactogenicity endpoint: 
1. Percentage of subjects with at least one severe solicited AE* within 7 days after any 
study vaccination (Days 0-6 and Days 84-90). 
*Solicited AEs include tenderness, swelling/induration, irritability, drowsiness, 
decrease of eating, vomiting, and fever 
2.3.2 Secondary immunogenicity endpoints: 
1. Percentage of subjects with rSBA titer ≥ 8 against serogroups A, C, W, Y and X at 
Visits Day 0, Day 28, Day 84 and Day 112. 
2. Percentage of subjects with rSBA titer ≥ 128 against serogroups A, C, W, Y and X at 
Visits Day 0, Day 28, Day 84 and Day 112. 
3. Percentage of subjects with fourfold rise in rSBA titers against serogroups A, C, W, Y 
and X at Visits Day 28 and Day 112. 
a. For subjects with a pre-vaccination rSBA titer < 8, a post-vaccination titer of ≥ 
32; 
b. For subjects with a pre-vaccination rSBA titer ≥ 8, an increase in rSBA titer of 
at least 4 times the pre-vaccination titer. 
4. rSBA GMT for serogroups A, C, W, Y and X at Visits Day 0, Day 28, Day 84 and Day 
112. 
2.3.3 Secondary safety endpoints: 
1. Solicited local and systemic AEs reported within 7 days after each vaccination 
(Days 0-6 and Days 84-90); 
2. Unsolicited AEs reported during 28 days after vaccination (Days 0-27 and Days 84-
111);  
3. AEs leading to premature withdrawal during the entire study period; 
4. SAEs reported during the entire study period. 
2.3.4 Exploratory immunogenicity endpoints: 
1. Percentage of subjects with hSBA titer ≥ 8 against serogroups A, C, W, Y and X at 
Visits Day 0, Day 28 and Day 112 (in a subset of subjects) 
2. Percentage of subjects with hSBA seroresponse against serogroups A, C, W, Y and 
X at Visits Day 28 and Day 112 (in a subset of subjects), defined as: 
- for subjects with baseline hSBA titer < 4, post vaccination hSBA titer ≥ 8;  
- for subjects with baseline hSBA titer ≥ 4, an increase of at least four times the pre-
vaccination hSBA 
3. hSBA GMTs for serogroups A, C, W, Y and X at Visits Day 0, Day 28 and Day 
112 (in a subset of subjects). 
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4. Percentage of subjects with rSBA titer ≥ 4, ≥ 16, ≥ 32, and ≥ 64 against serogroups 
A, C, W, Y and X at Visits Day 0, Day 28, Day 84 and Day 112. 
5. Percentage of subjects with a fourfold increase in rSBA titers against serogroups A, 
C, W, Y and X at Visits Day 28 and Day 112 with the following criteria: 
o For subjects with a pre-vaccination rSBA titer < 4, a post-vaccination titer 
of ≥ 16; 
o For subjects with a pre-vaccination rSBA titer ≥ 4, a post-vaccination titer 
of at least 4 times the pre-vaccination titer. 
6. Among subjects with a pre-vaccination rSBA titer ≥4, ≥8, ≥16, ≥ 32, ≥ 64, and ≥ 128, 
percentage of subjects with a post-vaccination titer of at least 4 times the pre-
vaccination titer at Visits Day 28 and Day 112. 
 
3 
STUDY DESIGN 
3.1 
Methodology 
Design: Phase 2, randomized (2:2:1), controlled, observer-blind, single-center study in 
healthy children 12 to 16 months of age with three study groups. 
Duration of the study: The study duration is approximately 6 months for each subject. 
Vaccination schedule: 0, 3 month. 
Study groups: 
- 
NmCV-5_non-adjuvanted group: approximately 150 subjects receiving the non-
adjuvanted formulation of NmCV-5 vaccine at Visit Day 0 and Visit Day 84. 
- 
NmCV-5_adjuvanted group: approximately 150 subjects receiving the adjuvanted 
formulation of NmCV-5 vaccine at Visit Day 0 and Visit Day 84. 
- 
ACWY-D group: approximately 75 subjects receiving the licensed MenACWY-D 
(Menactra®) vaccine at Visit Day 0 and Visit Day 84. 
 
Figure 3.1-1. Study design 
 
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Note: BS – blood sample; ACWY-D –Menactra® 
Randomization: At Visit Day 0, prior to the study vaccination, subjects will be randomized 
into the three study groups according to a 2:2:1 ratio.  
Blinding: Observer-blind study. 
Data collection: Electronic Case Reporting Form (eCRF). 
Blood sample schedule: Four blood samples (approximately 5 mL each) at Visit 1 (Day 0, 
first vaccination), Visit 3 (Day 28), Visit 4 (Day 84, second vaccination) and Visit 6 (28 
days after second vaccination). 
Study visits: Seven visits at Day 0, Day 7, Day 28, Day 84, Day 91 (7 days post Dose 2), 
Day 112 (28 days post Dose 2) and Day 168 (84 days post Dose 2). 
Solicited AEs: occurring during 7 days following each study vaccination will be assessed 
daily by site staff and recorded in the home visit worksheets and the CRF at Visit 2 and 
Visit 5. 
Unsolicited AEs: occurring within 28 days after each study vaccination will be collected 
weekly by site staff during home and site visits. 
AEs leading to study withdrawal and SAEs: will be collected during the entire study period. 
These data will be captured through the home visit worksheets, by interviewing the 
subjects’ parents / guardians during the home visits, the planned and unplanned site visits, 
and by review of available medical records. 
Written agreement to delay the EPI MenAfriVac dose scheduled at 9 months of age: Prior 
to written informed consent, subject’s parents/guardians may be asked to sign a pre-
screening agreement as early as 9 months of age in order to delay the EPI MenAfriVac dose 
until they can be considered for enrolment in the trial (trial subjects must be at least 12 
months of age, have not received any meningococcal vaccines and have not received any 
vaccinations in the past 28 days). 
Written informed consent will be obtained from the subject’s parents / guardians before 
conducting any study-specific procedures.   
After 
signing 
informed 
consent, 
a 
review 
of 
medical 
history 
and 
prior 
medications/vaccination, a physical examination, and confirmation of subject eligibility, 
subjects will be enrolled into the study. 
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Table 3.1-2: Times and Events Table 
Visit Number 
- 
1 
2 
3 
4 
5 
6 
7 
Visit Type 
- 
Clinic 
Visit 
Home or 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Home or 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Visit time and window 
- 
Day 0 
Day 7 (+3) 
Day 28 (+14) 
Day 84 (±14) 
Day 91 (+3) 
Day 112 (+14) 
Day 168 (±14) 
Time After Last Vaccination 
9-12 
months 
of age 
 
7 days post 
dose 1 
28 days post 
dose 1 
84 days post 
dose 1 
7 days post 
dose 2 
28 days post 
dose 2 
84 days post 
dose 2 
Agreement to delay MenA vaccination 
X 
 
 
 
 
 
 
 
Delayof MenA vaccination 
X 
 
 
 
 
 
 
 
Informed Consent 
 
Xa 
 
 
 
 
 
 
Demographic Data 
 
Xa 
 
 
 
 
 
 
Exclusion/Inclusion Criteria 
 
Xa 
 
 
 
 
 
 
Medical History 
 
Xa 
 
 
 
 
 
 
General Physical Examination b 
 
Xa 
X 
X 
Xa 
X 
X 
X 
Randomization 
 
Xa 
 
 
 
 
 
 
Eligibility for second vaccination/ delay c 
 
 
 
 
Xa 
 
 
 
Blood Collection d 
 
Xa 
 
X 
Xa 
 
X 
 
Study Vaccination 
 
X 
 
 
X 
 
 
 
30-Minute Post-Vaccination Assessment e 
 
X 
 
 
X 
 
 
 
Review of solicited and unsolicited AEs by 
medical staff 
 
X 
X 
X 
X 
X 
X 
X 
Recording of solicited AEs by field staff f 
 
Daily for 6 days 
 
Daily for 6 days 
 
 
Recording of unsolicited AEs by field staff g 
 
Daily for 6 days 
Weekly from 
Day 7 to Day 
28 
Daily for 6 days 
Weekly from 
Day 7 to Day 
28 post dose 2 
 
Reporting of SAEs 
 
from Day 0 to study completion 
Recording of concomitant medications and 
vaccinations  
 
From Day 0 to study completion 
Study Termination 
 
In case of termination before Visit 7:  early termination procedures must be followed. 
X 
a. 
Procedure to be performed prior to vaccination 
b. 
Physical examination must be performed by a qualified health professional in accordance with local regulations and licensing requirements designated within the Site 
Responsibility Delegation Log.    
c. 
Prior to the second vaccination investigator must check eligibility criteria for subsequent vaccination and criteria for vaccination delay as specified in sections 4.3 and 4.4. 
d. 
Approx. 5 mL of blood drawn at each specified visit. See section 4.4 for criteria of blood draw delay. 
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e. 
At least 30 minutes post-vaccination, immediate reactions will be evaluated by the investigator. Assessment of solicited local and systemic AEs and post-vaccination 
temperature measurement will be performed by study staff. Solicited local and systemic AEs, any unsolicited AEs, vital signs and body temperature will be recorded in source 
documents and eCRF. 
f. 
Beginning the day following study vaccination and subsequent 5 days, solicited local and systemic AEs and other indicators of reactogenicity (i.e. body temperature and use 
of analgesics/antipyretics) will be assessed daily by field staff and recorded in the home visit worksheets. 
g. 
Unsolicited AEs will be collected by field staff during weekly contacts of subject’s parents/guardians and recorded in the home visit worksheets. 
 
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Page 32 of 88 
 
4 
STUDY POPULATION 
This will be a single site study conducted at the Centre pour le Développement des Vaccins du 
Mali (CVD-Mali), Bamako, Mali. 
4.1 
Inclusion Criteria 
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described. 
1. Male and female children between 12 months and 16 months old inclusive (minimum 365 
days of age and maximum 16 months plus 29 days of age);  
2. For whom parent(s)/legal guardian(s) have given written informed consent after the nature 
of the study has been explained according to local regulatory requirements; 
3. Who the investigator believes that their parent(s)/ guardian(s) will be available for all the 
subject visits and would comply with the requirements of the protocol (e.g., timely reporting 
of adverse events, availability for study site visits and home visits); 
4. Individuals in good health as determined by the outcome of medical history, physical 
examination and clinical judgment of the investigator. 
5. Individuals who completed their local infant EPI schedule through 9 months of age (except 
MenAfriVac dose). A birth dose of OPV is not required. 
4.2 
Exclusion criteria 
In order to participate in this study, all subjects must meet NONE of the exclusion criteria 
described. 
1. History of any meningococcal vaccine administration. 
2. Current or previous, confirmed or suspected disease caused by N. meningitidis.   
3. Household contact with and/or intimate exposure to an individual with any laboratory 
confirmed N. meningitidis infection within 60 days of enrolment. 
4. History of severe allergic reactions after previous vaccinations or hypersensitivity to any 
study vaccine component including tetanus, diphtheria and diphtheria toxoid (CRM197). 
5. Acute or chronic, clinically significant pulmonary, cardiovascular, metabolic, neurological, 
hepatic, or renal functional abnormality, as determined by medical history or physical 
examination.  
6. Any confirmed or suspected condition with impaired/altered function of immune system 
(immunodeficient or autoimmune conditions). 
7. Have any bleeding disorder which is considered as a contraindication to intramuscular 
injection or blood draw. 
8. Severe acute malnutrition. 
9. A family history of congenital or hereditary immunodeficiency. 
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10. History of either hepatitis B or hepatitis C virus infection or human immunodeficiency virus 
infection.  
11. Major congenital defects.  
12. Chronic administration (defined as more than 14 days) of immunosuppressants or other 
immune-modifying drugs within three months prior to the study vaccination or planned use 
throughout the study period. (For corticosteroids, this means prednisone, or equivalent, ≥ 0.5 
mg/kg per day. Inhaled, intranasal and topical steroids are allowed). 
13. Administration of blood, blood products and/or plasma derivatives or any parenteral 
immunoglobulin preparation in the past 3 months or planned use throughout the study period. 
14. Administration of any vaccine within 28 days prior to enrolment in the study or planned 
administration of any vaccine within 14 days before or after any study vaccination. 
15. Use of any investigational or non-registered drug or vaccine within 30 days prior to the 
administration of study vaccines or planned during the study. 
16. Malaria infection as confirmed by a Rapid Diagnostic Test. 
Note: Subjects positive at screening may be treated for malaria as per national guidelines, 
and if subject remains eligible, vaccinated no earlier than five days after completing 
treatment. 
17. Individuals who are close family members of individuals conducting this study. 
18. Have experienced a moderate or severe acute infection and/or fever (defined as temperature 
≥ 37.5°C) within 3 days prior to enrolment. 
19. Have received systemic antibiotic treatment within 3 days prior to enrolment. 
20. Non-residence in the study area or intent to move out within six months. 
21. Any condition which, in the opinion of the investigator, might pose additional risk to the 
subject due to participation in the study. 
4.3 
Criteria for Administration of Second Study Vaccination 
Prior to receipt of the second dose of study vaccine, subjects must be evaluated to confirm that 
they are eligible for subsequent vaccination. If subjects meet any of the criteria listed below, they 
should not receive the second vaccination: 
1. Subjects who experienced any immediate allergic reaction after the previous study 
vaccination. 
2. Subjects who experience any serious adverse event judged to be related to study vaccination, 
including hypersensitivity reactions. 
3. Subjects who develop any clinically significant medical condition which, in the opinion of 
the investigator, may pose additional risk to the subject if he/she receives the second 
vaccination. 
Subjects who meet any of these criteria must not receive further study vaccinations. However, 
these subjects should be encouraged to continue study participation, as discussed in section 6.7. 
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4.4 
Criteria for Delay of Vaccination and/or Blood Sampling 
After enrolment, subjects may encounter clinical circumstances that warrant a delay in 
subsequent study vaccination. These situations are listed below. In the event that a subject meets 
a criterion for delay of vaccination, the subject may receive study vaccination once the window 
for delay has passed as long as the subject is otherwise eligible for study participation. 
1. Acute moderate or severe infection with or without fever within 3 days of intended study 
vaccination. 
2. Fever is defined as body temperature >37.5° C within 3 days of intended study vaccination. 
3. Malaria infection as confirmed by a Rapid Diagnostic Test (subject may be vaccinated no 
earlier than five days after completing treatment). 
4. Administration of any vaccine not foreseen by the study protocol within 14 days prior the 
intended study vaccination. 
There are also circumstances under which repeat vaccination is a contraindication in this study. 
These circumstances are presented in section 4.3. 
There is a clinical circumstance that warrants delay of blood collection for immunogenicity 
assessments in this study. This situation is listed below. In the event that a subject meets a 
criterion for delay of blood collection, blood collection may proceed once the window for delay 
has passed. 
1. Subject has received a dose of systemic antibiotics within 3 days before the intended blood 
collection. 
5 
TREATMENT OF SUBJECTS 
5.1 
Description of study vaccines 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are described 
below. 
Investigational vaccines 
The NmCV-5 investigational vaccine is a fixed-combination available as the lyophilized powder 
containing meningococcal groups A and X polysaccharides conjugated to tetanus toxoid and 
meningococcal groups C, W and Y polysaccharides conjugated to CRM197 protein. The vaccine 
will be reconstituted with either saline alone (non-adjuvanted formulation) or saline containing 
aluminum phosphate at 125 mcg Al3+ /dose (adjuvanted formulation) just prior to administration.  
N. meningitidis A, C, Y, W, and X polysaccharides are produced by cultivating cells in fed batch 
fermentation and purified after separation. Tetanus toxin is derived from Clostridium tetani 
grown in a modified medium and purified. CRM is expressed by Pseudomonas fluorescens strain 
and used after it is purified. Meningococcal polysaccharides are covalently conjugated to TT or 
CRM and purified to make the final formulated vaccine. 
The NmCV-5 lyophilized powder component contains sucrose, sodium citrate and trometamol 
as excipients. This component is presented as a freeze-dried powder in a five-dose vial. 
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The adjuvanted diluent containing aluminum phosphate used to prepare the adjuvanted NmCV-
5 is a sterile white homogeneous suspension presented in a five-dose glass ampoule containing 
an actual fill volume of 3.1 mL ± 0.1 mL. 
0.9% Sodium Chloride used to prepare the non-adjuvanted NmCV-5 vaccine is a clear, colorless 
liquid presented in 10 mL ampoules. A volume of 3.1 mL will be used to reconstitute the 
lyophilized component of NmCV-5 vaccine. 
After reconstitution the NmCV-5 vaccine formulations to be used will have the following 
composition per 0.5 mL of injectable solution: 
Table 5.1-1: Composition of reconstituted non-adjuvanted and adjuvanted formulations 
of NmCV-5 vaccine (per 0.5 mL dose) 
Vaccine component 
Non-adjuvantedNmCV-5 
(per 0.5 mL dose) 
AdjuvantedNmCV-5 
(per 0.5 mL dose) 
Meningococcal A polysaccharide1 
5 g 
5 g 
Meningococcal C polysaccharide2 
5 g 
5 g 
Meningococcal Y polysaccharide2 
5 g 
5 g 
Meningococcal W polysaccharide2 
5 g 
5 g 
Meningococcal X polysaccharide1 
5 g 
5 g 
Sucrose 
2.42 mg 
2.42 mg 
Sodium Citrate 
0.40 mg 
0.40 mg 
TRIS (Trometamol) 
0.098 mg 
0.098 mg 
Aluminum phosphate Al3+ 
- 
125 g /dose 
0.9% Sodium Chloride 
q. s.  
q. s.  
Tetanus Toxoid 
7.8 to 33.4 µg 
7.8 to 33.4 µg. 
CRM197 
11.7 to 50.1 µg 
11.7 to 50.1 µg 
Note: 1 each polysaccharide conjugated to Tetanus Toxoid; 2 each polysaccharide conjugated to CRM197; q.s. -Quantum satis 
Active comparator 
The licensed MenACWY-D polysaccharide conjugate vaccine (Menactra®, manufactured by 
Sanofi Pasteur Inc.) is supplied as a single 0.5 mL dose formulated in sodium phosphate buffered 
isotonic sodium chloride solution to contain 4 μg each of meningococcal A, C, Y, and W 
polysaccharides conjugated to approximately 48 μg of diphtheria toxoid protein carrier. No 
preservative or adjuvant is added during manufacture. Each 0.5 mL dose may contain residual 
amounts of formaldehyde of less than 2.66 µg. 
Table 5.1-2: Composition of MenACWY-D (per 0.5 mL dose) 
Vaccine component 
Per Dose of 0.5 mL 
Meningococcal group A polysaccharide 
4 g 
Meningococcal group C polysaccharide 
4 g 
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Meningococcal group Y polysaccharide 
4 g 
Meningococcal group W polysaccharide 
4 g 
Diphtheria toxoid protein total 
48 g 
Sodium phosphate 
0.7 mg 
Sodium chloride 
4.35 mg 
 
5.2 
Precautions to be observed in administrating study vaccines 
Prior to vaccination, subjects must be determined to be eligible for study vaccination and it must 
be clinically appropriate in the judgment of the investigator to vaccinate. Eligibility for 
vaccination prior to first study vaccine administration is determined by evaluating the inclusion 
/ exclusion criteria as specified in protocol sections 4.1 and 4.2. 
Eligibility for subsequent study vaccination is determined by following the criteria outlined in 
sections 4.3 and 4.4. 
Study vaccines should not be administered to individuals with known hypersensitivity to any 
component of the vaccines. 
Standard immunization practices are to be observed and care should be taken to administer the 
injection intramuscularly. Before administering vaccine, the vaccination site is to be disinfected 
with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. DO NOT inject 
intravascularly. 
As with all vaccines, appropriate medical treatment (like adrenaline 1:1000, anti-histamine 
[diphenhydramine], corticosteroids [hydrocortisone] and resuscitation equipment etc.) must 
be available at the site, and staff and supervision must be readily available in case of rare 
anaphylactic or any severe allergic reactions following administration of the study vaccine.   
Prompt use of resuscitation measure can be lifesaving and must be implemented at the first 
suspicion of anaphylaxis. 
5.3 
Preparation and administration of the study vaccine 
The adjuvanted NmCV-5 is prepared by aseptically injecting the whole content of a five dose 
single ampoule of adjuvant containing diluent into the five dose vial containing the lyophilized 
MenACYWX component. This reconstitutes the lyophilized MenACYWX component with 
gentle agitation. The final reconstituted vaccine (total volume approximately 0.6 mL per dose; 
injection volume 0.5 ml per dose) is then ready for administration. For the purpose of this study, 
one five dose vial of reconstituted adjuvanted NmCV-5 will be used to draw a single vaccine 
dose for one subject only. After reconstitution the vaccine must be used as soon as possible but 
not later than two hours, during which time it may be kept at room temperature but must not be 
frozen.  
The non-adjuvanted NmCV-5 is prepared by aseptically injecting approximately 3.1 mL of 0.9% 
Sodium Chloride diluent into the five dose vial containing the lyophilized MenACYWX 
component. This reconstitutes the lyophilized MenACYWX component with gentle agitation. 
The final reconstituted vaccine (total volume approximately 0.6 mL per dose; injection volume 
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0.5 ml per dose) is then ready for administration. For the purpose of this study, one five dose vial 
of reconstituted non-adjuvanted NmCV-5 will be used to draw a single vaccine dose for one 
subject only. After reconstitution the vaccine must be used as soon as possible but not later than 
two hours, during which time it may be kept at room temperature but must not be frozen. 
MenACWY-D (Menactra®) vaccine is prepared by aseptically withdrawing all fluid from the 
single-dose vial using a sterile needle and syringe. Vaccine must be administered within two 
hours of preparation. 
All study vaccines should be visually inspected after reconstitution. In the event of any foreign 
particulate matter and/or any unusual appearance of the study vaccine, please set the vial aside 
and inform the unblinded monitor. 
All study vaccines (injected volume of 0.5 mL) will be administered as per randomization 
schedule via intramuscular injection in the anterolateral area of the thigh on Visit Day 0 and Visit 
Day 84. 
The investigator or designee will be responsible for oversight of the administration of vaccine to 
subjects enrolled in the study according to the procedures presented in this study protocol. All 
vaccines will be prepared and administered only by designated unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the specific 
study site. 
All study vaccines to be administered to the subjects must be stored in a safe and locked place 
with no access by unauthorized personnel. 
The study vaccines will be stored at the defined temperature range (i.e. +2 to +8 C). The storage 
temperature of the vaccines will be monitored daily with temperature monitoring devices and 
will be recorded. 
Any temperature deviation, i.e. temperature outside the range (+2 to +8°C), must be reported to 
the sponsor as soon as detected. Following the exposure to such a temperature deviation, 
vaccines will not be used until written approval has been given by the sponsor. Expired vaccines 
must not be administered. 
 
5.4 
Vaccine supply, labelling, storage, accountability and disposal 
The sponsor will ensure the following: 
 Appropriate supply of the study vaccines; 
 Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 
The investigator must ensure the following: 
 Indication of appropriately trained unblinded site staff to manage vaccine supply, 
accountability, preparation and administration. 
 Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including confirmation that the vaccines: 
- 
were received in good condition; 
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- 
remained within the appropriate temperature range during shipment from the 
sponsor to the investigator’s designated storage location; 
- 
have been confirmed by the sponsor as authorized for use 
 Proper storage of the study vaccines, including: 
- 
storage in a secure, locked, temperature-controlled location; 
- 
proper storage according to the instructions specified on the labels; 
- 
appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature 
 Appropriate use of the study vaccines, including: 
- 
use only in accordance with the approved protocol; 
- 
proper handling, including confirmation that the vaccine has not expired prior to 
administration; 
- 
appropriate documentation of administration of vaccines to study subjects 
including: 
 date, dosage, batch number, expiration date, unique identifying numbers 
assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability 
log that will be reviewed by the unblinded site monitor; 
 proper reconciliation of all study vaccines received from the sponsor. 
Reconciliation is defined as maintaining records of which and how many 
vaccines were received, which vaccines (and volume thereof) were 
administered to subjects, and which vaccines were destroyed at the site. 
 Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
 Complete record keeping of vaccine use, wastage, or destruction, including documentation 
of: 
- 
copy of the site’s procedure for destruction of hazardous material; 
- 
number of doses destroyed, date of destruction, method of destruction, and name 
of individual performing destruction 
Vaccines that have been stored differently from the manufacturer’s instructions must not be used 
unless the sponsor provides written authorization for use. In the event that the use cannot be 
authorized, the sponsor will make every effort to replace the vaccine supply. All vaccines used 
in conjunction with this protocol must be stored separately from normal practice stocks to 
prevent unintentional use of study vaccines outside of the clinical trial setting. 
Monitoring of vaccine accountability will be performed by the unblinded study monitor during 
site visits and at the completion of the trial. 
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6 
STUDY PROCEDURES 
6.1 
General considerations 
The study will be conducted in accordance with the ICH Guideline for Good Clinical Practice 
(GCP), all applicable subject privacy requirements and the guiding principles of the Declaration 
of Helsinki. 
The study will be initiated only after approvals from relevant IRB/IECs and the National 
Regulatory Authority have been obtained.  
Freely given and written or witnessed/ thumb printed informed consent must be obtained from 
each subject’s parent(s)/guardian(s) prior to participation in the study. 
6.2 
Community permission 
Given the local social structure, once the ethical and regulatory approvals are in place, 
community meetings will be organized to present the study to the communities where the site 
team plans to conduct the study. These meetings will be organized following a specific site 
procedure:  
1. 
The informed consent forms will be translated into the local language and recorded onto 
an audiotape through a certified process; 
2. 
Community meetings will be scheduled with the elders, the religious representatives, the 
social leaders and village chiefs in each community where the study will be conducted. 
At these meetings, the study will be explained in detail and, when applicable, the 
audiotaped consent will be played;  
3. 
The study will be discussed and the study team will answer any questions. The 
community leaders would review the information and confirm their permission for the 
conduct of the study.  
4. 
The leaders or a local crier will announce the study and direct interested persons to the 
site. The study site team would then be allowed to start recruitment activities and 
approach potential subjects.  
6.3 
Recruitment 
The site will develop a study specific recruitment plan and will use several approaches for 
recruitment: 
 The list of children 8-15 months of age with their home addresses will be obtained from 
the demographic surveillance system.  Community liaisons/field workers will visit each 
household and inform parents/guardians about the study. If interested, the 
parent/guardian will be directed to visit the site clinic for more information. 
 The study team will collaborate with the community clinics to search potential subjects 
when they come for their EPI vaccinations. Study staff will be present at the community 
clinics during vaccination days. If interested, the parent/guardian will be referred to the 
site staff for information on the study. Further details are described in section 6.6.1. 
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6.4 
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal guardian to 
participate in research.  Consent must be given with free will of choice, and without inducement.  
The individual must have sufficient knowledge and understanding of the nature of the proposed 
research, the anticipated risks and potential benefits, and the requirements of the research to be 
able to make an informed decision. 
Informed consent of the parents/legal guardians following local IRB/EC guidance must be 
obtained before conducting any study-specific procedures.  
The informed consent will have a two-step process.  
 An initial informed consent process will be conducted as early as 9 months of age. At this 
stage, the parent(s)/guardian(s), based on their interest in the study would decide if they agree 
to delay the EPI MenAfriVac dose until their child is eligible to participate in the study (i.e. 
12 months). If they agree, subject’s parents/guardians will be asked to sign the pre-screening 
agreement (Delay of MenAfriVac agreement form) which is included in the informed 
consent document.  
 A second informed consent process will be conducted as early as 12 months of age. If the 
parent(s)/guardian(s) agree for their child to participate in the study, subject’s 
parents/guardians will be asked to sign the study consent form.  
The child would be considered enrolled in the study as soon as the two-step process for informed 
consent was completed and the parent(s)/guardian(s) have agreed to participation in the study. 
The process of obtaining agreement for delay of MenAfriVac and the process of obtaining 
informed consent for study participation should be documented in the source documents. Two 
originals of the informed consent form should be signed and dated for the delay of MenAfriVac. 
One original will be given to the parent(s)/guardian(s) and one original will be kept at the site. 
At the time of final informed consent, the same originals will be signed and dated for consent to 
participate in the study. One original will be returned to the parent(s)/guardian(s) and one 
original will be kept at the site. Additional specifics regarding the informed consent processes 
are located in section 11.3 of the protocol. 
If subject’s parent(s)/guardian(s) is unable to read, an impartial witness should be present during 
the entire informed consent discussion.  An impartial witness is defined as a person who is 
independent from study conduct, who cannot be unfairly influenced by those involved with the 
study, who attends the informed consent process if the subject's legally acceptable representative 
cannot read, and who reads the informed consent form and any other written information 
supplied to the parent/legal guardian.  After the written informed consent form and any other 
written information to be provided to subject’s parent/guardian, is read and explained to the 
subject’s guardian/parent and after the subject’s parent/guardian has verbally consented to the 
subject’s participation in the study and, if capable of doing so, has signed or fingerprinted and 
personally dated the informed consent form, the witness should sign and personally date the 
consent form. By signing the consent form, the witness attests that the information in the consent 
form and any other written information was accurately explained to, and apparently understood 
by, the subject’s parent/guardian and that informed consent was freely given by the subject’s 
parent/guardian. 
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6.5 
Randomization and Blinding Procedures 
6.5.1 Randomization  
At Visit Day 0 each subject will be randomized according to a 2:2:1 ratio into one of the three 
study groups using a randomization list. Randomization will occur on the day subjects are to 
receive their first study injection, after confirmation of eligibility and immediately prior to 
injection. 
The unblinded designated personnel will be provided with the randomization list that includes 
treatment assignment. Based on the assigned treatment the unblinded personnel will prepare the 
study vaccine to be given to each subject. The unblinded personnel will maintain the 
randomization list in a secure place. 
If for any reason, after signing the informed consent form, the subject (who has passed screening) 
fails to be randomized, the reason for not being randomized should be recorded in source 
documents. The information on these eligible subjects, who are not randomized, should be kept 
distinct in the source documentation from screen failures. 
6.5.2 Blinding 
The study is designed as an observer-blind study. Observer-blind means that during the course 
of study, the parents/guardians of the subjects and the study personnel responsible for the 
evaluation of any study endpoint (e.g. safety and reactogenicity) will be unaware which vaccine 
was administered. The vaccine preparation and administration will be done by designated 
unblinded personnel who will not participate in any of the clinical study evaluations.  
Unblinded study personnel will prepare the vaccine out of view of the subject, the subject’s 
parents/guardians and the blinded study personnel, and will administer the vaccine in a separate 
room. Considering the fact that all the three vaccines are likely to have distinct appearances, 
even when drawn into syringes, the syringes will be masked with an opaque wrapping before 
administration.    
The laboratories in charge of the serology testing will also be blinded in terms of subject 
identifier and study group. 
The treatment and sample blinding will be maintained during the entire study period. For the 
planned interim analysis, individual listings will not be generated and any access to subject-level 
information about study groups will be masked. 
The treatment code should only be broken if investigator/physician in charge of the subject feels 
that the case cannot be treated without knowing the identity of the study vaccine. 
If emergency unblinding is deemed to be necessary, and time permitting, the investigator is 
encouraged to discuss with the sponsor prior to retrieving the subject’s assigned vaccine code. 
6.6 
Delay of MenA vaccination 
At the time of signing of the agreement for delay of vaccination, a sequential ID number will be 
assigned to the child on a pre-screening log. 
The pre-screening agreement is not a consent or confirmation of the subject’s participation in the 
study. After signing the agreement, investigator will schedule a recruitment visit (Visit 1) at 12 
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months of age and provide parents/guardians a site card with date and time of the planned visit 
and a confirmation of meningococcal vaccination deferral. 
Every child who has delayed the MenAfriVac will be followed by the site until the child is either 
enrolled in the study or receives the MenAfriVac dose according to the EPI.  This will need to 
be documented in the source and the CRF. 
 
6.7 
Study visits 
The schedules of evaluations and procedures that must be performed at specific time points are 
described in the following sections. The Time and Event table (Table 3.1-2) summarizes the 
frequency and timings of various baseline, immunogenicity and safety evaluations. 
6.7.1 Visit #1 (Day 0): screening, enrolment, blood draw and first vaccination 
After the subject’s parent/guardian has consented to participate in the study and informed 
consent is signed, screening procedures will be performed for all subjects and will include the 
following: 
- 
Entry of the subject ID in the screening log 
- 
Confirm that the individual meets ALL inclusion and NO exclusion criteria (refer to sections 
4.1 and 4.2 for further details). 
- 
Review/collect demographic data such as age, gender and ethnicity. 
- 
Review/collect medical history. 
- 
Review/collect prior/concomitant medications and evidence of prior vaccinations. 
- 
Review of systems: an interview that queries the subject’s parent/guardian as to any clinical 
findings the subject has experienced across each organ system. The questions tend to be 
grouped by system organ class and are intended to remind the parent/guardian of any 
forgotten or medical conditions that may be relevant. 
- 
Perform a general physical examination including measurement of body temperature, 
height, weight, and resting vital signs: heart rate and respiratory rate. The height and 
weight need to be recorded in source documents. 
- 
Note: If the subject’s body temperature1 is ≥37.5°C, vaccination must be postponed until 
three days after the fever has resolved. Vaccination is also postponed for any clinically 
significant acute infection and/or systemic antibiotic use within 3 days (see section 4.4 for 
further details). 
- 
Perform Rapid Diagnostic Test for malaria. In case of a positive result, vaccination should 
be postponed until at least five days after completing treatment as per national guidelines.  
                                                 
 
1Axillary measurement of temperature with a digital thermometer is the preferred route for temperature 
measurement in this study; other routes of measurement are acceptable if axillary measurement is not 
possible. 
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Eligibility criteria must be reviewed on the day of vaccination. All screening procedures must 
be documented in the source documents.   
In the event that the individual is determined ineligible for study participation, he/she is 
considered a “screen failure”. The reason for screen failure must be documented in the Screening 
Log.  The individual should receive meningococcal group A vaccination, if it was not 
administered previously. 
Following procedures will be performed in case of eligible subjects  
 Study personnel will take a photo of subject and his/her parent/guardian for the study 
identification card. This study identification card and a copy of consent form will be given 
to each subject’s parent(s)/guardian(s). Both documents will have phone numbers with 24 
hours access in case of emergency.  
 Collect blood sample (approximately 5 mL) for serology testing. Refer to section 7.2 for 
further details regarding general handling of blood sample. 
 Unblinded staff will perform subject randomization (refer to section 6.5.1 for further details) 
and prepare vaccine following assigned study group. 
After confirming eligibility and enrolling subject into the study on Visit 1, study vaccination will 
be performed by unblinded study nurse according to the assigned study vaccine and according 
to the procedures described in section 6.5.2. 
After vaccination, the subject will be observed for at least 30 minutes for any immediate post-
vaccination reactions, with appropriate medical treatment readily available in case of a rare 
anaphylactic reaction following the administration of vaccines. Solicited local and systemic AEs, 
any unsolicited AEs, vital signs and body temperature will be recorded. All safety data collected 
within 30 minutes post-vaccination should be recorded in the subject’s source documents. 
. 
After all procedures have been completed, the investigator will remind the subject’s 
parents/guardians about safety evaluation during daily home visits within 6 days following study 
vaccination that will be performed by trained staff under investigator’s supervision and 
documented on the home visit worksheets.  
The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed. 
The subject’s parent/guardian will be reminded to contact the site if there are any questions. In 
addition, the subject’s parent/guardian will get an instruction to contact the site immediately if 
the subject has a medical condition that leads to a hospitalization or an emergency room visit. 
Subject’s parents/guardians will be reminded of the study Visit 2 (7 days after vaccination), 
which will be conducted by a designated medical staff at the site clinic or the subject’s home. 
6.7.2 Visit #2(Day 7[+3]): reactogenicity assessment 
Study subjects will return for follow-up evaluations to the clinical study site 7 days following 
vaccination. Alternatively, a home visit may be performed by a medically qualified site 
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personnel.  At this visit, investigator or delegate will perform the following procedures and 
evaluations in the following order: 
1. 
Review of solicited and unsolicited AEs collected during days 1-6 after vaccination 
using home visit worksheets; 
2. 
Assessment of any ongoing solicited AEs on Day 7 post-vaccination, including 
measurement of body temperature (note that all ongoing solicited AEs beyond day 7 
must be followed up daily by site staff until resolution); 
3. 
Medical interview of subject’s parents/guardians to assess any unsolicited AEs, SAEs 
since previous study visit; 
4. 
Collection of concomitant medications and vaccinations; 
5. 
Physical examination including assessment of vital signs (as in Visit 1). 
The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed.  
The subjects’ parents/guardians will be reminded to contact the site in case of any questions and 
to contact the site immediately if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. 
The investigator will remind the subject’s parents/guardians about weekly safety evaluations that 
will be performed by trained site staff at subject’s home or by phone. Information about 
unsolicited AEs will be documented on the home visit worksheets. 
All subject’s parents/guardians will be reminded to return to the clinic 28 days (0/+14 days) after 
vaccination for Visit 3.  
6.7.3 Visit # 3 (Day 28 [+14]): blood draw  
Study subjects will return for follow-up evaluations to the clinical study site 28 days following 
the first vaccination. At this visit, investigator or delegate will perform the following procedures 
and evaluations in the following order: 
1. 
Review of any unsolicited AEs collected during weekly contacts using home visit 
worksheets. 
2. 
Medical interview of subject’s parents/guardians to determine if any unsolicited AEs or 
SAEs occurred and if any concomitant medications or vaccines were taken / received 
since the last study visit. 
3. 
Check any ongoing AEs and concomitant medications since the last study visit (Visit 2) 
and record the resolution date (the end date), if available, in the source documents and 
CRF. 
4. 
Physical examination including assessment of vital signs (as in Visit 1). 
5. 
Check criteria for blood draw delay as specified in section 4.4. If criteria for blood draw 
delay are applied, re-schedule blood draw. 
6. 
Collection of blood sample (approximately 5 mL) for serology testing. Details regarding 
the volume of blood and testing to be performed are in section 7.   
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The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed. 
The subjects’ parents/guardians will be reminded to contact the site in case of any questions and 
to contact the site immediately if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit.  
All subject’s parents/guardians will be reminded to return to the clinic 84 days (-14/+14 days) 
after vaccination for Visit 4. 
6.7.4 Visit #4 (Day 84 [-14/+14]): blood draw and second vaccination 
Study subjects will return for follow-up evaluations to the clinical study site 84 days following 
the first vaccination. At this visit, investigator or delegate will perform the following procedures 
and evaluations in the following order: 
1. 
Medical interview of subject’s parents/guardians to determine if any SAEs occurred and 
if any concomitant medications or vaccines were taken / received since the last study 
visit. 
2. 
Check any ongoing AEs and concomitant medications since the last study visit (Visit 3) 
and record the resolution date (the end date), if available, in the source documents and 
CRF. 
3. 
Physical examination including assessment of vital signs (as in Visit 1). 
4. 
Check criteria for blood draw delay as specified in section 4.4. If criteria for blood draw 
delay are applied, re-schedule blood draw and second vaccination. 
5. 
Perform Rapid Diagnostic Test for malaria. In case of a positive result, vaccination 
should be postponed until at least five days after completing treatment as per national 
guidelines. 
6. 
Collection of blood sample (approximately 5 mL) for serology testing. Details regarding 
the volume of blood and testing to be performed are in section 7.   
7. 
Check any contraindication for study vaccination or criteria for vaccination delay as 
specified in sections 4.3 and 4.4. 
8. 
If subject eligible for study vaccination, study vaccine will be administered by unblinded 
study nurse according to the procedures described in sections 5.3 and 6.5.2. 
9. 
After vaccination, the subject will be observed for at least 30 minutes for any immediate 
post-vaccination reactions, with appropriate medical treatment readily available in case 
of a rare anaphylactic reaction following the administration of vaccines. Solicited local 
and systemic AEs, any unsolicited AEs, vital signs and body temperature will be 
recorded. All safety data collected within 30 minutes post-vaccination should be recorded 
in the subject’s source documents. 
After all procedures have been completed, the investigator will remind the subject’s 
parents/guardians about safety evaluation during daily home visits within 6 days following 
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second vaccination that will be performed by trained staff under investigator’s supervision and 
documented on the home visit worksheets.  
The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed. 
The subjects’ parents/guardians will be reminded to contact the site in case of any questions and 
to contact the site immediately if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit.  
All subject’s parents/guardians will be reminded of study visit 7 days (+3 days) after the second 
vaccination (Visit 5), which will be conducted by a designated medical staff at the site clinic or 
the subject’s home. 
6.7.5 Visit #5 (7 days after Visit 4 [+3]): reactogenicity assessment 
Study subjects will return for follow-up evaluations at study site 7 days following the second 
vaccination. Alternatively, a home visit may be performed by a medically qualified site personal. 
At this visit, investigator or delegate will perform the following procedures and evaluations in 
the following order: 
1. 
Review of solicited and unsolicited AEs collected during days 1-6 after second 
vaccination using home visit worksheets. 
2. 
Assessment of any ongoing solicited AEs 7 days post second dose, including 
measurement of body temperature (note that all ongoing solicited AEs beyond day 
7 must be followed up daily by site staff until resolution). 
3. 
Medical interview of subject’s parents/guardians to assess any unsolicited AEs, 
SAEs since previous study visit. 
4. 
Collection of concomitant medications and vaccinations. 
5. 
Physical examination including assessment of vital signs (as in Visit 1). 
The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed.  
The subjects’ parent/guardian will be reminded to contact the site in case of any questions and 
to contact the site immediately if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. 
The investigator will remind the subject’s parents/guardians about two weekly safety evaluations 
that will be performed by trained site staff at subject’s home or by phone. Information about 
unsolicited AEs will be documented on the home visit worksheets. 
All subject’s parent(s)/guardian(s) will be reminded to return to the clinic 28 days (0/+14 days) 
after the second vaccination for Visit 6.  
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6.7.6 Visit # 6 (28 days after Visit 4 [+14]): blood draw 
Study subjects will return for follow-up evaluations to the clinical study site 28 days following 
the second vaccination. At this visit, investigator or delegate will perform the following 
procedures and evaluations in the following order: 
1. 
Review of any unsolicited AEs collected during weekly contacts using home visit 
worksheets. 
2. 
Medical interview of subject’s parents/guardians to determine if any unsolicited AEs or 
SAEs occurred and if any concomitant medications or vaccines were taken / received 
since the last study visit. 
3. 
Check any ongoing AEs and concomitant medications since the last study visit (Visit 5) 
and record the resolution date (the end date), if available, in the source documents and 
eCRF. 
4. 
Physical examination including assessment of vital signs (as in Visit 1). 
5. 
Check criteria for blood draw delay as specified in section 4.4. If criteria for blood draw 
delay are applied, re-schedule blood draw. 
6. 
Collection of blood sample (approximately 5 mL) for serology testing. Details 
regarding the volume of blood and testing to be performed are in section 7.   
The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed. 
The subjects’ parents/guardians will be reminded to contact the site in case of any questions and 
to contact the site immediately if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit.  
All subject’s parents/guardians will be reminded to return to the clinic 84 days (-14/+14 days) 
after the second vaccination for Visit 7. 
6.7.7 Visit # 7 (84 days after Visit 4 [-14/+14]): study completion 
Study subjects will return to the clinical study site 84 days following the second vaccination for 
the end of study visit. At this visit, investigator or delegate will perform the following procedures 
and evaluations in the following order: 
1. 
Medical interview of subject’s parents/guardians to determine if SAEs occurred and if 
any concomitant medications or vaccines were taken / received since the last study 
visit. 
2. 
Check any ongoing AEs and concomitant medications since the last study visit (Visit 6) 
and record the resolution date (the end date), if available, in the source documents and 
eCRF. 
3. 
Physical examination including assessment of vital signs (as in Visit 1). 
The investigator or a delegate should ensure that all information is recorded in the source 
documents and accurately transcribed in the eCRF as soon as possible after the subject’s visit 
has been completed. 
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After collection of safety information, the site staff will review the plan of when information 
relating to the subject’s participation in the study may be available (e.g., study results and 
treatment assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the subject’s 
parent/guardian chooses to share this information. 
After this visit, the subject’s participation in the study will be completed. Source records will be 
completed and all information will be recorded in the eCRF (including “Study Termination” 
page). 
6.8 
Subject Withdrawal Criteria 
A subject may discontinue study participation at any time prior to the last planned study visit. 
This is referred to as premature withdrawal from the study (see below for a description of 
withdrawal from study vaccine which refers to those subjects who do not receive the second 
vaccination but continue in the study for safety follow-up and/or other procedures). 
From the analysis perspective, a ‘premature withdrawal’ from the study refers to any subject 
who was not available for the termination visit foreseen in the protocol (Visit 7). A subject is 
considered a ‘premature withdrawal’ from the study when no study procedure has occurred, no 
follow-up has been performed and no further information has been collected from this subject 
from the date of premature withdrawal / last contact. 
The reasons for premature withdrawal from the study include: 
 Adverse event 
 Death 
 Withdrawal of consent 
 Lost to follow-up 
 Administration reason 
 Protocol deviation 
 Other 
NOTE: Before entering any alternate category as the reason for the subject’s discontinuation 
from the study, the investigator should make every effort to investigate whether or not safety 
concerns (adverse event or death) may have been related to the subject’s discontinuation from 
the study. If a safety concern has been associated with the subject’s discontinuation, this must 
be described on the Termination eCRF page, even if it is not the primary reason for the subject’s 
discontinuation. 
Adverse event as reason for premature study withdrawal: 
For any subject withdrawing from study participation prior to Visit 7 (study completion visit), it 
is important to determine if an AE was associated with the reason for discontinuing the study. 
This AE must be identified on the CRF page by indicating “Withdrawn from study due to AE”. 
Death as reason for premature study withdrawal: 
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For any subject withdrawn from study participation due to death, this should be noted on the 
Termination eCRF page and the associated SAE that led to the death must be reported. 
Withdrawal of consent as reason for premature study withdrawal: 
The parents/guardians can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. 
Reason for early termination should be deemed as “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (i.e., reason other than AE). If the 
parent/guardian intends to withdraw consent from the study, the investigator should clarify if the 
subject will withdraw completely from the study or if the subject will continue study 
participation for safety or a subset of other study procedures. If complete withdrawal from the 
study by the subject is specified, no further study interventions will be performed with the 
subject. 
Date of Subject Termination: 
The date of termination is the date of the last contact (clinic or home visit or telephone contact) 
in which the subject’s health status was assessed or, in cases where the subject does not agree to 
any further safety follow-up; it is the date consent is withdrawn. 
Lost to follow-up as reason for premature study withdrawal: 
For subjects who fail to show up for scheduled visits (clinic or home visit), study staff are 
encouraged to make at least three documented attempts to contact the subject’s parents/guardians 
and encourage the completion of study termination procedures. These efforts to contact the 
subject’s parents/guardians should be recorded in the source documents. The termination date 
for the subject to be captured on the Termination eCRF page is the date of the last successful 
visit (clinic or telephone) with the subject. 
Administrative reason as reason for premature study withdrawal: 
For subjects who are withdrawn from the study due to sponsor decision (e.g., meeting pre-
specified withdrawal criteria or termination of study by the sponsor), this reason should be noted 
in the Termination eCRF page and any ongoing AEs at the time of study withdrawal must be 
followed until resolution/stabilization. 
Protocol deviation as reason for premature study withdrawal: 
In general, subjects associated with protocol deviations may remain in the study unless 
continuation in the study jeopardizes the subject’s health, safety, or rights. For subjects who are 
withdrawn from the study due to receipt of an excluded medication/vaccination or due to 
significant protocol non-compliance, this reason should be noted in the Termination eCRF page.  
Any ongoing AEs at the time of study withdrawal must be followed until resolution/stabilization. 
If a subject is withdrawn prematurely from the study for a reason other than those outlined above, 
this reason must be documented in the Termination eCRF page. 
In addition, subject may be “withdrawal of study vaccination”. Subjects may be withdrawn from 
the second study vaccination for several reasons including but not limited to: AE related to earlier 
vaccinations or failure to meet criteria for repeat vaccination (see section 4.3). Subjects who are 
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withdrawn from study vaccination should be encouraged to continue in the study for safety 
follow-up and other procedures as appropriate until the scheduled termination visit (Visit 7).  
Withdrawn subjects will not be replaced. 
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue this study at any time. If the clinical study is prematurely terminated, the investigator 
is to promptly inform the study subjects and local EC/IRB and should assure appropriate therapy 
and follow up for the subjects. All procedures and requirements pertaining to the archiving of 
study documents should be followed. All other study materials (study medication/vaccines, etc.) 
must be returned to the sponsor. 
6.9 
Prior and Concomitant therapy 
6.9.1 Prior Medications and Vaccines 
The following are considered prior medications for this protocol: 
 any investigational or non-registered product (drug or vaccine) received prior to enrolment; 
 any vaccine administered prior to enrolment; 
 any immunosuppressant or other immune-modifying drug including systemic steroids, 
within 3 months prior to enrolment; 
 any blood, blood product and/or plasma derivative or any parenteral immunoglobulin 
preparation within 3 months prior to enrolment; 
 any systemic antibiotic within 3 days prior to enrolment; 
 Any antipyretic/analgesic within 24 hours prior to first vaccination. 
If these medications were administered to the subject within the specified window prior to the 
first study vaccination, they must be recorded on the Concomitant Medications page of eCRF. 
 
6.9.2 Concomitant Medications and Vaccines 
At each study visit, the investigator will ask the parents about any prescription or over-the-
counter medication(s) taken since the last visit. Any medications taken at any time during the 
study period must be recorded on source documents and the case report form with trade and/or 
generic name, indication, dose, start and end dates.   
Any treatments and/or medications specifically contraindicated, e.g., any investigational or non-
registered product, any immunosuppressant and immune-modifying drug including systemic 
steroids, any immunoglobulin and blood product should be checked at each study visit 
subsequent to the study vaccination. If any became applicable during the study, it will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the per-
protocol analysis. See section 9.4 for definition of study populations to be evaluated. 
Any vaccine not foreseen in the study protocol in the period starting at Visit 1 (Day 0) and ending 
at Visit 7 must be recorded in the eCRF. 
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6.9.3 Prophylactic antipyretics / analgesics 
The use of prophylactic medications for potential adverse reactions during the study period will 
be discouraged.  
The use of antipyretics and/or analgesic medications within 24 hours prior to the study 
vaccination must be recorded in eCRF. The administration of antipyretics / analgesics within 7 
days after study vaccination must be identified and the reason for their use (prophylaxis versus 
treatment) must be described in the source documents and Concomitant Medications eCRF. 
Medications taken for prophylaxis are those administered in the absence of any symptom and 
intended to prevent the onset of post-vaccination symptoms. Medications taken for treatment are 
intended to reduce or eliminate the symptoms that are present. 
7 
ASSESSMENTS OF IMMUNOGENICITY 
The functional measure of immunogenicity used in this study, Serum Bactericidal Activity 
(SBA) Assay, is a measure of the ability of antibodies, in concert with complement, to kill 
meningococci. Two serum bactericidal assays will be employed in this study: SBA with rabbit 
complement (rSBA) and SBA with exogenous human complement (hSBA) for N. meningitidis 
serogroups A, C, W, Y and X test strains. 
The SBAs used to measure immunogenicity in this study are standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and extent 
of the immune response). 
However, the primary assay selected for this study will be the rSBA assay. A validated method 
will be used for groups A, C, Y and W. The assay for group X will be validated using samples 
from the Phase I clinical trial.  
In recent years, Serum Bactericidal Activity using human complement (hSBA) is deemed to 
represent a more specific assay for measuring high avidity functional antibody, although a good 
correlation is shown with SBA using rabbit complement.32 However, complement pooling and 
validation steps for hSBA imply increased complexity and costs. Hence hSBA in this study will 
be pursued only as an exploratory endpoint. The laboratory to conduct hSBA analysis has not 
been identified at this stage. 
7.1 
Specification of the immunogenicity parameters 
The measures of immunogenicity using rSBA assay will be rSBA GMTs, the percentages of 
subjects who achieve rSBA titers ≥ 8 and ≥ 128 and the percentage of subjects with four-fold 
rises in rSBA titer against serogroups A, C, W, Y and X. 
A post-vaccination rSBA titer ≥ 8 is used as an accepted correlate of protection against invasive 
meningococcal disease caused by serogroup C.33The rSBA titer ≥ 8 has been considered a 
surrogate level of short term protection and a titer ≥ 128 a surrogate of long term protection.34 
Immunogenicity testing for meningococcal polysaccharide A, C, Y, W, and X specific antibodies 
using rSBA assay will be performed on sera collected at baseline (Visit Day 0), at one and three 
months after the first vaccination (Visits Day 28 and Day 84) and at one month after the second 
vaccination (Visit Day 112). 
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The measures of immunogenicity using hSBA assay will be hSBA GMTs, the percentages of 
subjects who achieve hSBA titers ≥ 8 and the percentages of subjects with hSBA seroresponse 
against serogroups A, C, W, Y and X. 
A post-vaccination hSBA titer ≥ 8 is used as an accepted correlate of protection against invasive 
meningococcal disease.35, 36 
Immunogenicity testing using hSBA assay will be conducted in a randomly selected subset of 
subjects (50 subjects per arm) at baseline (Visit Day 0), at one month after the first vaccination 
(Visit Day 28) and at one month after the second vaccination (Visit Day 112). 
Table 7.1-1: Immunological readouts and priority testing  
Study Visit 
Sample time 
point 
Group 
Planned 
Number of 
subjects 
Assay (serogroup) 
Priority 
Rank 
Visits Day 0,  
Day 28,  
Day 84 and 
Day 112 
Baseline, 
1 month post-
Dose 1, 
Pre-Dose 2, 
1 month post-
Dose 2 
All groups 
375 
rSBA (serogroup A) 
1 
375 
rSBA (serogroup Y) 
2 
375 
rSBA (serogroup X) 
3 
375 
rSBA (serogroup C) 
4 
375 
rSBA (serogroup W) 
5 
Visits Day 0,  
Day 28 and 
Day 112 
Baseline, 
1 month post-
Dose 1, 
1 month post-
Dose 2 
All groups 
150 
hSBA (serogroup A) 
6 
150 
hSBA (serogroup Y) 
7 
150 
hSBA (serogroup X) 
8 
150 
hSBA (serogroup C) 
9 
150 
hSBA (serogroup W) 10 
Collected samples may be used in other assays, for test improvement or development of 
analytical methods related to the study vaccines or the disease under evaluation to allow a more 
reliable measurement of the vaccine response. Any sample testing will be done in line with the 
study protocol and with the consent of the individual subject’s parent / guardian.  
 
7.2 
Methods for processing, labelling and storage of serum samples 
An approximately 5 mL sample of blood will be drawn from all subjects at Visits Day 0, Day 
28, Day 84 and Day 112. The blood samples should be collected before the study vaccination 
when applicable. The blood volume of 5 mL at each time point is needed in order to provide the 
necessary serum volume (approximately 40% of the blood draw volume) for the serology assays. 
In order to minimize pain an anesthetic cream or patch (e.g. EMLA adhesives or cream) may be 
used at the site of blood sample draw, according to local practice. Not more than two attempts 
should be made to draw the required volume of blood. 
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The blood will be processed and aliquoted according to the Clinical Specimen Lab Manual. All 
aliquots will be stored at a temperature of -20°C or below. Each serum tube will be labeled with 
the labels provided by the Sponsor. Serum samples will be sent to the Sponsor or will be collected 
by a representative of the Sponsor. 
Serum samples will be labeled by a code that only the study site can link to the subject name. 
All stored research samples will be logged into a secure database. Any use of the samples will 
be documented. Complete instructions for labeling and storage of serum samples are included in 
the Clinical Specimen Lab Manual, which is stored in the Investigator Site File. 
Testing of samples will be performed at the Vaccine Evaluation Unit at Public Health England 
(PHE) in Manchester UK or a delegate laboratory. Samples may be stored at several different 
repositories and laboratories to complete the analyses required to meet study primary, secondary 
and exploratory analyses. 
Samples will be retained in accordance with regulatory guidance for retention of essential study 
documents as described in section 12. Subjects will be informed and asked to agree to long-term 
storage of specimens for use in future research through a specific consent form. At study closure, 
PATH and SIIPL will designate a storage facility for the retention of the consented samples. 
Should future research on the samples be initiated after study closure, a specific new study 
protocol will be developed and submitted to relevant Scientific and Ethics Committees following 
the informed consent requirements.  
 
7.3 
Biohazard Containment 
As transmission of blood-borne pathogens can occur through contact with contaminated needles, 
blood, and blood products, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and shipping and handling of all specimens for this study, as 
recommended by the United States Centers for Disease Control and Prevention (CDC). All 
biological specimens will be transported using packaging mandated by 42 CFR Part 72. All 
dangerous goods materials, including diagnostic specimens and infectious substances, must be 
transported according to instructions detailed in the International Air Transport Association 
(IATA) Dangerous Goods Regulations. 
Biohazardous waste will be contained according to institutional, transportation/carrier, and all 
other applicable regulations. 
8 
ASSESSMENT OF SAFETY 
8.1 
Specification of safety parameters 
Safety assessment includes occurrence of solicited local and systemic adverse reactions within 
7 days of each vaccine dose; unsolicited adverse events within 28 days after each vaccine dose, 
AEs leading to withdrawal and SAE throughout the entire study period.  
8.2 
Solicited adverse events 
The term “reactogenicity” refers to selected signs and symptoms (“adverse events”) occurring in 
the hours and days following a vaccination, to be collected at the study site at 30 (+15) minutes 
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post vaccination and by site staff during home visits for 6 consecutive days, using pre-defined 
home visit worksheets (i.e., solicited adverse events). 
The following adverse events are included in the home visit worksheet. Each adverse event is to 
be assessed using severity grading scale based on the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events provided in Appendix II. The grades 
are from Mild (Grade 1) to Life Threatening (Grade 4). In case a severe solicited AE is reported, 
the subject will be further assessed by the healthcare professional and the intensity score will be 
verified.  
The presence of any ongoing solicited AEs will be assessed by healthcare professional at site or 
home visit 7 days after each study vaccination. In case of ongoing solicited AEs, the site staff 
will continue contacting the subject daily until AE resolution. The last day of solicited symptom 
presence and the maximum intensity beyond 7 days post-vaccination will be recorded. 
Following are the local and systemic solicited AEs which are collected during study. 
Solicited local reactions: tenderness, swelling/induration. 
Solicited systemic reactions: irritability, drowsiness, decrease eating, vomiting, and fever. 
 
8.3 
Unsolicited Safety Measurements 
8.3.1 Unsolicited Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product at any dose that does not necessarily 
have to have a causal relationship with this treatment. Therefore, an AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the investigational product. This definition includes intercurrent illnesses 
or injuries and exacerbation of pre-existing conditions. 
As a consistent method for collecting unsolicited AEs, the subject’s parents / guardians should 
be asked a non-leading question such as: 
 ‘Has your child acted differently or felt different in any way since receiving the vaccine or since 
the last study visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g. hospital records, laboratory, and diagnostics reports) relative to the event. The investigator 
will then record all relevant information regarding an unsolicited AE/SAE on the eCRF or SAE 
Report screens as applicable.  
The investigator will attempt to establish a diagnosis pertaining to the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be documented 
as the AE/SAE and not the individual signs/symptoms. 
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The severity of AEs will be determined by the investigator. The AEs will be graded from Mild 
(Grade 1) to Death (Grade 5) based on the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events provided in Appendix II. 
The relationship of the study treatment to an AE will be determined by the investigator based on 
the following definitions: 
1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly indicates an 
alternative explanation. If the subject has not received the vaccine, the timing of the exposure to 
the vaccine and the onset of the AE are not reasonably related in time, or other facts, evidence 
or arguments exist that reasonably suggest an alternative explanation, then the AE is not related. 
2. Related 
The administration of the investigational vaccine and AE are considered reasonably related in 
time and the AE could be explained by exposure to the investigational vaccine or by other causes. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator. Solicited AEs will not be evaluated for relationship to study vaccine – all solicited 
AEs will be considered to be causally related to vaccination.  
The causality assessment is made on the basis of the available information at the reporting time 
point. Assessment of causality can change according to follow-up information. 
The actions taken in response to an unsolicited AE will be coded as below. One or more of these 
actions may be selected: 
0 - No action taken 
1 - Study vaccine temporarily interrupted 
2 - Study vaccine permanently discontinued due to this adverse event 
3 - Concomitant medication taken 
4 - Non-drug therapy given 
5 - Physician visit 
6 - Hospitalization/prolonged hospitalization 
Outcome of any unsolicited AE reported during the study period will be assessed as: 
 Recovered/resolved 
 Recovering/resolving 
 Not recovered/not resolved 
 Recovered with sequelae/resolved with sequelae 
 Fatal (SAEs only) 
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Please note: any solicited adverse event that meets any of the following criteria must also be 
entered as an adverse event on the Adverse Event eCRF: 
- 
Solicited local or systemic adverse event leading to the subject withdrawing from the study 
or the subject being withdrawn from the study by the investigator.  
- 
Solicited local or systemic adverse event that otherwise meets the definition of a serious 
adverse event. 
Treatment of any AE is at the sole discretion of the investigator and according to current good 
medical practice. Any medication administered for the treatment of an AE should be recorded in 
the subject’s eCRF. 
8.3.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose 
results in one or more of the following: 
- 
Death. 
- 
Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate risk 
of death from the event as it occurred); it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
- 
Required or prolonged hospitalization. 
- 
Persistent or significant disability/incapacity (i.e., the event causes a substantial disruption 
of a person’s ability to conduct normal life functions). 
- 
Congenital anomaly/or birth defect. 
- 
An important and significant medical event that may not be immediately life threatening or 
resulting in death or hospitalization but, based upon appropriate medical judgment, may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed 
above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a serious 
adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the SAE form as well as on the AE eCRF. All 
SAEs will be evaluated by the investigator for relationship of the event to study vaccination. 
The relationship of the study vaccination to an SAE will be determined by the investigator based 
on the following definitions: 
 Related/suspected: the SAE is judged by the investigator to be related to the study vaccine 
on the AE eCRF page; 
 Not Related: the SAE is not related if exposure to the study vaccine has not occurred, or 
the occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
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In addition, SAEs will be evaluated by the sponsor or designee for “expectedness.”  An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics or the 
Investigator’s Brochure or an event that is by nature more specific or more severe than a listed 
event. 
In addition, a pre-existing event or condition that results in hospitalization should be recorded 
on the Medical History eCRF.  If the onset of an event occurred before the subject entered the 
trial (e.g., any pre-planned hospitalization for a chronic condition or for non-emergency routine 
visits for a pre-existing condition), the hospitalization would not lead to an AE being classified 
as serious unless, in the view of the investigator, hospitalization was prolonged as a result of 
participation in the clinical trial or was necessary due to a worsening of the pre-existing 
condition. 
8.3.3 Methods for Assessing and Recording AEs and SAEs 
The period of observation for AEs extends from the time the subject signs informed consent until 
he or she completes the final study visit (Visit 7) or terminates the study early. AEs occurring 
after the informed consent form is signed but prior to receiving study vaccine will be documented 
as an adverse event and recorded on the Adverse Events eCRF and within source documents. 
However, AEs occurring prior to receipt of any study vaccine will be analyzed separately from 
“treatment emergent” AEs (AEs occurring after administration of the first study vaccine). 
All AEs meeting criteria for reporting, regardless of severity, will be monitored by the 
investigator until resolution or stabilization. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms subside 
and any abnormal laboratory values have returned to baseline, or until there is a satisfactory 
explanation for the changes observed, or until death, in which case a full pathologist’s report 
should be supplied, if possible. All findings must be reported on an Adverse Events eCRF and 
on the SAE form, if necessary, which is part of the Investigator Site File. All findings in subjects 
experiencing AEs must be reported also in the subject's medical records. 
All SAEs which occur during the course of the study, whether considered to be associated with 
the study vaccination or not, must be reported within 24 hours of the site becoming aware of 
the event by telephone, email or fax to PAREXEL. Contact details for submitting SAEs to 
PAREXEL and instructions for completion of documentation will be provided in a handout 
located in the Investigator Site File. 
The SAE form will always be completed as thoroughly as possible with all available details of 
the event. Even if the investigator does not have all information regarding an SAE, the SAE 
should still be submitted within 24 hours. Once additional relevant information is received, the 
SAE form should be updated within 24 hours. The investigator will always provide an 
assessment of causality at the time of the initial report. 
All SAEs are also to be documented on the Adverse Events eCRF. Any medication or other 
therapeutic measures used to treat the AE will be recorded on the appropriate eCRF(s) in addition 
to the outcome of the AE. 
After receipt of the initial report, representatives of sponsor will contact the investigator if it is 
necessary to obtain further information for assessment of the event. 
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All SAEs must be reported by the investigator to his/her corresponding EC/IRB or applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and adequate 
documentation of this notification must be provided to the sponsor. 
The Sponsor and its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of Suspected Unexpected Serious Adverse Reactions (also referred to as 
“SUSARs”) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other safety signal 
relating to use of one of the study vaccines is reported to the sponsor or its designee, the sponsor 
will communicate the information to the investigator and the investigator will be responsible for 
submitting this information to the EC/IRB and other relevant authorities. 
 
8.4 
Safety Laboratory Measurements 
This study has no safety laboratory measurements.  
8.5 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board will be set up for periodic review of safety 
data during the study conduct. The composition and responsibilities of DSMB members are 
presented in the DSMB charter. 
8.6 
Study pause 
The following study pause rules will pause or halt further vaccinations. However subjects 
already enrolled will continue to be followed for safety during the pause. These pause rules 
refer to suspected adverse reactions and will be triggered if any of the events described below 
are met during the conduct of the study:  
 Rule 1: 1 or more subjects experience any vaccine-related Grade 4 AE or SAE. 
 Rule 2: 1 or more subjects experience the following Grade 3 or greater local reaction 
classified as related to vaccination by the PI: ulceration, necrosis, or sterile abscess at 
the injection site requiring drainage or surgical intervention. 
 Rule 3: ≥ 10.0% of unique subjects experience the same vaccine-related Grade 3 
general solicited reactogenicity after vaccination, with severity and relatedness 
confirmed by the PI. In the case of fever, the episode must last longer than 24 hours and 
occur within 1 week post vaccination, and be confirmed by the PI without evidence of 
other medical causes (e.g., malaria, acute gastroenteritis). *Note: the 10.0% threshold 
will be calculated on an ongoing basis to adjust for a changing number of enrolled 
subjects. 
8.6.1 Study pause procedure 
If pause criteria have been met, the Sponsor Pharmacovigilance team (SIIPL, PATH & 
PAREXEL Medical Monitors) will be notified by the PAREXEL Pharmacovigilance Center 
and a meeting will be convened with the Principal Investigator for an ad hoc review. 
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 If the PI (or designee), the PAREXEL medical monitor, or any member of the Sponsor 
medical team identifies that a pause criterion may have been met or propose the study 
be paused on a discretionary basis, all vaccinations and enrollment will be suspended. 
The Sponsor Pharmacovigilance team will be notified and will expeditiously (within 48 
hours) convene to review all available, relevant information with the PI.  
 The Pharmacovigilance team and the PI reviews will be summarized with consensus 
decision whether the study should continue without change, be modified, or be stopped. 
 The DSMB will be notified if a pause rule has been met and will be kept informed of 
sponsor decision. DSMB may be asked to review pause reasons and events. 
 If at any time, a decision is made to discontinue administration of study product in all 
subjects, expeditious notification will be provided by the Sponsor to the NRA and by 
the PI to the IEC within 48 hours. 
 If the Sponsor with the PI decides to re-start the study after review, enrollment and 
vaccination may resume. The IEC will be notified of this decision. 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Overview and General Considerations 
This study is a Phase 2 observer-blind randomized, controlled clinical trial to assess the safety 
and immunogenicity of the adjuvanted and non-adjuvanted formulations of polyvalent conjugate 
vaccine composed of serogroups A, C, Y, W, and X Neisseria meningitidis capsular 
polysaccharides (NmCV-5). The primary objective is to evaluate the reactogenicity of 
adjuvanted and non-adjuvanted formulations of NmCV-5 vaccine in comparison with the 
licensed comparator (Menactra®). The secondary objectives are to assess safety and the immune 
response of adjuvanted and non-adjuvanted formulations of NmCV-5 vaccine. 
A detailed statistical analysis plan for preparation of the final study report will be created and 
made final prior to database lock and unblinding. All statistical analyses will be performed using 
SAS® software Version 9.3 or later. 
Medical history and AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). The frequency count and percentage of subjects will be 
summarized according to the coded terms of system organ class and preferred term. Subject-
wise data listing will be provided. 
9.2 
Randomization scheme 
The randomization scheme will be maintained by the Statistics and Product Support Services 
(SPSS) at PAREXEL. Subjects will be enrolled into the study and randomized as per a pre-
defined randomization list. The randomization list will include treatment assignment for 
subjects. It will be generated electronically by SPSS at PAREXEL and a print out of the same 
will be provided only to the designated unblinded site personnel. 
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9.3 
Sample size and power 
With 150 enrolled subjects per NmCV-5 arm and 75 subjects in the MenACWY-D arm, the 
study has a power of 80% to detect a 15.4% difference in proportion of subjects with severe 
solicited AEs reported within 7 days after any study vaccination between each NmCV-5 group 
and the MenACWY-D group, assuming the rate of severe reactions in the MenACWY-D group 
of 5%, a drop-out rate of 10%, and alpha of 0.05. 
Power to show comparability of immune response in terms of the percentage of subjects with 
antibody titer greater than or equal to the cut-off level, based on various group sizes and equal 
expected underlying percentages, was done using one-sided Miettinen and Nurminentest [21] 
and is provided in Table 9.3-1.  
Assuming the expected proportion of subjects with antibody response greater than or equal to 
the cut-off (e.g. rSBA titer ≥ 8) is at least 95% for each of the vaccine serogroups in the NmCV-
5 non-adjuvanted and MenACWY-D groups, then with 135 / 67 evaluable subjects per group, 
the study has power of 86% to demonstrate that the lower limit (LL) of 95% confidence interval 
(CI) for difference between the non-adjuvanted NmCV-5 group and MenACWY-D group is 
above -10% (commonly accepted non-inferiority margin) for each serogroup.  With the same 
assumptions, the overall power to demonstrate that the lower limit (LL) of 95% confidence 
interval (CI) for difference between the non-adjuvanted NmCV-5 group and MenACWY-D 
group is above -10% for all serogroups would be at least 46%. 
Table 9.3-1: Power to show comparability of immune response in terms of the percentage 
of subjects with antibody titer greater than or equal to the cut-off level, based on various 
group sizes and equal true underlying percentages 
Expected percentage 
of subjects who 
achieve titers ≥ cut-
off 
Number of 
evaluable 
subjects 
per group 
Power to demonstrate 
that the LL of 95% CI of 
the difference between 
groups is > -10% for an 
individual serogroup 
Overall power to demonstrate 
that the LL of 95% CI of the 
difference between groups is 
> -10% for all serogroups 
85% 
120 vs. 60 
47% 
2% 
135 vs. 67 
52% 
4% 
150 vs. 75 
56% 
5% 
90% 
120 vs. 60 
61% 
8% 
135 vs. 67 
65% 
12% 
150 vs. 75 
70% 
17% 
95% 
120 vs. 60 
81% 
36% 
135 vs. 67 
86% 
46% 
150 vs. 75 
89% 
56% 
Power to show that the ratio of rSBA GMT in the adjuvanted NmCV-5 group to that in the non-
adjuvanted NmCV-5 group is at least 2 was calculated using a two-sample t-test according to 
different expected rSBA GMTs in the non-adjuvanted NmCV-5 group and assumed standard 
deviations (SD) of log2-transferred rSBA titers and is provided in Table 9.3-2. 
 
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Table 9.3-2: Power to detect at least a 2-fold increase of rSBA GMTs after a 2-dose series 
with the adjuvanted NmCV-5 vs. non-adjuvantedNmCV-5, based on various group sizes 
and different assumed SD of log 2 rSBA titers 
Expected rSBA 
GMTs in non-
adjuvanted 
NmCV-5 group at 
1 month post-
Dose 2 
Assumed 
SD of log2 
rSBA 
titers 
Number of 
evaluable 
subjects per 
group 
Power to detect at 
least a 2-fold rSBA 
GMTs in adjuvanted 
NmCV-5 vs non-
adjuvanted NmCV-5 
for an individual 
serogroup 
Overall power to 
detect at least a 2-
fold rSBA GMTs in 
adjuvanted NmCV-5 
vs non-adjuvanted 
NmCV-5 for all 
serogroups 
500 to 1500 for 
various 
serogroups 
1.5 
150 vs. 150 
>99% 
> 99% 
135 vs. 135 
>99% 
> 99% 
120 vs. 120 
>99% 
> 99% 
2.0 
150 vs. 150 
99% 
95% 
135 vs. 135 
98% 
92% 
120 vs. 120 
97% 
86% 
2.5 
150 vs. 150 
93% 
70% 
135 vs. 135 
91% 
61% 
120 vs. 120 
87% 
50% 
3.0 
150 vs. 150 
82% 
37% 
135 vs. 135 
78% 
29% 
120 vs. 120 
73% 
21% 
3.5 
150 vs. 150 
69% 
16% 
135 vs. 135 
65% 
11% 
120 vs. 120 
60% 
8% 
Assuming the true standard deviation of log2 rSBA titers is below than or equal to 2.5 for each 
of the five vaccine serogroups, with 135 evaluable subjects per group, the study has power of 
91% to detect a 2-fold rSBA GMT increase in the adjuvanted NmCV-5 vs non-adjuvanted 
NmCV-5 for each serogroup. With the same assumptions, the overall power to detect a 2-fold 
rSBA GMT increase in the adjuvanted NmCV-5 vs non-adjuvanted NmCV-5 for all serogroups 
would be at least 61%. 
9.4 
Analysis Populations 
9.4.1 Enrolled Population 
All screened subjects who provide informed consent and received a subject ID, regardless of the 
subject’s randomization and treatment status in the trial. 
9.4.2 Exposed Population 
All subjects in the enrolled population who receive a study vaccination. 
9.4.3 Immunogenicity Populations 
Immunogenicity analyses will be performed on both the Full Analysis (FA) Population and Per 
Protocol (PP) Population.  
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Full Analysis Population   
All subjects in the enrolled population who were randomized, received a study vaccination, and 
provide an evaluable serum sample at least at one time point post-vaccination. 
The analysis based on this population will serve as supportive results for all secondary 
immunogenicity objectives.  
Subjects in the FA population will be analyzed “as randomized” (i.e., according to the vaccine a 
subject was designated to receive, which may be different from the vaccine the subject actually 
received).  
Per Protocol Population 
All subjects in the FA Population who correctly received two doses of study vaccine per 
randomization with no major protocol violations that are determined to potentially interfere with 
the immunogenicity assessment of the study vaccines. This population will serve as the primary 
analysis population for all immunogenicity objectives. 
Due to unpredictability of some irregularities, the criteria for exclusion of subjects from the Per 
Protocol Population will be determined before the database is locked and will be based on the 
blind review of protocol violations.  
9.4.4 Safety Population 
All subjects in the enrolled population who received a study vaccination and had any safety data 
available. 
Subjects will be analyzed as "treated" (i.e., according to the actual vaccine received at the first 
dose). All safety analyses will be performed using this population. The denominators for 
different safety endpoints may vary according to the number of subjects with available data for 
the specific endpoint. For example, the solicited adverse event endpoints will be based only on 
those who have the corresponding CRF data regardless of other safety follow-up data. 
9.5 
Analysis Plan 
9.5.1 Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for age, 
height and weight at enrolment will be calculated by overall and by vaccine group. 
Distributions of subjects by gender, race and ethnicity will be summarized overall and by vaccine 
group. 
Using the World Health Organization Drug Dictionary (WHO DD), prior and concomitant 
medications will be tabulated by drug classification, preferred drug name and study group. 
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9.5.2 Statistical Methods for Primary Objective 
Precision estimates of the percentages of subjects with at least one severe solicited AE reported 
within 7 days after any vaccination will be computed by vaccine group using the two-sided 95% 
Clopper-Pearson confidence intervals.37 
The differences between groups (Group NmCV-5_non-adjuvanted - Group MenACWY-D and 
Group NmCV-5_adjuvanted - Group MenACWY-D) in the percentages of subjects with at least 
one severe solicited AE reported within 7 days after any vaccination will be provided along with 
their two-sided 95% CIs obtained by the Miettinen and Nurminen method.38 
The analyses of primary endpoint will be descriptive.   
9.5.3 Statistical Methods for Secondary Objectives 
9.5.3.1 Secondary Safety Objectives 
The design of the study allows a comparison among groups after each vaccination and after any 
vaccination. 
9.5.3.1.1 Analysis of Extent of Exposure 
The extent of exposure for subjects in each study group will be described. 
9.5.3.1.2 Analysis of Solicited Adverse Events 
All solicited adverse events will be summarized according to defined severity grading scales. 
Frequencies and percentages of subjects experiencing each adverse event will be presented for 
each symptom severity. Summary tables showing the occurrence of any local or systemic adverse 
event overall and at each time point will also be presented. The difference between groups 
(Group NmCV-5_non-adjuvanted - Group MenACWY-D and Group NmCV-5_adjuvanted - 
Group MenACWY-D) in percentage of subjects with at least one local or systemic adverse event 
overall and at each time point will be calculated along with their two-sided 95% CIs obtained 
using the Miettinen and Nurminen method. 
Post-vaccination solicited adverse events reported from Day 0 to Day 6 and from Day 84 to Day 
90 will be summarized by maximal severity and by vaccine group. Separate analysis will be 
performed for solicited AEs reported 30 minutes after vaccination. All the solicited reactions 
occurring up to 7 days after each vaccination will be summarized according to severity grading 
based on the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events provided in Appendix II. 
Each solicited local and systemic adverse event will also be further summarized as “none” versus 
“any”. 
Use of antipyretics and analgesics will be summarized by frequency, by type of use (prophylactic 
versus treatment) and percentage of subjects reporting use. 
Body temperature will be summarized separately according to the 2 schemes described below 
and will be broken down according to route of measurement:  
▫ 
by 0.5 °C increments from 36.0°C up to ≥40°C 
▫ 
<36.0, ≥36.0-<37.0, ≥37.0-<38.0, ≥ 38.0-<39.0, ≥39.0-<40, ≥40°C 
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9.5.3.1.3 Analysis of Unsolicited Adverse Events 
All the adverse events occurring during the study, judged either as related, or not related to 
vaccination by the investigator, will be recorded. 
The original verbatim terms used by investigators to identify adverse events in the eCRFs will 
be mapped to preferred terms using the MedDRA dictionary. The adverse events will then be 
grouped by MedDRA preferred terms into frequency tables according to system organ class. All 
reported adverse events, as well as adverse events judged by the investigator as related to study 
vaccine, will be summarized according to system organ class and preferred term within system 
organ class. When an adverse event occurs more than once for a subject, it will be considered as 
multiple events and each event will be presented distinctly.   
The summaries will be presented by period of onset and will include frequency distributions of 
the different adverse events: 
- 
All unsolicited AEs reported within 28 days after each vaccination;  
- 
AEs leading to premature withdrawal from the study during the entire study period; 
- 
SAEs reported during the entire study period. 
The analysis of unsolicited adverse events comprises the following categories: 
- 
Any unsolicited AEs; 
- 
Related unsolicited AEs; 
- 
SAEs; 
- 
Related SAEs; 
- 
Unsolicited AEs leading to withdrawal from the study; 
- 
Unsolicited AEs leading to withdrawal from study vaccination but remaining in the study; 
- 
Unsolicited AEs leading to hospitalization; 
- 
Any AEs leading to death. 
Data listings of all adverse events will be provided by subject.  
9.5.3.2 Analysis of Secondary Immunogenicity Objectives 
For each N. meningitidis serogroup the percentages of subjects with rSBA titers ≥ 8 and rSBA 
titers ≥ 128 and the corresponding exact two-sided 95% CIs based on Clopper-Pearson method 
will be calculated for each study group at baseline, one and three months after the first 
vaccination and one month after the second vaccination.  
The rSBA titers at each visit for each study group will be logarithmically transformed (base10) 
to fulfill the normal distribution assumption. For each N. meningitidis serogroup, the GMTs and 
GMRs (post vaccination / baseline) will be calculated with their associated two-sided 95% CIs, 
by exponentiating the corresponding log-transformed means and their 95% CIs.  
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Percentages of subjects with four-fold titer rise and the corresponding exact two-sided 95% CIs 
based on the Clopper-Pearson method against these serogroups will be calculated for each study 
group at one month after the first vaccination and one month after the second vaccination (Visit 
Day 28 and Visit Day 112). The ratio of GMTs and GMRs between the study groups and the 
corresponding CI will be constructed by exponentiating the mean difference and the confidence 
limits in log10 (titer), using ANOVA. The difference in percentages between groups will be 
provided along with the two-sided 95% CIs that will be constructed using the method of 
Miettinen and Nurminen. In addition, a reverse cumulative distribution plot of each measure will 
be created. 
9.5.4 Statistical Methods for Exploratory Immunogenicity Objective 
For each N. meningitidis serogroup the percentages of subjects with hSBA titers ≥ 8 and the 
corresponding exact two-sided 95% CIs based on Clopper-Pearson method will be calculated for 
each study group at baseline, one month after the first vaccination and one month after the second 
vaccination.  
The hSBA titers at each visit for each study group will be logarithmically transformed (base10) 
to fulfill the normal distribution assumption. For each N. meningitidis serogroup, the GMTs and 
GMRs (post vaccination / baseline) will be calculated with their associated two-sided 95% CIs, 
by exponentiating the corresponding log-transformed means and their 95% CIs.  
Percentages of subjects with hSBA seroresponse rise and the corresponding exact two-sided 95% 
CIs based on the Clopper-Pearson method against these serogroups will be calculated for each 
study group at one month after the first vaccination and one month after the second vaccination 
(Visit Day 28 and Visit Day 112). The ratio of GMTs and GMRs between the study groups and 
the corresponding CI will be constructed by exponentiating the mean difference and the 
confidence limits in log10 (titer), using ANOVA. The CIs for the rate difference will be 
constructed using the method of Miettinen and Nurminen.38 In addition, a reverse cumulative 
distribution plot of each measure will be created. 
For each N. meningitidis serogroup the percentages of subjects with rSBA ≥4, ≥16, ≥ 32, and ≥ 
64 and the corresponding exact two-sided 95% CIs based on Clopper-Pearson method will be 
calculated for each study group at baseline, one and three months after the first vaccination and 
one month after the second vaccination. 
Percentages of subjects with four-fold titer rise with criteria described in exploratory 
immunogenicity endpoints and the corresponding exact two-sided 95% CIs based on the 
Clopper-Pearson method against these serogroups will be calculated for each study group at one 
month after the first vaccination and one month after the second vaccination. 
9.5.5 Handling of Dropouts and Missing Data 
Missing data will not be imputed and will be analyzed as if they were randomly missing. 
9.5.6 Multiplicity 
Due to hypothesis generating nature of this study, all statistical comparisons for reactogenicity, 
safety, and immunogenicity endpoints will be carried out without an adjustment for multiple 
comparisons. All statistical tests except for non-inferiority will be two-sided with a type I error 
rate of 5%. The 95% confidence interval will be presented for estimations, as appropriate.   
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9.6 
Analyses Sequence 
Serology testing will be prioritized in the order of that rSBA testing of samples collected at 
baseline and 1 month after each study vaccination will be performed first and then rSBA testing 
of samples taken at 3 months after the first vaccination.  
According to this order of testing, analyses will be performed stepwise as follows: 
 An interim analysis including safety, reactogenicity and immunogenicity results (rSBA) at 
1 month after the first vaccination will be performed. Individual listings will not be 
generated at this point and any access to subject-level information about study groups will 
be masked. 
 The final safety, reactogenicity and immunogenicity analysis (rSBA) will be performed at 3 
months after the second vaccination. 
 
 
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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Pre-study Documentation 
Prior to enrolment of subjects at the study site, specific regulatory documents must be 
available, such as Institutional Ethics Committee (IECs) approvals; curriculum vitae for 
investigator and study staff; standard operating procedures (SOPs) and other essential 
documents. Sponsor/designee will inform the investigator which documents need to be 
provided according to the applicable regulatory requirements. 
10.2 Monitoring 
Sponsor monitoring responsibilities will be provided through qualified and appropriately 
trained individuals designated by PAREXEL to carefully monitor all aspects of the study. 
A site initiation visit will be conducted prior to the beginning of the study and monitoring 
will be conducted during and at closeout of the study by the study monitor. 
During the course of the study, the monitors will visit the clinical sites at intervals in order 
to verify that: 
 The data are authentic, accurate and complete 
 The safety and rights of subjects are being protected 
 The study is conducted in accordance with the approved protocol (and any 
subsequent amendment), GCP and all applicable regulatory requirements 
Monitors will periodically contact the site and perform site visits. The extent, nature and 
frequency of site visits will be decided before the start of the study and will be based on 
considerations as study objectives, study design and complexity, and enrolment rate. 
During these contacts, the monitor will: 
 Check and assess the progress of the study 
 Review study data collected 
 Perform source data verification, identify any issues and address their resolution 
Monitoring will be conducted according to ICH-GCP. The individuals responsible for 
monitoring the study will have access to all records necessary to ensure the 
integrity/validity of the recorded data and will periodically review the progress of the 
study. 
The investigator must agree to allow the monitor direct access to all relevant documents 
and to allocate his/her time and the time of his/her staff to the monitor to discuss findings 
and any relevant issues. 
The monitor must contact the site prior to the start of the study to discuss the protocol and 
data collection procedures with the site personnel. 
The investigator should allow representatives of the Ethics Committee, Regulatory 
Authority and the sponsor to visit the study site. 
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10.3 Data Management and Processing 
The site PI is responsible for ensuring the accuracy, completeness, and timelines of the 
data reported. Data collection is the responsibility of the clinical trial staff at the study site 
under the supervision of the site PI. PAREXEL is responsible for data management 
activities, including quality review, analysis and reporting of the study data according to 
SOPs. 
Data Collection 
Data will be entered electronically by site study staff over the Internet in eCRF. The data 
system includes password protection and internal quality checks, such as automatic range 
checks to identify data that appear inconsistent, incomplete or inaccurate. Instructions for 
use of the system are included in the eCRF User’s guide.  
Clinical data will be entered directly from the source documents. All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data. 
All the information required by the study protocol must be entered into eCRF. An 
explanation must be provided for any missing data. Source documentation supporting the 
eCRF data should document the dates and details of study procedures, AEs and subject 
status. The PI/site staff will maintain information in the eCRFs and all source documents 
that support the data collected from each subject. 
The study monitor will check for completeneess and accuracy of eCRF during the 
monitoring visits.  
Data Management Procedures 
The site staff should complete the eCRFs as soon as possible after the information is 
collected. Completed eCRFs must be submitted for each screened subject who signs the 
study specific ICF. PAREXEL is responsible for data management activities, including 
quality review, analysis and reporting of the study data according to the SOPs. 
Internal data quality  checks such as automatic range checks, checks to identify data that 
appear inconsistent, incomplete or inaccurate are programmed into eCRF that does real 
time review of the data as and when clinical data is entered into the system by the site 
staff. 
The Data Management team will review the data for quality and will provide several 
quality assurance reports to ensure that study data are clean and complete. Quality 
assurance reports will include, but are not limited to, the following: missing forms, 
missing values and out of range values, automated data queries, and manual review of 
study data. Data queries will be distributed to the sites at scheduled time period for the 
site staff to review and update the database. 
Coding 
All medical verbatim terms will be coded by a medical doctor according to MedDRA 
(adverse events, medical history and concomitant diseases) and the WHO Drug Dictionary 
enhanced version (concomitant medication). 
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Database Lock Procedures 
Database will be locked upon completion of the following activities: 
 All subjects have completed the follow up visits 
 All the subjects data have been entered in the database 
 All data anomalies have been resolved 
 Study monitoring has been completed  
 All the listings of the database have been reviewed and discussed for assessment 
of consistency and medical plausibility. 
Procedures for Analysis  
The data will be analyzed as per the pre-specified Statistical Analysis Plan (SAP) after 
the database lock. An audit trail will be kept of all subsequent changes to the data. 
10.4 Study and Site Closure 
Upon completion of the study, the monitor and the investigator will conduct the following 
activities: 
 Data clarification and/or resolution 
 Accounting, reconciliation and return to sponsor or destruction at sites of used and 
unused vaccines 
 Review of site study records for completeness 
 Return of all study data to Sponsors or designee. 
Sponsors reserve the right to temporarily suspend or prematurely discontinue this study at 
any time for any other reason. 
If the study is stopped or suspended prematurely, Sponsor will inform the investigator(s) 
as well as the regulatory authorities about the decision and the reasons for termination or 
suspension. If such action is taken, all effort must be made to ensure the safety of the 
subjects enrolled in the study. The investigator(s) will inform the responsible IECs/IRBs 
and provide the reason for the suspension or termination. 
In case of premature study or study site closure, the monitor will conduct all activities as 
indicated above. 
10.5 Audits and Inspections 
For the purpose of compliance with ICH-GCP and regulatory guidelines, it may be 
possible that the sponsor/designee or a national regulatory authority may conduct a site 
audit/inspection. This may occur at any time from start to after conclusion of the study. 
The investigator agrees to allow the auditor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the auditor to discuss findings and any 
relevant issues. 
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If a regulatory authority requests an inspection, the investigator must inform the sponsor 
or its designee immediately about this request. The investigator(s) and the study 
coordinator(s) must make the relevant records available for inspection and must be 
available to respond to reasonable requests and audit queries made by authorized 
representatives of regulatory agencies. The sponsor will provide any needed assistance in 
responding to regulatory audits or correspondence.  
 
 
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11 REGULATORY AND ETHICAL REQUIREMENTS 
11.1 Ethics committee review and communication 
It is the investigator’s responsibility to ensure that this protocol is reviewed and approved 
by the IECs responsible for the study sites. The IECs must also review and approve the 
Informed Consent Form and any other written information to be provided to the subject. 
Written IECs approval shall be obtained prior to study start. 
No deviations from, or changes to, the protocol shall be initiated without prior written IEC 
approvals of an appropriate amendment, except when necessary to eliminate immediate 
hazards to the subjects or when the change(s) involves only logistical or administrative 
aspects of the study (e.g., change of monitor(s), telephone number(s)). The investigator 
shall provide to the sponsors a statement from the IEC confirming the IEC is organized 
and operates according to GCP and applicable laws and regulations. 
11.2 Protocol Amendments 
Any significant change in the study protocol shall be addressed in a written protocol 
amendment, which will be signed by the investigator(s) and the sponsors. It is the 
investigator’s responsibility to submit protocol amendments to the IECs) and to obtain 
written approval where required.  
A protocol amendment may be implemented after it has been approved by IECs. In the 
case of a protocol change intended to eliminate an apparent immediate hazard to subjects, 
the change may be implemented immediately. In this case, the change must be later 
documented in an amendment and reported to the IECs as soon as possible. Amendments 
affecting only logistical or administrative aspects of the study may not require formal IEC 
approval. Logistical and administrative amendments (e.g., concerning a change of 
telephone number) shall be submitted to the IECs for information purposes. However, the 
investigator must provide the sponsors with written verification that such logistical or 
administrative amendments are submitted to the relevant IECs. 
11.3 Subject Information and Informed Consent 
The investigator or his/her designee shall inform the parent of all pertinent aspects 
pertaining to the study. The process for obtaining the agreement of the parent for delay of 
vaccination and the informed consent of the parent for the child to participate in the study 
shall be in accordance with ICH GCP, the Declaration of Helsinki and all applicable 
regulatory requirements. 
The investigator shall describe the study to the subject/parent. The investigator shall give 
the parent ample time and opportunity to inquire about details of the study and ask any 
questions.  
In case of illiterate individuals, the study will be explained to them by the investigator or 
his/her designee and the Informed consent form(ICF) read for them in the presence of an 
impartial witness. The witness shall personally sign and date the consent form/agreement 
while a fingerprint will be requested from illiterate individuals.The process of agreement 
for delay of vaccination and informed consent for study participation should be described 
in the site procedures/source.   
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Original ICF must be kept on file by the investigator for possible inspection by IEC 
members, regulatory authorities and the sponsors (or their designees). The parent must 
receive a copy of the signed ICF, and any subsequent updates or amendments. 
Prior to including any subject in the clinical study, his/her parent’s/guardian’s free and 
expressed informed consent must be obtained in writing. The written informed consent 
must be signed and dated by both investigator/designee and by the parent/guardian prior 
to any study related procedure. In case the parent/guardian is illiterate, he/she will affix a 
thumbprint on the consent form to confirm his/her consent. In this case, the impartial 
witness will also sign the informed consent to confirm the process has been soundly and 
transparently performed.  
The study monitor shall check the documentation of the individual ICF during each 
monitoring visit. 
11.4 Subject Confidentiality 
The investigator(s) must ensure that subject confidentiality is maintained. Personal 
identifiers will not be included in any study reports. The subjects will be identified by the 
subject number and by subject initials. If a subject’s name appears on any other document 
(e.g., pathologist report), it will be obliterated before the copy of the document is supplied 
to the sponsor. Study findings stored on a computer will be subject to local data protection 
laws. The parent will be informed that representatives of the sponsor, IEC, or regulatory 
authorities may inspect their medical records to verify the information collected, and that 
all personal information made available for inspection will be handled in the strictest 
confidence.  
11.5 Ethical conduct of the study 
This study will be conducted in compliance with the approved clinical trial protocol, IEC 
and the following guidelines: 
1. Declaration of Helsinki (Revised Fortaleza, 2013) (Appendix I).  
2. ICH Harmonized Tripartite Guideline for Good Clinical Practice E6 (R2). 
3. NRA guidelines. 
 
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11.6 Minimizing Risk 
Delay of EPI MenAfriVac dose 
This study requires a temporary delay in the MenAfriVac dose recommended to be received as 
part of the EPI in Mali at 9 months. This is necessary to ensure subjects enrolled at 12 months 
did not receive a Men A containing vaccine in order to evaluate the Men A component of the 
study vaccine. 
Men A epidemics have practically disappeared in the region since the introduction of 
MenAfriVac in the 1 to 29 years age group in the West African Region. Mali’s first Men A case 
since 2010 was reported in Kieneba district in March 2016. This case occurred in a 15 year old 
who had not been vaccinated as part of the campaign that took place in that district in 2011. 
However, pockets of disease have occurred, such as in neighbouring Guinea where the 
MenAfriVac campaign was delayed to 2015 due to the Ebola crisis.16, 17, 25-28 
In February 2017, Mali introduced the MenAfriVac in the EPI schedule at 9 months for all 
children. In addition, from 5 to 14 June 2017, Mali conducted a National Catch-up Campaign for 
the unvaccinated cohorts 1 to 5 years of age. The reported coverage rates for the campaign were 
104.7% nationally and 112% in the study area.30, 31 
The recent implementation of these interventions lead to a new umbrella of protection (herd 
immunity effect) preventing the circulation of the Men A pathogen in the study area for years to 
come. In this context, the risk of Men A exposure falls dramatically close to zero for subjects 
deferring the MenAfriVac. 
Nevertheless, all delayed subjects will be closely followed by the site with routine monthly 
checks to ensure that they are fine. Parents/guardian would be briefed on meningitis symptoms 
and any suspicion of meningitis would need to be reported to site for adequate treatment response 
following national guidelines. Delayed subjects would be scheduled to return to the clinic as 
soon as they will potentially meet the study criteria, hence delay will be limited to no more than 
3 months. 
In case a subject will not be enrolled in the study, the site will follow-up to ensure they are 
offered a dose of MenAfrivac to comply with the EPI schedule. 
 
Safety Risks from Vaccine 
As with all injectable vaccines, appropriate medical treatment and supervision should always be 
readily available in case of a rare anaphylactic event following the administration of the vaccine. 
The mainstay in the treatment of severe anaphylaxis is the prompt use of adrenaline, which can 
be lifesaving.  
Post vaccination, the subject should remain under observation for no less than 30 minutes for 
occurrences of immediate or early allergic reactions. Corticosteroids and antihistaminics should 
also be available in addition to supportive measures such as oxygen inhalation and intravenous 
fluids (IV fluids).  
Satisfactory safety and immunogenicity results were obtained after 3 months following a single 
dose in 40 healthy adults in the Phase I trial conducted in the USA (20 doses adjuvanted and 20 
doses non-adjuvanted) allowing us to proceed to Phase II. However, this Phase II trial is the first 
time this vaccine will be administered to children. Specific pause criteria and a DSMB have been 
put in place to ensure adequate controls for early signal detection. 
 
Risks from inadequate Men A protection 
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As previously discussed, the risk of Men A exposure has become extremely low. Nevertheless, 
the Menactra vaccine is a licensed vaccine conferring protection against Men A as does the 
MenAfriVac. However, there is no guarantee at this time that the NmCV-5 vaccine will provide 
adequate protection to immunized children against Men A. It is likely that immunogenicity 
results obtained after the second dose of this trial will be able to confirm the subjects’ protection 
against Men A. In case, results are unsatisfactory, the site will ensure subjects who received 
NmCV-5 during the study will be offered a dose of MenAfriVac after the completion of the 
study. 
 
Risk of inadequate protection against other Neisseria meningitidis strains 
Currently, no multivalent conjugate meningitis vaccines are routinely available in Mali to 
prevent epidemic meningitis. It is worth noting that subjects participating in this study will 
receive a multivalent meningitis vaccine that could provide protection against other circulating 
strains of Neisseria meningitidis. In particular, strains that continue to cause epidemics in Sub-
Saharan Africa, such as Men C, W, Y and X.  
However, at this time, such benefit is guaranteed only for those in the control group receiving 
the licensed Menactra with established evidence of protection against Men C, W, and Y. The 
results from the Phase 1 study for NmCV-5 in adults are promising and include an additional 
strain: the Men X, but there is no guarantee that the results would replicate in the younger age 
group. 
 
Risks from blood draw 
Drawing peripheral blood can cause discomfort; it might cause minor bleeding and/or bruising 
where the needle enters the skin, and very rarely might cause infection. This risk will be 
mitigated by ensuring that only study staff members who are adequately trained in safe drawing 
of blood conduct this portion of the study. It is not anticipated that the risks in any one of the 
vaccine groups would be higher than others. 
 
Risks from participating in a clinical trial 
In addition to the risks described above, all clinical trial subjects are likely to experience 
increased inconvenience due to the visits as they may be of longer duration than standard 
treatment, which might cause more anxiety. They also incur additional risks to their privacy from 
participating in a clinical trial. This risk will be minimized by ensuring that subject 
confidentiality is maintained by enforcing appropriate data collection, storage, and analysis 
techniques and employing the use of unique identifiers with carefully stored linking files. There 
may be additional risks to study trial participation that we do not know about. 
 
 
12 DATA HANDLING AND RECORD KEEPING 
Investigators must retain all study records required by Sponsors and by the applicable regulations 
in a secure and safe facility. The investigator must consult a sponsor’s representative before 
disposal of any study records, and must notify the sponsor of any change in the location, 
disposition, or custody of the study files. Essential documents must be retained until at least 2 
years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
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“Essential documents” are defined as documents that individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced (e.g. signed protocol and 
all amendments; ethics committee approval for the study protocol and all amendments; all source 
documents; eCRF records; subjects’ Informed Consent etc.). These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the sponsor. The Committee for Human Medicinal Products for Human 
Use (CHMP) requires retention for the maximum period of time permitted by the institution, but 
not less than 15 years (ICH E6, 4.9.5). It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained (ICH E6, 
5.5.12). The documents should not be destroyed without the written permission from the sponsor. 
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 
 
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13 INSURANCE OF STUDY SUBJECTS 
Pending IRB approval, subjects will be compensated for their time in this study, and be 
reimbursed for travel to attend study visits. The study ICF will state the plan for 
reimbursement and health care treatment. Study subjects will not be charged for study 
vaccinations, research clinic visits, research-related examinations, or research-related 
laboratory tests. 
All the subjects participating in this study are insured by Sponsor against any injury 
caused by any AE causally related to the study investigational product. The cost of 
medical care needed for treatment of vaccine related AEs (including SAEs) occurring 
among trial subjects will be borne by sponsor and as required by the Rules and Regulations 
passed by NRA. 
All the subjects participating in this study will be covered by the Sponsor for any illness 
or condition diagnosed during trial participation. For these events, the study site medical 
team will attend the subject following the local standard of care and the national 
guidelines, free of charge to the subject for the duration of the study. At the end of the 
study, in case of further treatment required, the study team will provide adequate referrals 
in the health care system, but further treatment will not be covered.  
 
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14 PUBLICATION POLICY & CONFIDENTIALITY 
PATH and SIIPL hold the exclusive rights to publish the study results. Due credit will be 
given to the investigators and their team in case the results of the study are published.  
All proprietary or confidential information communicated to the investigator by or for 
PATH/SIIPL or communicated to the investigator during the course of and/or as a result 
of the clinical study is the exclusive property of Sponsors, and the investigator shall ensure 
that the same shall be kept strictly confidential by him/her and any other person connected 
with the clinical study and shall not be disclosed, either orally or in written form, by 
him/her or such person to any third party without the prior written consent of Sponsors. 
The investigator shall communicate the results of the clinical study promptly to 
PATH/SIIPL. 
All rights and interests worldwide in any inventions, know-how, or other intellectual or 
industrial property rights which arise during the course of and/or as a result of the clinical 
study which is the subject of this protocol or which otherwise arise from the information 
or materials supplied under this protocol, shall be assigned to, vest in and remain the 
property of Sponsors. 
 
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15 REFERENCES 
 
 
1.  Hedari CP, Khinkarly RW, Dbaibo GS. Meningococcal serogroups A, C, W-135, and Y 
tetanus toxoid conjugate vaccine: a new conjugate vaccine against invasive 
meningococcal disease. Infect Drug Resist 2014;7:85-99. 
 
2.  Stephens DS. Biology and pathogenesis of the evolutionarily successful, obligate 
human bacterium Neisseria meningitidis. Vaccine 2009;27 Suppl 2:B71-B77. 
 
3.  Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. 
Vaccine 2009;27 Suppl 2:B51-B63. 
 
4.  WHO-WER. Meningococcal vaccines: WHO position paper, November 2011. Wkly 
Epidemiol Rec 2011;86(47):521-539. 
 
5.  Molesworth AM, Thomson MC, Connor SJ et al. Where is the meningitis belt? 
Defining an area at risk of epidemic meningitis in Africa. Trans R Soc Trop Med Hyg 
2002;96(3):242-249. 
 
6.  Al-Tawfiq JA, Clark TA, Memish ZA. Meningococcal disease: the organism, clinical 
presentation, and worldwide epidemiology. J Travel Med 2010;17 Suppl:3-8. 
 
7.  Sow SO, Okoko BJ, Diallo A et al. Immunogenicity and safety of a meningococcal A 
conjugate vaccine in Africans. N Engl J Med 2011;364(24):2293-2304. 
 
8.  Altmann D, Aseffa A, Bash M et al. Priorities for research on meningococcal disease 
and the impact of serogroup A vaccination in the African meningitis belt. Vaccine 
2013;31(11):1453-1457. 
 
9.  Borrow R, Tang Y, Yakubu A, Kulkarni PS, LaForce FM. MenAfriVac as an 
Antitetanus Vaccine. Clin Infect Dis 2015;61 Suppl 5:S570-S577. 
 10.  Frasch CE, Preziosi MP, LaForce FM. Development of a group A meningococcal 
conjugate vaccine, MenAfriVac(TM). Hum Vaccin Immunother 2012;8(6):715-724. 
 11.  Kristiansen PA, Diomande F, Ba AK et al. Impact of the serogroup A meningococcal 
conjugate vaccine, MenAfriVac, on carriage and herd immunity. Clin Infect Dis 
2013;56(3):354-363. 
 12.  Kristiansen PA, Ba AK, Ouedraogo AS et al. Persistent low carriage of serogroup A 
Neisseria meningitidis two years after mass vaccination with the meningococcal 
conjugate vaccine, MenAfriVac. BMC Infect Dis 2014;14:663. 
 13.  LaForce FM, Okwo-Bele JM. Eliminating epidemic Group A meningococcal 
meningitis in Africa through a new vaccine. Health Aff (Millwood ) 2011;30(6):1049-
1057. 
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 14.  Okwo-Bele JM, LaForce FM, Borrow R, Preziosi MP. Documenting the Results of a 
Successful Partnership: A New Meningococcal Vaccine for Africa. Clin Infect Dis 
2015;61 Suppl 5:S389-S390. 
 15.  Novak RT, Kambou JL, Diomande FV et al. Serogroup A meningococcal conjugate 
vaccination in Burkina Faso: analysis of national surveillance data. Lancet Infect Dis 
2012;12(10):757-764. 
 16.  Epidemic meningitis control in countries of the African meningitis belt, 2016. Wkly 
Epidemiol Rec 2017;92(13):145-154. 
 17.  Meningitis control in countries of the African meningitis belt, 2015. Wkly Epidemiol 
Rec 2016;91(16):209-216. 
 18.  Sanofi Pasteur Menactra® Package Insert. FDA, 2016 (Accessed April 27, 2017 
https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/
UCM131170.pdf). 
 19.  Nimenrix® Summary Product Characteristics. EMA, 2017 (Accessed April 27, 2017 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002226/WC500127663.pdf). 
 20.  MENVEO® Package Insert. FDA, 2017 (Accessed April 27, 2017 
https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/
UCM201349.pdf). 
 21.  Ali A, Jafri RZ, Messonnier N et al. Global practices of meningococcal vaccine use and 
impact on invasive disease. Pathog Glob Health 2014;108(1):11-20. 
 22.  Maiden MC. The impact of protein-conjugate polysaccharide vaccines: an endgame for 
meningitis? Philos Trans R Soc Lond B Biol Sci 2013;368(1623):20120147. 
 23.  Jafri RZ, Ali A, Messonnier NE et al. Global epidemiology of invasive meningococcal 
disease. Popul Health Metr 2013;11(1):17. 
 24.  Meningococcal Vaccine Information Statements. CDC, 2017 (Accessed April 27, 2017 
https://www.cdc.gov/vaccines/hcp/vis/vis-statements/mening.html). 
 25.  Meningitis Weekly Bulletin Week 12, 2016. WHO Inter Country Support Team - West 
Africa, 2017 (Accessed April 27, 2017 
http://www.who.int/csr/disease/meningococcal/Bulletin_Meningite_S12_2016.pdf?ua=
1). 
 26.  Meningitis Weekly Bulletin Week 48-52, 2016. WHO Inter Country Support Team - 
West Africa, 2017 (Accessed April 27, 2017 
http://www.who.int/csr/disease/meningococcal/Bulletin_Meningite_S48_52_2016.pdf?
ua=1). 
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 27.  Meningitis Weekly Bulletin Week 15, 2017. WHO Inter Country Support Team - West 
Africa, 2017 (Accessed April 27, 2017 
http://www.who.int/csr/disease/meningococcal/epidemiological/en/). 
 28.  Meningitis Weekly Bulletin Week 49-53, 2015. WHO Inter Country Support Team - 
West Africa, 2017 (Accessed April 27, 2017 
http://www.who.int/csr/disease/meningococcal/Bulletin_Meningite_S49_53_2015.pdf?
ua=1). 
 29.  Meningitis Weekly Bulletin Week 49-52, 2014. WHO Inter Country Support Team - 
West Africa, 2017 (Accessed April 27, 2017 
http://www.who.int/csr/resources/publications/meningitis/BulletinMeningite_S49_52_2
014.pdf?ua=1). 
 30.  Ministère de la santé et de l'hygiène publique du Mali. Situation épidémiologique de la 
24ème semaine de l'année 2017. Ministry of Hygiene and Public Health of Mali Website, 
2017 (Accessed August 11, 2017 
http://www.sante.gov.ml/index.php/epidemie/situation‐epide‐mio/item/2986‐
situation‐epidemiologique‐de‐la‐24e‐semaine‐de‐l‐annee‐2017). 
 31.  Ministère de la santé et de l'hygiène publique du Mali. Rapport technique de la 
campagne de vaccination de rattrapage au Mali des enfants âgés de 1 à 5 ans contre la 
méningite à méningocoque . 2017 
 32.  Gill CJ, Ram S, Welsch JA, Detora L, Anemona A. Correlation between serum 
bactericidal activity against Neisseria meningitidis serogroups A, C, W-135 and Y 
measured using human versus rabbit serum as the complement source. Vaccine 
2011;30(1):29-34. 
 33.  Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for 
meningococcal C conjugate vaccine by using efficacy estimates from postlicensure 
surveillance in England. Clin Diagn Lab Immunol 2003;10(5):780-786. 
 34.  Balmer P, Borrow R. Serologic correlates of protection for evaluating the response to 
meningococcal vaccines. Expert Rev Vaccines 2004;3(1):77-87. 
 35.  Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the 
meningococcus. I. The role of humoral antibodies. J Exp Med 1969;129(6):1307-1326. 
 36.  Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the 
meningococcus. II. Development of natural immunity. J Exp Med 1969;129(6):1327-
1348. 
 37.  Clopper CJ, Pearson ES. The use of confidential or fiducial limits illustrated in the case 
of the binomial. Biometrika 1934;(26):401-403. 
 38.  Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4(2):213-
226. 
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16 APPENDIX I: WORLD MEDICAL ASSOCIATION. DECLARATION OF 
HELSINKI: ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS (FORTALEZA, 2013) 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient’s best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician’s knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
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evaluated continually through research for their safety, effectiveness, efficiency, accessibility 
and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects must 
always rest with the physician or other health care professionals and never with the research 
subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on patients 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
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17.       All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop 
the study. 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices 
or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
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Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the laws 
and regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or eliminate 
any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by the 
committee. After the end of the study, the researchers must submit a final report to the committee 
containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25.       Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must be informed of the right to refuse 
to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the physician 
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or may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, and 
the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorised representative. The potential subject’s 
dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research  group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. Consent 
to remain in the research must be obtained as soon as possible from the subject or a legally 
authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive any 
intervention less effective than the best proven one, placebo, or no intervention will not be 
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subject to additional risks of serious or irreversible harm as a result of not receiving the best 
proven intervention. Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all subjects who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to subjects during the informed 
consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for 
the completeness and accuracy of their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, re-establishing health 
or alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
 
 
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17 APPENDIX II: DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE 
SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS, VERSION 2.1. 
[MARCH 2017]. 
 
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Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events 
 
Version 2.1 
March 2017 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
 
 
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Table of Contents 
Glossary and Acronyms .................................................................................................................. 1 
Introduction ..................................................................................................................................... 3 
Instructions for Use ......................................................................................................................... 4 
Major Clinical Conditions............................................................................................................... 7 
Cardiovascular .......................................................................................................................... 7 
Dermatologic............................................................................................................................. 9 
Endocrine and Metabolic ........................................................................................................ 10 
Gastrointestinal ....................................................................................................................... 12 
Musculoskeletal ...................................................................................................................... 14 
Neurologic............................................................................................................................... 15 
Pregnancy, Puerperium, and Perinatal .................................................................................... 17 
Psychiatric ............................................................................................................................... 18 
Respiratory .............................................................................................................................. 19 
Sensory .................................................................................................................................... 20 
Systemic .................................................................................................................................. 21 
Urinary .................................................................................................................................... 23 
Site Reactions to Injections and Infusions .................................................................................... 24 
Laboratory Values ......................................................................................................................... 25 
Chemistries ............................................................................................................................. 25 
Hematology ............................................................................................................................. 29 
Urinalysis ................................................................................................................................ 31 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates .......................................... 32 
 
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DAIDS AE Grading Table Version 2.1-March 2017 
Page 1 
Glossary and Acronyms 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atrioventricular 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP 
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS.  It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency.  
INR 
International normalized ratio  
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Glossary and Acronyms 
DAIDS AE Grading Table Version 2.1- March 2017 
Page 2 
Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event.  
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE 
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc  Interval 
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
 
Adults 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization  
WNL 
Within normal limits 
 
 
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Introduction 
The Division of AIDS (DAIDS) oversees more than 300 clinical trials domestically and 
internationally, which evaluate the safety and efficacy of therapeutic products, vaccines, and 
other preventive modalities.  Adverse event (AE) data collected during these clinical trials form 
the basis for subsequent safety and efficacy analyses of pharmaceutical products and medical 
devices.  Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants and 
future patients using pharmaceutical products.  
 
Over the years, DAIDS scientific knowledge and experience have expanded necessitating a 
revision of the DAIDS grading table, which serves as a guide for assessing the severity of AEs 
(including clinical and laboratory abnormalities) in participants enrolled in DAIDS-sponsored 
and -supported clinical trials.  The Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Version 2.0 replaces the grading table published in 2004 and 
updated in 2009.  In version 2.0, AEs not previously included in the DAIDS grading table, but 
which now are deemed medically important events, are included while other AEs have been 
removed.  Some AE severity grading descriptions have been revised to more appropriately 
reflect the presentation of these events in clinical settings and their impact on clinical trials.  For 
example, DAIDS performed an extensive literature search and reviews of select DAIDS clinical 
trial data in revising certain hematology parameters (i.e., hemoglobin, white cell counts, and 
absolute neutrophil counts).  DAIDS also took into consideration the U.S. Food and Drug 
Administration’s guidance regarding the use of local laboratory reference values and ethnic 
differences among certain healthy adolescent and adult populations in defining parameter limits.  
Finally, the revised DAIDS grading table also contains an updated glossary and acronyms 
section, an expanded instructions for use section, and an appendix that provides more age-
specific information for an AE of concern to DAIDS. 
 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were instrumental 
in the revision of the DAIDS grading table. 
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Instructions for Use 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are written 
to maintain data consistency across clinical trials.  However, since some parameters can be 
reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
 
The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with 
descriptions for each AE based on the following general guidelines:  
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
 
Other points to consider include: 
• Use age and sex values as applicable. 
• Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges. 
• Where applicable, Standard International (SI) units are included in italics. 
 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency.  
 
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When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions.  
 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction  
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
 
Determining Severity Grade for Parameters between Grades  
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the clinical case report forms.  
 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
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value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
 
Appendix Usage 
Appendix A takes priority over the main grading table in all assessments of total bilirubin for 
term and preterm neonates. 
 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1-3 (see below) as the primary 
grading tables for these areas.  Although these grading tables are used specifically in microbicide 
studies, they may be used in other protocols as adjuncts to the main grading table (i.e., the 
Division of AIDS (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0).  It should be clearly stated in a protocol which addendum is being used as the 
primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion.  
• Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies- 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• Addendum 3 – Rectal Grading Table for Use in Microbicide Studies – 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5.  
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities 
with intervention or 
hospitalization 
indicated 
Potentially life-threatening 
symptoms causing inability 
to perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
 
 
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Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arrhythmia   
(by ECG or physical 
examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms  AND 
Non-urgent 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th  
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile  
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention 
indicated (e.g., 
oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
                                                          
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 
2011; DOI: 10.1542/peds.2009-2107C. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion indicated 
Symptoms AND 
Transfusion of  ≤ 2 
units packed RBCs 
indicated  
Life-threatening 
hypotension OR 
Transfusion of  > 2 units 
packed RBCs (for 
children, packed RBCs  
> 10 cc/kg) indicated 
Prolonged PR Interval  
or AV Block 
Report only one 
> 16 years  of age 
PR interval 0.21 to 
< 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block  
≤ 16 years of age 
1st degree AV block 
(PR interval  
> normal for age 
and rate) 
Type I 2nd degree 
AV block  
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular 
dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated  
Symptoms AND 
Intervention 
indicated  
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus)  
 
 
                                                          
2 As per Bazett’s formula. 
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Dermatologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Alopecia (scalp only)  
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities  
NA 
Rash 
Specify type, if 
applicable 
Localized rash  
Diffuse rash OR 
Target lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving 
two or more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis  
 
                                                          
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
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Endocrine and Metabolic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure)  
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal 
laboratory value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
                                                          
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes  
NA 
                                                          
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
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Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation)  
Constipation 
NA 
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent 
episodes of 
unformed stools OR 
Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to  6 
stools over baseline 
per 24-hour period 
Increase of  ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or  
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral intake 
for 24 to 48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention 
indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or  
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 
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Musculoskeletal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform 
basic self-care functions  
Myalgia (generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score  
-2.5 to -1 
NA 
NA 
NA 
   < 30 years of age 
BMD z-score  
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA  
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
 
                                                          
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment 
of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for 
Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.  
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Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below)  
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional 
activities 
Delirium OR  
Obtundation OR  
Coma 
Ataxia  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function  
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional 
activities  
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and painful 
neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal  
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or  paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA  
1 to  3 seizures  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with  
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality  
(e.g., severity or  
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR 
Difficult to control (e.g., 
refractory epilepsy) 
Syncope  
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
 
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Pregnancy, Puerperium, and Perinatal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Stillbirth (report using 
mother’s participant ID) 
Report only one 
NA 
NA 
Fetal death occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Birth (report 
using mother’s 
participant ID) 
Live birth at 34 to  
< 37 weeks  
gestational age 
Live birth at 28 to  
< 34 weeks 
gestational age 
Live birth at 24 to  
< 28 weeks 
gestational age 
Live birth at < 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriage7 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
 
                                                          
7 Definition:  A  pregnancy loss occurring at < 20 weeks gestational age. 
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Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Insomnia  
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional activities  
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal interference 
with usual social & 
functional activities 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early causing 
inability to perform 
usual social & 
functional activities 
requiring intervention 
or hospitalization 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial 
or complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
 
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Respiratory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to  
≥ 70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to  
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to  
< 50% OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation  
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal  
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 
90 to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 
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Sensory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hearing Loss 
≥ 12 years of age 
 
NA 
 
Hearing aid or 
intervention not 
indicated 
 
Hearing aid or 
intervention indicated 
 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 4, 
6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss 
at  ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing 
aids 
Audiologic indication 
for cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention 
not indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medical intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional 
activities 
Disabling visual loss in 
affected eye(s) 
 
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Systemic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Allergic 
Reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion)  
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain9 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Pain causing inability 
to perform usual 
social & functional 
activities  
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
                                                          
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).   
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Serum Sickness10 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight11 
> 5 to 19 years of 
age 
WHO BMI z-score 
< -1 to -2 
WHO BMI z-score 
< -2 to -3 
WHO BMI z-score  
< -3 
WHO BMI z-score  
< -3 with life-threatening 
consequences 
2 to 5 years of age 
WHO BMI z-score  
< -1 to -2 
WHO Weight-for-
height z-score  
< -2 to -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences 
< 2 years of age 
WHO BMI z-score  
< -1 to -2 
WHO Weight-for-
length z-score  
< -2 to -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences 
Unintentional 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
 
                                                          
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnea. 
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:  
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and  
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 
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Urinary 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Urinary Tract 
Obstruction  
NA 
Signs or symptoms 
of urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
 
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Site Reactions to Injections and Infusions 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Injection Site Pain or  
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social 
& functional 
activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated 
Injection Site Erythema 
or Redness12 
Report only one 
> 15 years of age 
 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25  to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus  
 
Itching localized to 
the injection site 
that is relieved 
spontaneously or in 
< 48 hours of 
treatment  
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities  
NA 
                                                          
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 
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Laboratory Values*  
Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0  
≥ 20  to < 30  
< 2.0  
< 20  
NA 
Alkaline Phosphatase,  
High 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT or SGPT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0  
11.0  to < 16.0  
8.0  to < 11.0  
8.0  to < 11.0  
< 8.0  
< 8.0  
Bilirubin 
Direct Bilirubin13, 
High 
> 28 days of age 
 
 
NA 
 
NA 
 
> ULN with other 
signs and symptoms 
of hepatotoxicity. 
 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
 
1.1 to < 1.6 x ULN 
 
1.6 to < 2.6 x ULN 
 
2.6 to < 5.0 x ULN 
with other signs and 
symptoms of 
hepatotoxicity. 
 
≥ 5.0 x ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure). 
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
                                                          
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be reported to DAIDS in an 
expedited time frame unless it meets protocol-specific reporting requirements. 
 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5  
2.88  to < 3.13 
12.5   to < 13.5  
3.13  to < 3.38 
≥  13.5  
≥  3.38 
< 7 days of age 
11.5  to < 12.4  
2.88  to < 3.10 
12.4  to < 12.9  
3.10  to < 3.23 
12.9  to < 13.5  
3.23  to < 3.38 
≥  13.5 
≥  3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8  
≥ 7.2 
≥ 1.8  
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4  
1.95  to < 2.10 
7.0   to < 7.8  
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1  
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN  to 4.0  
< LLN  to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9  
< 3.2 
< 0.8  
Cardiac Troponin I, 
High  
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
*Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 to 
< 1.5 x participant’s 
baseline 
> 1.8  to < 3.5  
x ULN OR Increase 
to 1.5 to < 2.0 x 
participant’s baseline 
≥ 3.5 x ULN OR 
Increase of  ≥ 2.0 x 
participant’s baseline 
Creatinine Clearance14 
or eGFR, Low 
*Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2  
OR 
10 to < 30% decrease  
from participant’s 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
 30 to < 50% 
decrease from 
participant’s baseline 
< 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 50% decrease from 
participant’s baseline or 
dialysis needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
 
 
110 to 125 
6.11 to < 6.95 
 
 
> 125 to 250 
6.95 to < 13.89 
 
 
 > 250 to 500  
13.89 to < 27.75 
 
 
≥  500  
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89  
> 160 to 250 
8.89 to < 13.89 
> 250  to 500 
13.89  to < 27.75  
≥  500 
≥ 27.75  
                                                          
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
  
*Reminder: Choose the method that selects for the higher grade. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glucose, Low  
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64  
3.05  to <3.55  
40  to < 55 
2.22  to < 3.05  
30  to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
< 1 month of age 
50 to 54 
2.78  to < 3.00  
40 to < 50 
2.22 to < 2.78  
30 to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders  
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
 
200  to < 240 
5.18  to < 6.19  
 
240  to < 300  
6.19  to < 7.77  
 
≥  300 
≥  7.77  
 
NA 
< 18 years of age 
170  to < 200 
4.40  to < 5.15  
200 to < 300 
5.15  to < 7.77  
≥  300  
≥  7.77  
NA 
LDL, Fasting, High 
≥ 18 years of age 
 
130  to < 160  
3.37  to < 4.12  
 
160 to < 190  
4.12  to < 4.90  
 
≥ 190  
≥ 4.90  
 
NA 
> 2 to < 18 years of 
age 
110  to < 130  
2.85  to < 3.34  
130 to < 190  
3.34  to < 4.90  
≥ 190 
≥ 4.90  
NA 
Triglycerides, Fasting, 
High 
150 to 300  
1.71 to 3.42  
>300  to 500  
>3.42 to 5.7  
>500 to < 1,000  
>5.7 to 11.4  
> 1,000  
> 11.4 
Magnesium15, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4  
0.60  to < 0.70  
0.9  to < 1.2  
0.45  to < 0.60  
0.6  to < 0.9  
0.30  to < 0.45  
< 0.6  
< 0.30  
Phosphate, Low  
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.65 to < LLN 
1.4 to < 2.0 
0.45 to < 0.65  
1.0 to < 1.4 
0.32 to < 0.45  
< 1.0 
< 0.32  
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13  
2.5  to < 3.0 
0.81  to < 0.97  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45  
2.5  to < 3.5 
0.81  to < 1.13  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0  
6.0  to < 6.5 
6.0  to < 6.5  
6.5  to < 7.0 
6.5  to < 7.0  
≥ 7.0 
≥ 7.0  
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4  
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5  
< 2.0 
< 2.0  
                                                          
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150  
150  to < 154 
150  to < 154  
154  to < 160 
154  to < 160  
≥ 160 
≥ 160  
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135  
125  to < 130 
125  to < 130 
121  to < 125 
121  to < 125  
≤ 120 
≤ 120  
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59  
10.0  to < 12.0 
0.59  to < 0.71  
12.0  to < 15.0 
0.71  to < 0.89  
≥ 15.0 
≥ 0.89  
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Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
300 to < 400 
300 to < 400 
 
 
 
200 to <  300 
200 to < 300 
 
 
 
100 to < 200 
100  to < 200 
 
 
 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low  
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
600  to < 650 
0.600 x 109  to 
< 0.650 x 109 
 
 
 
500  to < 600 
0.500 x 109  to 
< 0.600 x 109 
 
 
 
350 to < 500 
0.350 x 109  to 
< 0.500 x 109 
 
 
 
< 350 
< 0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
 
 
 
600 to 799 
0.600 x 109 to 0.799 
x 109 
 
 
 
400 to 599 
0.400 x 109 to 0.599 
x 109 
 
 
 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109 
750 to 999 
0.750 x 109 to 0.999 
x 109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109 
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100  to < 200 
1.00 to < 2.00  
OR 
0.75 to < 1.00 
x LLN 
75  to < 100 
0.75  to < 1.00  
OR 
≥ 0.50 to < 0.75 
x LLN  
50  to < 75 
0.50  to < 0.75  
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50  
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin16, Low 
(g/dL; mmol/L)17 
≥ 13 years of age  
(male only) 
 
 
10.0 to 10.9 
6.19 to 6.76 
 
 
 
9.0 to < 10.0 
5.57 to < 6.19 
 
 
7.0 to < 9.0 
4.34 to < 5.57 
 
 
< 7.0 
< 4.34 
≥ 13 years of age  
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
                                                          
16 Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on hormone 
therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify (i.e., a transgender 
female should be graded using the female sex at birth hemoglobin laboratory values). 
 
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using appropriate conversion 
factor for the particular laboratory.  
 
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Page 30 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
57 days of age to < 13 
years of age  
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin  
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.66  
x ULN 
1.66 to < 2.33  
x ULN 
2.33 to < 3.00  
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 125,000  
100.000 x 109  to 
< 125.000 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000  
25.000 x 109  to  
< 50.000 x 109 
< 25,000  
< 25.000 x 109 
PT, High  
(not on anticoagulation 
therapy 
1.1  to < 1.25  
x ULN 
1.25  to < 1.50  
x ULN 
1.50  to < 3.00  
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
 
 
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109 
 
 
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109 
 
 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109 
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109 
< 2,500 
< 2.500 x 109 
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Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to   
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
 
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Appendix A.  
Total Bilirubin Table for Term and Preterm Neonates 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Total Bilirubin18, High 
(mg/dL; µmol/L)19 
 
Term Neonate20 
 < 24 hours of age 
 
4 to < 7  
68.4 to < 119.7  
7 to < 10  
119.7 to < 171  
10  to < 17  
171  to < 290.7  
≥ 17 
≥ 290.7  
24 to < 48 hours of 
age 
5 to < 8  
85.5 to < 136.8  
8 to < 12  
136.8 to < 205.2  
12  to < 19  
205.2  to < 324.9  
≥ 19  
≥ 324.9  
48 to < 72 hours of 
age 
8.5 to < 13  
145.35 to < 222.3  
13 to < 15  
222.3 to < 256.5  
15  to < 22  
256.5  to < 376.2  
≥ 22  
≥ 376.2  
72 hours to < 7 days 
of age 
11 to < 16  
188.1 to < 273.6  
16 to < 18  
273.6 to < 307.8  
18  to < 24  
307.8  to < 410.4 
≥ 24  
≥ 410.4  
7 to 28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
Preterm Neonate20  
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
32 to < 35 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
10 to < 14  
171 to < 239.4 
≥ 14  
≥ 239.4 
28 to < 32 weeks  
gestational age and  
< 7 days of age 
NA 
NA 
6 to < 10  
102.6 to < 171  
≥ 10  
≥ 171  
< 28 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
 5 to < 8  
85.5 to < 136.8  
≥ 8  
≥ 136.8  
7 to  28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
 
                                                          
18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first 
week of life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this 
appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 
4. 
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
20 Definitions: Term is defined as ≥ 37 weeks  gestational age; near-term, as ≥ 35 weeks  gestational age; preterm, as < 35 weeks 
gestational age; and neonate, as 0 to 28 days of age. 
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