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Sanofi Pasteur MSD Td5aP-IPV (REPEVAX®) and Td5aP (COVAXiS®)

Name of Sponsor / Company Sanofi Pasteur MSD S.N.C. Name of Finished Products REPEVAX®, COVAXiS®, TETRAVAC®

Individual Study Table referring to part of the dossier Volume

(For National Authority use only)

Name of Active Ingredients REPEVAX® (Td5aP-IPV): Diphtheria, Tetanus, 5-component acellular Pertussis and Inactivated Poliomyelitis Vaccine COVAXiS® (Td5aP): Diphtheria, Tetanus, 5-component acellular Pertussis Vaccine TETRAVAC® (DT2aP-IPV): Diphtheria, Tetanus, 2-component acellular Pertussis and Inactivated Poliomyelitis Vaccine

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METHODOLOGY

Part I: Open, randomised, controlled study. Children aged 3.5 to 5 years, already primed with Diphtheria, Tetanus, and whole cell Pertussis (DTwP) vaccine at least 3 years ago were randomised to 1 of the following groups and vaccinated with 1 of the 3 study vaccines:

Group 1: One single injection of study vaccine 1 (REPEVAX®, Td5aP-IPV) Group 2: One single injection of study vaccine 2 (COVAXiS®, Td5aP) and administration of oral poliomyelitis vaccine (OPV) Group 3: One single injection of study vaccine 3 (TETRAVAC®, Td2aP-IPV)

All subjects received measles, mumps, and rubella (MMR) live attenuated vaccine concomitantly. Part II: All the children who completed Part I were asked to return for blood samplings, 1 year (Visit 3), 3 years (Visit 4), and 5 years (Visit 5) after receipt of study vaccine(s). No further vaccines were given.

NUMBER OF SUBJECTS ANALYSED

Table 1: Subjects disposition (Randomised subjects)

REPEVAX®

(Td5aP-IPV) COVAXiS® + OPV

(Td5aP+OPV)TETRAVAC®

(DT2aP-IPV)

Randomised Subjects n 100 100 100

Visit 3 completed n (%) 68 (68.0%) 75 (75.0%) 74 (74.0%) Serology available at Visit 3 and Visit 5 completed n (%) 37 (37%) 47 (47%) 33 (33%) Visit 4 completed n (%) 47 (47.0%) 60 (60%) 48 (48.0%) Serology available at Visit 4 and Visit 5 completed n (%) 36 (36%) 48 (48%) 29 (29%) Consent given at Visit 5 n (%) 49 (49.0%) 56 (56.0%) 41 (41.0%)

Consented but no blood sample taken n (%) 1 (1.0%) (a) 2 (2.0%) (b) 3 (3.0%) (c) Visit 5 completed (d) n (%) 48 (48.0%) 54 (54.0%) 38 (38.0%) % are calculated based on the number of randomised subjects

(a) subject 97 (b) subjects 250 and 282 (c) subjects 42, 161 and 203 (d) intent-to-treat population at Visit 5

Table 1 shows the number of subjects who had serology results available at Visit 3 and completed Visit 5 and the number of subjects who had serology results available at Visit 4 and completed Visit 5. It should be noted that these 2 sub-populations do not necessarily include individuals who attended all 3 follow-up visits (i.e. Visits 3, 4 and 5). This explains the number of subjects that varies from visit to visit. No analysis was done on the sub-population of subjects having attended the 3 follow-up visits due to the limited number of subjects.

U01-Td5I-303 Part II (Visit 5) CSR_v1 (final)_18NOV2008 /10 CONFIDENTIAL






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DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Part II – Visit 5: All the children enrolled in Part I were eligible for Part II. However, parents (or legal guardian) had to sign an informed consent form for a blood sample at the time of Visit 5.

STUDY VACCINES, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS (PART I)Study vaccine 1: REPEVAX® (Td5aP-IPV), Diphtheria, Tetanus, Pertussis (5 acellular components) and Poliomyelitis (inactivated) vaccine, adsorbed, reduced antigen(s) content - Presentation and mode of administration: Vial containing one 0.5 mL liquid dose for

intramuscular (IM) injection into the right deltoid region - Storage: between +2°C and +8°C - Batch number: C0528AAStudy vaccine 2: COVAXiS® (Td5aP), Tetanus, Diphtheria and 5-component acellular Pertussis vaccine

- Presentation and mode of administration: Vial containing one 0.5 mL liquid dose for IM injection into the right deltoid region

- Storage: between +2°C and +8°C - Batch number: C0632AB Study vaccine 3: TETRAVAC® (DT2aP-IPV), Diphtheria, Tetanus, Pertussis (2 acellular components) and Poliomyelitis (inactivated) vaccine, adsorbed

- Presentation and mode of administration: Prefilled syringe containing one 0.5 mL liquid dose for IM injection into the right deltoid region

- Storage: between +2°C and +8°C - Batch numbers: T0015 and U0169-1

CONCOMITANT VACCINES, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS (PART I)Concomitant vaccine 1: OPV, Oral Poliomyelitis vaccine

- Presentation and mode of administration: Single dose container for oral administration (3 drops)

- Storage: between +2°C and +8°C - Batch number: Not applicable (vaccine sourced from commercial stock: OPV,

GlaxoSmithKline)Concomitant vaccine 2: MMR, Measles, Mumps, and Rubella live attenuated vaccine

- Presentation and mode of administration: Vial of freeze-dried product, and vial or syringe of diluent for IM injection into the left deltoid region

- Storage: between +2°C and +8°C - Batch number: Not applicable (vaccine sourced from commercial stock: M-M-R�II, Sanofi

Pasteur MSD)







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DURATION OF FOLLOW-UP

Part - VII isit 5: One single visit 5 years after administration of the study vaccine(s)

CRITERIA FOR EVALUATION

Part – IMMU

II Visit 5: NOGENICITY: Long term immunogenicity of the study vaccines was assessed by a

s to the vaccine antigssay of specific

antibodie ens 5 years after booster administration. SA TFE Y: Protocol-related serious adverse events which occurred at the 5-year follow-up visit had to be reported.

STATISTI

Part II – h (i.e. subjects vaccinated during Part I with a blood sample available at Visit 5). Descriptive statistics were

ered for the persistence of antibodies. were calculated by

lisation [SN]): geometric mean titre (GMT), and number and percentage [n ren with antibody titres 0.01, 0.1, 1 and 10 international unit (IU)/mL

iomyelitis types 1, 2, and 3 (SN): GMT, and n (%) of children with antibody titre 1:8 (dilution

Reverse cumulative distribution curves (RCDC) were produced for all antigens by group and all groups together.

CAL METHODS

Visit 5: The immunogenicity analysis was performed based on an intent-to-treat (ITT) approac

used as the study was not powThe following serological parameters and their 95% confidence intervals (95% CIs)group and all groups together:

Diphtheria (seroneutra(%)] of childTetanus (Enzyme-linked immunosorbent assay [ELISA]): GMT, and n (%) of children with antibody titres 0.01, 0.1, and 1 and 10 IU/mL PT, FHA, PRN, and FIM pertussis antigens (ELISA): GMT (ELISA unit [EU]/mL) Polunit)







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SUMMARY – CONCLUSIONS

udy changed between Visits 3 and 4.

Th w

Co oand pertussis ELISA tests.

of subjects having attended the 3 follow-up visits was not studied due to the limited number of individual subjects, and (2) the change of laboratory between Visit 3 and Visit 4. Only descriptive statistics were planned to be used in this Part II study, not powered to show differences in terms of antibody persistence between groups. Although 95% CIs are presented for each result, the observation that they overlap or not does not allow for accurate conclusions regarding the differences between groups: specifically, slightly overlapping CIs may hide statistically significant differences. In addition, the drop-out rate (60%-70%) is also a clear limitation for comparing groups. In addition, to avoid misinterpretation following retrospective multiple testing, one variable was analysed per antigen. When antibody protective levels are commonly accepted, they were favoured as they are clinically more relevant than GMTs.

DEMOGRAPHY

The clinical study report presents the data at Visit 5 and in addition the antibody data of Visits 3 to 4, i.e. the 1- and 3-year follow-up data for the sub-population of subjects included in the ITT population at Visit 5. The laboratory performing the immunogenicity tests of this stConsequently, some immunogenicity results obtained at Visit 3 were converted in order to be presented in the same table as for Visits 4 and 5 data in this report.

is as the case for: Diphtheria SN assay; Tetanus ELISA: in addition to the conversion factor applied, the unit was changed from EU/mL (Visit 3 tests) to IU/mL (Visits 4 and 5 tests); Poliomyelitis SN assays for polio serotypes 1 and 2.

nc rdance tests showed that it was not necessary to use a conversion factor for poliomyelitis serotype 3

No longitudinal evaluation of antibody persistence between 1 and 5 years was done because of (1) the sub-population

Refer to Table 2. Table 2: Demographics at Visit 5 (Intent-to-Treat Population at Visit 5)

REPEVAX®

(Td5aP-IPV) N=48

COVAXiS® + OPV (Td5aP+OPV)

N=54

TETRAVAC®

(DT2aP-IPV) N=38

Age (Years) Mean ± SD Median

9.07 ± 0.37 8.97

9.05 ± 0.27 9.02

9.06 ± 0.35 8.98

Gender Male n (%) 21 (43.75%) 18 (33.33%) 21 (55.26%) Female n (%) 27 (56.25%) 36 (66.67%) 17 (44.74%)

SD: standard deviation







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SUMMARY – CONCLUSIONS (continued)

IMMUNOGENICITY RESULTSFor diphtheria, an antibody concentration between 0.01 and 0.09 IU/mL may be regarded as giving basic immunity, whereas a higher titre may be needed for full protection. In this report, titres 0.1 IU/mL are considered as seroprotection rates.

ntitoxin Responses (IU/mL - SN) (IntentTable 3: Diphtheria A -to-Treat Population at Visit 5) REPEVAX®

(Td5aP-IPV)COVAXiS® + OPV

(Td5aP+OPV)TETRAVAC®

(DT2aP-IPV)N=48 N=54 N=38

Visi 37 47 33 t 3* (1 year post-vaccination) n data 0.01 IU/ml n (%)

[95% CI] 37 (100)

[90.59; 100] 47 (100)

[92.44; 100] 33 (100)

[89.57; 100] 0.1 IU/ml n (%) 33 (89.19) 45 (95.74) 32 (96.97)

[95% CI] [75.29; 95.71] [85.75 %; 98.83] [84.68; 99.46] GMT [95% CI] 0.985 [0.616; 1.575] 1.104 [0.761; 1.603] 1.422 [0.879; 2.299]

Visit 4 (3 years post-vaccination) n data 36 48 29 0.01 IU/ml n (%)

[95% CI] 36 (100)

[90.36; 100] 48 (100)

[92.59; 100] 29 (100)

[88.30; 100] 0.1 IU/ml n (%)

[95% CI] 26 (72.22)

[56.01; 84.15] 36 (75.00)

[61.22; 85.08] 20 (68.97)

[50.77; 82.72] GMT [95% CI] 0.222 [0.142; 0.346] 0.277 [0.192; 0.399] 0.291 [0.170; 0.497]

Visit 5 (5 years post-vaccination) n data 48 54 38 0.01 IU/ml n (%)

[95% CI] 48 (100)

[92.59; 100] 54 (100)

[93.36; 100] 38 (100)

[90.82; 100] 0.1 IU/ml n (%)

[95% CI] 36 (75.00)

[61.22; 85.08] 36 (66.67)

[53.36; 77.76] 30 (78.95)

[63.65; 88.93] GMT [95% CI] 0.226 [0.145; 0.354 ] 0.232 [0.162; 0.333 ] 0.338 [0.218; 0.524 ]

* converted data As shown in Table 3, all the children attending Visit 5 had diphtheria antitoxin titres 0.01 IU/mL.

ere 0.1 IU/mL for 75%, 67% and 79% of children having received REPEVAX ®,

Antibody titres wCOVAXiS® + OPV, and TETRAVAC®, respectively.







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SUMMARY – CONCLUSIONS (continued) For tetanus, antitoxin concentrations of at least 0.1�0.2 IU/mL are defined as positive when standard

REPEVAX COVAXiS + OPV TETRAVAC

ELISA techniques are used. In this report, titres 0.1 IU/mL are considered as seroprotection rates. Table 4: Tetanus Antitoxin Responses (IU/mL - ELISA) (Intent-to-Treat Population at Visit 5)

® ® ®

(Td5aP-IPV) N=48

(Td5aP+OPV) N=54

(DT2aP-IPV) N=38

Visit 3* (1 year post-vaccination) n data 37 47 33

0.01 IU/ml n (%) [95% CI]

37 (100) 100] [90.59;

47 (100) [9 0] 2.44; 10

33 (100) [89.5 7; 100]

0.1 IU/ml n (%) [95% CI]

0) [ ; 100]

[92. 00]

33[89.57

37 (1090.59

47 (100)44; 1

(100) ; 100]

GMT [95% CI .93 ] 2.9 2.14 ] 3.05 [2.37; 3 9 [2.29; 3.90 ] [1.54; 2.98 ]Visit 4 (3 years post-vaccination) n data 36 48 29

0.01 IU/ml ] n (%) [95% CI

36 (100) [90.36; 100]

48 (100) [92.59; 100]

29 (100) [88.30; 100]

0.1 IU/ml I] n ) (%[95% C

36 (100) [9 ; 100] 0.36

47 (97.92) [89.1 .63] 0; 99

27 (93.10) [78.04; ] 98.09

GMT [95% CI] 1.07 [0.83; 1.38 ] 1.2 0.79 7 [0.96; 1.69 ] [0.54; 1.15 ]Visit 5 ( st-v5 years po accination) n data 48 54 38

0.01 IU/ml I] n (%) [95% C

48 (100) [92.59; 100]

54 (100) [93.36; 100]

38 (100) [90.82; 100]

0.1 IU/ml [ % CI] n (%) 95

48 (100) [92.59; 100]

52 (96.30) [87.46; 98.98]

34 (89.47) [75.87; 95.83]

GMT [95% CI] 0.74 7; 0.97 ] 0.83 [ 1.11 ] 0.44 [0.3 ] [0.5 0.62; 1; 0.62

As shown in able 4, al r tres Visit 5, and respectively and 89% of chi ren ha X® n ® e es

0

* conver data ted

T l the child en iEPEVA had t 0.01 IU/mL at

®, % 100%, 96

ld ving received R , COVAXiS , a d TETRAVAC r spectively had titr.1 IU/mL.







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SUMMARY – CONCLUSIONS (continued) For pertussis, according to GMTs presented in Table 5, REPEVAX®, COVAXiS® + OPV, and TETRAVAC® provided immunity persisting for 5 years, except for PRN and FIM in the TETRA ®VAC

Table 5: Pertussis Responses (EU/mL - ELISA) ( reat VisiVAX®

-IPV) N=48

PV +OPV)

4(D V)

group as these antigens are not contained in TETRAVAC®. Intent-to-T Population at t 5)

RE (Td5aP

PE CO S® + OVAXi(Td5aP

N=5

TET ®RAVACT2aP-IP

N=38PERTUS Visit 3 n 37 SIS PT 46 32 (EU/mL) (1 year post-vacc GMT

[95% C.51 ; 41.61] .77]

Visit 4 n

ination) I] [16.8

26936

32.96 [22.28; 48

47

12.86 [ ]

28 8.40; 19.67

(3 years post-vac ) GM[95% CI

08; 8.34] 2.44] [3. ]

Visit 5 n 38

cination T 5.83] .[4

7.88 [ 1

41 4.99;

6.24 9 9

33 8; 9.7

(5 years post-vac GMT [95% C

98; 13.05]

PERTUSSIS Visit 3 n

cination) I] [4.8

7.8

37

8.06 [4.76; 13.66]

47

4.98 [3.23; 7.67]

FHA 33 (EU/mL 1 year post) ( -vaccinat GM

[95% CI

01; 32.35] 14] [26. Visit 4 n 36

ion) T 22.76] .[16

29.69 [2 ; 40.

45 1.96

36.85 1 .01]

29 1; 52

(3 years post-vac GMT [95% C

.99 ; 25.34]

Visit 5 n

cination) I] [11.3

16946

32.13 [21.46; 48.10]

54

38.99 [ ]

38 24.19; 62.86

years post-vaccination) GM[95% CI] [20.64; 34.95] [28.53; 52.71] [29.71; 57.38]

PERTUSSIS PRN Visit 3 n 37 47 33

(5 T 26.86 38.77 41.29

(EU/mL) (1 year post-vaccination) GMT [95% CI]

40.16 [24.72; 65.24]

54.33 [33.36; 88.48]

2.98 [2.16; 4.11]

Visit 4 n 36 48 29 (3 years post-vaccination) GMT

[95% CI] 18.51

[12.60; 27.18] 30.89

[21.21; 44.99] 3.64

[2.74; 4.82] Visit 5 n 47 54 38 (5 years post-vaccination) GMT

[95% CI] 18.13

[12.95; 25.39] 26.82

[18.14; 39.67] 3.84

[2.90; 5.08] PERTUSSIS FIM Visit 3 n 36 47 33 (EU/mL) (1 year post-vaccination) GMT

[95% CI] 126.00

[65.45; 242.56] 154.86

[96.78; 247.79] 14.70


[95% CI] 66.56

[46.05; 96.21] 90.43

[64.42; 126.95] 11.56


[95% CI] 63.62

[42.93; 94.28] 74.32

[52.39; 105.42] 10.21

[6.39; 16.33]







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SUMMARY – CONCLUSIONS (continued) For poliomyelitis, persons are presumed to be protected against disease caused by a particular type of poliovirus if they develop type-specific serum neutralizing antibody. In this report, titres 1:8 (dilution unit) are considered as seroprotection rates. Table 6: Poliomyelitis Responses (Reverse Dilution - SN) (Intent-to-Treat Population at Visit 5)

POLI ITIS(dilution unit)

REPEVAX (Td5aP-IP

N=48(Td5

N=5

OMYEL ® COVV)

AXiS® + OPV aP+OPV)

4

TETRAVAC®

(DT2aP-IPV) N=38

TYPE 37 46 1 Visit 3* n data 32 ost-vaccinat

[95% CI]7 (100)

1046 (1

[92.

[95% CI] 33 7.04; 429.6 112.42 [89.95; 52] 322.89 [2 ; 443.94] Visit 4 36 47

(1 year p ion) 1:8 n (%) 3[90.59; 0]

00) 29; 100]

32 (100)[89.28; 100]

GMT 8.74 [26 9] 140. 34.85n data 29

(3 years post-vaccination) [95% CI]

0) [90.36; 100]

47[92.44; 1 [88. 00]

8 95.41; 414. 112.09 [81.16 357.74 [ 525.80] Visit 5 n data

1:8 n (%) 36 (10 (100) 00]

29 (100) 30; 1

GMT [95% CI] 2 4.59 [1 45] ; 154.80] 243.40;47 53 38

ccina 1:8 n (%) 46 (97.87) 9; 99.62]

51 (96.2[87.25; 9

3 ) [9 0]

1 ; .01 [ 12 .34] TYPE Visit 3* 37 46

(5 years post-va tion) [95% CI]

GMT [95% CI][88.8

3) 8.96]

8 (1000.82; 10

01.85 [73.86 140.43] 64 46.87; 87.42] 4.55 [90.01; 1722 n data 32

(1 year post-vaccinat 7 (100) 10

46 (1[92.

[95% CI] 47 6.21; 624.3 167.23 [135.32 67] 531.83 [3 ; 777.38] Visit 4 36 47

ion) 1:8 n (%) [95% CI]

3[90.59; 0]

00) 29; 100]

32 (100)[89.28; 100]

GMT 1.59 [35 5] ; 206. 63.84n data 29

(3 years post-vaccination) [95% CI]

0[90.36; 100]

4[92.44; 1 [88. 00]

34 52.84; 461. 91 [115.1 393.60 [ 602.21] Visit

1:8 n (%) 36 (10 ) 7 (100) 00]

29 (100) 30; 1

GMT [95% CI]n data

1.72 [2 84] 153. 6; 205.69] 257.25;5 47 53 38

(5 years post-vaccina 1:8 n (%) ) .44; 100]

53 ([93.24; [90 0]

0 .58 [ 211. 9.90] TYPE Visit 3

tion) [95% CI]

GMT [95% CI] 2

47 (100[92

100) 100]

3 ) 8 (100.82; 10

2.19 [164.58; 37

248.39] 106 84.37; 134.64] 46

37 [144.17; 303 n data 32

(1 year post-vaccina 7 (100) 10

46 (1[92.

3 )

[95% CI] 104 4; 33 [7 1104. 50]36 47

tion) 1:8 n (%) [95% CI]

3[90.59;

37 [711.20] 1530. 98.

00) 29; 100] 1.42; 38]

2 (100[89.28; 100]

65 [770. ; 1583.GMT 3. 58] 135. 60Visit 4 n data 29

post-vaccina[95% CI]

29

4[88.

1 48.34; 691. 38.19 [28.8 ] 389.05 633.19] Visit 5

(3 years tion) 1:8 n (%) 35 (97.[85.83; 9

2) .51]

6 (97.87) 89; 99.62]

28 (96.55) [82.8 .39] 2; 99

GMT [95% CI] 4n data

4.27 [2 09] 5; 50.56 [239.04; 47 53 38

(5 years post-vaccina 1:8 n (%) 745; 98.83]

44 ([70.77; 9 [86. 53]

4 1; .75 [ 145. 7.76]

tion) [95% CI]

GMT [95% CI] 1

45 (95. ) [85.7

83.02) 0.80]

37 ) (97.3751; 99.

7.26 [101.8 213.00] 16 13.07; 21.47] 43 [101.79; 20* converted data







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SUMMARY – CONCLUSIONS (continued)

As presented in Table 6, at Visit 5, the seroprotection rates for poliomyelitis type 1 were 98%, 96% and 100% for REPEVAX®, COVAXiS® + OPV and TETRAVAC®, respectively, and 100% for poliomyelitis type 2 in the 3 vaccine groups. For poliomyelitis type 3, 10 children did not meet the threshold in the

for R d 97% for TETRAVAC .

SAFETY

COVAXiS® + OPV group, leading to a response rate of 83% in that group at Visit 5, which was 96%®EPEVAX® an

RESULTS

N proto d t was reported linked to Visit

o col-related serious a verse even 5.

CONCLUSION

REPEVAX® provided good persistent immunity s uSimilar r were generally seen in the d

igenXiS® OPV anfor all ant p t fter receipt of the booster.

TETR AC® groups. o 5 years a

esults COVA + AV

Date of the report: 218-November- 008


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