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GlaxoSmithKline BiologicalsRue de l'Institut 89

1330 Rixensart, BelgiumConfidential & Proprietary Information

Final Study Report for Clinical Trial 209762/147(MeMuRu-147)

Title: Phase IV open study to assess the safety, reactogenicity andimmunogenicity of GlaxoSmithKline (GSK) Biologicals’ live attenuatedMeasles-Mumps-Rubella (MMR) vaccine when given to healthy childrenat the age of 12 to 18 months in Singapore.

Study Vaccine: GSK Biologicals’ live attenuated Measles(Schwarz strain) - Mumps (RIT 4385 strain) -Rubella (RA 27/3 strain) vaccine Priorix™

CPMS Study No.: 209762/147 (MeMuRu-147)

Indication: Immunization against measles, mumps andrubella diseases in healthy infants aged 12 to 18months

Principal Investigator: Dr.

Date of First Visit: 23 November 2000

Date of Last Visit: 17 April 2001

Coordinating Author:

Other Contributing Authors: Director Clinical R & D/MedicalAffairs (Singapore, Malaysia, Indonesia andPhilippines)

Clinical Research Associate Statistician

The trial was performed according to the Good Clinical Practice guidelines inoperation at the time of the initiation of the trial.

Report Date: 6 March 2002 (Final)

6 March 2002 GlaxoSmithKline BiologicalsFinal Study Report 209762/147 (MeMuRu-147)

Confidential and Proprietary Information

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Synopsis of Final Study Report 209762/147(MeMuRu-147)

Name of Company: GlaxoSmithKlineBiologicals, Rixensart, BelgiumName of Finished Product: Priorix™Name of active substance: Liveattenuated measles (Schwarz strain),mumps (RIT 4385 strain), rubella vaccine(RA 27/3 strain)

TABULAR FORMATREFERRING TO PARTOF THE DOSSIERVolume:

Page:

(for nationalauthority only)

Title of the study: 209762/147 (MeMuRu-147)Phase IV open study to assess the safety, reactogenicity and immunogenicity ofGlaxoSmithKline (GSK) Biologicals’ live attenuated Measles-Mumps-Rubella (MMR) vaccinewhen given to healthy children at the age of 12 to 18 months in Singapore.Principal Investigator: Dr. Study Center:

Singapore Publication (reference): Not published as of 6 March 2002 .Study period: Date of first visit: 23 November 2000

Date of last visit: 17 April 2001Clinical phase: IV

Objectives:Primary Objectives:• To assess the safety and reactogenicity of GSK Biologicals’ live attenuated Measles-

Mumps-Rubella (MMR) vaccine.Secondary Objectives:• To assess the antibody response to the vaccine antigens: measles, mumps and rubellaMethodology:Study design: An open study with one group conducted at one study site.Number of subjects:Planned and enrolled: 150Completed: 138

Analysed for safety (according-to-protocol, ATP cohort): 139Analysed for immunogenicity (ATP): 133

Diagnosis and criteria for inclusion:Infants aged between 12 and 18 months, free of obvious health problems, without previousmeasles, mumps or rubella vaccination or disease. Written informed consent obtained fromparents/guardians of the subjects prior to study entry.Test product, dose, mode of administration, lot No.:Vaccination schedule/site: Subjects received one dose (0.5 ml) of GSK Biologicals’ MMRvaccine given as a subcutaneous injection in the upper left arm on Day 0.Vaccine composition/dose/lot number: Each 0.5 ml dose contained the following doses of virustiters: Not less than 103.0 TCID50 Measles component

Not less than 103.7 TCID50 Mumps componentNot less than 103.0 TCID50 Rubella component

Lot no. MJR289A42C. The vaccine was reconstituted with a diluent of lot no. 136.Duration of treatment: Approximately 43 days per subject.Reference therapy, dose and mode of administration, batch number: Not applicable.Criteria for evaluation:Primary endpoint: After a single-dose vaccination:• Occurrence of solicited symptoms (during the 4-day follow-up period after a single-dose)• Occurrence of unsolicited symptoms (during the 43-day follow-up period after a single-dose)• Occurrence of serious adverse events

209762/147 (MeMuRu-147) Synopsis page 1 of 4



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Secondary endpoints: 43 days after a single-dose vaccination:• Anti-measles, anti-mumps and anti-rubella antibodies (Geometric Mean Titers) and

seroconversion ratesStatistical methods:Demography: Demographic characteristics (age, gender) were summarized by using descriptivestatistics (mean, standard deviation) for the total cohort, for the ATP safety cohort and for theATP immunogenicity cohort.Safety: Analyses were performed on the total cohort and on the ATP cohort with the analyseson the ATP cohort being the primary analysis. Incidence, intensity and relationship tovaccination of solicited symptoms and unsolicited symptoms reported during the follow-upperiod after vaccination (4-day follow-up period for solicited local symptoms, drowziness, lossof appetite and irritability and 43-day follow-up period for fever, meningism, parotid/salivarygland swelling and unsolicited symptoms) was tabulated. Serious adverse events (SAEs)occurring throughout the study period were reported.Immunogenicity: Analyses were performed on the total cohort and on the ATP cohort with theanalyses on the ATP cohort being the primary analysis. A subset analysis was performed oninitially seronegative subjects included in the ATP cohort. Seroconversion rates (appearance ofdetectable level of antibodies - measles: ≥ 150 mIU/ml, mumps: ≥ 231 U/ml, rubella: ≥ 4IU/ml) with 95% confidence intervals and GMTs for measles, mumps and rubella with 95%confidence intervals were calculated at Day 42.SUMMARY-CONCLUSIONS:Demography: The mean age of the subjects was 15.2 months with a standard deviation of 0.55months. All subjects were oriental. The male/female ratio was 1.1:1 in the total cohort.Safety results:• Unsolicited symptoms: A total of 36.7% of subjects reported at least one unsolicited

symptom during the 43-day follow-up period after vaccination. The most frequently reportedunsolicited symptoms were related to respiratory system (23% coughing and 19.4% rhinitis).Four subjects (2.2%) reported at least one unsolicited symptom determined by theinvestigator to be related to the vaccination.

These symptoms resolved within three days of onset. These symptoms resolved

within two days of onset.• Solicited symptoms: Redness (8.7%) followed by pain (7.2%) at injection site was the most

commonly reported local symptoms. There were no reports of Grade “3” solicited localsymptoms. All local symptoms resolved within the 4-day follow-up period after vaccination.There were no reports of Grade “3” drowziness, irritability and loss of appetite. Majority ofthese symptoms reported (drowziness, irritability and loss of appetite) were determined bythe investigator to be related to vaccination. Fever (42.8%) was the most commonly reportedsolicited general symptom. However, none of the cases of fever reported in this study weredetermined by the investigator to have a relationship to vaccination. Fever (5.1%) andmeningism (0.7%) were the only Grade “3” solicited general symptoms that were reported.

No cases of parotid/salivary gland swelling occurredduring the 43-day follow-up period.

• SAEs: One subject reported SAE.




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The boy was treated and recovered and the SAE wasconsidered to be not related to vaccination.

Reactogenicity results for the ATP safety cohort are as follows:Solicited local symptoms reported during the 4-day follow-up period after vaccination.

Symptom Intensity (N = 138)n % 95% CI

Pain Any 10 7.2 3.5 12.9Redness Any 12 8.7 4.6 14.7Swelling Any 5 3.6 1.2 8.3Solicited general symptoms reported during the 4-day and 43-day follow-up period aftervaccination.Symptoms reported during the 4-day follow-up period

Drowziness Any 10 7.2 3.5 12.9Related 7 5.1 2.1 10.2

Irritability Any 11 8.0 4.0 13.8Related 8 5.8 2.5 11.1

Loss of appetite Any 10 7.2 3.5 12.9Related 9 6.5 3.0 12.0

Symptoms reported during the 43-day follow-up periodMeningism Any 1 0.7 0.0 4.0

Grade “3” 1 0.7 0.0 4.0Fever Any 59 42.8 34.4 51.5

> 39 °C 7 5.1 2.1 10.2Treatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects with symptom sheet completed for local/general symptomn (%): number/percentage of subjects reporting a specified symptomRelated: symptoms determined by the investigator to have relationship to study vaccine95% CI: exact 95% confidence intervals, lower and upper limits

Immunogenicity results:• All subjects who were seronegative at pre-vaccination for anti-measles antibodies

seroconverted after vaccination.•

• All subjects who were seronegative for anti-rubella antibodies at pre-vaccinationseroconverted after vaccination.




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Immunogenicity results of all subjects for the ATP cohort are as follows:Seroconversion rates and GMTs of all subjects for all antibodies against vaccine antigens (ATPimmunogenicity cohort) were as follows:

Antibody Prevacc. Timing N n % 95% CI GMTstatus 95% CI

Anti-measles S– Pre 104 - - - - - - -Post 104 104 100.0 96.5 100.0 3018.5 2703.2 3370.5

S+ Pre 12 12 100.0 73.5 100.0 3348.4 2308.7 4856.2Post 12 12 100.0 73.5 100.0 2832.2 2001.1 4008.4

Total Pre 116 12 10.3 5.5 17.4 111.1 89.5 137.9Post 116 116 100.0 96.9 100.0 2998.6 2703.6 3325.8

Anti-mumps S– Pre 112 - - - - - - -Post 108 106 98.1 93.5 99.8 1132.7 978.2 1311.6

S+ Pre 4 4 100.0 39.8 100.0 6881.9 2631.8 17995.4Post 4 4 100.0 39.8 100.0 11849.9 8487.0 16545.3

Total Pre 116 4 3.4 0.9 8.6 133.0 115.7 152.8Post 112 110 98.2 93.7 99.8 1231.8 1046.0 1450.6

Anti-rubella S– Pre 115 - - - - - - -Post 115 115 100.0 96.8 100.0 78.1 69.2 88.1

S+ Pre 1 1 100.0 2.5 100.0 365.0 - -Post 1 1 100.0 2.5 100.0 350.0 - -

Total Pre 116 1 0.9 0.0 4.7 2.1 1.9 2.3Post 116 116 100.0 96.9 100.0 79.1 70.0 89.4

Treatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: Pre: pre-vaccination blood sample at Day 0; Post: post-vaccination blood sample at Day42N: number of subjects with immunogenicity data availablen (%): number (percentage) of subjects with titers ≥ assay cut off (≥ 150 mIU/ml for measles, ≥231 U/ml for mumps and ≥ 4 IU/ml for rubella)S–: seronegative at pre-vaccination timepointS+: seropositive at pre-vaccination timepoint95% CI: 95% confidence intervals, lower and upper limits

Conclusions:In conclusion, the GSK Biologicals’ live attenuated measles-mumps-rubella vaccine Priorix™was shown to be safe, well tolerated and immunogenic in this cohort of healthy children aged12-18 months.Date of report: 6 March 2002 (Final)




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CONTENTS: TEXT

1. INTRODUCTION/RATIONALE...................................................................................... 14

2. STUDY OBJECTIVES ....................................................................................................... 14

2.1 PRIMARY OBJECTIVE......................................................................................................... 142.2 SECONDARY OBJECTIVE.................................................................................................... 14

3. METHODOLOGY.............................................................................................................. 14

3.1 STUDY DESIGN................................................................................................................... 153.2 INVESTIGATORAND TRIAL CENTER..................................................................................... 153.3 ETHICS .............................................................................................................................. 15

3.3.1 Protocol amendments/modifications....................................................................... 153.4 SELECTION OF STUDY POPULATION.................................................................................... 16

3.4.1 Inclusion criteria..................................................................................................... 163.4.2 Exclusion criteria.................................................................................................... 163.4.3 Elimination criteria................................................................................................. 173.4.4 Contraindications to vaccination............................................................................ 17

3.5 STUDY VACCINE AND ADMINISTRATION............................................................................. 173.5.1 Study Vaccine composition ..................................................................................... 173.5.2 Dosage and administration..................................................................................... 18

3.6 TREATMENT ALLOCATION AND RANDOMIZATION .............................................................. 183.7 BLINDING .......................................................................................................................... 183.8 STUDY PROCEDURES ......................................................................................................... 183.9 SUBJECT COMPLETION AND DROP-OUT .............................................................................. 193.10 ASSESSMENT OF SAFETY VARIABLES ................................................................................. 20

3.10.1 Biochemical assays ................................................................................................. 233.10.2 Pregnancy ............................................................................................................... 233.10.3 Prior and concomitant medication ......................................................................... 23

3.11 ASSESSMENT OF IMMUNOGENICITY VARIABLES................................................................. 243.11.1 Intervals between study visits.................................................................................. 243.11.2 Laboratory assays and timepoints .......................................................................... 24

3.12 DATA QUALITY ASSURANCE .............................................................................................. 253.13 STATISTICAL METHODS...................................................................................................... 25

3.13.1 Primary endpoints................................................................................................... 253.13.2 Secondary endpoint ................................................................................................ 253.13.3 Target sample size................................................................................................... 253.13.4 Study cohorts/data sets analysed ............................................................................ 263.13.5 Analysis of demographics ....................................................................................... 263.13.6 Analysis of safety .................................................................................................... 263.13.7 Analysis of immunogenicity .................................................................................... 27

3.14 CHANGES IN PLANNED ANALYSES...................................................................................... 27



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4. STUDY POPULATION...................................................................................................... 28

4.1 STUDY DATES.................................................................................................................... 284.2 SUBJECT ELIGIBILITY AND ATTRITION FROM STUDY........................................................... 28

4.2.1 Number and distribution of subjects ....................................................................... 284.2.2 Study completion and drop-out............................................................................... 284.2.3 Eligibility for analysis............................................................................................. 294.2.4 Compliance with protocol specified procedures..................................................... 30

4.3 DEMOGRAPHIC CHARACTERISTICS..................................................................................... 304.3.1 Total cohort ............................................................................................................ 304.3.2 Subjects included in the ATP analysis of safety ...................................................... 31

5. ANALYSIS OF SAFETY ................................................................................................... 32

5.1 OVERALL INCIDENCE OF SYMPTOMS.................................................................................. 325.2 SOLICITED LOCAL SIGNS AND SYMPTOMS .......................................................................... 325.3 SOLICITED GENERAL SIGNS AND SYMPTOMS ...................................................................... 335.4 UNSOLICITED SYMPTOMS .................................................................................................. 345.5 CONCOMITANT MEDICATIONS/VACCINATIONS ................................................................... 365.6 BIOCHEMICAL ANALYSES .................................................................................................. 365.7 PREGNANCY...................................................................................................................... 365.8 SERIOUS ADVERSE EVENTS................................................................................................ 36

6. ANALYSIS OF IMMUNOGENICITY ............................................................................. 37

6.1 DATA SETS ANALYSED....................................................................................................... 376.2 ACCORDING TO PROTOCOL ANALYSIS............................................................................... 37

6.2.1 Anti-measles antibody response.............................................................................. 376.2.2 Anti-mumps antibody response ............................................................................... 386.2.3 Anti-rubella antibody response............................................................................... 39

6.3 ANALYSIS OF TOTAL COHORT ............................................................................................ 40

7. DISCUSSION/CONCLUSION .......................................................................................... 41

8. REFERENCES.................................................................................................................... 42



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CONTENTS: REPORT TABLES AND FIGURES

TABLE 1: OUTLINE OF STUDY PROCEDURES..................................................................................... 19TABLE 2: LOCAL AND GENERAL SYMPTOMS SOLICITED DURING THE STUDY .................................... 20TABLE 3: ASSESSMENT OF INTENSITY.............................................................................................. 21TABLE 4: REASONS FOR DROP OUT .................................................................................................. 28TABLE 5: THE NUMBER OF SUBJECTS ENROLLED/RANDOMIZED INTO THE STUDY AS WELL AS THE

NUMBER EXCLUDED FROM ANALYSES .................................................................................... 30TABLE 6: DEMOGRAPHICS: TOTAL COHORT .................................................................................... 31TABLE 7: DEMOGRAPHICS: ATP SAFETY COHORT........................................................................... 31TABLE 8: OVERALL INCIDENCE OF SYMPTOMS REPORTED DURING THE 43-DAY FOLLOW-UP PERIOD

AFTER VACCINATION (ATP SAFETY COHORT) ........................................................................ 32TABLE 9: INCIDENCE OF SOLICITED LOCAL SYMPTOMS REPORTED DURING THE 4-DAY FOLLOW-UP

PERIOD AFTER VACCINATION (ATP SAFETY COHORT) ............................................................ 33TABLE 10: INCIDENCE OF SOLICITED GENERAL SYMPTOMS (ANY, GRADE “3” AND RELATED)

REPORTED DURING THE 4-DAY AND 43-DAY FOLLOW-UP PERIODS AFTER VACCINATION (ATPSAFETY COHORT) ................................................................................................................... 34

TABLE 11: PERCENTAGE OF SUBJECTS REPORTING UNSOLICITED SYMPTOMS CLASSIFIED BY WHOPREFERRED TERM AS RELATED TO VACCINATION REPORTED DURING THE 43-DAY FOLLOW-UP

PERIOD AFTER VACCINATION (ATP SAFETY COHORT) ............................................................ 36TABLE 12: PRE-VACCINATION SEROLOGICAL STATUS (ATP IMMUNOGENICITY COHORT)................ 37TABLE 13: SEROCONVERSION RATES AND GMTS FOR ANTI-MEASLES ANTIBODIES (ATP

IMMUNOGENICITY COHORT) ................................................................................................... 38TABLE 14: SEROCONVERSION RATES AND GMTS FOR ANTI-MUMPS ANTIBODIES (ATP

IMMUNOGENICITY COHORT) ................................................................................................... 39TABLE 15: SEROCONVERSION RATES AND GMTS FOR ANTI-RUBELLA ANTIBODIES (ATP

IMMUNOGENICITY COHORT) ................................................................................................... 40



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CONTENTS: SUPPLEMENTARY TABLES

SUPPLEMENTARY TABLE 1: DEMOGRAPHICS: ATP IMMUNOGENICITY COHORT.............................. 43SUPPLEMENTARY TABLE 2: OVERALL INCIDENCE OF SYMPTOMS REPORTED DURING THE 43-DAY

FOLLOW-UP PERIOD AFTER VACCINATION (TOTAL COHORT)................................................... 43SUPPLEMENTARY TABLE 3: INCIDENCE OF SOLICITED LOCAL SYMPTOMS REPORTED DURING THE 4-

DAY FOLLOW-UP PERIOD AFTER VACCINATION (TOTAL COHORT) ........................................... 43SUPPLEMENTARY TABLE 4: INCIDENCE OF SOLICITED GENERAL SYMPTOMS (ANY, GRADE “3” AND

RELATED) REPORTED DURING THE 4-DAY AND 43-DAY FOLLOW-UP PERIOD AFTER

VACCINATION (TOTAL COHORT) ............................................................................................. 44SUPPLEMENTARY TABLE 5: PERCENTAGE OF SUBJECTS REPORTING UNSOLICITED SYMPTOMS

CLASSIFIED BY WHO PREFERRED TERM AS RELATED TO VACCINATION REPORTED DURING THE

43-DAY FOLLOW-UP PERIOD AFTER VACCINATION (TOTAL COHORT)...................................... 45SUPPLEMENTARY TABLE 6: PERCENTAGE OF SUBJECTS REPORTING UNSOLICITED SYMPTOMS

CLASSIFIED BY WHO PREFERRED TERM REPORTED DURING THE 43-DAY FOLLOW-UP AFTER

VACCINATION (ATP SAFETY COHORT) ................................................................................... 46SUPPLEMENTARY TABLE 7: PERCENTAGE OF SUBJECTS REPORTING UNSOLICITED SYMPTOMS

CLASSIFIED BY WHO PREFERRED REPORTED AFTER THE 43-DAY FOLLOW-UP AFTER

VACCINATION (ATP SAFETY COHORT) ................................................................................... 47SUPPLEMENTARY TABLE 8: DISTRIBUTION OF ANTI-MEASLES ANTIBODY TITERS (ATP

IMMUNOGENICITY COHORT) ................................................................................................... 47SUPPLEMENTARY TABLE 9: DISTRIBUTION OF ANTI-MUMPS ANTIBODY TITERS (ATP

IMMUNOGENICITY COHORT) ................................................................................................... 48SUPPLEMENTARY TABLE 10: DISTRIBUTION OF ANTI-RUBELLA ANTIBODY TITER (ATP

IMMUNOGENICITY COHORT) ................................................................................................... 49SUPPLEMENTARY TABLE 11: PRE-VACCINATION SEROLOGICAL STATUS (TOTAL COHORT).............. 50SUPPLEMENTARY TABLE 12: SEROCONVERSION RATES AND GMTS FOR ANTI-MEASLES ANTIBODIES

(TOTAL COHORT) ................................................................................................................... 51SUPPLEMENTARY TABLE 13: SEROCONVERSION RATES AND GMTS FOR ANTI-MUMPS ANTIBODIES

(TOTAL COHORT) ................................................................................................................... 51SUPPLEMENTARY TABLE 14: SEROCONVERSION RATES AND GMTS FOR ANTI-RUBELLA ANTIBODIES

(TOTAL COHORT) ................................................................................................................... 52



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APPENDICES

CLINTRIAL ELIGIBILITY CODES ........................................................................................................ 53NOTES FOR APPENDIX TABLES ......................................................................................................... 55

APPENDICES: INDIVIDUAL LISTINGS

I A ELIMINATION CODES

B DEMOGRAPHY

C DATES OF BIRTH AND VACCINATION

D GENERAL MEDICAL HISTORY - PHYSICAL EXAMINATION

E STUDY CONCLUSION

II A SOLICITED LOCAL ADVERSE EVENTS

Bi SOLICITED GENERAL ADVERSE EVENTS

Ci UNSOLICITED ADVERSE EVENTS WITHIN 42 DAYS POST VACCINATION

Cii UNSOLICITED ADVERSE EVENTS STARTED MORE THAN 42 DAYS POST VACCINATION

Di CONCOMITANT MEDICATION

Dii CONCOMITANT VACCINATION

III A IMMUNOGENICITY

APPENDICES: SERIOUS ADVERSE EVENTS− CIOMS− SERIOUS ADVERSE EVENTS TABLE

APPENDICES: STUDY INFORMATION− PROTOCOL− REPRESENTATIVE SUBJECT INFORMATION SHEET− RELEVANT PAGES OF CRF− RANDOMISATION LIST− ONE PAGE CV FOR PRINCIPAL INVESTIGATOR(S)− PUBLICATIONS REFERENCED IN THE REPORT



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List of Abbreviations and Definitions of Terms

AAP American Academy of PediatricsACIP Advisory Committee on Immunization PracticesAE Adverse eventCI Confidence IntervalCRF case report formELISA Enzyme-linked immunosorbent assayEL.U ELISA UnitGMT Geometric Mean antibody TiterGSK GlaxoSmithKlineIgG Immunoglobulin GIU International UnitsmIU milli-International Unitsml MilliliterMeMuRu Measles, mumps, rubellaMMR Measles, mumps, rubellaSD Standard DeviationTCID tissue culture infective doseU/ml Units/milliliterWHO World Health Organization



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Glossary of Terms

Adverse event: Any noxious, pathologic or unintended change inanatomical, physiologic and/or laboratory changesoccurring in any phase of the clinical trial whetherassociated with vaccine or whether or not consideredvaccine related. This included an exacerbation of pre-existing condition or event, intercurrent illnesses ordrug interactions.

ATP cohort: Includes all subjects enrolled in the study who metthe criteria defined in the protocol for the consideredanalysis (safety or immunogenicity).

Case Report Form: Hard copy standardized form for recording individualsubject data.

Completed: Subjects who completed at least the last study visit

Diary card: Individual card provided by the sponsor for eachvaccinee after administration of the study vaccinedose, designed to document the presence of solicitedlocal and general adverse events as well as any othersign/symptom the vaccinee might experience duringthe four days after vaccination (Days 0 to 3).

Drop-out: Subjects who did not come at least for the last studyvisit.

Evaluable: Meeting all eligibility criteria, complying with theprocedures defined in the protocol, and, therefore,included in analysis

Seroconversion: The appearance of antibodies to vaccine antigencomponent in a serum sample from a subject withpreviously undetectable antibody (i.e., titer below thelaboratory defined assay cut-off).

Seronegative: Antibody titer below the laboratory defined assay cut-off value.

Seropositive: Antibody titer greater than or equal to the laboratory



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defined assay cut-off value.

Subject(s)/ Vaccinee(s): Terms used throughout to denote the enrolled/vaccinated individual(s).

Symptom sheets: The specific pages in the individual case report formsonto which the investigator transcribed diary carddocumentation of solicited symptom(s) reported forthe subject (one sheet for solicited local symptoms,one sheet for solicited general symptoms).

Total cohort: All enrolled subjects for whom data were available.



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1. Introduction/Rationale

The safety and immunogenicity of GlaxoSmithKline (GSK) Biologicals’ trivalentlive attenuated measles-mumps-rubella (MMR) vaccine Priorix™, containing theSchwarz measles strain, the RIT 4385 mumps strain and the RA 27/3 rubellastrain, has already been demonstrated in more than 7,000 children in clinical trials.This vaccine was first approved for commercial use in Europe in 1997. Therationale for this present study was to evaluate the safety, reactogenicity andimmunogenicity of GlaxoSmithKline Biologicals’ MMR vaccine Priorix™administered according to local immunization recommendations.

2. Study Objectives

2.1 Primary Objective

• To assess the safety and reactogenicity of GSK Biologicals’ live attenuatedMMR vaccine.

2.2 Secondary Objective

• To assess the antibody response to the vaccine antigens: measles, mumps andrubella.

3. Methodology

Report appendices contain the study protocol, a representative subject informationsheet and relevant pages of the individual case report form used in the study.



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3.1 Study design

This was an open study with one group conducted at one study

site.

Visit 1 (Day 0)12-18 months of age

Visit 2 (Day 42)

GSK Biologicals’ MMR vaccine Priorix™ (N = 150)� �

Vaccination Follow-up visit

N: number of subjects enrolled

3.2 Investigator and trial center

The principal investigator for this study was Dr. and the studycenter was Singapore

3.3 Ethics

The study was conducted according to Good Clinical Practice and in accordancewith the Declaration of Helsinki as amended in Somerset West, Republic of SouthAfrica, October 1996 and the local rules and regulations. The protocol dated 19July 2000 and the statement of informed consent were approved by

Singapore

Written informed consent was obtained from parent/guardian of the subject priorto entry into the study.

Case Report Forms (CRF) were provided for each subject’s data to be recorded.Report appendices contain the subject information sheet and relevant pages of theindividual case report form used in the study.

3.3.1 Protocol amendments/modifications

None.



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3.4 Selection of study population

Healthy male and female infants (12 to 18 months of age) for whom theinvestigator believed the requirements of the protocol would be complied with(e.g. completion of diary cards, return for follow-up) were recruited for enrollmentin the study.

3.4.1 Inclusion criteria

All subjects satisfied the following criteria at the time of enrollment:

• A male or female infant between 12 and 18 months of age at the time of thevaccination.

• Written informed consent obtained from the parents or guardians of thesubject.

• Free of obvious health problems as established by medical history and clinicalexamination before entering into the study.

3.4.2 Exclusion criteria

The following criteria were checked at the time of study entry. If any applied atthe time of study entry, the subject was not included in the study:

• Use of any investigational or non-registered drug or vaccine other than thestudy vaccine during the study period or within 30 days preceding the dose ofstudy vaccine

• Administration of chronic (defined as more than 14 days) immunosuppressantsor other immune-modifying drugs within six months of vaccination (Forcorticosteroids, this meant prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaledand topical steroids were allowed.)

• Planned administration/ administration of a vaccine not foreseen by the studyprotocol (with the exception of the DTPw booster vaccination).

• Previous vaccination against mumps and/or rubella• History of, or intercurrent, measles, mumps, and/or rubella disease• Known exposure to measles, mumps or rubella within 30 days prior to start of

the study• Any confirmed or suspected immunosuppressive or immunodeficient

condition, including human immunodeficiency virus (HIV) infection.• Any major congenital defects• Any serious chronic illness• History of allergic disease or reactions likely to be exacerbated by any

component of the vaccines, including obvious allergic reactions to neomycin,egg proteins, and/or gelatin

• History of convulsions (including febrile convulsions, epilepsy) or any othersigns of central nervous system disease



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• Acute febrile illness or obvious upper respiratory tract symptoms at the time ofplanned vaccination

• Axillary temperature of ≥ 37.5 °C at the time of vaccination• Administration of immunoglobulins and/or any blood products within 3

months preceding the dose of study vaccine or planned administration/administration during the study period

3.4.3 Elimination criteria

Not applicable.

3.4.4 Contraindications to vaccination

Since this is a single dose study, all absolute contraindications to vaccination werelisted as exclusion criteria.

3.5 Study vaccine and administration

The study vaccine used in this study was developed and manufactured byGlaxoSmithKline Biologicals.

The Quality Control Standards and Requirements for GSK Biologicals’ MMRvaccine Priorix™ are described in separate release protocols and the requiredapprovals were obtained. The vaccine release protocols are archived in the studyfile and are available upon request.

3.5.1 Study Vaccine composition

The measles and mumps virus strains are produced on chicken embryo fibroblasts.The rubella virus strain is produced on human diploid cells (MRC5).

GlaxoSmithKline Biologicals’ trivalent measles-mumps-rubella vaccine (MMR)Priorix™ contained the Schwarz measles strain, the RIT 4385 mumps strain andthe RA 27/3 rubella strain.

The vaccine was supplied in monodose vials containing a freeze-dried pellet thatwas reconstituted with an individual ampoule of water for injection just prior tovaccination.

Vaccine Lot : MJR289A42CDiluent Lot : 136

Each 0.5 ml dose of the study vaccine Priorix™ contained not less than 103.0

TCID50 of measles, not less than 103.7 TCID50 of mumps and not less than 103.0

TCID50 of rubella virus titers.



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3.5.2 Dosage and administration

One dose of the MMR vaccine Priorix™ (0.5 ml) was administeredsubcutaneously in the left upper arm (deltoid region) of the subjects using a needleof 1 inch (2.54 cm) length and 25 gauge.

The vaccinees were observed closely for at least 30 minutes, with appropriatemedical treatment readily available in case of a rare anaphylactic reactionfollowing the administration of the study vaccine.

3.6 Treatment allocation and randomization

No randomization was performed as this study included only a single group.Subjects received a study number in the order in which they were enrolled into thestudy and this number served as subject identification for all data collected underthe study.

3.7 Blinding

This was an open study as all the subjects in the study received the same marketedstudy vaccine (MMR).

3.8 Study procedures

Table 1 summarizes the procedures that were performed at each time point duringthe study.



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Table 1: Outline of study procedures

Visit VISIT 1 VISIT 2Timing Day 0 Day 42

Sampling timepoint Pre-vacc Post vacc IInformed consent •Check of inclusion criteria •Check of exclusion criteria •Medical history •Physical examination • •Pre-vaccination assessment of adverse events •Blood samplingfor serology (3.0 ml) • •Vaccination •Daily post-vaccination recording of solicited symptoms(Days 0 – 3) by parents/guardian

•

Follow-up contact either by phone or home visit on Day5 post-vaccination

•

Recording of unsolicited adverse events occurring Days0 – 42 post-vaccination, by investigator

•

Return of diary cards •Diary card transcription •Recording medication • •Reporting of Serious Adverse Events occurringthroughout the study period, by investigator • •Study Conclusion •• is used to indicate a study procedure which required documentation in the individual CRF.

3.9 Subject completion and drop-out

A ‘drop-out’ was defined as any subject who did not come back at least for theconcluding visit foreseen in the protocol. The investigator attempted to contact theparents/guardians of those subjects who did not return for scheduled follow-upvisit. Information gathered was specified on the Study Conclusion page of thecase report form. Following were possible reasons for the subject to have droppedout from the study:

• Serious adverse event• Non-serious adverse event• Protocol violation (specific reason was to be recorded)• Consent withdrawal, not due to an adverse event• Migration from the study area• Lost to follow-up• Other (any other reason was to be specified)



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3.10 Assessment of safety variables

On the day of vaccination, diary cards were distributed to the parents/guardians torecord local and general signs and symptoms or illnesses (both solicited andunsolicited) occurring during the follow-up period. Parents/guardians wereinstructed to return the completed diary card at the next visit. Diary cards werechecked by the investigator and data transcribed into the appropriate sections ofthe CRFs.

Table 2: Local and general symptoms solicited during the study

Days 0 to 3 Local (Injection site) Symptoms General Symptoms

Pain Drowsiness Redness Irritability/Fussiness Swelling Loss of appetite

Days 0 to 42 Fever* (axillary temperature in °C)

Parotid/salivary gland swelling Signs of meningism

* Fever was defined as axillary temperature ≥ 99.5 °F (37.5 °C)

Assessment of intensity:

Intensity of solicited symptoms were assessed by the investigator as described inTable 3.



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Table 3: Assessment of intensity

Adverse Event Intensity grade ParameterSolicited local symptomsPain at injection site 0 Absent

1 Minor reaction to touch2 Cried/protested on touch3 Cried when limb was moved/spontaneously painful

Redness at injection site Recorded greatest surface diameter in mmSwelling at injection site Recorded greatest surface diameter in mmSolicited general symptomsFever* Recorded axillary temperature in °CIrritability/Fussiness 0 Behaviour as usual

1 Crying more than usual/ no effect on normalactivity

2 Crying more than usual/ interfered with normalactivity

3 Crying that could not be comforted/ preventednormal activity

Drowsiness 0 Behaviour as usual1 Drowsiness easily tolerated2 Drowsiness that interfered with normal activity3 Drowsiness that prevented normal activity

Loss of appetite 0 Normal1 Eating less than usual/ no effect on normal activity2 Eating less than usual/ interfered with normal

activity3 Not eating at all

* Fever was defined as axillary temperature ≥ 99.5 °F (37.5 °C)

The maximum intensity of injection site redness/swelling was scored at GSKBiologicals as:

0: Absent1: < 5 mm diameter2: 5 – 20 mm diameter 3: > 20 mm diameter

Axillary temperature was recorded in the evening. Parents/guardians were askedto first qualitatively assess presence or absence of fever by means of a temperaturesensitive pad (liquid crystals) to be put on the child’s forehead. If this pad showeda sign other than ‘no fever’ or if any other clinical signs indicated possible fever,accurate temperature measurement was performed using the thermometer supplied(axillary route).

If temperature measurement was additionally performed at another time of day,the highest temperature was recorded. The maximum intensity of fever, i.e.,axillary temperature ≥ 37.5 °C, was scored at GlaxoSmithKline Biologicals as:



22

0: < 37.5 °C1: 37.5 °C – 38.0 °C2: 38.1 °C – 39 °C3: > 39 °C

Parotid/salivary gland swelling was assessed at the initial visit (Day 0) and on adaily basis (Day 0 – 42) by the parents/guardians of the vaccinee. In case of asuspected parotitis (swelling/tenderness in the mandibular/submandibular region),the child was to be presented to the investigator. If parotitis or salivary glandswelling were confirmed, the investigator graded the intensity of the swelling asfollows:

1: Swelling, without difficulty in moving the jaw2: Swelling, with difficulty in moving the jaw3: Swelling and additional general symptoms

Parents/guardians were instructed that should the child exhibit febrile convulsionsor any other neurological signs or symptoms indicative of meningism (e.g.vomiting, neck stiffness, photophobia) between Day 0 and the follow-up visit atDay 42, the child should undergo neurological examination according to currentlocal medical practice including (at the discretion of the treating physician) alumbar puncture.

Any adverse event occurring during the study period that was not a solicited signor symptom was recorded by the investigator as an unsolicited symptom in theCRF. This was given the intensity grading (1 – 3) as shown below.

1: Adverse event which was easily tolerated, causing minimal discomfort and notinterfering with everyday activities

2: Adverse event sufficiently discomforting to interfere with daily activities3: Adverse event that prevented normal everyday activities

The relationship of all solicited general symptoms and unsolicited adverse eventsfollowing vaccination was assessed by the investigator and recorded in the CRF.Relationships were assessed as either:

NO : The adverse event was not causally related to administration of thestudy vaccine. There were other, more likely causes andadministration of the study vaccine was not suspected to havecontributed to the adverse event.

YES : There was a reasonable possibility that the study vaccinecontributed to the adverse event.



23

All local (injection site) symptoms reported were considered to be related to thestudy vaccine.

Serious adverse events:

Parents/guardians were instructed to contact the investigator immediately shouldthe subject manifest any signs or symptoms they perceived as serious.

The investigator was required to notify GlaxoSmithKline within 24 hours of theoccurrence of any serious adverse event reported by the parent/guardian of thesubject, during the clinical trial or within 42 days of receiving the dose of studyvaccine. A serious adverse event was defined as any event that was fatal, lifethreatening, disabling/incapacitating, resulted in hospitalization, prolonged ahospital stay or associated with congenital abnormality in offspring, cancer oroverdose. In addition, any event which the investigator regarded as serious orwhich suggested any significant hazard, contraindication, side effect or precautionthat might be associated with the use of the vaccine was to be documented as aserious event.

Treatment of any adverse event was at the discretion of the investigator andaccording to current Good Clinical Practice (GCP). Treatment measures werereported in the appropriate CRF. The investigator was to follow patients withadverse events until the event subsided or until the condition had stabilized.

Assessment of outcome:

The outcome of all adverse events was indicated as follows:1: Recovered2: Recovered with sequelae3: Ongoing4: Died5: Unknown

3.10.1 Biochemical assays

None.

3.10.2 Pregnancy

Not applicable.

3.10.3 Prior and concomitant medication

At each study visit/contact, the investigator questioned the subjects’ parent/guardian or their legal representative about any medication given to the subject.



24

Any immunosuppressants or other immune-modifying drugs or treatments, anyvaccine other than the study vaccine and any antipyretics administered at any timeduring the period starting 30 days prior to the administration of the study vaccineand ending 42 days after the administration of study vaccine was recorded in theCRF with trade name and/or generic name of the medication, medical indication,total daily dose, route of administration, start and end dates of treatment.

Any other concomitant medication administered prophylactically in anticipationof reaction to the vaccination was also recorded in the CRF with trade nameand/or generic name of the medication, total daily dose, route of administration,start and end dates of treatment and coded as ‘Prophylactic’.

3.11 Assessment of immunogenicity variables

Evaluation of vaccine efficacy was based upon assessment of immunogenicity ofthe vaccines, i.e., antibody response to the vaccine antigen components.

3.11.1 Intervals between study visits

To adequately assess the immune response elicited by the vaccines, the timeinterval to have been respected between visits was specified in the protocol. Therange of days defined in the protocol between vaccination and the follow-up visitwas 42 ± 7 days. However, the adapted interval that served as the absolutecriterion for the exclusion of subjects from the ATP analyses was 35-56 days.

3.11.2 Laboratory assays and timepoints

A minimum of 3 ml whole blood was taken for serology before (Visit 1: Day 0)and after vaccination (Visit 2: Day 42).

Separated pre- and post-vaccination serum samples were stored at – 20 °C untilassays were performed at GlaxoSmithKline Biologicals’ laboratory in Rixensart,Belgium.

Pre- and post-vaccination serum samples of all subjects were tested for antibodiesagainst all vaccine antigens (measles, mumps and rubella).

Antibody titers were determined using commercial immunoassays according tothe manufacturer’s instructions:

• For measles – Enzygnost anti-measles virus/IgG (Behring); expressed inmIU/ml with a cut-off of 150 mIU/ml

• For mumps – Enzygnost anti-mumps virus/IgG (Behring); expressed in U/mlwith a cut-off of 231 U/ml



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• For rubella – Enzygnost anti-rubella virus/IgG (Behring): expressed in IU/mlwith a cut-off of 4 IU/ml.

3.12 Data quality assurance

To ensure that study procedures conformed across all investigator sites, theprotocol, case report form and safety reporting were reviewed with theinvestigator and his/her personnel responsible for the conduct of the study by theCompany representative(s) at the investigator site.

Adherence to the protocol requirements and verification of data generationaccuracy was achieved through monitoring visits to each investigator site. Allprocedures were performed according to methodologies detailed in GSK StandardOperating Procedures (SOPs).

No study specific audits were performed for this study.

3.13 Statistical methods

3.13.1 Primary endpoints

After a single-dose of vaccination:

• Occurrence of solicited symptoms (during the 4-day follow-up period after asingle-dose)

• Occurrence of unsolicited symptoms (during the 43-day follow-up period aftera single-dose)

• Occurrence of serious adverse events

3.13.2 Secondary endpoint

42 days after a single-dose vaccination:

• anti-measles, anti-mumps, anti-rubella antibodies (Geometric Mean Titers)and seroconversion rates

3.13.3 Target sample size

A total of 150 subjects were planned to be enrolled. With a sample of 150 subjectsand an expected incidence of any local symptoms after 15% of doses, the medianwidth of the 95% CI would be of 12% [10%; 12%].

With a sample of 150 subjects and an expected seroconversion rate of 95%, themedian width of the 95% CI would be of 8% [90%; 98%].



26

3.13.4 Study cohorts/data sets analysed

Total cohort

The total cohort included all enrolled (i.e. randomized or vaccinated) subjects forwhom data was available. The total cohort analysis of safety included allvaccinated subjects for whom safety data was available. The total cohort analysisof immunogenicity included all vaccinated subjects for whom data concerningimmunogenicity endpoint measures were available.

According-To-Protocol (ATP) cohort for analysis of safety

The ATP cohort for analysis of safety excluded all subjects for whom adifferential treatment effect on safety was unlikely. The ATP cohort for analysisof safety included all subjects:

• who received the study vaccine• with sufficient data to perform an analysis of safety• who did not receive a vaccine not specified or forbidden in the protocol

ATP cohort for analysis of immunogenicity

The ATP cohort for analysis of immunogenicity served as the cohort of primaryinterest in this study and included all subjects for whom data concerningimmunogenicity endpoint measures were available. This included subjects forwhom assay results were available for antibodies against at least one studyvaccine antigen component for post-vaccination timepoint.

3.13.5 Analysis of demographics

Demographic characteristics (age, gender) were summarized by groups by usingdescriptive statistics (mean, standard deviation, n) for the total cohort, for the ATPsafety cohort and for the ATP immunogenicity cohort.

3.13.6 Analysis of safety

Two analyses were performed: a first one on the ATP safety cohort and a secondone on the total cohort.

The overall incidence of documented doses followed by reports of local, general,and both local and general symptoms after the vaccination were determined.

The incidence of local and general solicited symptoms over the entire follow-upperiod (4 or 43 days depending on the nature of the solicited symptom) wascalculated in addition to intensity and relationship.



27

The incidence (yes/no) of pain, redness, swelling at the injection site during the 4-day follow-up period was calculated.

The incidence (yes/no) of fever, drowsiness, irritability, loss of appetite during the4-day follow-up period was calculated.

The number of subjects who reported at least one unsolicited symptom in the 43-day follow-up period, classified by WHO Preferred terms, was tabulated inaddition to relationship.

The number of subjects who reported at least one serious adverse event was alsoreported.

3.13.7 Analysis of immunogenicity

Two analyses were performed: the first one on the ATP immunogenicity cohortand the second one on the total cohort.

A subset analysis, which was regarded as the principal analysis ofimmunogenicity, was performed for those subjects included in the ATP analysisof immunogenicity who were seronegative for antibody to the specific vaccineantigen at the time of study vaccination.

Anti-measles, anti-mumps, anti-rubella antibody

The percentage of seroconverted subjects (with two-sided 95 % confidenceintervals) was calculated for each group. The cut-off value was defined by thelaboratory before the analysis and is described in Section 3.11.2.

A seronegative subject was a subject whose antibody titers were below the assaycut-off value. A seropositive subject was a subject whose antibody titers weregreater than or equal to the cut-off value. Seroconversion was defined as theappearance of antibodies (i.e. antibody titers ≥ cut-off) in the serum of subjectsseronegative before vaccination.

Geometric mean titers (GMTs) with their 95% Confidence Interval (CI) werecalculated for antibodies to all vaccine antigen components at each bloodsampling time point, by taking the log-transformation of individual titers andcalculating the anti-log of the mean of these transformed values. Antibody titersbelow the cut-off of the assay were given an arbitrary value of half the cut-off forthe purpose of GMT calculation.

3.14 Changes in planned analyses

None.



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4. Study Population

4.1 Study dates

The first volunteer was enrolled in the study on 23 November 2000 and the laststudy visit was on 17 April 2001. See Appendix Table IC for individual subjectdata on dates of visits, vaccination and blood sampling.

4.2 Subject eligibility and attrition from study

4.2.1 Number and distribution of subjects

A total of 150 subjects were enrolled after checking the inclusion and exclusioncriteria.

4.2.2 Study completion and drop-out

Table 4 details the reasons for drop-out.

Of the 150 subjects enrolled, 12 subjects dropped out from the study. The reasonswere as follows:

•

•

Table 4: Reasons for drop out

Study cohortNumber of subjects planned 150Number of subjects enrolled 150Number of subjects completed 138Reasons for drop-out:Consent withdrawal 2Lost to follow-up for the final blood sample 10

Source: Individual subject data on study conclusion can be found in Appendix Table IE.Treatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: Planned: Number of subjects planned to be enrolled in the studyCompleted: number of subjects who completed at least the last study visitDrop out: a subject who did not come back at least for the last study visit.



29

4.2.3 Eligibility for analysis

Table 5 presents the number of subjects enrolled/randomized into the study aswell as the number excluded from analyses.

Elimination Codes (Clintrial Eligibility Codes) are defined on the first page of theAppendix Tables. Individual subject data for elimination codes can be found inAppendix Table IA.

Of the 150 subjects enrolled, 11 subjects were eliminated from the ATP analysisof safety for the following reasons:

•

•

Of the 139 subjects included in the ATP analysis of safety, 6 subjects wereeliminated from the ATP analysis of immunogenicity. The reasons were asfollows:

• Three subjects received the code 2040 for administration of medicationforbidden in the protocol.

• Two subjects received the code 2100 for essential serological data missing.

•



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Table 5: The number of subjects enrolled/randomized into the study as well as thenumber excluded from analyses

Title Total Percent MMRNumber of subjects planned 150 150Number of subjects enrolled 150 100.00 150Administration of vaccine(s) forbidden in the protocol (code1040)

1 1

Essential data missing (code 1080) 10 10Number of subjects in the ATP cohort for safety 139 92.67 139Administration of any medication forbidden by the protocol(code 2040)

3 3

Essential serological data missing (code 2100) 2 2Non compliance with blood sampling schedule (including wrongand unknown date) (code 2090)

1 1

Number of subjects in the ATP cohort for immunogenicity 133 88.67 133Source: Individual subject data on elimination codes can be found in Appendix Table IA.Treatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no. MJR289A42C)Notes: Percentage is calculated using the number of subjects in the total cohort as denominator.Subjects may have one or more elimination code(s) assigned in which case the lowest code number islisted in the figure. Codes are given based on a ranking order. The code number listed in the figure arepresented in order of ranking; therefore, for example, code 1040 was assigned preferentially to 1080when the subject was eligible for elimination on both counts. Elimination codes are defined on the firstpage of the Appendix Tables.

4.2.4 Compliance with protocol specified procedures

All vaccine doses except one was administered according-to-protocol.

Of the 150 doses administered, 139 were documented in symptom sheets forsolicited general and local symptoms to give 92.7% compliance for the totalcohort.

Of the 139 doses administered to subjects in ATP safety cohort, 138 doses weredocumented in symptom sheets for solicited general and local symptoms to give99.3% compliance for the ATP safety cohort.

4.3 Demographic characteristics

4.3.1 Total cohort

Table 6 presents the demographics of the total cohort.

The mean age of the subjects was 15.2 months with a standard deviation of 0.55months. All subjects were oriental. The male/female ratio was 1.1:1.



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Table 6: Demographics: Total cohort

Characteristics Parameters or MMR (N = 150)Categories Value/n %

Age (in months) Mean 15.2 -SD 0.55 -Median 15 -Minimum 14 -Maximum 17 -

Gender Male 79 52.7Female 71 47.3

Race White 0 0.0Black 0 0.0Oriental 150 100.0Other 0 0.0

Source: Individual subject data on demography can be found in Appendix IBTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjectsValue/n (%): value for parameters of age/number (percentage) of subjects of subjects in a givencategoryS.D.: Standard Deviation

4.3.2 Subjects included in the ATP analysis of safety

Table 7 presents the demographics of the ATP safety cohort.

The mean age of the subjects was 15.2 months with a standard deviation of 0.54months. The subjects were all oriental. The male/female ratio was 1.2:1.

Table 7: Demographics: ATP safety cohort

Characteristics Parameters or (N = 139)Categories Value/n %



Race Whites 0 0.0Black 0 0.0Oriental 139 100.0Other 0 0.0

Source: Individual subject data on demography can be found in Appendix IBTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjectsValue/n (%): value for parameters of age/number (percentage) of subjects of subjects in a givencategoryS.D.: Standard Deviation



32

Supplementary Table 1 presents the demographics of the ATP immunogenicitycohort.

Individual subject data on demography can be found in Appendix Table IB.

5. Analysis of safety

Individual subject data on reactogenicity can be found in Appendix Tables IIA - C

5.1 Overall incidence of symptoms

Table 8 presents the overall incidence of symptoms reported during the 43-dayfollow-up period after vaccination for the ATP safety cohort. SupplementaryTable 2 presents the same data for the total cohort.

Table 8: Overall incidence of symptoms reported during the 43-day follow-upperiod after vaccination (ATP safety cohort)

Any Symptoms General Symptoms Local SymptomsN n % 95% CI N % 95% CI n % 95% CI

139 84 60.4 51.8 68.6 79 56.8 48.2 65.2 20 14.4 9.0 21.3Source: Individual subject data on solicited/unsolicited symptoms can be found in AppendixTables IIA-CTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: total number of subjects with at least one documented dose for any (local/general)symptomn (%): number (percentage) of subjects who experienced any (general, local) symptom at leastonce95% CI: exact 95% confidence intervals, lower and upper limit

5.2 Solicited local signs and symptoms

Table 9 presents the incidence of solicited local symptoms and those graded “3” inintensity reported during the 4-day follow-up period after vaccination for the ATPsafety cohort. Supplementary Table 3 presents the same data for the total cohort.

• Redness (8.7%) followed by pain (7.2%) at injection site was the mostcommonly reported local symptoms.

• There were no reports of Grade “3” solicited local symptoms.

• All solicited local symptoms resolved within the 4-day follow-up period aftervaccination.



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Table 9: Incidence of solicited local symptoms reported during the 4-day follow-up period after vaccination (ATP safety cohort)

Symptom (N = 138)n % 95% CI

Pain 10 7.2 3.5 12.9Redness 12 8.7 4.6 14.7Swelling 5 3.6 1.2 8.3Source: Individual subject data on solicited local symptoms can be found in Appendix Table IIATreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: n (%): number (percentage) of subjects reporting a specified symptom95% CI: exact 95% confidence intervals, lower and upper limits

Individual subject data on solicited local symptoms can be found in AppendixTable IIA.

5.3 Solicited general signs and symptoms

Table 10 presents the incidence of solicited general symptoms (any, Grade “3”and related) reported during the 4-day and 43-day follow-up periods aftervaccination for the ATP safety cohort. Supplementary Table 4 presents the samedata for the total cohort.

Symptoms reported during the 4-day follow-up period after vaccination

• There were no reports of Grade “3” drowziness, irritability and loss ofappetite. Majority of these symptoms reported (drowziness, irritability andloss of appetite) were determined by the investigator to be related tovaccination.

Symptoms reported during the 43-day follow-up period after vaccination

• Any fever (42.8%) was the most commonly reported solicited generalsymptom. However, none of the cases of fever reported in this study weredetermined by the investigator to have a relationship to vaccination.

• Fever (5.1%) and meningism (0.7%) were the only Grade “3” symptoms thatwere reported.

See section 5.8 fordetails. No cases of parotid/salivary gland swelling occurred during the 43-dayfollow-up period.



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Table 10: Incidence of solicited general symptoms (any, Grade “3” and related)reported during the 4-day and 43-day follow-up periods after vaccination (ATP

safety cohort)

Symptom Intensity (N = 138)N % 95% CI

Symptoms reported during the 4-day follow-up periodDrowziness Any 10 7.2 3.5 12.9

Grade “3” 0 0.0 0.0 2.6Related 7 5.1 2.1 10.2

Irritability Any 11 8.0 4.0 13.8Grade “3” 0 0.0 0.0 2.6Related 8 5.8 2.5 11.1

Loss of appetite Any 10 7.2 3.5 12.9Grade “3” 0 0.0 0.0 2.6Related 9 6.5 3.0 12.0


Grade “3” 1 0.7 0.0 4.0Related 0 0.0 0.0 2.6

Parotid gland Any 0 0.0 0.0 2.6swelling Grade “3” 0 0.0 0.0 2.6

Related 0 0.0 0.0 2.6Fever* Any 59 42.8 34.4 51.5

> 39 °C 7 5.1 2.1 10.2Related 0 0.0 0.0 2.6

Source: Individual subject data on solicited general symptoms can be found in Appendix TableIIBiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: Any: incidence of solicited general symptom regardless of intensity or relationshipGrade “3”drowziness, irritability and loss of appetite: see Table 3Grade “3” meningism: febrile convulsions or vomiting, neck stiffness, photophobia* axillary temperature was recordedn (%): number (percentage) of subjects reporting a specified symptom95% CI: exact 95% confidence intervals, lower and upper limits

Individual subject data on solicited general symptoms can be found in AppendixTable IIBi. Individual subject data on fever can be found in Appendix Table III.

5.4 Unsolicited symptoms

In addition to the solicited symptoms reported, any other symptoms that werereported to the investigator were documented under “others” in the case reportform. Symptoms designated as solicited in diary cards were also included underunsolicited symptoms if they started outside the protocol specified follow-upperiod for solicited symptoms. Unsolicited signs and symptoms were coded by useof the World Health Organization’s (WHO) Dictionary for Adverse ReactionTerminology; every verbatim term was matched to the appropriate WHOpreferred term. The count of WHO preferred terms may not necessarilycorrespond to the number of subjects having developed an adverse event. Indeed,



35

a person may have developed the same sign and symptom at different timeperiods, or a person may have developed different signs and symptoms coded todifferent WHO body system classes.

Table 11 presents the percentage of subjects reporting unsolicited symptomsclassified by WHO Preferred Term as related to vaccination reported during the43-day follow-up period after vaccination for the ATP safety cohort.Supplementary Table 5 presents the same data for the total cohort. SupplementaryTable 6 presents the percentage of subjects reporting unsolicited symptomsclassified by WHO Preferred reported during the 43-day follow-up aftervaccination for the ATP safety cohort. Supplementary Table 7 presents thepercentage of subjects reporting unsolicited symptoms classified by WHOPreferred reported after the 43-day follow-up after vaccination for the ATP safetycohort.

• A total of 36.7% of subjects reported at least one unsolicited symptom duringthe 43-day follow-up period after vaccination.

• The most frequently reported unsolicited symptoms were related to respiratorysystem (23% coughing and 19.4% rhinitis).

• Four subjects (2.2%) reported at least one unsolicited symptom determined bythe investigator to be related to the vaccination.

•

These symptoms resolved within three days of onset).

• These symptoms resolved within two days of onset.



36

Table 11: Percentage of subjects reporting unsolicited symptoms classified byWHO Preferred Term as related to vaccination reported during the 43-day

follow-up period after vaccination (ATP safety cohort)

WHO Body System (CODE) WHO Preferred term (CODE) (N = 139)s % 95% CI

At least one symptom 3 2.2 0.4 6.2Application site (1820) Injection site reaction (0058) 1 0.7 0 3.9Gastrointestinal system (600) Anorexia (0165) 2 1.4 0.2 5.1Psychiatric (500) Nervousness (0188) 1 0.7 0 3.9Source: Individual subject data on unsolicited symptoms can be found in Appendix Table IICiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: At least one symptom: at least one symptom experienced (without taking into account thepreferred term)N: total number of subjects with documented doses (%): number (percentage) of subjects reporting at least once a specified symptom within 43 daysafter vaccination95% CI: Exact 95% confidence interval, lower and upper limits

Individual subject data on unsolicited symptoms can be found in Appendix TableIICi and IICii.

5.5 Concomitant medications/vaccinations

A total of 71% subjects were given concomitant medication.

5.6 Biochemical analyses

None.

5.7 Pregnancy

Not applicable.

5.8 Serious adverse events

The boy was treated and recovered and the SAE was considered to benot related to vaccination.



37

Suspect Adverse Reaction Reports (SARR) and the SAE Table for all SAEs areincluded in report appendix for serious adverse events.

6. Analysis of immunogenicity

Individual subject data for immunogenicity can be found in Appendix table IIDii

6.1 Data sets analysed

Two analyses were performed for immunogenicity: one on the ATP cohort and theother on the total cohort. The analysis of ATP cohort was the principal analysis.Results from the ATP cohort are presented in the following sections. Summariesfrom the total cohort are presented as supplements.

6.2 According To Protocol analysis

Table 12 presents the pre-vaccination serological status for the ATPimmunogenicity cohort.

Table 12: Pre-vaccination serological status (ATP immunogenicity cohort)

Antibody (N = 133)n %

Anti-measles S– 104 89.7S+ 12 10.3

Unknown 17 -Anti-mumps S– 112 96.6

S+ 4 3.4Unknown 17 -

Anti-rubella S– 115 99.1S+ 1 0.9

Unknown 17 -Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: n (%): number (percentage) of subjects with a given serological statusS–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointCut-off values: measles: 150 mIU/ml, mumps: 231U/ml, rubella: 4 IU/ml


6.2.1 Anti-measles antibody response

Table 13 presents the seroconversion rates and GMTs for anti-measles antibodiesfor the ATP immunogenicity cohort.



38

• All subjects who were seronegative at pre-vaccination seroconverted aftervaccination.

Table 13: Seroconversion rates and GMTs for anti-measles antibodies (ATPimmunogenicity cohort)

Prevacc. Timing N ≥≥≥≥ 150 mIU/ml GMTstatus n % 95% CI mIU/ml 95% CI

S– Pre 104 - - - - - - -Post 104 104 100.0 96.5 100.0 3018.5 2703.2 3370.5

S+ Pre 12 12 100.0 73.5 100.0 3348.4 2308.7 4856.2Post 12 12 100.0 73.5 100.0 2832.2 2001.1 4008.4

Total Pre 116 12 10.3 5.5 17.4 111.1 89.5 137.9Post 116 116 100.0 96.9 100.0 2998.6 2703.6 3325.8

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects in the with immunogenicity data availablePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seronegative or seropositive at pre-vaccination (sum of S– and S+)n (%): number (percentage) of subjects with titers ≥ assay cut off (i.e., ≥ 150 mIU/ml)GMT: geometric mean titer calculated on all subjects with an arbitrary value of half the cut-off forseronegative titers95% CI: 95% confidence intervals, lower and upper limits

Supplementary Table 8 presents the distribution of anti-measles antibody titers forATP immunogenicity cohort. Supplementary Figure 1 presents the RCC for anti-measles antibody titers for the ATP immunogenicity cohort.


6.2.2 Anti-mumps antibody response

Table 14 presents the seroconversion rates and GMTs for anti-mumps antibodiesfor the ATP immunogenicity cohort.

•



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Table 14: Seroconversion rates and GMTs for anti-mumps antibodies (ATPimmunogenicity cohort)

Prevacc. Timing N ≥≥≥≥ 231 U/ml GMTstatus n % 95% CI U/ml 95% CI

S– Pre 112 - - - - - - -Post 108 106 98.1 93.5 99.8 1132.7 978.2 1311.6

S+ Pre 4 4 100.0 39.8 100.0 6881.9 2631.8 17995.4Post 4 4 100.0 39.8 100.0 11849.9 8487.0 16545.3

Total Pre 116 4 3.4 0.9 8.6 133.0 115.7 152.8Post 112 110 98.2 93.7 99.8 1231.8 1046.0 1450.6

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects in the with immunogenicity data availablePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seronegative or seropositive at pre-vaccination (sum of S– and S+)n (%): number (percentage) of subjects with titers ≥ assay cut off (i.e., ≥ 231 U/ml)GMT: geometric mean titer calculated on all subjects with an arbitrary value of half the cut-off forseronegative titers95% CI: 95% confidence intervals, lower and upper limits

Supplementary Table 9 presents the distribution of anti-mumps antibody titers forATP immunogenicity cohort. Supplementary Figure 2 presents the RCC for anti-mumps antibody titers for the ATP immunogenicity cohort.

Individual subject data for immunogenicity can be found in Appendix table IIDii.

6.2.3 Anti-rubella antibody response

Table 15 presents the seroconversion rates and GMTs for anti-rubella antibodiesfor the ATP immunogenicity cohort.

• All subjects who were seronegative at pre-vaccination seroconverted aftervaccination.



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Table 15: Seroconversion rates and GMTs for anti-rubella antibodies (ATPimmunogenicity cohort)

Prevacc. Timing N ≥≥≥≥ 4 IU/ml GMTstatus n % 95% CI IU/ml 95% CI

S– Pre 115 - - - - - - -S– Post 115 115 100.0 96.8 100.0 78.1 69.2 88.1S+ Pre 1 1 100.0 2.5 100.0 365.0 - -S+ Post 1 1 100.0 2.5 100.0 350.0 - -

Total Pre 116 1 0.9 0.0 4.7 2.1 1.9 2.3Total Post 116 116 100.0 96.9 100.0 79.1 70.0 89.4

Source: Individual subject data for immunogenicity can be found in Appendix table IIDii.Treatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects in the with immunogenicity data availablePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seronegative or seropositive at pre-vaccination (sum of S– and S+)n (%): number (percentage) of subjects with titers ≥ assay cut off (i.e., ≥ 4 IU/ml)GMT: geometric mean titer calculated on all subjects with an arbitrary value of half the cut-off forseronegative titers95% CI: 95% confidence intervals, lower and upper limits

Supplementary Table 10 presents the distribution of anti-rubella antibody titers forATP immunogenicity cohort. Supplementary Figure 3 presents the RCC for anti-rubella antibody titers for the ATP immunogenicity cohort.

Individual subject data for immunogenicity can be found in Appendix table IIDii.

6.3 Analysis of total cohort

Supplementary Table 11 presents the pre-vaccination serological status for thetotal cohort. Supplementary Table 12, Supplementary Table 13 andSupplementary Table 14 presents the seroconversion rates and GMTs for anti-measles, anti-mumps and anti-rubella antibodies respectively, for the total cohort.

The results of the total cohort analysis are similar to those obtained from theanalysis performed on the ATP immunogenicity cohort. This was expected sincemost of the subjects excluded from the ATP were drop-outs and/or had essentialserological data missing.

Individual immunogenicity data for all subjects can be found in Appendix TableIIDii.



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7. Discussion/Conclusion

A total of 150 children with a mean age of 15.2 months were enrolled andvaccinated at one study center with one lot of GSK Biologicals’ live attenuatedmeasles (Schwarz strain) – mumps (RIT 4385 strain) – rubella (RA 27/3 strain)vaccine in this open, single group study.

Local injection site symptoms (pain, redness, swelling) were reported by 27subjects in the 4-day follow-up period after vaccination. There were no reports ofGrade “3” local symptoms. Redness (8.7% subjects) followed by pain (7.2%subjects) at injection site was the most commonly reported local symptoms.However, swelling at the injection site was reported rarely (reported by 3.6%subjects).

Any fever (reported by 42.8% subjects) was the most commonly reported solicitedgeneral symptom during the 43-day follow-up period. None of the cases of feverreported were determined by the investigator to have a relationship to vaccination.No parotid/salivary gland swelling was reported. One case of meningismincluding febrile convulsions was reported. However, this was determined to benot related to the study vaccination.

A total of 51 unsolicited symptoms classified by WHO Preferred Term werereported during the 43-day follow-up period after vaccination. Of these, only foursubjects reported at least one unsolicited symptom determined by the investigatorto be related to the vaccination.

Only one SAE was reported in this study. However, the SAE was considered to benot related to vaccination.

After the vaccination, all vaccinees were seropositive for anti-measles antibodieswith GMT of 2998.6 mIU/ml, 98.2% of vaccinees were seropositive for anti-mumps antibody with GMT of 1231.8 U/ml and all vaccinees were seropositivefor anti-rubella antibody with GMT of 79.1 IU/ml.

Both safety and immunogenicity profile observed in this study were in line withprevious results1.

In conclusion, the GSK Biologicals’ live attenuated measles-mumps-rubellavaccine Priorix™ was shown to be safe, well tolerated and immunogenic in thiscohort of healthy children aged 12-18 months.



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8. References

1. Usonis V., Bakasenas V., Kaufhold A., et al. Reactogenicity andimmunogenicity of a new live attenuated combined measles, mumps andrubella vaccine in healthy children. Pediatr Infect Dis J. 1999; 18: 42–48.



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Supplementary Table 1: Demographics: ATP immunogenicity cohort

Characteristics Parameters or (N = 133)Categories Value %



Race White 0 0.0Black 0 0.0Oriental 133 100.0Other 0 0.0

Source: Individual subject data on demography can be found in Appendix IBTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects%: percentage calculated using N as denominatorValue/n (%): value for parameters of age/number (percentage) of subjects of subjects in a givencategoryS.D.: Standard Deviation

Supplementary Table 2: Overall incidence of symptoms reported during the 43-day follow-up period after vaccination (Total cohort)

Any Symptoms General Symptoms Local SymptomsN n % 95% CI n % 95% CI n % 95% CI

140 85 60.7 52.1 68.9 79 56.4 47.8 64.8 21 15.0 9.5 22.0Source: Individual subject data on solicited/unsolicited symptoms can be found in AppendixTables IIA-CTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: total number of subjects with at least one documented dosen (%): number (percentage) of subjects presenting at least one type of symptom95% CI: exact 95% confidence intervals, lower and upper limit

Supplementary Table 3: Incidence of solicited local symptoms reported during the4-day follow-up period after vaccination (Total cohort)

Symptoms (N = 139)n % 95% CI

Pain 11 7.9 4.0 13.7Redness 12 8.6 4.5 14.6Swelling 5 3.6 1.2 8.2Source: Individual subject data on solicited local symptoms can be found in Appendix Table IIATreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: n (%): number (percentage) of subjects reporting a specified symptom95% CI: exact 95% confidence intervals, lower and upper limits



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Supplementary Table 4: Incidence of solicited general symptoms (any, Grade “3”and related) reported during the 4-day and 43-day follow-up period after

vaccination (total cohort)

Symptom Intensity (N = 139)n % 95% CI

Symptoms reported during the 4-day follow-up periodDrowziness Any 10 7.2 3.5 12.8

Grade “3” 0 0.0 0.0 2.6Related 7 5.0 2.0 10.1

Irritability Any 11 7.9 4.0 13.7Grade “3” 0 0.0 0.0 2.6Related 8 5.8 2.5 11.0

Loss of appetite Any 10 7.2 3.5 12.8Grade “3” 0 0.0 0.0 2.6Related 9 6.5 3.0 11.9


Grade “3” 1 0.7 0.0 3.9Related 0 0.0 0.0 2.6

Parotid gland Any 0 0.0 0.0 2.6Swelling Grade “3” 0 0.0 0.0 2.6

Related 0 0.0 0.0 2.6Fever* Any 59 42.4 34.1 51.1

> 39 °C 7 5.0 2.0 10.1Related 0 0.0 0.0 2.6

Source: Individual subject data on solicited general symptoms can be found in Appendix TableIIBiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: Any: incidence of solicited general symptom regardless of intensity or relationshipGrade “3” drowziness, irritability and loss of appetite: See Table 3Grade “3” parotid gland swelling: swelling and additional general symptomsGrade “3” meningism: febrile convulsions or vomiting, neck stiffness, photophobia* axillary temperature was recordedn (%): number (percentage) of subjects reporting a specified symptom95% CI: exact 95% confidence intervals, lower and upper limits



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Supplementary Table 5: Percentage of subjects reporting unsolicited symptomsclassified by WHO Preferred Term as related to vaccination reported during the

43-day follow-up period after vaccination (Total cohort)

WHO Body System (CODE) WHO Preferred Term (CODE) (N = 140)s % 95% CI

At least one symptom 3 2.1 0.4 6.1Application site (1820) Injection site reaction (0058) 1 0.7 0 3.9Gastrointestinal system (600) Anorexia (0165) 2 1.4 0.2 5.1Psychiatric (500) Nervousness (0188) 1 0.7 0 3.9Source: Individual subject data on unsolicited symptoms can be found in Appendix Table IICiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: At least one symptom: at least one symptom experienced (without taking into account thepreferred term)N: total number of subjects with documented doses (%): number (percentage) of subjects reporting at least once a specified symptom within 43 daysafter vaccination95% CI: Exact 95% confidence interval, lower and upper limits



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Supplementary Table 6: Percentage of subjects reporting unsolicited symptomsclassified by WHO Preferred Term reported during the 43-day follow-up after

vaccination (ATP safety cohort)

WHO Body System (CODE) WHO Preferred term (CODE) (N = 139)s % 95% CI

At least one symptom 51 36.7 28.7 45.3Application site (1820) Injection site reaction (0058) 1 0.7 0 3.9Body as a whole general(1810)

Fever (0725) 1 0.7 0 3.9

Central and peripheral nervoussystem (410)

Fever convulsions (1357) 1 0.7 0 3.9

Gastrointestinal Anorexia (0165) 4 2.9 0.8 7.2system (600) Constipation (0204) 1 0.7 0 3.9

Diarrhea (0205) 3 2.2 0.4 6.2Gastroenteritis (0293) 1 0.7 0 3.9Vomiting (0228) 3 2.2 0.4 6.2

Psychiatric (500) Nervousness (0188) 3 2.2 0.4 6.2Psychiatric (500) Somnolence (0197) 1 0.7 0 3.9Resistance Infection viral (0740) 3 2.2 0.4 6.2mechanism (1830) Upper resp tract infection

(0543)5 3.6 1.2 8.2

Respiratory system (1100) Coughing (0513) 32 23 16.3 30.9Pharyngitis (0523) 1 0.7 0 3.9Pneumonia (0528) 1 0.7 0 3.9Rhinitis (0539) 27 19.4 13.2 27

Skin and appendages (100) Rash (0027) 1 0.7 0 3.9Rash erythematous (0028) 1 0.7 0 3.9

Source: Individual subject data on unsolicited symptoms can be found in Appendix Table IICiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: At least one symptom: at least one symptom experienced (without taking into account thepreferred term)N: total number of subjects with documented doses (%): number (percentage) of subjects reporting at least once a specified symptom within 43 daysafter vaccination95% CI: Exact 95% confidence interval, lower and upper limits



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Supplementary Table 7: Percentage of subjects reporting unsolicited symptomsclassified by WHO Preferred reported after the 43-day follow-up after

vaccination (ATP safety cohort)

WHO Body System (CODE) WHO Preferred term(CODE) (N = 139)s % 95% CI

At least one symptom 2 1.4 0.2 5.1Resistance mechanism (1830) Infection viral (0740) 1 0.7 0 3.9Respiratory system(1100) Asthma (1367) 1 0.7 0 3.9

Rhinitis (0539) 1 0.7 0 3.9Source: Individual subject data on unsolicited symptoms can be found in Appendix Table IICiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: At least one symptom: at least one symptom experienced (without taking into account thepreferred term)N: total number of subjects with documented doses (%): number (percentage) of subjects reporting at least once a specified symptom after 43-dayfollow-up period95% CI: Exact 95% confidence interval, lower and upper limits

Supplementary Table 8: Distribution of anti-measles antibody titers (ATPimmunogenicity cohort)

Timing Prevacc. N < 150 ≥≥≥≥ 150 ≥≥≥≥ 300 ≥≥≥≥ 600 ≥≥≥≥ 1200Status mIU/ml mIU/ml mIU/ml mIU/ml mIU/ml

n % n % n % n % n %Pre S– 104 104 100.0 0 0.0 0 0.0 0 0.0 0 0.0

S+ 12 0 0.0 12 100.0 12 100.0 12 100.0 11 91.7Post S– 104 0 0.0 104 100.0 104 100.0 103 99.0 98 94.2

S+ 12 0 0.0 12 100.0 12 100.0 12 100.0 11 91.7Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects with available datan (%): number (percentage) of subjects with specified pre-vaccination status within the specifiedrangePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative at pre-vaccination timepointS+: seropositive at pre-vaccination timepointTotal: subjects either seropositive or seronegative at pre-vaccination (sum of S– and S+)



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Supplementary Figure 1: Reverse Cumulative Curve for anti-measles antibodytiters in initially seronegative subjects (ATP immunogenicity cohort)

Individual subject data for immunogenicity can be found in Appendix table IIDiiAll subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no. MJR289A42C)

Supplementary Table 9: Distribution of anti-mumps antibody titers (ATPimmunogenicity cohort)

Timing Prevacc. N < 231 U/ml ≥≥≥≥ 231 U/ml ≥≥≥≥ 460 U/ml ≥≥≥≥ 920 U/mlStatus n % n % n % n %

Pre S– 112 112 100.0 0 0.0 0 0.0 0 0.0S+ 4 0 0.0 4 100.0 4 100.0 4 100.0

Post S– 108 2 1.9 106 98.1 97 89.8 66 61.1S+ 4 0 0.0 4 100.0 4 100.0 4 100.0

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects with available datan (%): number (percentage) of subjects with specified pre-vaccination status within the specifiedrangePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seropositive or seronegative at pre-vaccination (sum of S– and S+)



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Supplementary Figure 2: Reverse Cumulative Curve for anti-mumps antibodytiters in initially seronegative subjects (ATP immunogenicity cohort)


Supplementary Table 10: Distribution of anti-rubella antibody titer (ATPimmunogenicity cohort)

Timing Prevacc. N < 4 IU/ml ≥≥≥≥ 4 IU/ml ≥≥≥≥ 10 IU/ml ≥≥≥≥ 16 IU/ml ≥≥≥≥ 32 IU/mlStatus n % n % n % n % n %

Pre S– 115 115 100.0 0 0.0 0 0.0 0 0.0 0 0.0S+ 1 0 0.0 1 100.0 1 100.0 1 100.0 1 100.0

Post S– 115 0 0.0 115 100.0 114 99.1 113 98.3 105 91.3S+ 1 0 0.0 1 100.0 1 100.0 1 100.0 1 100.0

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects with available datan (%): number (percentage) of subjects with specified pre-vaccination status within the specifiedrangePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seropositive or seronegative at pre-vaccination (sum of S– and S+)



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Supplementary Figure 3: Reverse Cumulative Curve for anti-rubella antibodytiters in initially seronegative subjects (ATP immunogenicity cohort)


Supplementary Table 11: Pre-vaccination serological status (Total cohort)

Antibodies Prevacc. (N = 150)status n %

Anti-measles S– 120 90.9S+ 12 9.1

Unknown 18 -Anti-mumps S– 128 97.0

S+ 4 3.0Unknown 18 -

Anti-rubella S– 131 99.2S+ 1 0.8

Unknown 18 -Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjectsn (%): number (percentage) of subjects with a given serological status.S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointCut-off values: measles: 150 mIU/ml, mumps: 231U/ml, rubella: 4 IU/ml



51

Supplementary Table 12: Seroconversion rates and GMTs for anti-measlesantibodies (Total cohort)

Prevacc. Timing N ≥≥≥≥ 150 mIU/ml GMTstatus n % 95% CI mIU/ml 95% CI

S– Pre 120 0 0.0 0.0 3.0 75.0 75.0 75.0Post 109 109 100.0 96.7 100.0 3021.1 2715.3 3361.3

S+ Pre 12 12 100.0 73.5 100.0 3348.4 2308.7 4856.2Post 12 12 100.0 73.5 100.0 2832.2 2001.1 4008.4

Total Pre 132 12 9.1 4.8 15.3 105.9 87.5 128.2Post 121 121 100.0 97.0 100.0 3001.8 2714.6 3319.3

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects in the with immunogenicity data availablePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seronegative or seropositive at pre-vaccination (sum of S– and S+)n (%): number (percentage) of subjects with titers ≥ assay cut off (i.e., ≥ 150 mIU/ml)95% CI: 95% confidence intervals, lower and upper limits

Supplementary Table 13: Seroconversion rates and GMTs for anti-mumpsantibodies (Total cohort)

Prevacc. Timing N ≥≥≥≥ 231 U/ml GMTstatus n % 95% CI U/ml 95% CI

S– Pre 128 0 0.0 0.0 2.8 115.5 115.5 115.5Post 113 110 97.3 92.4 99.4 1120.6 967.9 1297.4

S+ Pre 4 4 100.0 39.8 100.0 6881.9 2631.8 17995.4Post 4 4 100.0 39.8 100.0 11849.9 8487.0 16545.3

Total Pre 132 4 3.0 0.8 7.6 130.7 115.7 147.7Post 117 114 97.4 92.7 99.5 1214.7 1033.0 1428.4

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects in the with immunogenicity data availablePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seronegative or seropositive at pre-vaccination (sum of S– and S+)n (%): number (percentage) of subjects with titers ≥ assay cut off (i.e., ≥ 231 U/ml)95% CI: 95% confidence intervals, lower and upper limits



52

Supplementary Table 14: Seroconversion rates and GMTs for anti-rubellaantibodies (Total cohort)

Prevacc. Timing N ≥≥≥≥ 4 IU/ml GMTstatus n % 95% CI IU/ml 95% CI

S– Pre 131 0 0.0 0.0 2.8 2.0 2.0 2.0Post 120 120 100.0 97.0 100.0 78.8 70.2 88.4

S+ Pre 1 1 100.0 2.5 100.0 365.0 - -Post 1 1 100.0 2.5 100.0 350.0 - -

Total Pre 132 1 0.8 0.0 4.1 2.1 1.9 2.2Post 121 121 100.0 97.0 100.0 79.8 70.9 89.7

Source: Individual subject data for immunogenicity can be found in Appendix table IIDiiTreatment: All subjects received GSK Biologicals’ MMR vaccine Priorix™ (lot no.MJR289A42C)Notes: N: number of subjects in the with immunogenicity data availablePre: pre-vaccination blood sample at Day 0Post: post-vaccination blood sample at Day 42S–: seronegative subjects at pre-vaccination timepointS+: seropositive subjects at pre-vaccination timepointTotal: subjects either seronegative or seropositive at pre-vaccination (sum of S– and S+)n (%): number (percentage) of subjects with titers ≥ assay cut off (i.e., ≥ 4 IU/ml)95% CI: 95% confidence intervals, lower and upper limits



53

Clintrial Eligibility CodesElimination from reactogenicity and serology analysis1010 Subject or vaccine number not allocated

Vaccine not administered at allNo subject allocated to the randomisation number

1030 Study vaccine dose not administered but subject number allocatedVaccine dose not administered at allAt least one dose not administered

1040 Administration of vaccine(s) forbidden in the protocol1050 Randomisation failure

Wrong vaccine vial given1060 Randomisation code broken at the investigator site1070 Study vaccine dose not administered according to protocol

Side, site or route of study vaccine administration unknownSide, site or route of study vaccine administration wrong

1080 Essential data missingDate of vaccination unknownAny data which prevent the analysis

Elimination from serology analysis2010 protocol violation

Demographics: Too youngToo oldUnknown age, sexGender not according to the protocol

Others2020 Initially seropositive or unknown antibody status

Preliminary lab results not according to protocolAbnormal value

2030 Biochemistry, hematology and other laboratory values outside rangebefore any vaccination

2040 Administration of any medication forbidden by the protocol2050 Underlying medical condition forbidden by the protocol2060 Concomitant infection related to the vaccine which may influenceimmune response

Infection related to any of the vaccine components2070 Concomitant infection not related to the vaccine which may influenceimmune response2080 Non compliance with vaccination schedule (including wrong andunknown dates)2090 Non compliance with blood sampling schedule (including wrong andunknown dates)2100 Essential serological data missing

Blood sample lost



54

Blood sample unable to test (haemolysis, insufficient volume, etc)Absence of parallelism

2110 Blood sample available but not yet tested (interim analysis)2120 Obvious incoherence or abnormality or error in data

Wrong labeling in BSAbnormal serology evolution

2130 Subject not planned to be bled for all blood sampling visits2500 Others



55

NOTES TO APPENDIX TABLESThe following abbreviations are common throughout the Appendix tables:Sub. No. : subject numberElig : eligibilityElim : eliminated from analysis (es)I : elimination from immunogenicity analysisE : elimination from reactogenicity analysisF : femaleM : male

Appendix table ICPre : pre vaccination blood samplingPI (d42) : blood sampling obtained 42 days after vaccination

Appendix table IDpast : medical historycurrent : present at the physical examination

Appendix table IIAP? : According to protocol? Y / N: Yes / NoL? : Any solicited local symptom reported? Y / N: Yes / NoSite : site of vaccinationSide : Left / RightExp : adverse experience: Y / N : Yes / NoOut : Outcome : 1 = recovered

2 = recovered with sequelae3 = ongoing4 = died5 = unknown

Cor : Corrective therapyPA : Pain: scored as Empty / 0: Absent

1: Minor reaction to touch.2: Cries/protests on touch.3: Cries when limb is moved/spontaneously painful.

RE : Redness : in mm (greatest diameter)SW : Swelling : in mm (greatest diameter)

Appendix table IIBG? : Any solicited general symptom reported? Y / N: Yes / NoExp : adverse experience: Y / N: Yes / NoOut : Outcome : 1 = recovered


RTE : Route (for body temperature recording) :O = oralA = axillaryR = rectalT = tympanic



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REL : Relationship : N = not relatedY = related

SymptomsIR : Irritability/fussinessDR : DrowsinessLO : Loss of appetiteFC : Febrile convulsionsPS : Parotid gland swellingTE : Temperature

IR/FU, DR, LO, FC, PS, TE scored asEmpty / 0: Absent1: The adverse experience was easily tolerated, causing minimal discomfort

and not interfering with everyday activities.2: The adverse experience was sufficiently discomforting to interfere with

normal everyday activities.3: An adverse event which prevented normal, everyday activities.Appendix table IIC

Verbatim : description of experience as recorded in the case report formKeyword : description of experience as listed in the Clintrial databaseWHO code: code for WHO preferred term, a WHO adverse reaction classification

systemPreferred term: specific identification terminology linked to WHO

classification codesBody syst : code of the body system to which the preferred term is linkedPrDo : vaccine dose administered prior to the adverse experienceREL : Relationship : NR = not related

UL = unlikelySU = suspectedPB = probable

Start date : date of onset of adverse experienceDay onset : number of days since last vaccine doseEnd date : date of end of adverse experienceDur (d): duration (days)Int. : intensity Scored as:Empty / 0: Absent1: The adverse experience was easily tolerated, causing minimal discomfort

and not interfering with everyday activities.2: The adverse experience was sufficiently discomforting to interfere with

normal everyday activities.3: An adverse event which prevented normal, everyday activities.L/G : local or generalOut : outcome : 1 = recovered




57

Sit : site of vaccination : T = ThighSid : side i.e. L = left; R = rightTher : corrective therapy requiredSer : serious adverse experience : N/Y = No/yesAEGIS No.: GlaxoSmithKline Biologicals' code for case identification of

serious adverse events

Appendix table IIDRel. day of onset : number of days of onset of medication, relative to day of

vaccination (0)Start date : date of start of medicationEnd date : date of end of medicationDUR (d) : duration (days)Code : treatment code; a direct link was recorded between theadverse event and the medication

AE1, AE2, AE3 : adverse event 1, 2 or 3 as detailed on CRFP : prophylacticNA : not applicableTE = temperature, etc.

Appendix table IIIPRE : pre-vaccination blood sampleBS ND: blood sample not done

This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

CIOMS

This section contained patient narratives which are textual descriptions of medical history,

treatment and outcome for individual patients who experienced a clinically important adverse

event including serious adverse events during the trial. They have been excluded to protect

patient privacy. This data may be made available subject to an approved research proposal and

a determination of the ability to provide information from the specific narratives whilst protecting

the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

Serious AdverseEvents Table

AppendicesStudy Information

Protocol

Protocol Agreement

Sample CRF

CONFIDENTIAL

CASE REPORT FORM

209762/147 (MeMuRu-147)

Subject number

|__|__|__|__|__|

Subject identification

|__|__| |__|__| First name Family name

Center

|__|__|__|

SmithKline Beecham Biological s.a.

Rue de l'Institut 89, B - 1330 Rixensart, BelgiumTel: Fax:

Version 11.1

GENERAL INSTRUCTIONS

Print clearly in CAPITAL LETTERS using a black fountain or ball-point pen and press firmly so that all copies are legible.Insert the writing board beneath all copies of the form being completed. Fill in the subject number on every page and answerall questions except where otherwise indicated.

Do not write in shaded areas which are qualified �For SB�. Information written in these areas are not the responsibilityof the investigator.For each subject�s INITIALS, please enter the first two letters of the first name and the first two letters of the familyname.

ABBREVIATIONS: Abbreviations for medical conditions, clinical events or drug names should not be used. Units androute of administration of medication may be abbreviated. NA: not applicable.

IMPORTANT: Errors should be crossed out with a single line and the alteration made as near to the original as possible.All alterations must be printed, initialed and dated by the investigator or authorized staff.

DATEUse the following three-letter abbreviations for each month:

January = JANFebruary = FEBMarch = MARApril = APRMay = MAYJune = JUNJuly = JULAugust = AUGSeptember = SEPOctober = OCTNovember = NOVDecember = DEC

Example: 0 1 J A N 2 0 0 0 = 1st January 2000|__|__| |__|__|__| |__|__|__|__| day month year

TIMEUnless specified otherwise, use the 24 hour clock:

Example: 1 5 3 0 = 3.30 p.m.|__|__| : |__|__| hours min

The Medication section, the Concomitant Vaccination section, the Non-Serious Adverse Events section and theSerious Adverse Event (SAE) form must be checked for final assessment at the end of the study.

For all subjects enrolled, please complete the Study Conclusion form.

ADVERSE EVENT DEFINITIONS

INTENSITY FOR SOLICITED SYMPTOMS

INTENSITY FOR NON-SOLICITED SYMPTOMS0 : No adverse event.1 : An adverse event which is easily tolerated by the subject, causing minimal discomfort and not interfering with

everyday activities.2 : An adverse event which is sufficiently discomforting to interfere with normal everyday activities.3 : An adverse event which prevents normal, everyday activities

(In a young child, such an adverse event would, for example, prevent attendance at school/ kindergarten/ a day-care center and would cause the parents/ guardians to seek medical advice).

CAUSALITYIn your opinion, did the vaccine(s) possibly contribute to the adverse event? NO : The adverse event is not causally related to administration of the study vaccine(s). There are other, more likely

causes and administration of the study vaccine(s) is not suspected to have contributed to the adverse event. YES : There is a reasonable possibility that the vaccine contributed to the adverse event.

OUTCOME1 : Recovered2 : Recovered with sequelae3 : Ongoing at subject study conclusion4 : Died5 : Unknown

SERIOUS ADVERSE EVENTSA serious adverse event is any untoward medical occurrence that:

1 : results in death

2 : is life threatening

3 : results in persistent or significant disability / incapacity

4 : requires in-patient hospitalization

5 : prolongation of existing hospitalization

6 : is a congenital anomaly / birth defect in the offspring of a study subject

7 : In addition, important medical events that may jeopardize the patient or may require intervention to prevent oneof the other outcomes listed above should be considered serious. (Examples of such events are intensive treatmentin an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not resultsin hospitalization; or development of drug dependency or drug abuse).

For each serious adverse event, please fill in the Serious Adverse Event (SAE) form and contact SmithKline Beecham within24 hours (one calendar day).

Although not considered as �serious adverse events�, cancers must be reported in the same way as serious adverse events.

Pain at injection site0 : Absent1 : Minor reaction to touch2 : Cries/protests on touch3 : Cries when limb is moved /spontaneously painful

FLOW SHEET

209762/147 (MeMuRu-147)

Age 12-18 months at the time of vaccinationVisit VISIT 1 42 ± 7 DAYS INTERVAL VISIT 2

Timing Day 0 Day 42Sampling timepoint Pre Post vacc I

Informed consent ●Check of inclusion criteria ●Check of exclusion criteria ●Medical history ●Physical examination ● ●Pre-vaccination assessment of adverseexperiences

●

Blood samplingfor serology (3.0 ml) ● ●Vaccination* ●Daily post-vaccination recording ofsolicited symptoms (days 0-3) byparents/guardian

● ●

Follow-up contact either by phone orhome visit on Day 5 post-vaccination ☎Recording of unsolicited adverseexperiences occurring days 0-42 post-vaccination, by investigator

●

Return of diary cards ●Diary card transcription ●Recording medication ● ●Reporting of Serious Adverse Eventsoccurring throughout the study period,by investigator

● ● ●

Study Conclusion ●

* SB MMR vaccine (PRIOrixTM)

n is used to indicate a study procedure which requires documentation in the individual CRF.

It is the investigator’s responsibility to ensure that the intervals betweenvisits/contacts are strictly followed. These intervals determine a subject’sevaluability in the according to protocol analyses.

Intervals between study visits during the active phase of the study*Interval Size of interval

1 (Visit 1→Visit 2) 35-49 days

* The date of the previous visits the reference date.

Informed Consent has to be obtainedprior to any study procedure

VISIT 1

DAY 0

VACCINATION

Protocol

ELIGIBILITY CHECKLIST

2009762/147 (MeMuRu-147)

INCLUSION CRITERIA

All subjects must satisfy the following criteria at the time of enrolment:1. A male or female infant between 12 and 18 months of age at the time of the vaccination

2. Written informed consent obtained from the parents or guardians of the subject.

3. Free of obvious health problems as established by medical history and clinical examination before entering into thestudy.

EXCLUSION CRITERIA FOR ENROLMENT

The following criteria should be checked at the time of study entry. If any apply at the time of study entry, the subjectmust not be included in the study:

4. Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) during the study periodor within 30 days preceding the dose of study vaccine

5. Administration of chronic (defined as more than 14 days) immunosuppressants of other immune-modifying drugswithin six months of vaccination (For corticosteroids, this will mean prednisone, or equivalent, ³ 0.5 mg/kg/day.Inhaled and topical steroids are allowed.)

6. Planned administration/ administration of a vaccine not foreseen by the study protocol (with the exception of theDTPw booster vaccination).

7. Previous vaccination against mumps and/or rubella

8. History of, or intercurrent, measles, mumps, and/or rubella disease

9. Known exposure to measles, mumps or rubella within 30 days prior to the start of the study

10. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiencyvirus (HIV) infection.

11. Any major congenital defects

12. Any serious chronic illness

13. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, including obviousallergic reactions to neomycin, egg proteins, and/or gelatine

14. History of convulsions (including febrile convulsions, epilepsy) or any other signs of central nervous system disease

15. Acute febrile illness or obvious upper respiratory tract symptoms at the time of planned vaccination

16. Axillary temperature of ³37.5°C at the time of vaccination

17. Administration of immunoglobulins and/or any blood products within 3 months preceding the dose of studyvaccine or planned administration/administration during the study period


1

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


DEMOGRAPHICS

Subject initials: |__|__| |__|__|First name Family name

Date of birth: |__|__| |__|__|__| |__|__|__|__| day month year

Gender: c Male

c Female

Race: c (WH) White

c (BL) Black

c (OR) Oriental

c (OT) Other, please specify: ______________________________

Weight: |__|__|__| . |__| kg

Is the subject eligible for the study, according to the criteria listed hereby?

c Yes

c No, please give the corresponding criterion number(s):

_______________________________

I certify that Informed Consent has been obtained prior to any study procedure.

Informed Consent date: |__|__| |__|__|__| |__|__|__|__|day month year

Visit

|__|__| |__|__|__| |__|__|__|__|day month year

Visit

VISIT 1

Center

|__|__|__|

2

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


GENERAL MEDICAL HISTORY / PHYSICAL EXAMINATION

Are you aware of any pre-existing conditions or signs and/or symptoms present in the subject prior to the start of the study?c Noc Yes, please check appropriate box(es) and give diagnosis

PAST CURRENT DIAGNOSIS

�� 10 Cutaneous 1 _______________________________________________________________

2 _______________________________________________________________

�� 5 Eyes 1 _______________________________________________________________

2 _______________________________________________________________

�� 6 Ears-nose-throat 1 _______________________________________________________________

2 _______________________________________________________________

�� 2 Cardiovascular 1 _______________________________________________________________

2 _______________________________________________________________

�� 3 Respiratory 1 _______________________________________________________________

2 _______________________________________________________________

�� 1 Gastrointestinal 1 _______________________________________________________________

2 _______________________________________________________________

�� 7 Musculoskeletal 1 _______________________________________________________________

2 _______________________________________________________________

�� 8 Neurological 1 _______________________________________________________________

2 _______________________________________________________________

�� 12 Genitourinary 1 _______________________________________________________________

2 _______________________________________________________________

�� 11 Haematology 1 _______________________________________________________________

2 _______________________________________________________________

�� 4 Allergies 1 _______________________________________________________________

2 _______________________________________________________________

�� 9 Endocrine 1 _______________________________________________________________

2 _______________________________________________________________

�� 99 Other (specify) 1 _______________________________________________________________

2 _______________________________________________________________

Please report medication(s) as specified in the protocol and fill in the Medication section.

Visit

VISIT 1

3

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


PRE-VACCINATION ASSESSMENT

PRE-VACCINATION TEMPERATURE

Temperature: |__|__| . |__| °C à Route: c Axillary

c Oral

c Rectal

LABORATORY TESTS

BLOOD SAMPLE

Has a blood sample been taken? c Yes

c No

Visit

VISIT 1

4

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


VACCINE ADMINISTRATION(only one box must be checked)

c SB Bio 's MeMuRu Vaccine

c Replacement vial (*)

c Wrong vial number (*)

c Not injected (*)

Side / siteroute

Left

Upper arm

S.C.

(deltoid region)

VACCINE ADMINISTRATION

Please complete the following table

Has the study vaccine been administeredaccording to the protocol?

c Yesc No à please check all items

Side: Site: Route:c Upper left c Deltoid c I.M.c Lower left c Thigh c S.C.c Upper right c Buttockc Lower right

(*) Comments: __________________________________________________________________________________

NB: any other vaccines administered during the study period must be recorded in the Concomitant Vaccinationsection.

POST-VACCINATION OBSERVATION

If any adverse events occurred during the immediate post-vaccination time specified in the protocol,

à please fill in the Solicited Adverse Events section, the Non-Serious Adverse Events section or the SeriousAdverse Event form.

MEDICATION

If any prophylactic medication has been administered in anticipation of study vaccine reactions,

à please complete the Medication section.

Visit

VISIT 1VACCINATION

5

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


SOLICITED ADVERSE EVENTS - LOCAL SYMPTOMS

Has the subject experienced any of the following local (at injection site) solicited signs/symptoms during the solicitedperiod?

c Unknown

c No

c Yes, please check a No/Yes box for each symptom. If Yes is checked, please fill in the complete line.

VACCINATION

LOCAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoingafter day 3?

Date of last day of symptomsday month year

Rednessc Noc Yes Å size (mm): _____ _____ _____ _____

c No

c Yes Å |__|__| |__|__|__| |__|__|__|__|

Swellingc Noc Yes Å size (mm): _____ _____ _____ _____

c No

c Yes Å |__|__| |__|__|__| |__|__|__|__|

Painc Noc Yes Å intensity: |___| |___| |___| |___|

c No

c Yes Å |__|__| |__|__|__| |__|__|__|__|

Intensity: 0123

Å If any of these adverse events are serious according to protocol definition,Å please report event to SB monitor by telephone or fax within 24 hours (see protocol)

and complete the Serious Adverse Event form.

6

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


SOLICITED ADVERSE EVENTS - GENERAL SYMPTOMS

Has the subject experienced any of the following general solicited signs or symptoms during the solicited period?

c Unknown

c No

c Yes, please check a No/Yes box for each symptom. If Yes is checked, please fill in the complete line.

VACCINATION

GENERAL SYMPTOMS Day 0 Day 1 Day 2 Day 3 Ongoingafter day 3?

Date of last day of symptomsday month year Causality?

Irritability/Fussinessc Noc Yes Å intensity: |___| |___| |___| |___|

c Noc Yes Å |__|__| |__|__|__| |__|__|__|__|

c Noc Yes

Drowsinessc Noc Yes Å intensity: |___| |___| |___| |___|

c Noc Yes Å |__|__| |__|__|__| |__|__|__|__|

c Noc Yes

Loss of appetitec Noc Yes Å intensity: |___| |___| |___| |___|

c Noc Yes Å |__|__| |__|__|__| |__|__|__|__|

c Noc Yes

Intensity: 0123

Fever:Axillary > 37.5°COral > 37.5°CRectal > 38°C

Fever c Noc Yes Å please complete the Temperature Section

Parotid/salivary gland swelling c Noc Yes Å please complete the Parotid/Salivary Gland Swelling Section

Febrile convulsions – suspectedsigns of meningism

c Noc Yes Å please complete the Febrile Convulsions - Suspected Signs of

Meningism Section

Å If any of these adverse events are serious according to protocol definition,Å please report event to SB monitor by telephone or fax within 24 hours

(see protocol) and complete the Serious Adverse Event form.

Intensity: 0123

VISIT 2

DAY 42

POSTVACCINATION

REMINDER

ADVERSE EVENTS

à Please report adverse events as specified in the protocol and fill in the Non-Serious AdverseEvents section or the Serious Adverse Event (SAE) form, as appropriate.

MEDICATION

à Please report medication as specified in the protocol and fill in the Medication section.à Please report concomitant vaccination in the Concomitant Vaccination section.

7

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


LABORATORY TESTS

BLOOD SAMPLE

Has a blood sample been taken? c Yes

c No

Visit

|__|__| |__|__|__| |__|__|__|__|day month year

Visit

VISIT 2

TEMPERATURE

8

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


FEVER EPISODE

In case of fever, please use one line by episode to record temperatures

Definition of fever : Rectal > 38°CAxillary > 37.5°COral > 37.5°C

Please indicate the day of onset post vaccination for each episode

Episode No DAY ___ DAY ___ DAY ___ DAY ___ DAY ___ DAY ___ DAY ___ DAY ___ DAY ___ DAY ___ DAY ___

1 Rectal Axillary Oral

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C



____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C



____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C



____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C



____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C



____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

____ . __

°C

For each episode, please complete the corresponding Fever Events Section.

9

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


DAY 0 TO DAY 42

FEVER EXPERIENCES

Please report below all fever experiences that occurred within 42 days post-vaccination.

Episode Number 1 2 3 4 5 6

FeverExperiences

Day of onsetpost vaccination

|__|__|day

|__|__|day

|__|__|day

|__|__|day

|__|__|day

|__|__|day

Day of end |__|__|day

|__|__|day

|__|__|day

|__|__|day

|__|__|day

|__|__|day

CausalityIn your opinion, did the vaccinepossibly contribute to thisepisode?

No c

Yes c

No c

Yes c

No c

Yes c

No c

Yes c

No c

Yes c

No c

Yes c

Outcome1 : Recovered2 : Recovered with Sequelae3 : Ongoing at subject study conclusion4 : Died5 : Unknown

1 c

2 c

3 c

4 c

5 c

1 c

2 c

3 c

4 c

5 c

1 c

2 c

3 c

4 c

5 c

1 c

2 c

3 c

4 c

5 c

1 c

2 c

3 c

4 c

5 c

1 c

2 c

3 c

4 c

5 c

PAROTID /SALIVARY GLAND

SWELLING

10

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


Description ________________________________ ________________________________ ________________________________

________________________________ ________________________________ ________________________________

________________________________ ________________________________ ________________________________

PA No. PA. 1 PA. 2 PA. 3

Date Started |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| day month year day month year day month year

Date Stopped |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__| day month year day month year day month year

Intensity c 1 Swelling without c 1 Swelling without c 1 Swelling withoutdifficulties to move difficulties to move difficulties to movethe jaw the jaw the jaw

c 2 Swelling with c 2 Swelling with c 2 Swelling withdifficulties to move difficulties to move difficulties to movethe jaw the jaw the jaw

c 3 Swelling & additional c 3 Swelling & additional c 3 Swelling & additionalgeneral symptoms general symptoms general symptoms

CausalityIn your opinion, did c No c No c Nothe vaccine possibly c Yes c Yes c Yescontribute to this AE?

Outcome c 1 Recovered c 1 Recovered c 1 Recoveredc 2 Recovered with c 2 Recovered with c 2 Recovered with

sequelae sequelae sequelaec 3 Ongoing at subject c 3 Ongoing at subject c 3 Ongoing at subject

study conclusion study conclusion study conclusionc 4 Died c 4 Died c 4 Diedc 5 Unknown c 5 Unknown c 5 Unknown

ForSB

PAROTID / SALIVARY GLAND SWELLING EVENTS

Please report any parotid / salivary gland swelling that occurred within 43 days post-vaccination.

If you consider any of these adverse events to be serious, please report the event to the SmithKlineBeecham

monitor by telephone or fax within 24 hours (see protocol) and complete the Serious Adverse Event form.

DAY 0 TO DAY 43

FEBRILECONVULSIONS -

SUSPECTED SIGNS OFMENINGISM

11

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


ForSB

Description ________________________________ ________________________________ ________________________________

________________________________ ________________________________ ________________________________

________________________________ ________________________________ ________________________________

FC No. FC. 1 FC. 2 FC. 3



Was a neurological No No No

examination been performed ? Yes Yes Yes

â if yes, â if yes, â if yes,Was a lumbar puncture Was a lumbar puncture Was a lumbar punctureperformed ? performed ? performed ?

No No No

Yes Yes Yes

â if yes, â if yes, â if yes,please send copy please send copy please send copyof medical report of medical report of medical report

Intensity c 1 c 1 c 1c 2 c 2 c 2c 3 c 3 c 3





FEBRILE CONVULSIONS - SUSPECTED SIGNS OF MENINGISM EVENTS

Please report any febrile convulsion and any suspected signs of meningism that occurred within 43 days post-vaccination.

If you consider any of these adverse events to be serious, please report the event to the SmithKline Beecham

monitor by telephone or fax within 24 hours (see protocol) and complete the Serious Adverse Event form.

DAY 0 TO DAY 42

CONCOMITANTVACCINATION

12

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


Trade / Generic Name Administration dateday month year

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

|__|__| |__|__|__| |__|__|__|__|

ForSB

CONCOMITANT VACCINATIONHas any vaccine other than the study vaccine(s) been administered at ANY time during the study period or within 30 daysprior to the first dose of study vaccine(s)? c No

c Yes, please record concomitant vaccination with trade nameand / or generic name, and vaccine administration date.

MEDICATION

MEDICATION ROUTE

CODE LABEL

EXT externalID IntradermalIH InhalationIM IntramuscularIR IntraarticularIT IntrathecalIV IntravenousNA IntranasalOTH OtherPE ParenteralPO OralPR RectalSC SubcutaneousSL SublingualTD TransdermalTO TopicalUNK UnknownVA Vaginal


13

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


Total Start and end date or check boxTrade / Generic Name Medical Indication daily dose Route if continuing at end of study

day month year

Start: |__|__| |__|__|__| |__|__|__|__|

c Prophylactic End: |__|__| |__|__|__| |__|__|__|__| cForSB

Start: |__|__| |__|__|__| |__|__|__|__|


Start: |__|__| |__|__|__| |__|__|__|__|


Start: |__|__| |__|__|__| |__|__|__|__|


Start: |__|__| |__|__|__| |__|__|__|__|


Start: |__|__| |__|__|__| |__|__|__|__|


Start: |__|__| |__|__|__| |__|__|__|__|


MEDICATIONà Any immunosuppressants or other immune-modifying drugs or treatments and any antipyretics administered at ANY time during the period starting

30 days prior to the first dose of study vaccine(s) and ending 42 days after the last dose of study vaccine(s) must be recorded with trade name and/orgeneric name of the medication, medical indication, total daily dose, route of administration, start and end dates of treatment.

à Any other concomitant medication administered prophylactically in anticipation of reaction to the vaccination must also be recorded with trade name and/or generic name of the medication, medical indication (check box if prophylactic), total daily dose, route of administration, start and end dates of treatment.

Have any of the above mentioned medications/treatments been administered during the study period?c Noc Yes, please complete the following table.

NON-SERIOUSADVERSEEVENTS

14

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


Description ________________________________ ________________________________ ________________________________

c Local c Local c Local(injection site) (injection site) (injection site)

c General c General c General(non injection site) (non injection site) (non injection site)

AE No. AE. 1 AE. 2 AE. 3

ForSB


c during immediate post-vaccination c during immediate post-vaccination c during immediate post-vaccinationperiod specified in protocol period specified in protocol period specified in protocol







NON-SERIOUS ADVERSE EVENTS

(Please report all serious adverse events on the Serious Adverse Event (SAE) form).

Has any non-serious adverse event occurred within 43 days post-vaccination, excluding those recorded on the SolicitedAdverse Events pages? c No

c Yes, please complete the following table.

15

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


NON-SERIOUS ADVERSE EVENTS (continued)

Description ________________________________ ________________________________ ________________________________

c Local c Local c Local(injection site) (injection site) (injection site)

c General c General c General(non injection site) (non injection site) (non injection site)

AE No. AE. 4 AE. 5 AE. 6


c during immediate post-vaccination c during immediate post-vaccination c during immediate post-vaccinationperiod specified in protocol period specified in protocol period specified in protocol







ForSB

SERIOUS ADVERSEEVENTS

INSTRUCTIONS FOR REPORTING SERIOUS ADVERSE EVENT (SAE)

SAE's MUST BE REPORTED TO SMITHKLINE BEECHAM WITHIN 24 HOURS.

1. COMPLETE THE SAE PAGES OPPOSITEPlease complete these pages as fully and accurately as possible in order to minimize the timeyou spend dealing with data queries.

If the SAE is still ongoing at the time of reporting, please leave "Outcome" blank and updateit later.

2. PLEASE ENSURE THAT ALL INFORMATION ON THE SAE PAGES IS CONSISTENTWITH THE FOLLOWING OTHER CRF PAGES:

v Demographicsv General Medical History / Physical Examinationv Vaccine Administration page(s) (for doses administered)v Medicationv Concomitant Vaccination

3. SIGN AND DATE THE SAE PAGES 2 (AND 3). COMPLETE PAGE 3 OF THE SAEFORM IF NEEDED ONLY.

4. PHOTOCOPY THE SAE PAGES (DO NOT SEPARATE THE NCR PAGES) ANDFAX THE COPY OF THE SAE PAGES TO:

à The study contact(see Investigator Site File for appropriate fax number).

à If no photocopier OR fax is available, please telephoneto the study contact

5. FOR ADDITIONAL INFORMATION, PLEASE CHECK THE "ADDITIONAL INFO"BOX AND FOLLOW THE PROCEDURE EXPLAINED AT POINT 4

16

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


SERIOUS ADVERSE EVENT (SAE)

c (1) Initial report c (3) Additional infoc (2) Additional info c (4) Additional info

Adverse Event (please print clearly)Diagnosis (or signs and symptoms if not known)

________________________________________________________________________________________

________________________________________________________________________________________

________________________________________________________________________________________

For SB

Date and time started |__|__| |__|__|__| |__|__|__|__| |__|__|:|__|__|(Adverse event first symptoms) day month year hours min

Date and time stopped |__|__| |__|__|__| |__|__|__|__| |__|__|:|__|__|(if ongoing please leave blank) day month year hours min

Intensity c 1

(maximum) c 2

c 3

In your opinion, did the vaccine possiblycontribute to the SAE c No ù

c Yes û

Outcome c 1 Recoveredc 2 Recovered with sequelaec 3 Ongoingc 4 Died

Action taken with c Nonerespect to c Vaccination course postponedStudy Vaccine c Vaccination course stopped

Events after further c Event reappearedvaccination c Event did not reappear

c Unknown at this timec Not applicable

Subject DemographyInitials: |__|__| |__|__|

First name Family name

Date of birth: |__|__| |__|__|__| |__|__|__|__|day month year

Gender: c Malec Female

Center

|__|__|__|

Country

Other possible contributors: (mark all that apply)

c Medical history (record in section 15)

c Other medication (record in section 14)

c Protocol required procedure

c Other procedure

c Lack of efficacy

c Erroneous administration

c Other, specify: _________________________

(Record additional information in section 19)

Was subject withdrawn due to thisspecific SAE?

c Noc Yes

t Specify criteria for consideringthis as a Serious Adverse Event(mark all that apply).

1 c Results in death ® Autopsy? c No c Yes

¯send autopsy report when available

2 c Life threatening

3 c Results in persistent or significantdisability/ incapacity

4 c Requires in-patient hospitalization

Admission |__|__| |__|__|__| |__|__|__|__|date: day month year

Discharge |__|__| |__|__|__| |__|__|__|__|date: day month year

5 c Prolongation of existinghospitalizationDischarge |__|__| |__|__|__| |__|__|__|__|date: day month year

6 c Congenital anomaly / birth defectin the offspring of a study subject

7 c "Medically important" event -specify:_______________________________________________

t Other events (not SAE) to bereported in the same way:c Cancer

1

2

3

4

5

6

7

8

9

12

11

10

SB Receipt Date

|__|__| |__|__|__| |__|__|__|__|day month year

17

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


SAE (continued)

13

15

18

14

16

17

Study vaccine informationVaccine (specify mixed or separate) Dose No Lot No Route / Site Date

|__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__|

Concomitant medication / vaccination that could have contributed to this SAEDrug / vaccine Dosage Frequency Route Start date End date

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

Relevant intercurrent illness & medical history that could have contributed to this SAE(including allergies).

Condition: still present?: No c Yes c

Condition: still present?: No c Yes c

Drug(s) used to treat this SAEDrug Dosage Frequency Route Start date End date

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

|__|__| |__|__|__| |__|__|__|__| |__|__| |__|__|__| |__|__|__|__|

Surgical treatment for this SAE (please specify)

Description (provide a brief narrative description of the SAE including relevant diagnostic findings, lab data & evolution of the events etc…)_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Investigator signature (1) (2) (3) (4)

Date |__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

Please PRINT name:

AEGIS Number: |__|__|__|__|__|__|__|__|__|__| . |__|__|

18

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


SAE (continued)

19Comments ( provide further comments concerning the case).

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Investigator signature (1) (2) (3) (4)

Date |__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

|__|__| |__|__|__| |__|__|__|__| day month year

Please PRINT name:

STUDYCONCLUSION

19

Subject number

|__|__|__|__|__|

209762/147 (MeMuRu-147)

Protocol

209762/147


INVESTIGATOR SIGNATURE

I certify that I have reviewed the data in this case report form, the Adverse Events and Serious Adverse Eventsections including any laboratory data (if appropriate) and that all information is complete and accurate.

Date: |__|__| |__|__|__| |__|__|__|__| Investigator signature:day month year

STUDY CONCLUSION

Has the subject dropped out of the study?(a drop out is a subject who did not come back for the concluding visit foreseen in the protocol.)

c Noc Yes, please mark the ONE most appropriate category for drop out

��c (SAE) Serious adverse event(complete the Serious Adverse Event form)

��c (AEX) Non-serious adverse event, (complete the Non-Serious Adverse Events section)

please specify AE No.: ___________________________________________________________________________________________

��c (PTV) Protocol violation, please specify: ______________________________________________________________________________

��c (CWS) Consent withdrawal, not due to an adverse event

��c (MIG) Migrated / moved from the study area

��c (LFU) Lost to follow-up

��c (OTH) Others, please specify: ___________________________________________________________________________________________

�� Date of last contact: |__|__| |__|__|__| |__|__|__|__| day month year

Was the subject in good condition at date of last contact?

c No, please give details within the Adverse Events section

c Yes

Randomisation List

Randomisation list

MeMuRu_147(Local) (A.25OCT2001)

Subjects for center -------------------------------------

Sub. Gr. Bl. Group Sub. Gr. Bl. Group No. Elig nb nb Treatment label No. Elig nb nb Treatment label ------------------------------------------------------------------------ ------------------------------------------------------------------------

1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) I 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) I 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) I 1 Priorix (MJR289A42C) I 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) I 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C)

Randomisation list



Sub. Gr. Bl. Group Sub. Gr. Bl. Group No. Elig nb nb Treatment label No. Elig nb nb Treatment label ------------------------------------------------------------------------ ------------------------------------------------------------------------

1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) I 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) E 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C)

Randomisation list



Sub. Gr. Bl. Group No. Elig nb nb Treatment label ------------------------------------------------------------------------

1 Priorix (MJR289A42C) 1 Priorix (MJR289A42C)

Investigator CV

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

Publications referenced inthe report

This section contained journal publication(s), which are protected by copyright laws and therefore have been excluded.

Documents

In February 2013, GlaxoSmithKline (GSK) announced …...GlaxoSmithKline Biologicals Rue de l'Institut 89 1330 Rixensart, Belgium Confidential & Proprietary Information Final Study