1.0
Table of Contents
Page
1.0 General Information ………..……………………………………………………………... 3
PRODUCT NAME
PRODUCT COMPOSITION
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.
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
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
|
|
|
|
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 |
