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					Sanofi Pasteur MSD                                                                              ProQuad®


SYNOPSIS
 Name of Sponsor/Company                          Individual Study Table              (For National
 Sanofi Pasteur MSD S.N.C.                        referring to part of the dossier    Authority use only)
 Name of Finished Products:                       Volume
 ProQuad®
 Name of Active Ingredients:                      Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 TITLE OF THE STUDY: An open, randomised, comparative, multicentre study of the immunogenicity and
 safety of ProQuad® when administered by intramuscular (IM) route or subcutaneous (SC) route to
 healthy children aged 12 to 18 months
 Study Identification Number: F05-MMRV-304
 EudraCT number: 2006-001986-40

 PRINCIPAL INVESTIGATOR: Dr Hervé HAAS, MD

 STUDY CENTRES: Forty-one (41) centres in France

 PUBLICATION: None

 STUDY PERIOD (YEARS)                           PHASE OF DEVELOPMENT: Phase IIIb
 First Visit First Subject: 06 October 2006
 First Visit Last Subject: 29 January 2007
 Last Visit Last Subject: 11 May 2007
 OBJECTIVES
 Primary objective
 To demonstrate that two doses of ProQuad® administered by the IM route is as immunogenic as two
 doses of ProQuad® administered by the SC route to healthy children 12 to 18 months of age in terms of
 antibody response rates to measles, mumps and rubella as measured by ELISA and to varicella as
 measured by gpELISA at 42 days following the second dose of ProQuad®.
 For each of the four antigens tested (i.e., measles, mumps, rubella and varicella), the primary hypothesis
 was that the IM route would be non-inferior to the SC route.
 Secondary objectives
   • To describe the antibody response rates to measles, mumps, rubella and varicella 30 days after the
     first dose of ProQuad® administered by the IM or SC route.
   • To describe the antibody titres to measles, mumps, rubella and varicella 30 days after the first dose
     of ProQuad® and 42 days after the second dose of ProQuad®, both administered by the IM or
     SC route.
   • To describe the safety profile of each of the two doses of ProQuad®, both administered either by
     the IM or SC route.




F05-MMRV-304                        CSR_Synopsis_v1final_19FEB2009                              Page 1/13
                                          CONFIDENTIAL
Sanofi Pasteur MSD                                                                                                  ProQuad®


 Name of Sponsor/Company                                    Individual Study Table                       (For National
 Sanofi Pasteur MSD S.N.C.                                  referring to part of the dossier             Authority use only)
 Name of Finished Products:                                 Volume
 ProQuad®
 Name of Active Ingredients:                                Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 METHODOLOGY
 Open-label, randomised, comparative, multicentre study with two parallel groups.
                                            Table 1: Flow Chart of Assessments
  Age                                  12–18 months
  Visit                                   Visit 1                             Visit 2                         Visit 3
  Blood sample                        Blood Sample 1                     Blood Sample 2                  Blood Sample 3
  (3 mL each)                             (BS1)                              (BS2)                           (BS3)
  Vaccination with                   Group 1: IM route                  Group 1: IM route
  ProQuad®                           Group 2: SC route                  Group 2: SC route
  BS1=collected after the subject’s eligibility had been verified, after the Informed Consent Form was signed, within 7 days
   before or at the time of Visit 1, and before the first vaccination.
  BS2=collected between Day 30 and Day 44 after the first vaccination, before or at the time of Visit 2, and before the second
   vaccination.
  BS3=collected between Day 42 and Day 56 after the second vaccination, before or at the time of Visit 3.



 NUMBER OF SUBJECTS (PLANNED AND RANDOMISED)
 See Table 2
 Planned: 380 subjects (190 per group)
 Randomised: 405 subjects: Group 1 (IM): N=202, Group 2 (SC): N=203
                                              Table 2: Disposition of Subjects
                                                                        Group 1                 Group 2
                                                                   INTRAMUSCULAR            SUBCUTANEOUS
                                                                         n (%)                   n (%)
                 N randomised (1)                                      202 (100)               203 (100)
                 N vaccinated with Dose 1                              202 (100)               203 (100)
                 N vaccinated with Dose 2                              202 (100)               203 (100)
                 N completed                                           201 (99.5)              200 (98.5)
                 N withdrawn                                             1 (0.5)                 3 (1.5)
                     withdrawn due to lost to follow-up                  1 (0.5)                 2 (1.0)
                     withdrawn due to non-compliance with
                                                                              0                    1 (0.5)
                     protocol (last visit not done)
                 (1) 6 additional subjects were screened and not randomised
                         Percentages were calculated based on the number of randomised subjects




F05-MMRV-304                               CSR_Synopsis_v1final_19FEB2009                                               Page 2/13
                                                 CONFIDENTIAL
Sanofi Pasteur MSD                                                                             ProQuad®


 Name of Sponsor/Company                         Individual Study Table               (For National
 Sanofi Pasteur MSD S.N.C.                       referring to part of the dossier     Authority use only)
 Name of Finished Products:                      Volume
 ProQuad®
 Name of Active Ingredients:                     Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 The main reason for excluding subjects from the PPS was for lack of appropriate randomisation
 procedure, i.e., some investigators did not randomise some subjects chronologically. Retrospectively, it
 was difficult to assess in these centres when the procedure was followed and when it was not.
 Consequently, this led to the exclusion of a total of 73 subjects (IM group: 37 subjects and SC group: 36
 subjects) from three centres of the South-east geographic region.
 DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION
 Healthy infants aged 12 to 18 months; consent form signed by both parents or by the legal representative;
 no vaccination history and/or suspected clinical history and/or exposure in past 30 days to measles,
 mumps, rubella, varicella and/or zoster; no history of febrile illness in the past three days; no known
 sensitivity and/or allergy to any component of the study vaccine; no impairment of the immune system
 (including corticosteroids); no receipt of inactivated or live vaccine in the past 30 days.
 TEST/REFERENCE VACCINES, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS
 ProQuad®: measles, mumps, rubella and varicella vaccine (live).
    • Presentation: Powder and diluent for suspension for injection.
    • Dose: 0.5 mL
    • On site storage: +2°C to +8°C
    • Batch numbers:
           o Powder 0652834 (expiry 31 December 2007)
           o Diluent 0380F (expiry 30 September 2008)
 VACCINATION SCHEDULE
 Group 1: First dose of ProQuad® administered by the IM route at 12 to 18 months of age and second
 dose of ProQuad® administered by the IM route 30 days later.
 Group 2: First dose of ProQuad® administered by the SC route at 12 to 18 months of age and second
 dose of ProQuad® administered by the SC route 30 days later.
 FOLLOW-UP DURATION
 Between 30 to 44 days follow-up after the first dose of ProQuad® and between 42 to 56 days follow-up
 after the second dose i.e., between 72 to 100 days follow-up after the first dose of ProQuad® in each
 group.
 CRITERIA FOR EVALUATION
 Immunogenicity:
     •   Primary criterion: Antibody response rates* to measles, mumps, rubella and varicella measured
         six weeks after the second dose of ProQuad® in both groups (BS3).
     •   Secondary criteria:
             o Antibody response rates* to measles, mumps, rubella and varicella measured four weeks
                after the first dose of ProQuad® in both groups (BS2).

F05-MMRV-304                       CSR_Synopsis_v1final_19FEB2009                              Page 3/13
                                         CONFIDENTIAL
Sanofi Pasteur MSD                                                                                 ProQuad®


 Name of Sponsor/Company                           Individual Study Table             (For National
 Sanofi Pasteur MSD S.N.C.                         referring to part of the dossier   Authority use only)
 Name of Finished Products:                        Volume
 ProQuad®
 Name of Active Ingredients:                       Page
 Measles, mumps, rubella and varicella
 vaccine (live)
              o Antibody titres to measles, mumps, rubella and varicella measured four weeks after the
                  first dose of ProQuad® (BS2) and six weeks after the second dose of ProQuad® (BS3) in
                  both groups.
              o Rates of subjects with varicella antibody titres >=1.25 gpELISA units/mL in subjects
                  whose baseline varicella antibody titre (BS1) was <1.25 gpELISA units/mL, four weeks
                  after the first dose of ProQuad® (BS2) and six weeks after the second dose of ProQuad®
                  (BS3) in both groups.
 *Response rates were defined as measles antibody titre >=255 mIU/mL in those with baseline measles
 titre <255 mIU/mL; mumps antibody titre >=10 ELISA Ab units/mL in those with baseline mumps titre
 <10Ab units/mL; rubella antibody titre >=10 IU/mL in those with baseline titre <10 IU/mL; and varicella
 antibody titre >=5 gpELISA units/mL in those with baseline antibody titre <1.25 gpELISA units/mL.
 Antibody response to measles, mumps and rubella were measured by ELISA and antibody response to
 varicella by gpELISA.
 Safety:
   • From Day 0 to Day 4 following each dose: Solicited injection-site adverse reactions:
          o Injection-site erythema.
          o Injection-site swelling.
          o Injection-site pain.
   • From Day 0 to Day 28 following each dose: unsolicited injection-site adverse reactions and
     systemic adverse events:
          o Unsolicited injection-site adverse reactions, including injection-site erythema, injection-
              site swelling and injection-site pain starting from Day 5 to Day 28.
          o Rectal temperature >=38.0°C (or, if missing, axillary temperature >=37.1°C).
          o Rectal temperature >=39.4°C (or, if missing, axillary temperature >=38.5°C).
          o Measles-like rash.
          o Mumps-like illness.
          o Rubella-like rash.
          o Varicella-like rash.
          o Zoster-like rash.
          o Other systemic adverse events.
   • From Day 0 to the last visit of the concerned subject:
          o Serious adverse events.
 [ Rectal temperature = axillary temperature + 0.9°C according to the thermometer instructions]

 STATISTICAL METHODS
 Immunogenicity:
     •    Primary criteria:
               o    The main analysis evaluated the immunogenicity after the second dose of ProQuad®
                    based on the Per Protocol Sets Post-dose 2 stratified by region (i.e., pooled centres based


F05-MMRV-304                              CSR_Synopsis_v1final_19FEB2009                            Page 4/13
                                                CONFIDENTIAL
Sanofi Pasteur MSD                                                                                       ProQuad®


 Name of Sponsor/Company                          Individual Study Table             (For National
 Sanofi Pasteur MSD S.N.C.                        referring to part of the dossier   Authority use only)
 Name of Finished Products:                       Volume
 ProQuad®
 Name of Active Ingredients:                      Page
 Measles, mumps, rubella and varicella
 vaccine (live)
                 on geographic location); the statistical analysis was based on two-sided 95% (adjusted
                 for multiplicity) confidence interval (CI) around the difference in response rates
                 [Group 1 (IM) – Group 2 (SC)] for each valence. The non-inferiority criterion was
                 achieved if the lower bound of the 95% CI was >-10 percentage points.
                  o   The supportive analysis evaluated the immunogenicity based on the Per Protocol Sets
                      Post-dose 2 not stratified by region and on the Full Analysis Set (stratified by region and
                      not stratified).
     •    Secondary criteria: A descriptive analysis within each group was performed for measles,
          mumps, rubella and varicella including the calculation after each dose of the GMTs (and 95%
          CIs), the response rates (and 95% CIs) and the rates (and 95% CIs) of subjects with varicella
          antibody titres >=1.25 gpELISA units/mL in subjects whose baseline varicella antibody titre was
          <1.25 gpELISA units/mL (seronegative antibody titre).
 Safety: The safety profile of each dose of ProQuad® is described for injection-site adverse reactions,
 systemic adverse events, daily temperatures and rashes.

 SUMMARY – CONCLUSIONS
 DEMOGRAPHY
                      Table 4: Demographic and Other Baseline Characteristics ─ Randomised set
                                                  Group 1 – INTRAMUSCULAR                 Group 2 – SUBCUTANEOUS
                                                              N=202                                   N=203
   Age at first         Mean (SD)                          13.72 (1.44)                           13.65 (1.53)
   vaccination          Median                                 13.30                                   13.30
   (months)
                        Minimum – Maximum                   11.9 - 18.0                            11.7 - 18.3
   Gender               Male                                97 (48.0%)                            109 (53.7%)
                        Female                             105 (52.0%)                             94 (46.3%)
   Weight (kg)          Mean (SD)                            10.0 (1.1)                              9.9 (1.1)
                        Median                                  10.0                                    10.0
                        Minimum – Maximum                      7 - 13                                  7 - 13
   Height (cm)          Mean (SD)                            77.3 (3.2)                             77.0 (3.3)
                        Median                                  77.5                                    77.0
                        Minimum – Maximum                     70 - 89                                 66 - 87
   SD: Standard deviation, Percentages were calculated based on the number of randomised subjects




F05-MMRV-304                             CSR_Synopsis_v1final_19FEB2009                                   Page 5/13
                                               CONFIDENTIAL
Sanofi Pasteur MSD                                                                                                 ProQuad®


 Name of Sponsor/Company                                    Individual Study Table                       (For National
 Sanofi Pasteur MSD S.N.C.                                  referring to part of the dossier             Authority use only)
 Name of Finished Products:                                 Volume
 ProQuad®
 Name of Active Ingredients:                                Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 IMMUNOGENICITY RESULTS
     •    Primary objective
               o       Main analysis
 For both IM and SC groups, the antibody response rates to measles, mumps, rubella and varicella were
 >99% six weeks after the second dose of ProQuad® for the subjects initially seronegative to measles,
 mumps, rubella or varicella (see Table 5).
 Table 5: Antibody Response Rates to Measles, Mumps, Rubella and Varicella 6 Weeks after the Second Dose
 of ProQuad® for Subjects Initially Seronegative to Measles, Mumps, Rubella or Varicella ─ Antigen specific
                                        Per Protocol Set Post-dose 2
                        Group 1 – INTRAMUSCULAR                                   Group 2 – SUBCUTANEOUS
                   N           Number of            [95% CI]             N           Number of              [95% CI]
                               responders                                            responders
                             (Response rate)                                      (Response rate)
  Measles        153            153 (100)          [97.6 ; 100]         147           147 (100)           [97.5 ; 100]
  Mumps          152            151 (99.3)         [96.4 ; 100]         148           147 (99.3)          [96.3 ; 100]
  Rubella        129            129 (100)          [97.2 ; 100]         132           131 (99.2)          [95.9 ; 100]
  Varicella      138            138 (100)          [97.4 ; 100]         134           133 (99.3)          [95.9 ; 100]
  Response rates were defined as:
      Measles antibody titre >=255 mIU/mL in subjects with baseline titre <255 mIU/mL.
      Mumps antibody titre >=10 ELISA Ab units/mL in subjects with baseline titre <10 ELISA Ab units/mL.
      Rubella antibody titre >=10 IU/mL in subjects with baseline titre <10 IU/mL.
      Varicella antibody titre >=5 gpELISA units/mL in subjects with baseline titre <1.25 gpELISA units/mL.

 The primary immunogenicity hypothesis of the non-inferiority of the IM route of administration
 compared to the SC route was met (main analysis, stratified by region) since the lower bound of the
 95% CI on the difference was greater than -10 percentage points, meaning that the difference is
 statistically significantly lower than the pre-defined clinically relevant non-inferiority margin of
 10 percentage points. (see Table 6).
   Table 6: Non-inferiority Analysis (Stratified by Region) of Antibody Response Rates to Measles, Mumps,
   Rubella and Varicella 6 weeks after the Second Dose of ProQuad® for Subjects Initially Seronegative to
            Measles, Mumps, Rubella or Varicella ─ Antigen specific Per Protocol Set Post-dose 2
                                        Estimate of the difference
                                     Group 1 INTRAMUSCULAR ─                [95% CI]         Non-inferiority
                                       Group 2 SUBCUTANEOUS
                   Measles                        0.0%                      [-2.5 ; 2.6]            Yes
                   Mumps                          0.1%                      [-3.0 ; 3.3]            Yes
                   Rubella                        0.7%                      [-2.3 ; 4.1]            Yes
                   Varicella                      0.7%                      [-2.1 ; 4.1]            Yes
                   Centres were pooled based on geographic location in 3 regions in France. In the analysis, the
                   weight of each stratum was proportional to the number of subjects included in the stratum.



F05-MMRV-304                               CSR_Synopsis_v1final_19FEB2009                                          Page 6/13
                                                 CONFIDENTIAL
Sanofi Pasteur MSD                                                                                                 ProQuad®


 Name of Sponsor/Company                                    Individual Study Table                      (For National
 Sanofi Pasteur MSD S.N.C.                                  referring to part of the dossier            Authority use only)
 Name of Finished Products:                                 Volume
 ProQuad®
 Name of Active Ingredients:                                Page
 Measles, mumps, rubella and varicella
 vaccine (live)
                o    Supportive analyses
  The analyses done on each PPS2 not stratified by region as well as the analyses done on the FAS
  (stratified by region or not) gave comparable results to the region-stratified analysis performed on each
  PPS2.

     •     Secondary objectives
                o    Antibody response rates after the first dose of ProQuad®
  Four weeks after the first dose of ProQuad®, response rates for measles, rubella and varicella were
  numerically similar in both groups (see Table 7). The response rate for mumps was numerically higher
  in the IM group. The second dose of ProQuad® increased in both groups the mumps and varicella
  antibody response rates (see Table 5). Results were similar in the FAS.
 Table 7: Antibody Response Rates to Measles, Mumps, Rubella and Varicella 4 Weeks after the First Dose of
  ProQuad® for Subjects Initially Seronegative to Measles, Mumps, Rubella or Varicella ─ Antigen specific
                                        Per Protocol Set Post-dose 1
                             Group 1 – INTRAMUSCULAR                              Group 2 – SUBCUTANEOUS
                         N           Number of         [95% CI]             N           Number of          [95% CI]
                                     responders                                         responders
                                  (Response rate)                                    (Response rate)
         Measles        153           153 (100)       [97.6 ; 100]        148            144 (97.3)       [93.2 ; 99.3]
         Mumps          152           148 (97.4)      [93.4 ; 99.3]       149            136 (91.3)       [85.5 ; 95.3]
         Rubella        129           127 (98.4)      [94.5 ; 99.8]       133            133 (100)        [97.3 ; 100]
         Varicella      138           136 (98.6)      [94.9 ; 99.8]       136            134 (98.5)       [94.8 ; 99.8]
         Response rates were defined as:
             Measles antibody titre >=255 mIU/mL in subjects with baseline titre <255 mIU/mL.
             Mumps antibody titre >=10 ELISA Ab units/mL in subjects with baseline titre <10 ELISA Ab units/mL.
             Rubella antibody titre >=10 IU/mL in subjects with baseline titre <10 IU/mL.
             Varicella antibody titre >=5 gpELISA units/mL in subjects with baseline titre <1.25 gpELISA units/mL.

               o    Antibody titres (GMT) after the first and second doses of ProQuad®
 Measles, mumps, rubella and varicella GMTs were similar in the two groups after the first and the second
 doses of ProQuad®. Measles GMTs were also similar after the first and the second doses. There was a
 numerical increase in mumps, rubella and varicella GMTs after the second dose of ProQuad® compared
 to GMTs measured after the first dose, the most robust boosting effect being observed for varicella (see
 Table 8). Results were similar in the FAS (see Table 9).




F05-MMRV-304                               CSR_Synopsis_v1final_19FEB2009                                           Page 7/13
                                                 CONFIDENTIAL
Sanofi Pasteur MSD                                                                                           ProQuad®


 Name of Sponsor/Company                                Individual Study Table                     (For National
 Sanofi Pasteur MSD S.N.C.                              referring to part of the dossier           Authority use only)
 Name of Finished Products:                             Volume
 ProQuad®
 Name of Active Ingredients:                            Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 Table 8: Antibody Titres (GMT) to Measles, Mumps, Rubella and Varicella 4 Weeks after the First Dose and
 6 Weeks after the Second Dose of ProQuad® for Subjects Initially Seronegative to Measles, Mumps, Rubella
                              or Varicella - Antigen Specific Per Protocol Sets
                                                           Group 1                                Group 2
                                                    INTRAMUSCULAR                           SUBCUTANEOUS
                                              N      GMT           [95% CI]          N      GMT           [95% CI]
   Measles                     Post-dose 1   153    4058.7     [3643.1 ; 4521.8]    148     3327.0    [2835.4 ; 3903.9]
   (mIU/mL)                    Post-dose 2   153    3953.7     [3497.2 ; 4469.9]    147     3748.6    [3270.9 ; 4296.0]
   Mumps                       Post-dose 1   152     120.0      [102.2 ; 140.9]     149      101.9      [84.2 ; 123.2]
   (ELISA Ab units/mL)         Post-dose 2   152     157.9      [138.6 ; 180.0]     148      168.8     [146.9 ; 194.0]
   Rubella                     Post-dose 1   129     46.9         [39.7 ; 55.4]     133      50.9        [44.9 ; 57.7]
   (IU/mL)                     Post-dose 2   129     92.8        [82.4 ; 104.5]     132      94.2       [83.2 ; 106.6]
   Varicella                   Post-dose 1   138     25.0         [22.5 ; 27.7]     136      23.6        [20.9 ; 26.7]
   (gpELISA units/mL)          Post-dose 2   138     358.1      [300.1 ; 427.4]     134      261.8     [216.7 ; 316.4]


 Table 9: Antibody Titres (GMT) to Measles, Mumps, Rubella and Varicella 4 Weeks after the First Dose and
                       6 Weeks after the Second Dose of ProQuad® - Full Analysis Set
                                                          Group 1                                Group 2
                                                   INTRAMUSCULAR                           SUBCUTANEOUS
                                              N     GMT           [95% CI]          N     GMT            [95% CI]
  Measles                   Post-dose 1      200    4109.6    [3726.7 ; 4531.8]    203    3515.6     [3074.8 ; 4019.6]
  (mIU/mL)                  Post-dose 2      200    4106.7    [3694.4 ; 4565.2]    198    3800.2     [3390.4 ; 4259.5]
  Mumps                     Post-dose 1      200     131.5     [113.9 ; 151.8]     203    104.9        [89.1 ; 123.6]
  (ELISA Ab units/mL)       Post-dose 2      200     166.0     [149.1 ; 184.9]     198    169.1       [150.9 ; 189.5]
  Rubella                   Post-dose 1      200     53.2        [46.4 ; 61.1]     203     55.3         [49.4 ; 61.8]
  (IU/mL)                   Post-dose 2      200     104.3      [94.1 ; 115.5]     198    101.3        [91.8 ; 111.7]
  Varicella                 Post-dose 1      200     24.7        [22.5 ; 27.1]     203     24.6         [22.2 ; 27.3]
  (gpELISA units/mL)        Post-dose 2      200     336.7     [291.6 ; 388.9]     198    293.7       [252.1 ; 342.1]

              o   Rates of subjects with varicella antibody titre >=1.25 gpELISA units/mL after the first
                  and second doses of ProQuad®
 Following both the first and second doses of ProQuad®, the rates of subjects with varicella antibody titre
 >=1.25 gpELISA units/mL were similar in both groups (see Table 10).
 Table 10: Rates of Subjects with Varicella antibody titre >=1.25 gpELISA units /mL 4 Weeks after the First
 Dose and 6 Weeks after the Second Dose of ProQuad® ─ Per Protocol Sets Post-dose 1 and Post-dose 2 for
                                                  Varicella
    Varicella antibody titre        Group 1 - INTRAMUSCULAR                        Group 2 - SUBCUTANEOUS
    >=1.25 gpELISA units /mL       N    n subjects (%)  [95% CI]              N       n subjects (%)  [95% CI]
            Post-dose 1           138       138 (100)  [97.4; 100]           136         135 (99.3)  [96.0; 100]
            Post-dose 2           138       138 (100)  [97.4; 100]           134         133 (99.3)  [95.9; 100]



F05-MMRV-304                           CSR_Synopsis_v1final_19FEB2009                                         Page 8/13
                                             CONFIDENTIAL
Sanofi Pasteur MSD                                                                              ProQuad®


 Name of Sponsor/Company                         Individual Study Table                (For National
 Sanofi Pasteur MSD S.N.C.                       referring to part of the dossier      Authority use only)
 Name of Finished Products:                      Volume
 ProQuad®
 Name of Active Ingredients:                     Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 SAFETY RESULTS
 Table 11 summarises reported adverse events by group in the Safety Set Post-dose 1.
            o After the first dose of ProQuad®
  From Day 0 to Day 28 after the first dose, 17.8% of subjects in the IM group reported at least one
  injection-site adverse reaction, compared to 28.6% in the SC group. The imbalance in favour of the
  IM route was mainly related to two of the three injection-site adverse reactions solicited between
  Day 0 and Day 4, namely erythema (5.0% vs. 14.3%, IM vs. SC group, respectively) and swelling
  (1.0% vs. 3.9%, IM vs. SC group, respectively). A reverse trend was observed for pain (10.9% vs. 5.9%,
  IM vs. SC group, respectively) (see Table 11). None of the injection-site adverse reactions were of
  severe intensity.
  Regarding body temperature, 15.6% in the IM group and 18.1% in the SC group reported temperature
  >=39.4°C (rectal equivalent) (see Table 12). 50.5% in the IM group and 71.4% in the SC group
  reported temperature >=38°C between 5 and 12 days after vaccination.
  The percentage of subjects reporting systemic adverse events, including vaccine-related adverse events,
  were similar in both groups. Excluding the adverse event pyrexia, the only vaccine-related systemic
  adverse event of severe intensity reported after the first dose was 'parotid gland enlargement', reported
  by one subject of the IM Group (see mumps/mumps-like illness in Table 11), approximately 13 days
  post-vaccination. All other vaccine-related systemic adverse events were of mild or moderate intensity.
  A total of 20 subjects reported rashes of interest (measles/measles-like, or rubella/rubella-like or
  varicella/varicella-like rashes) with similar percentages in both groups.
  Two subjects in each group reported non vaccine-related serious adverse events (for details see the
  footnote of Table 11). Following the first dose of ProQuad®, no vaccine-related serious adverse event
  was reported; specifically no vaccine-related anaphylactic event or vaccine-related febrile seizure was
  reported.

  In conclusion, the safety profile after the first injection of ProQuad® was similar in both groups,
  although the number of subjects reporting injection-site adverse reactions was lower in the IM group.




F05-MMRV-304                       CSR_Synopsis_v1final_19FEB2009                               Page 9/13
                                         CONFIDENTIAL
Sanofi Pasteur MSD                                                                                                         ProQuad®


 Name of Sponsor/Company                                       Individual Study Table                          (For National
 Sanofi Pasteur MSD S.N.C.                                     referring to part of the dossier                Authority use only)
 Name of Finished Products:                                    Volume
 ProQuad®
 Name of Active Ingredients:                                   Page
 Measles, mumps, rubella and varicella
 vaccine (live)
                                   Table 11: Summary of Safety ─ Safety Set Post-dose 1
                                                                                                      Group 1             Group 2
                                                                                                      INTRA-            SUBCUTA-
                                                                                                   MUSCULAR               NEOUS
                                                                                                       N=202               N=203
                                                                                                   n (1)    (%)         n (1)   (%)
  Injection-site adverse reaction or systemic adverse event from Day 0 to Day 28                   163     80.7         175    86.2
      Injection-site adverse reaction or vaccine-related systemic adverse event from               105     52.0         114    56.2
      Day 0 to Day 28
  Injection-site adverse reaction from Day 0 to Day 28                                               36        17.8       58       28.6
      Solicited injection-site adverse reaction from Day 0 to Day 4                                  31        15.3       44       21.7
            Injection-site erythema                                                                  10         5.0       29       14.3
            Injection-site swelling                                                                   2         1.0        8        3.9
            Injection-site pain                                                                      22        10.9       12        5.9
      Unsolicited injection-site adverse reaction from Day 0 to Day 28                                6         3.0       18        8.9
            Unsolicited injection-site erythema                                                       4         2.0       13        6.4
      Injection-site rash of interest from Day 0 to Day 28                                            0          0       2 (2)      1.0
  Systemic adverse event from Day 0 to Day 28                                                       158        78.2      167       82.3
      Pyrexia from Day 0 to Day 28                                                                  115        56.9      125       61.6
      Other systemic adverse event from Day 0 to Day 28                                             122        60.4      121       59.6
            Other vaccine-related systemic adverse event                                             18         8.9       17        8.4
      Non-injection-site rash of interest from Day 0 to Day 28                                        9         4.5       11        5.4
            Measles/ measles-like rash                                                                1         0.5        4        2.0
            Rubella/ rubella-like rash                                                                6         3.0        6        3.0
            Varicella/ varicella-like rash                                                            2         1.0        1        0.5
            Zoster/ zoster-like rash                                                                  0          0         0         0
      Mumps/mumps-like illness                                                                        1         0.5        0         0
  Serious adverse event from Day 0 to Visit 2                                                       2 (3)        1       2 (4)       1
      Vaccine-related serious adverse event from Day 0 to Visit 2                                     0          0         0         0
  (1) Number of subjects reporting the event at least once
  (2) One rubella-like rash and one varicella-like rash
  (3) Viral gastroenteritis starting 27 days after first dose (subject 31002) and viral tonsillitis starting 30 days after first dose
       (subject 47017)
  (4) Gastroenteritis starting 5 days after first dose (subject 35005) and febrile convulsion starting 31 days after first dose, with
       fever at 40°C due to tonsillitis and conjunctivitis (subject 48062)
                Percentages were calculated based on the number of vaccinated subjects with follow-up data Post-dose 1.




F05-MMRV-304                                 CSR_Synopsis_v1final_19FEB2009                                               Page 10/13
                                                   CONFIDENTIAL
Sanofi Pasteur MSD                                                                                               ProQuad®


 Name of Sponsor/Company                                  Individual Study Table                      (For National
 Sanofi Pasteur MSD S.N.C.                                referring to part of the dossier            Authority use only)
 Name of Finished Products:                               Volume
 ProQuad®
 Name of Active Ingredients:                              Page
 Measles, mumps, rubella and varicella
 vaccine (live)
   Table 12: Maximal Daily Temperature (rectal equivalent) from Day 0 to Day 28 (Safety Set Post-Dose 1)
                                           Group 1 - INTRAMUSCULAR                 Group 2 - SUBCUTANEOUS
                                                       N = 202                                  N = 203
                                            n subjects             %                n subjects              %
           Temperature >=38.0°C                132                66.3                 142                 71.4
           Temperature >=39.4°C                 31                15.6                  36                 18.1
        Percentages were calculated based on the number of vaccinated subjects with safety follow-up data Post-dose 1.

 Table 13 summarises all reported adverse events by group in the Safety Set Post-dose 2.
             o After the second dose of ProQuad®
  From Day 0 to Day 28 after the second dose, 20.4% of subjects in the IM group reported at least one
  injection-site adverse reaction, compared to 29.5% in the SC group. Similar to what was observed after
  the first dose, the imbalance in favour of the IM route was mainly related to two of the three injection-
  site adverse reactions solicited from Day 0 and Day 4: erythema (15.4% vs. 27.0%, IM vs. SC group,
  respectively) and swelling (6.0% vs. 12.5%, IM vs. SC group, respectively), since an equal number of
  subjects reported pain (10.0% in both groups) (see Table 13). Only one subject reported an injection-
  site adverse reaction of severe intensity (pain, in the IM group).
  Regarding body temperature both groups reported similar rates of fever, as 14.3% and 15.9% of
  subjects in the IM and SC groups, respectively, reported temperature >=39.4°C (rectal equivalent) (see
  Table 14).
  In terms of systemic adverse events both groups were also similar. All vaccine-related systemic adverse
  events were of mild or moderate intensity.
  Twelve subjects reported rashes of interest (measles/measles-like, or rubella/rubella-like or
  varicella/varicella-like rashes) with similar percentages in both groups, except that no subject in the
  IM group reported varicella/varicella-like rashes compared to four subjects in the SC group.
  One subject in each group reported non vaccine-related serious adverse events (for details see the
  footnote of Table 13). Similar to what was observed after the first dose of ProQuad®, no vaccine-related
  serious adverse event was reported after the second dose ProQuad®; specifically neither anaphylactic
  event nor vaccine-related febrile seizure were reported in this study, however the clinical trial was
  admittedly not powered to evaluate such rare events.

  In conclusion, the safety profile after a second dose of ProQuad® was similar in both groups although
  the number of subjects reporting injection-site adverse reactions was lower in the IM group.
  Overall, the second dose of ProQuad® was generally better tolerated than the first dose, as numerically
  fewer subjects reported injection-site adverse reactions and vaccine-related systemic adverse events
  from Day 0 to Day 28: 34.8% (IM group) and 42.5% (SC group) after the second dose compared to
  52.0% (IM group) and 56.2% (SC group) after the first dose.




F05-MMRV-304                             CSR_Synopsis_v1final_19FEB2009                                          Page 11/13
                                               CONFIDENTIAL
Sanofi Pasteur MSD                                                                                                   ProQuad®


 Name of Sponsor/Company                                   Individual Study Table                      (For National
 Sanofi Pasteur MSD S.N.C.                                 referring to part of the dossier            Authority use only)
 Name of Finished Products:                                Volume
 ProQuad®
 Name of Active Ingredients:                               Page
 Measles, mumps, rubella and varicella
 vaccine (live)
                                Table 13: Summary of Safety ─ Safety Set Post-dose 2
                                                                                             Group 1            Group 2
                                                                                             INTRA-           SUBCUTA-
                                                                                           MUSCULAR             NEOUS
                                                                                              N=201              N=200
                                                                                           n (1)   (%)       n (1)    (%)
  Injection-site adverse reaction or systemic adverse event from Day 0 to Day 28            150   74.6       144     72.0
      Injection-site adverse reaction or vaccine-related systemic adverse event from        70    34.8        85     42.5
      Day 0 to Day 28
  Injection-site adverse reaction from Day 0 to Day 28                                         41    20.4       59        29.5
      Solicited injection-site adverse reaction from Day 0 to Day 4                            41    20.4      59         29.5
            Injection-site erythema                                                           31     15.4      54         27.0
            Injection-site swelling                                                           12      6.0      25         12.5
            Injection-site pain                                                               20     10.0      20         10.0
      Unsolicited injection-site adverse reaction from Day 0 to Day 28                          0      0        1          0.5
      Injection-site rash of interest from Day 0 to Day 28                                      0      0     1 (2)         0.5
  Systemic adverse event from Day 0 to Day 28                                                 136    67.7      122        61.0
      Pyrexia from Day 0 to Day 28                                                             89    44.3       82        41.0
      Other systemic adverse event from Day 0 to Day 28                                       114    56.7       98        49.0
            Other vaccine-related systemic adverse event                                      12      6.0      10          5.0
      Non-injection-site rash of interest from Day 0 to Day 28                                  4     2.0       8          4.0
            Measles/ measles-like rash                                                          0      0        2          1.0
            Rubella/ rubella-like rash                                                          4     2.0       2          1.0
            Varicella/ varicella-like rash                                                      0      0        4          2.0
            Zoster/ zoster-like rash                                                            0      0        0           0
      Mumps/mumps-like illness                                                                  1     0.5       0           0
  Serious adverse event from Visit 2 to Visit 3                                              1 (3)    0.5    1 (4)         0.5
      Vaccine-related serious adverse event from Day 0 to Visit 2                              0       0        0           0
  (1) Number of subjects reporting the event at least once
  (2) Measles-like rash
  (3) Gastroenteritis starting 25 days after second dose (subject 19001)
  (4) Digital distal amputation (traumatic) occurring 37 days after second dose (subject 48041)
       Percentages were calculated based on the number of vaccinated subjects with follow-up data Post-dose 2.


 Table 14: Maximal Daily Temperature (rectal equivalent) from Day 0 to Day 28 - Safety Set Post-Dose 2
                                            Group 1 - INTRAMUSCULAR                 Group 2 - SUBCUTANEOUS
                                                        N = 200                                N = 201
                                             n subjects          %                  n subjects          %
             Temperature ≥38.0°C                110             56.1                   108             55.4
             Temperature ≥39.4°C                 28             14.3                    31             15.9
         Percentages were calculated based on the number of vaccinated subjects with safety follow-up data Post-dose 2.



F05-MMRV-304                              CSR_Synopsis_v1final_19FEB2009                                          Page 12/13
                                                CONFIDENTIAL
Sanofi Pasteur MSD                                                                           ProQuad®


 Name of Sponsor/Company                        Individual Study Table              (For National
 Sanofi Pasteur MSD S.N.C.                      referring to part of the dossier    Authority use only)
 Name of Finished Products:                     Volume
 ProQuad®
 Name of Active Ingredients:                    Page
 Measles, mumps, rubella and varicella
 vaccine (live)
 CONCLUSION
  Two doses of ProQuad® administered by the IM route of administration were as immunogenic as two
  doses administered by the SC route in terms of antibody response rates and antibody titres to measles,
  mumps, rubella and varicella. In addition, two doses of ProQuad® were more immunogenic than a
  single dose in terms of seroconversion rates and GMTs.
  ProQuad® demonstrated an acceptable safety profile when given by either route of administration, IM
  or SC. The safety profile was comparable for both groups, although fewer subjects experienced
  injection-site adverse reactions in the IM group after each dose. The second dose of ProQuad® was
  generally better tolerated than the first dose in both groups.


 Date of the report: 19 February 2009




F05-MMRV-304                      CSR_Synopsis_v1final_19FEB2009                            Page 13/13
                                        CONFIDENTIAL

				
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