Vaccines and Related Biological Products Advisory Committee

 

Meeting Date:  September 22, 2004

 

 

 

 

 

 

 

 

 

 

FDA Clinical Briefing Document for

 

 

Aventis Pasteur Inc.

MenactraTM: Tetravalent Meningococcal Conjugate Vaccine

 

 

 

 

 

 

 

 

 

Lucia H. Lee, M.D.

CBER/FDA

 


 

1.0     

Table of Contents

                                                                                                                                                Page

 

1.0    General Information  ………..……………………………………………………………...          3

         PRODUCT NAME

         PRODUCT COMPOSITION

            PROPOSED INDICATION

         PROPOSED AGE GROUP

         DOSING REGIMEN AND ROUTE OF ADMINISTRATION

2.0    Introduction and Background  …………….…………………………………………..…            4

2.1       EPIDEMIOLOGY OF MENIGOCOCCAL INFECTIONS IN ADOLESCENTS AND ADULTS         4

2.2       IMMUNE CORRELATE: SERUM BACTERICIDAL ANTIBODY                                                               4

         2.3       EGULATORY BACKGROUND                                                                                                                       4               

3.0    Clinical Overview  …………………………………………………………………………..         5

4.0    Efficacy Data (Immunogenicity)  …………………………………………………………..          11

4.1     MTA-02: Safety, Immunogenicity in Adolescents 11-18 years old  …………………….    12

4.2       MTA-09: Safety, Immunogenicity in Adults 18-55 years old  ………………………..            14

5.0     Safety Data  ………………………………………………………………………………….   17

5.1    MTA-04: Expanded Safety Study in Adolescents 11-18 years old  ……………………    19

5.2      MTA-02: Safety, Immunogenicity in Adolescents 11-18 years old  ……………………… 22

5.3      MTA-09: Safety, Immunogenicity in Adults 18-55 years old  …………………………    23

5.4    MTA-14: Lot consistency in Adults 18-55 years old  ………………………………….   27  

5.5    Serious Adverse Events and safety assessment 6 months post-vaccination  ……………   29

6.0    Concurrent Immunization  ………………………………………………………………….   29 

6.1    MTA-11: Concomitant Administration with TyphimViâ Vaccine in Adults  …………      29  

6.2    MTA-12: Concomitant Administration with Td vaccine in Adolescents  ……………..     38              

7.0     Lot Consistency ……………………………………………………………………………..  46

          7.1      MTA-14: Lot consistency in Adults 18-55 years old  …………………………………    46

 

REFERENCES ………………………………………………………………………………………  48

 


 

1.0            General Information

 

Product name

Generic name:                              Meningococcal (Groups A,C,Y,W135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine 

                                            

Proposed trade name:                  Menactra

 

 

Product composition:                   Each 0.5ml dose contains

·         4ug of polysaccharide (PS) for serogroup A

·         4ug of polysaccharide (PS) for serogroup C

·         4ug of polysaccharide (PS) for serogroup Y

·         4ug of polysaccharide (PS) for serogroup W135

·         48ug diphtheria toxoid protein total (Each PS is conjugated to diphtheria toxoid)

·         0.6 mg sodium phosphate

·         4.4mg sodium chloride

 

                                                The vaccine contains neither an adjuvant nor preservative.

 

Sponsor:                                        Aventis Pasteur Inc.

 

 

 

Proposed indication:                     Active immunization of adolescents and adults for prevention of invasive disease caused by Neisseria meningitidis serogroups A, C, Y and W135               

 

Proposed age group:                    11-55 years old                                                                                        

 

Dosing regimen and                    

Route of administration:               Single dose, intramuscularly


 

2.0  Introduction and Background

 

2.1          Epidemiology of meningococcal infections in adolescents and adults

Meningitis and meningococcemia are common manifestations of invasive disease due to Neisseria meningitidis (N. meningitidis).  Other clinical presentations of meningococcal disease include pneumonia and occult bacteremia.  During 1991-1998, increased numbers of meningococcal cases were reported in the United States among persons aged 18-23 years old (1.4/106 population), compared with the general population (1.1/ 106 population).1  The highest rate of meningococcal disease continues to occur in children younger than one year of age.  Approximately 50% of meningococcal disease in this age group is due to serogroup B.1

The epidemiology of meningococcal disease in the United States has changed in the last 15 years. 

The proportion of meningococcal disease due to serogroup Y increased from 2%, during 1989-1991, to 30% during 1992-1996.2  There have also been increased reports of localized serogroup C outbreaks.  Eight outbreaks occurred during a two-year timeframe [1991-1993], compared with 13 outbreaks in the previous decade [1980-1990].3  Cases of serogroup W135 meningococcal disease were also reported in association with an outbreak among travelers returning from the Hajj, in 2000-2001.4  The mortality rate due to meningococcal disease overall is 7 to 19%, and for meningococcemia, 18-53%.  The case-fatality rate due to serogroup W135, C and Y, during 1992-1996 was 21%, 14%, and 9%, respectively.2  Despite susceptibility of N. meningitidis to many antibiotics, approximately 10-20% of individuals with meningococcal disease experience permanent sequelae (e.g. limb loss, neurosensory hearing loss, cognitive deficits, seizure disorder).5-7 

 

2.2                        Immune Correlate: Serum Bactericidal Antibody

The presence of bactericidal antibody has been shown to correlate with both natural and vaccine-induced protection against meningococcal disease.  The basis for accepting serum bactericidal antibody as an immunologic correlate originated from studies conducted in the 1960’s. 8,9  Military recruits with naturally acquired bactericidal antibody were shown to be protected from meningococcal group C disease.  The presence of bactericidal antibody was determined using a serum bactericidal assay (SBA) with a human complement (HC) source.  A positive result, which indicated the presence of complement mediated anti-meningococcal group C antibody killing, was qualitatively measured at an estimated dilution of 1: 4. 

In vitro measurement of bactericidal antibody was indicative of functional activity in vivo, and serum bactericidal antibody was hence considered to be a reliable predictor of vaccine effectiveness for serogroups A, C, Y and W135.  

 

2.3          Regulatory background

 

2.3.1            Use of Immunologic Correlates for Licensure of Meningococcal Vaccines

Demonstration of efficacy, inferred from immunogenicity data, was an approach used as a basis for U.S. licensure of a meningococcal quadrivalent polysaccharide (PS) vaccine, Menomuneâ.  The primary measure of immune response was the proportion of participants who achieved a four-fold or greater increase in serum bactericidal antibody to each serogroup.  Use of immunologic correlates, as a basis of vaccine effectiveness, was discussed at a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting on September 15, 1999,10 as an approach to support approval of new meningococcal conjugate vaccines.  The outcomes of the VRBPAC meeting which pertain to the proposed age group in this biologics license application, are as follows: 

Ø          Use of an immunologic correlate to determine effectiveness of new meningococcal conjugate vaccines is acceptable

Ø          In individuals for which the current meningococcal PS vaccine is licensed, serum bactericidal antibody can be used as a predictor of vaccine efficacy

 

2.3.2            Basis for Licensure

Proposed licensure of Menactra is based on the following aspects

·             Demonstration of efficacy (immunogenicity) compared to Menomuneâ

·             Demonstration of safety compared to Menomuneâ

·             Demonstration of lot consistency

 

3.0         Clinical Studies- Overview

The license application included safety and immunogenicity data from six clinical studies and one supplemental study.  Safety data from two additional supporting studies was also included.

 

Study

Description

Study

Subjects: Menactra: Menomuneâ (Ma:Me)

Protocol:

 

Population

Planned

Enrolled

 

 

 

N

Ma:Me

N

Ma:Me

Pivotal Studies

 

 

 

 

 

 

MTA-02

Safety +

11-18 yrs

812

406: 406

881

440: 441

USA

Immunogenicity

 

 

 

 

 

MTA-04

Safety

11-18 yrs

3178

2222: 956

3242

2270: 972

USA

 

 

 

 

 

 

MTA-09

Safety +

18-55 yrs

2455

1333: 1122

2554

1384: 1170

USA

Immunogenicity

 

 

 

 

 

MTA-14

 

18-55 yrs

2039

1599+

2040

1582+

USA

Lot consistency

26-55 yrs

 

440

 

458

 

 

 

 

 

 

 

MTA-11

Concomitant Vaccination:

18-55 yrs

890

Gr A: 445

945

Gr A: 469

USA

Typhim Vi eval.

 

 

Gr B: 445

 

Gr B: 476

MTA-12

Concomitant Vaccination:

11-17 yrs

1024

Gr A: 512

1081

Gr A: 509

USA

Td eval.

 

 

Gr A: 512

 

Gr B: 512

Supplemental Studies- adults

 

 

 

 

 

603-01

Dose escalation,

18-55 yrs

 

30*:0

 

30*:0

USA

Safety + Immuno

 

 

 

 

 

 

 

 

 

 

 

 

Total 11-55y:

 

Planned:

 N= 10, 428

Enrolled:

N= 10, 713

 

 

 

 

Menactra: 7504

 

Menactra: 7672

 

 

 

 

Menomune: 2924

 

Menomune: 3041

 

+MTA-14: Menactra [n= 533 planned per lot]; [n= 527 enrolled for lots 1&3 (each), n= 528 enrolled for lot 2]

*603-01: 30 adult participants received a 4ug dose, the dose selected for the final formulation.  Sixty additional adults were enrolled and received a 1 or 10ug Menactra dose (n= 30 subjects/ dose).

 

    Other supporting studies: 

·         Study 603-02, a safety and immunogenicity study in healthy U.S. children 2-10 years old

·         Study MTA-08, an expanded safety study in healthy U.S. and Chilean children 2-10 years old

 

3.1       Control vaccine: Menomuneâ A/C/Y/W135

The active control vaccine implemented in the comparative immunogenicity and safety studies was Menomuneâ A/C/Y/W135.  Each 0.5 ml dose contains 50ug of “isolated product” from each serogroup, and is formulated as lyophilized powder in a single-dose vial.  Lactose is added as a stabilizer (2.5-5 mg).  Following reconstituted with sterile water, the vaccine appears as a clear, colorless, liquid.  A single dose was administered subcutaneously. 

3.2       Menactra bactericidal antibody results, using baby rabbit and human complement, compared to Menomuneâ:

Human sera that lack anti-meningococcal antibodies are a difficult source of exogenous complement to locate.  In contrast, baby rabbit sera are widely available, and assay results using this complement source are highly reproducible.  Serogroup C meningococcal antibody titers, generated from an assay with a rabbit complement source, have been shown to be elevated relative to results using human complement.  Consequently, SBA-BR results might overestimate efficacy against group C meningococcus.   Less bactericidal antibody data, generated from assays with the two complement sources, are available for serogroups A, Y and W135.

The sponsor was asked to test sera from Menactra and Menomuneâ participants vaccinated in the same clinical studies, with both a bactericidal assay using baby rabbit complement and an assay using exogeneous human complement.  Analyses were based on the participants for whom sufficient sera were available.  Pre- and post-vaccination sera were collected from 165 (Menactra n= 84, Menomune®, n=81) non-randomized participants enrolled in study MTA-02 (11-18 years old), and 100 (n= 50 per group) participants in study MTA-09 (18-55 years old).  Antibody results for serogroups C, Y and W135 were generated from sera obtained from study MTA-02, and data for serogroups Y and W135, from study MTA-09.  Sera from separate subset of 102 MTA-02 participants were used for serogroup A antibody results. 

Immune responses were assessed by reverse cumulative distribution curves, seroresponse and seroconversion rates.  The seroresponse rate was defined as the proportion of participants with > four-fold increase in SBA-BR titer post-vaccination, compared to baseline.  Seroconversion rate was defined as the proportion of participants with SBA-BR antibody titer less than 1:8 pre-vaccination, who subsequently achieved a four-fold or greater increase in SBA-BR antibody titer 28 days following vaccination.  For SBA-H results, seroresponse rate was defined as the proportion of participants with SBA-H titer > 4 post-vaccination.  Seroconversion rate was also defined as the proportion of participants with SBA-H antibody titer less than 1:4 pre-vaccination, who subsequently achieved a titer of >1: 4, twenty-eight days following vaccination. 

Menactra SBA antibody responses, compared to Menomune, showed general agreement by comparison of reverse cumulative distributions curves, seroresponse and seroconversion rates.  The sample size, however, was not large enough to make definite conclusions.  Assay sensitivity and specificity were not noticeably different among two populations (adolescents, adults), serogroup (A, C, Y, W135), or vaccine (polysaccharide, conjugate).  Misclassification of seroresponders that might occur when SBA results are generated with a rabbit complement source were similarly represented in the two vaccine groups and results were without bias towards Menomune® or Menactra.  True susceptible individuals, predicted by a SBA-H titer < 4, however, were not the same susceptible individuals identified by the SBA-BR assay.   Thus, the SBA-BR assay has utility as an indicator of vaccine –induced antibody response on a population basis, and is less predictive of individual susceptibility to meningococcal disease. 

 


SBA-BR Reverse cumulative distributions curves (11-18 years old)

          Serogroup A                                                                                                 Serogroup C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 
 
 
 
 
 
 
 
 
 

          Serogroup Y                                                                                                 Serogroup W135

 


 

SBA-H Reverse cumulative distributions curves (11-18 years old):

          Serogroup A                                                                                                   Serogroup C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


          Serogroup Y                                                                                                   Serogroup W135

 


11-18 years old:

Seroresponse Rate:

SBA-BR

Serogroup

Menomune (Me)

Menactra (Ma)

Diff

95% CI for the Difference

(Me-Ma)

 

N

Proportion

N

Proportion

 

 

A

52

0.98

50

0.88

0.1

-0.00, 0.22

C

81

0.9

84

0.89

0.01

-0.09, 0.11

Y

62

0.81

65

0.94

-0.13

-0.26, -0.02

W

58

0.97

61

0.97

0

-0.09, 0.08

 

SBA-H

Serogroup

Menomune (Me)

Menactra (Ma)

Diff

95% CI for the Difference

(Me-Ma)

 

N

Proportion

N

Proportion

 

 

A

52

0.96

50

0.94

0.02

-0.08, 0.13

C

81

0.86

84

0.94

-0.08

-0.18, 0.02

Y

62

0.95

65

0.94

0.01

-0.08, 0.11

W

58

0.93

61

0.98

-0.05

-0.15, 0.03

 

 

 

 

Seroconversion Rate:

SBA-BR

Serogroup

(11-18 yrs old)

Menomune (Me)

Menactra (Ma)

Diff

95% CI for the Difference

(Me-Ma)

 

N

Proportion

N

Proportion

 

 

A

11

1

12

1

0

-0.29, 0.27

C

62

0.9

57

0.95

-0.04

-0.15, 0.06

Y

39

0.9

41

0.93

-0.03

-0.18, 0.11

W

23

1

22

0.95

-0.05

-0.11, 0.23

 

SBA-H

Serogroup

(11-18 yrs old)

Menomune (Me)

Menactra (Ma)

Diff

95% CI for the Difference

(Me-Ma)

 

N

Proportion

N

Proportion

 

 

A

11

0.91

12

0.92

-0.01

-0.34, 0.31

C

62

0.82

57

0.91

-0.09

-0.22, 0.04

Y

39

0.92

41

0.93

-0.004

-0.15, 0.13

W

23

0.83

22

0.95

-0.13

-0.35, 0.08

 


18-55 year old:

 

SBA-BR

Serogroup

Menomune (Me)

Menactra (Ma)

Diff

95% CI

(Me-Ma)

 

N

Proportion

N

Proportion

 

 

Seroresponse Rate

 

 

 

 

 

 

50

0.72

50

0.80

-0.08

-0.25, 0.09

 

50

0.94

50

0.96

-0.02

-0.13, 0.08

Seroconversion Rate

 

 

 

 

 

Y

17

0.88

18

1

-0.12

-0.37, 0.08

W

9

1

8

0.89

0.11

-0.26, 0.48

 

SBA-H:

Serogroup

Menomune (Me)

Menactra (Ma)

Diff

95% CI

(Me-Ma)

 

N

Proportion

N

Proportion

 

 

Seroresponse Rate

 

 

 

 

 

Y

50

1

50

0.96

0.04

-0.03, 0.14

W

50

1

50

1

0

-0.07, 0.07

Seroconversion Rate

 

 

 

 

 

Y

17

1

18

0.89

0.11

-0.10, 0.35

W

9

1

8

1

0

-0.35, 0.37

 


 

4.0        Efficacy Data (Immunogenicity)

 

Immunogenicity data from the following clinical trials were the basis of inferring the efficacy of Menactra:

·          Study MTA-02: A Comparative Trial of the Safety and Immunogenicity of Menactra versus Menomune® A/C/Y/W-135 in Adolescents 11-18 years old 

·          Study MTA-09: A Comparative Trial of the Safety and Immunogenicity of Menactra versus Menomune® A/C/Y/W-135 in Adults 18-55 years old

The primary endpoint, vaccine administration, surveillance, laboratory methods, and population for analysis were the same in both trials, as are described below:

 

Assessment of Immunogenicity:

The primary endpoint was the proportion of participants achieving a four-fold or greater increase in serum bactericidal antibody, to serogroups A, C, Y, and W135.   Other parameters of immune response were also provided (seroconversion, GMT, geometric mean fold rise, reverse cumulative distribution curve, group-specific anti-meningococcal PS antibody measured by ELISA).

 

Vaccine Administration

Menactra was administered as a single dose intramuscularly.  

 

Control vaccine

The active control vaccine implemented in both studies was Menomuneâ A/C/Y/W135.  Each 0.5 ml dose contains 50ug of “isolated product” from each serogroup, and is formulated as lyophilized powder in a single-dose vial.  Lactose is added as a stabilizer (2.5-5 mg).  Following reconstituted with sterile water, the vaccine appears as a clear, colorless, liquid.  A single dose was administered subcutaneously. 

 

Surveillance (Immunogenicity):

Serum samples were obtained pre- and 28 days post-vaccination.  For all study participants, functional antibody activity to each serogroup, was determined using a serum bactericidal assay.  In a subset of 160 MTA-02 participants, group-specific IgG and IgM antibody were measured by ELISA. 

 

Laboratory Methods

All assays were performed at Aventis Pasteur, Inc. 

Anti-Meningococcal Antibody Determination by Serum Bactericidal Assay

Functional antibody activity to each serogroup was determined using a serum bactericidal assay, which is an adaptation of the CDC method recommended by the WHO Expert Committee of the Department of Vaccines and Biologicals.11,12 The lower limit of detection for this assay, using baby rabbit complement, is a titer of 1: 8.

IgG and IgM Anti-Meningococcal Antibody Determination

IgG and IgG antibody activity for anti-meningococcal antibody to serogroups A, C, Y, and W-135 was measured using an indirect ELISA.

 

Populations for Analysis

Per-protocol population for immunogenicity:

The per-protocol population included all eligible participants who received one dose of vaccine according to the treatment assignment, who complied with scheduled visits for blood specimens, and for whom a sufficient quantity of paired sera was available for analysis.  The primary analysis was based on the per-protocol population.

 

Intent-to-treat population for immunogenicity:

The intent-to-treat population consisted of all enrolled participants who received one dose of vaccine and underwent the first blood draw.  Analyses were performed according to the vaccine received. 

For analysis purposes, if the SBA-BR antibody titer to any serogroup was reported below the limit of detection, the antibody titer assigned was a value equal to the limit of detection. 

 

4.1                        Study MTA-02

 

Title:   A Comparative Trial of the Safety and Immunogenicity of One Dose of an Experimental Tetravalent (A, C, Y, and W-135) Meningococcal Diphtheria Conjugate Vaccine versus Menomune® A/C/Y/W-135 in Healthy Adolescents in the U.S.

 

Immunogenicity Objectives

·         Primary objective: To describe and compare the antibody response to serogroups A, C, Y, W135, using baby rabbit complement (SBA-BR), among healthy adolescents immunized with Menactra with the SBA-BR responses following vaccination with a licensed meningococcal polysaccharide vaccine.

·         Other objectives:

ü      To describe and compare the SBA-BR response to each serogroup pre- and 28 days post-vaccination for Menactra and Menomune® recipients.

ü      To compare serogroup-specific IgG and IgM antibody levels pre- and 28 days post-vaccination in a subset of Menactra and Menomune® recipients.

ü      To describe and compare the proportion of participants who achieve seroconversion 28 days following a single dose of either Menactra or Menomune®.

 

Design: The study was a randomized, modified double blind, multi-center, active-controlled trial.  Participants were randomized in a 1: 1 (Menactra: Menomune®) ratio.  Participants were enrolled at eleven study centers in the United States. 

 

Primary Immunogenicity Endpoint

The proportion of participants with a >4-fold rise in SBA-BR titer for N. meningitidis serogroups A, C, Y and W-135 28 days post-vaccination, compared to baseline.

 

Statistical plan

Primary Hypothesis

To demonstrate that 28 days after vaccination, Menactra is non-inferior to Menomune® by proportion of participants with a >4-fold rise in SBA-BR titer for N. meningitidis serogroups A, C, Y and W-135. 

 

This hypothesis would be supported by the data if the upper limit of the one-sided 95% confidence interval (CI) of pMenomune® – pMenactra is less than 0.10, where p represents the proportion of participants with a >4-fold rise in SBA-BR titer as compared to baseline, for each serogroup, respectively.  The sample size provided 90% power, overall, to achieve the primary hypothesis for serogroups C, Y and W135.  All tests of the primary hypothesis were conducted at the 0.05 significance level.  The primary hypothesis was modified during the trial to include demonstration of equivalence for serogroup A.  Hence, the sample size and power calculations do not include hypothesis testing for this serogroup.  The primary analysis was based on data generated from the per-protocol population.

 

CBER recommendations for non-inferiority hypothesis testing have evolved since the conduct of this trial.  Comparisons are currently based on the upper limit of the two-sided 95% confidence interval for the difference in two proportions.

Results

A total of 881 (Menactra n=440, Menomune® n= 441) adolescents were enrolled, and 871 (Menactra n=436, Menomune® n= 435) individuals completed the study.  The per protocol population for immunogenicity included 425 Menactra and 423 Menomune® participants. 

Demographic characteristics:  The distribution of participants, based on age, gender, race and ethnicity, was similar among the two vaccine groups.  The study population enrolled was predominately Caucasian (95.2%), but also included African American (3.3%), Hispanic (0.3%), Asian populations (0.2%) and individuals with mixed racial background (0.9%).

 

MTA-02: Primary Hypothesis Testing

Number and Proportion of Participants 11-18 Years Old with a >Four-fold Increase in SBA-BR Titer

 

Menomune®

Menactra

 

Upper Limit of the

Upper Limit of the

Serogroup

N= 423

N= 423

Difference

1-sided 95% CI

2-sided 95% CI

 

n*

pMenomune®†

n*

PMenactra‡

(pMenomune® - pMenactra)

of the Difference§

of the Difference§

A

391

0.924

392

0.926

-0.002

0.027

0.033

C

375

0.886

388

0.917

-0.031

0.003

0.009

Y

339

0.801

346

0.818

-0.017

0.028

0.036

W-135

403

0.952

409

0.966

-0.014

0.008

0.013

*n: number of participants with 4-fold rise from baseline SBA-BR titer.  N: total number of participants with valid serology data.

† pMenomune®: proportion of Menomune® participants with a 4-fold rise in SBA-BR titer post-vaccination compared with baseline.

‡ pMenactra: proportion of Menactra participants with a 4-fold rise in SBA-BR titer post-vaccination compared with baseline.

§ CI: Confidence interval.

 

Serum bactericidal antibody:

 

MTA-02:  Number and Percentage of Participants 11-18 Years Old Achieving a > Four-fold Increase in SBA-BR Antibody Titer, with 95%CI

 

Menomune®

Menactra

Serogroup

N= 423

N= 423

 

n*

%†

95% CI

n*

%†

95% CI§

A

391

92.4%

89.5, 94.8

392

92.7%

89.8, 95.0

C

375

88.7%

85.2, 91.5

388

91.7%

88.7, 94.2

Y

339

80.1%

76.0, 83.8

346

81.8%

77.8, 85.4

W-135

403

95.3%

92.8, 97.1

409

96.7%

94.5, 98.2

*n: number of participants with 4-fold rise from baseline SBA-BR titer.  N: total number of participants with valid serology data.

† %: percentage of participants with a 4-fold rise in SBA-BR titer post-vaccination compared with baseline.

§ CI: Confidence interval.

Seroconversion rate was defined as the proportion of participants with SBA-BR antibody titer less than 1:8 pre-vaccination, who subsequently achieved a four-fold or greater increase in SBA-BR antibody titer 28 days following vaccination.  In both groups, all participants with serogroup A SBA-BR antibody less than 1:8 pre-vaccination, achieved seroconversion.  For serogroup C, seroconversion was observed in 98.7% [153/155] of Menactra recipients and 99.3% [151/152] of Menomune® recipients.  For the remaining serogroups, of those participants who received Menactra, 98.4% [60/61] and 98.2% [161/164] responded with a >4-fold antibody rise to serogroups Y and W135, respectively, compared with 100% [47/47] and 83% [138/139] of individuals who received Menomune®.


Serogroup-specific IgG and IgM antibody:

Serogroup-specific IgG and IgM antibody levels, measured by ELISA, were assessed in a subset of 161 participants [Menactra n=82, Menomune® n=79].

 

MTA-02: Comparison of Serogroup-specific IgG and SBA-BR GMT Post-vaccination

Serogroup

Vaccine

Post-vaccination results

 

Group

IgG (µg/mL)

95% CI

SBA-BR GMT

95% CI

A

Menomune®

11.6

 8.8, 15.3

3245.7

2910.0, 3620.1

 

Menactra

18.1

13.6, 24.1

5483.2

 4920.1, 6110.7

C

Menomune®

 8.1

 5.4, 12.2

1638.9

1405.6, 1910.9

 

Menactra

 5.5

3.9, 8.0

1924.4

1662.1, 2228.0

Y

Menomune®

9.2

6.6, 12.8

1228.3

1088.2, 1386.4

 

Menactra

4.4

2.7, 7.1

1322.3

1161.9, 1504.8

W-135

Menomune®

 4.9

3.5, 7.0

1545.0

1383.6, 1725.2

 

Menactra

3.0

2.0, 4.3

1407.2

1232.8, 1607.3

Note: The SBA-BR GMT analysis was based on 846 participants [Menactra n=423, Menomune® n=423] with valid serology data.

 

MTA-02: Serogroup-specific IgM Geometric Mean Concentrations Post-vaccination, with 95% CI

Serogroup

Vaccine

 

 

 

Group

IgM (µg/mL)

95% CI

A

Menomune®

12.0

9.7, 14.9

 

Menactra

17.8

14.7, 21.6

C

Menomune®

1.7

1.4, 2.1

 

Menactra

1.6

1.2, 2.0

Y

Menomune®

3.5

2.9, 4.2

 

Menactra

3.5

2.8, 4.3

W-135

Menomune®

1.7

1.4, 2.0

 

Menactra

1.9

1.6, 2.3

 

4.2                        Study MTA-09:

 

Title:   A Comparative Trial of the Safety and Immunogenicity of One Dose of an Experimental Tetravalent (A, C, Y, and W-135) Meningococcal Diphtheria Conjugate Vaccine versus Menomune® A/C/Y/W-135 in Healthy Adolescents in the U.S.

 

Immunogenicity Objectives

·         Primary objective:

ü      To compare the bactericidal antibody response to serogroups A, C, Y, W135, using baby rabbit complement (SBA-BR), among healthy adults immunized with Menactra with the SBA-BR responses following vaccination with a licensed meningococcal polysaccharide vaccine.

 

·         Other objectives:

ü      To describe and compare the SBA-BR response to each serogroup pre- and 28 days post-vaccination for Menactra and Menomune® recipients.

ü      To describe and compare the proportion of participants who achieve seroconversion 28 days following a single dose of either Menactra or Menomune®.

 

 

Design

The study was a randomized, modified double blind, multi-center, active-controlled trial.  Enrollment was stratified by two age groups (18-25 years, 26-55 years) to ensure adequate representation of participants in each age group.  Participants were randomized in a 1: 1 (Menactra: Menomune®) ratio.  Participants were enrolled at thirty-three study centers in the United States.

 

Primary Immunogenicity Endpoint

The proportion of participants with a >4-fold rise in SBA-BR titer for N. meningitidis serogroups A, C, Y and W-135. 

 

Secondary Immunogenicity endpoint

SBA-BR GMT for serogroups A,C,Y,W135 in the Menactra group, compared to corresponding GMTs in the Menomune group. 

 

Statistical plan

Primary hypothesis:

To demonstrate that 28 days after vaccination, Menactra is non-inferior to Menomune® by proportion of participants with a >4-fold rise in SBA-BR titer for N. meningitidis serogroups A, C, Y and W-135. 

This hypothesis would be supported by the data if the upper bound of the two-sided 95% CI of pMenomune®– pMenactra is less than 0.10, where p represents the proportion of participants with a >4-fold rise in SBA-BR titer as compared to baseline, for each serogroup, respectively.  The sample size provided 99.9% power, overall, to achieve the primary hypothesis for serogroups A, C, Y and W135.  All tests of the primary hypothesis used a type I error of 0.025.  The primary analysis was based on data generated from the per-protocol population.

The confidence interval used for primary immunogenicity hypothesis testing was modified during the trial, from a two-sided 90% CI to a two-sided 95% CI, due to changed criteria preferred by CBER for one-sided equivalence trials.

 

Secondary Hypothesis: To demonstrate that 28 days after vaccination, the GMT for serogroups A,C,Y,W135 in the Menactra group is non-inferior to corresponding GMTs in the Menomune group.  This hypothesis would be supported by the data if the upper limit of the two-sided 95% CI of GMTMenactra/ GMTMenomune <log2 (2) for each serogroup.  GMTs are calculated as a log base 2 titer, and adjusted for baseline disparities in pre-existing antibody, using an analysis of covariance with baseline outcome as a covariate.  Analyses of the secondary point were performed on both per-protocol and intent-to-treat populations. 

 

Results

A total of 2554 (Menactra n=1384, Menomune® n= 1170) adults were enrolled, and 2400 (Menactra n=1301, Menomune® n= 1099) individuals completed the study.  The per protocol population for immunogenicity included 1280 Menactra and 1098 Menomune® participants. 

 

Immunogenicity population:

One hundred forty-six (Menactra n=84, Menomune® n=62) of 301participants with a protocol violation were considered evaluable for the per-protocol analysis, since the violation related to safety data collection, rather than sera collection or processing.  Forty-three participants, for whom Day 8 safety follow-up was either outside the window or not done, were considered evaluable for the per-protocol analysis; of these participants, 81% [35/43] were enrolled at a single study site.  Twelve Menactra participants and 9 Menomune participants, while not listed for protocol violations, were excluded from the per-protocol population.

Demographic characteristics:  The distribution of participants, based on age, gender, race and ethnicity, was similar among the two vaccine groups.  The study population enrolled was predominately Caucasian (85.0%), but also included African American (5.1%), Hispanic (5.8%), Asian populations (2.7%) and individuals with mixed racial background (1.4%).

 

MTA-09: Primary Hypothesis Testing

Number and Proportion of Participants 18-55 Years Old with a > Four-fold Increase in SBA-BR Titer

 

Menomune®

Menactra

 

Upper Limit of the

Serogroup

N= 1098

N= 1280

Difference

2-sided 95% CI

 

n*

pMenomune®†

n*

pMenactra‡

(pMenomune® - pMenactra)

of the Difference§

A

929

0.846

1030

0.805

0.041

0.072

C

985

0.897

1133

0.885

0.012

0.037

Y

872

0.794

941

0.735

0.059

0.093

W-135

1036

0.944

1144

0.894

0.050

0.072

 *n: number of participants with 4-fold rise in SBA-BR titer from baseline.  N: total number of participants with valid serology data.

† pMenomune®: proportion of Menomune® participants with a 4-fold rise in SBA-BR titer post-vaccination compared with baseline.

‡ pMenactra: proportion of Menactra participants with a 4-fold rise in SBA-BR titer post-vaccination compared with baseline.

§ CI: Confidence interval.

 

Serum bactericidal antibody:

 

MTA-09: Number and Percentage of Participants 18-55 Years Old Achieving a > Four-fold Increase in SBA-BR Antibody Titer, with 95%CI

 

Menomune®

Menactra

Serogroup

N= 1098

N= 1280

 

n*

%†

95% CI

n*

%†

95% CI§

A

929

84.6%

82.3, 86.7

1030

80.5%

78.2, 82.6

C

985

89.7%

87.8, 91.4

1133

88.5%

86.6, 90.2

Y

872

79.4%

76.9, 81.8

941

73.5%

71.0, 75.9

W-135

1036

94.4%

92.8, 95.6

1144

89.4%

87.6, 91.0

*n: number of participants with 4-fold rise in SBA-BR from baseline.  N: total number of participants with valid serology data.

† %: percentage of participants with a 4-fold rise in SBA-BR titer post-vaccination, compared with baseline.

§ CI: Confidence interval.

 

SBA-BR GMT:

 

MTA-09: SBA-BR Geometric Mean Antibody Titer Pre- and 28 days Post-vaccination

 

 

Menomune®

Menactra

 

 

N= 1098

N= 1280

 

 

SBA-BR

 

SBA-BR

 

Serogroup

Timepoint

 GMT

95% CI

 GMT

95% CI

A

Day 0

203.6

180.3, 229.9

223.8

200.1, 250.4

 

Day 28

4114.1

3832.2, 4416.8

3896.9

3647.0, 4164.0

C

Day 0

51.7

45.4, 56.0

56.8

50.2, 64.4

 

Day 28

3469.4

3148.4, 3823.1

3231.1

2954.9, 3533.2

Y

Day 0

127.2

111.8, 144.8

123.2

109.1, 139.0

 

Day 28

2448.6

2237.0, 2680.2

1750.4

1597.0, 1918.5

W-135

Day 0

30.9

27.8, 34.4

33.1

29.9, 36.7

 

Day 28

1871.2

1722.8, 2032.4

1271

1171.9, 1378.4

N: total number of participants with valid serology data. 

 

 

SBA-BR geometric mean titer, using the baseline titer as a covariate:

The upper limit of the two-sided 95% CI for the anti-log of the treatment effect for each serogroup was less than log2 (2), which indicated that the post-vaccination SBA-BR GMT, for each serogroup, did not differ between the two vaccine groups when adjusted for baseline disparities in pre-existing antibody. 

 

MTA-09: Treatment Effect on SBA-BR GMT, Adjusted by Baseline Covariate

 

 

Baseline

Estimate of

Difference of the

Anti-Log of

95% CI for Anti-Log

 

Vaccine

SBA-BR

Baseline

Treatment Effect

Treatment Effect*

of the Treatment Effect

Serogroup

Group

GMT

GMT Effect

(Menomune®- Menactra)

(Menomune®- Menactra)

(Menomune®- Menactra)

A

Menomune®

203.6

-0.849

0.099

1.071

0.975, 1.177

 

Menactra

223.8

 

 

 

 

C

Menomune®

51.7

-0.771

0.134

1.097

0.968, 1.244

 

Menactra

56.8

 

 

 

 

Y

Menomune®

127.2

-0.743

0.472

1.387

1.229, 1.567

 

Menactra

123.2

 

 

 

 

W-135

Menomune®

30.9

-0.764

0.581

1.496

1.339, 1.672

 

Menactra

33.1

 

 

 

 

* Anti-Log of the treatment effect is calculated as 2 to the treatment effect (Menomune-Menactra) power.

Seroconversion rate was defined as the proportion of participants with SBA-BR antibody titer less than 1:8 pre-vaccination, who subsequently achieved a four-fold or greater increase in SBA-BR antibody titer 28 days after vaccination.  All Menactra recipients with SBA-BR antibody titer less than 1:8 pre-vaccination, and 99.3% [143/144] of corresponding Menomune® recipients achieved this criterion for serogroup A.  For serogroup C, seroconversion was observed in 99.4% [343/345] of Menactra recipients and 97.7% [297/304] of Menomune® recipients.  For the remaining serogroups, 90.7% [253/279] and 96.5% [360/373] of Menactra participants responded with a >4-fold antibody rise to serogroups Y and W135, respectively, compared with 96.9% [221/228] and 99.1% [325/328] of individuals who received Menomune®.

 

5.0        Safety Data

The epidemiology of meningococcal disease in the United States and ACIP recommendations for the prevention of meningococcal disease among college freshmen projected frequent use of this vaccine in adolescents and young adults.  Hence, particular attention was given to characterizing the safety profile in the 15-25 year old age group.   The number of participants enrolled for all studies combined is summarized in the following table:

Overall Safety Database

 

 

# Participants enrolled

Age group

Menactra

Menomune®

 

n

n

11-14 years

1636

490

15-25 years

4078

1578

26-55 years

1957

973

Total for 11-55y*

7672

3041

Clinical studies MTA-04 and MTA-09 included non-inferiority comparisons of adverse events as a primary hypothesis, and studies MTA-02 and MTA-14 included safety comparisons as a secondary hypothesis.  Study design elements that pertain to the safety assessment, and were uniform across all studies, are the following:

Vaccine administration

Each group received a single dose of vaccine.  Menactra was administered intramuscularly, and the control vaccine, Menomune®, given subcutaneously.   Since the route of administration for the study vaccine differed from the control vaccine, study personnel who administered the vaccine differed from the personnel collecting the safety data. 

 

Monitored parameters:

·         Immediate reactions: 30 minutes post-vaccination

·         Local and systemic adverse events: reactogenicity was assessed during Days 0-7 (day of vaccination = Day 0).  The events were recorded on a diary card, and also collected by study personnel through telephone interview eight days after vaccination.  Pre-specified local reactions were erythema, swelling, induration, pain.   In studies MTA-04, MTA-09, MTA-14, information was obtained for fever measured by oral temperature, headache, fatigue, chills, arthralgia, anorexia, vomiting, diarrhea, seizures, malaise and rash.  If rash was reported, the investigator was prompted to record additional details on a separate case report form.  In study MTA-02, which was conducted early in clinical development, the same systemic reactions were collected except for arthalgia and chills.  The presence of rash was assessed qualitatively, but prompts for additional details were not included on the case report form. 

·         Unsolicited adverse events: Days 0-28.  Information about these events was obtained by telephone interview eight and twenty-eight days after vaccination.

·         Significant adverse events: Day 0- 6 months.  These events consisted of visits to an emergency room, or unexpected visits to an office physician were collected via scripted telephone interview.

·         Serious adverse events were reported and recorded during the 6-month study period following vaccination.  A serious adverse event was defined as any untoward medical occurrence resulting in death, life-threatening experience, inpatient hospitalization, prolonged existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect.  In addition to these events. 

 

Primary Endpoint

The proportion of participants with a least one solicited systemic reaction reported as severe during the 7-day period following vaccination.

 

Populations for analysis

Intent-to-treat population for safety:

The intent-to-treat population consisted of all participants who received one dose of vaccine and for whom safety information was available.  Analyses were performed according to the vaccine received. 

Per-protocol population for safety:

Eligible participants who received the vaccine according to the treatment assignment were included in the per-protocol population.  Although this population was defined, all analyses were performed on the intent-to-treat population.

 


 

5.1                        Study MTA-04

 

Title: A Comparative Trial of the Safety of One Dose of an Experimental Tetravalent (A, C, Y, and W135) Meningococcal Diphtheria Conjugate Vaccine Versus Menomune® A/C/Y/W-135 in Healthy Children in the U.S. Aged 11-18 Years

 

Objectives

·         Primary objective:

ü      To describe the safety profile after a single dose of Menactra

ü      To compare the relative frequency of a solicited systemic reaction reported as severe among Menactra and Menomune® recipients

 

Design

The study was a randomized, modified double blind, multi-center, active-controlled trial.  Participants were enrolled at thirty-two study centers in the United States.  Enrollment was stratified by two age groups (11-14 years, 15-18 years) to ensure adequate representation of participants in each age group.  Participants were randomized in a 2.5: 1 (Menactra: Menomune®) ratio.

 

Primary Endpoint:

The proportion of participants with a least one solicited systemic reaction reported as severe during the 7-day period following vaccination.

 

Statistical plan

Primary Hypothesis:

To demonstrate that Menactra is non-inferior to Menomune® in the proportion of participants with a least one solicited systemic reaction reported as severe during the 7 day period following vaccination.

This hypothesis would be supported by the data if the upper limit of the two sided 90% CI of pMenactra / pMenomune® is less than 3, where p represents the proportion of participants with at least one severe solicited systemic reaction in the Menactra and Menomune® groups, respectively.  The sample size provided 80% power to achieve the primary hypothesis, assuming that the expected proportion of subjects with at least one systemic reaction in the Menomune group is 1%.  Primary hypothesis testing was conducted at the 0.05 significance level.  CBER recommendations for non-inferiority hypothesis testing have evolved since the conduct of this trial.  Comparisons are currently based on the upper limit of the two-sided 95% confidence interval.  The sponsor also included primary safety analysis results according to current CBER recommendations.

Although enrollment was stratified by two age groups (11-14 years, 15-18 years) to ensure adequate representation of participants in each age group, the analyses were based upon the total study population, regardless of stratified age group.  In addition, all rashes occurring during the first 7 days after vaccination were designated, for the purpose of analysis, as a severe solicited systemic reaction. 

 

Results

A total of 3242 (Menactra n=2270, Menomune® n= 972) adolescents were enrolled, and 3211 (Menactra n= 2250, Menomune® n=961) individuals completed the study.   The intent-to-treat population for safety included 3242 participants (Menactra n=2270, Menomune® n= 972).   Participants completing the safety assessment 6 months after vaccination are summarized in section 6.5.

 


Local Reactions

 

MTA-04: Local adverse reactions (Days 0-7)

 

 

Menactra

Menomune®

 

 

N= 2264

N= 970

Reaction

Severity

n*

%†

95% CI

n*

%†

95% CI

Redness

 

 

 

 

 

 

 

 

Any

247

10.9

9.7, 12.3

55

5.7

4.3, 7.3

< 1 inch

Mild

197

8.7

7.6, 9.9

51

5.3

3.9, 6.7

1 – 2 inches

Moderate

37

1.6

1.2, 2.3

4

0.4

0.1, 1.1

> 2 inches

Severe

13

0.6

0.3, 1.0

0

0

0.0, 0.3

Swelling

 

 

 

 

 

 

 

 

Any

245

10.8

9.6, 12.2

35

3.6

2.5, 5.0

< 1 inch

Mild

191

8.4

7.3, 9.7

32

3.3

2.3, 4.6

1 – 2 inches

Moderate

43

1.9

1.4, 2.6

3

0.3

0.1, 0.9

> 2 inches

Severe

11

0.5

0.2, 0.9

0

0

0.0, 0.3

Induration

 

 

 

 

 

 

 

 

Any

355

15.7

14.2, 17.2

50

5.2

3.9, 6.7

< 1 inch

Mild

292

12.9

11.5, 14.4

45

4.6

3.4, 6.2

1 – 2 inches

Moderate

56

2.5

1.9, 3.2

5

0.5

0.2, 1.2

> 2 inches

Severe

7

0.3

0.1, 0.6

0

0

0.0, 0.3

Pain

 

 

 

 

 

 

 

 

Any

1340

59.2

57.1, 61.2

278

28.7

25.8, 31.6

 

Mild

1045

46.2

44.1, 48.2

253

26.1

23.3, 29.0

 

Moderate

289

12.8

11.4, 14.2

25

2.6

1.7, 3.8

 

Severe

6

0.3

0.1, 0.6

0

0

0.0, 0.3

*n: number of participants reporting at least one event in this category.  Six Menactra and 2 Menomune participants did not provide any data.  Percentages are based on the total number of participants who did submit safety information at each time point. 

†%: n/N expressed as a percentage.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2= (moderate) limits usual arm movement, 3= (severe) disabling

 

Systemic Reactions

 

MTA-04: Systemic adverse reactions (Days 0-7)

 

 

Menactra

Menomune®

 

 

N= 2265

N= 970

Reaction

Severity

n*

%†

95% CI

n*

%†

95% CI

Fever

 

 

 

 

 

 

 

 

Any

115

5.1

4.2, 6.1

29

3.0

2.0, 4.3

38.0ºC-38.9ºC

Mild

102

4.5

3.7, 5.4

25

2.6

1.7, 3.8

39.0ºC-39.9ºC

Moderate

13

0.6

0.3, 1.0

3

0.3

0.1, 0.9

> 40.0ºC

Severe

0

0.0

0.0, 0.1

1

0.1

0.0, 0.6

Headache

 

 

 

 

 

 

 

 

Any

807

35.6

33.7, 37.6

284

29.3

26.4, 32.3

 

Mild

566

25.0

23.2, 26.8

217

22.4

19.8, 25.1

 

Moderate

217

9.6

8.4, 10.9

63

6.5

5.0, 8.2

 

Severe

24

1.1

0.7, 1.6

4

0.4

0.1, 1.1

 

Cont. MTA-04: Systemic adverse reactions (Days 0-7)

 

 

Menactra

Menomune®

 

 

N= 2265

N= 970

Reaction

Severity

n*

%

95% CI

n*

%

95% CI

Fatigue

 

 

 

 

 

 

 

 

 

Any

679

30.0

28.1, 31.9

243

25.1

22.4, 27.9

 

 

Mild

484

21.4

19.7, 23.1

181

18.7

16.3, 21.3

 

 

Moderate

169

7.5

6.4, 8.6

60

6.2

4.8, 7.9

 

 

Severe

26

1.1

0.8, 1.7

2

0.2

0.0, 0.7

 

Malaise

 

 

 

 

 

 

 

 

 

Any

496

21.9

20.2, 23.7

163

16.8

14.5, 19.3

 

 

Mild

340

15.0

13.6, 16.6

126

13.0

10.9, 15.3

 

 

Moderate

131

5.8

4.9, 6.8

33

3.4

2.4, 4.7

 

 

Severe

25

1.1

0.7, 1.6

4

0.4

0.1, 1.1

 

Arthralgia

 

 

 

 

 

 

 

 

 

Any

394

17.4

15.9, 19.0

99

10.2

8.4, 12.3

 

 

Mild

304

13.4

12.0, 14.9

78

8.0

6.4, 9.9

 

 

Moderate

82

3.6

2.9, 4.5

20

2.1

1.3, 3.2

 

 

Severe

8

0.4

0.2, 0.7

1

0.1

0.0, 0.6

 

Chills

 

 

 

 

 

 

 

 

 

Any

158

7.0

6.0, 8.1

34

3.5

2.4, 4.9

 

 

Mild

115

5.1

4.2, 6.1

29

3.0

2.0, 4.3

 

 

Moderate

38

1.7

1.2, 2.3

4

0.4

0.1, 1.1

 

 

Severe

5

0.2

0.1, 0.5

1

0.1

0.0, 0.6

 

Anorexia

 

 

 

 

 

 

 

 

 

Any

243

10.7

9.5, 12.1

75

7.7

6.1, 9.6

 

Skips 1 meal

Mild

190

8.4

7.3, 9.6

62

6.4

4.9, 8.1

 

Skips 2 meals

Moderate

46

2.0

1.5, 2.7

11

1.1

0.6, 2.0

 

Skips > 3 meals

Severe

7

0.3

0.1, 0.6

2

0.2

0.0, 0.7

 

Vomiting

 

 

 

 

 

 

 

 

 

Any

44

1.9

1.4, 2.6

14

1.4

0.8, 2.4

 

1 episode

Mild

29

1.3

0.9, 1.8

6

0.6

0.2, 1.3

 

2 episodes

Moderate

9

0.4

0.2, 0.8

5

0.5

0.2, 1.2

 

>3 episodes

Severe

6

0.3

0.1, 0.6

3

0.3

0.1, 0.9

 

Diarrhea

 

 

 

 

 

 

 

 

 

Any

271

12.0

10.7, 13.4

99

10.2

8.4, 12.3

 

1-2 episodes

Mild

228

10.1

8.9, 11.4

86

8.9

7.2, 10.8

 

3-4 episodes

Moderate

36

1.6

1.1, 2.2

13

1.3

0.7, 2.3

 

> 5 episodes

Severe

7

0.3

0.1, 0.6

0

0.0

0.0, 0.3

 

Seizures (Y/N)

 

 

 

 

 

 

 

 

Yes

Days 0-3

0

0.0

0.0, 0.1

0

0.0

0.0, 0.3

 

Yes

Days 4-7

0

0.0

0.0, 0.1

0

0.0

0.0, 0.3

 

Yes

Days 0-7

0

0.0

0.0, 0.1

0

0.0

0.0, 0.3

 

Rash

 

 

 

 

 

 

 

 

Any rash

Days 0-3

23

1.0

0.6, 1.5

10

1.0

0.5, 1.9

 

Any rash

Days 4-7

23

1.0

0.6, 1.5

7

0.7

0.3, 1.5

 

Any rash

Days 0-7

37

1.6

1.2, 2.2

14

1.4

0.8, 2.4

 

*n: number of participants reporting at least one event in this category.  Five Menactra and 2 Menomune® participants did not provide any data.  Percentages are based on the total number of participants who did submit safety information at each time point. 

Headache, chills, arthralgia, fatigue, malaise: 0= none, 1= aware, easily tolerated, 2= interferes with usual activities, 3= disabling

Reviewer comment: Excluding rashes, 108 severe systemic reactions occurred in 61 Menactra participants, and 18 severe reactions in 12 Menomune® participants.  Twenty-four of 61 (39%) Menactra participants reported two or more severe systemic reactions.  In the Menomune group, 3 of 12 (25%) participants reported two or more severe systemic reactions.  

 

Eleven Menactra and three Menomune® participants, respectively, reported localized rash either at or near the injection site.  Lesions appeared mainly within the first two days post-vaccination (range 0-5 days), and were described as red or pink, macular or papular, and primarily non-itchy.  The mean duration of the rash was 27 hours (range: 1hr-72hr).  For the remaining participants with localized rash, rashes described were non-specific, located more often on the extremities than on the trunk, neck or face, and lasted a median of 2 days (range: 40 minutes to 2 months).  Three participants reported generalized rash.  One participant in each group described the rash as itchy, blanching; one participant required benedryl.  The third participant [Menactra] reported a generalized, non-blanching, red, raised rash that occurred two days post-vaccination, and lasted 4 days

 

Primary Hypothesis Testing

The proportion of Menactra participants with at least one severe systemic reaction during Days 0-7 was 0.043 (4.3%) and 0.041 (4.1%) in the Menomune® group.  The upper limit of the two-sided 90% CI, and 95% CI, for the difference in two proportions was 0.020 (2.0%), and 0.024 (2.4%), respectively.

 

MTA-04: Number and Proportion of Parti