FinOM-rokotetutkimuksen tulosten esitys FDA:n asiantuntijakokouksessa
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Transcript of FinOM-rokotetutkimuksen tulosten esitys FDA:n asiantuntijakokouksessa
FinOM Efficacy Trial of 7-Valent
Pneumococcal Conjugate Vaccine
Terhi Kilpi
National Public Health Institute (KTL)
Finland
2
FinOM Study Group
• Principal investigator
• Study coordination
• Bacteriology
• Immunology
• Otorhinolaryngology
• Biostatistics
• Data management
• Virology
• Study clinic personnel
• Senior adviser
• Juhani Eskola, Terhi Kilpi
• Arto Palmu , Kari S Lankinen
• Elja Herva, Maija Leinonen
• Helena Käyhty, Heidi Åhman
• Pekka Karma
• Jukka Jokinen, Mika Lahdenkari,
Jouko Verho
• Jaason Haapakoski, Esa
Ruokokoski, Marko Grönholm
• Tapani Hovi
• Wilhelm Bredenberg, Heljä
Savolainen, Ritva Syrjänen
• P Helena Mäkelä
FinOM Vaccine Trial
3
FinOM Vaccine Trial
• evaluated efficacy of two 7-valent pneumococcal (Pnc)
conjugate vaccines for prevention of AOM due to
vaccine serotypes in children less than 2 years of age
• clinical phase from December 1995 to March 1999
• 2 497 children enrolled (55 % of the birth cohort) in
Tampere area
4
Study design
• All children were randomized to receive PncCRM
(Prevnar®, Prevenar®), PncOMPC, or control (HBV)
vaccine at 2, 4, 6, and 12 mo
• Follow-up from 2 to 24 mo at the study clinic
• All respiratory infections requiring medical attention
were evaluated and treated at the study clinic
FinOM Vaccine Trial
5
Definition of AOM
• Symptoms
– At least one of the following: fever, earache, irritability,
diarrhea, vomiting, acute otorrhea not caused by otitis
externa, or other symptoms of respiratory infection
• Signs
– A visually abnormal tympanic membrane (in regard of color,
position and/or mobility) suggesting middle ear effusion
FinOM Studies
6
Acute Otitis Media (AOM)
• Myringotomy with aspiration performed in AOM with
effusion
• Middle ear fluid (MEF) sample for bacterial culture,
pneumococcal serotyping and pneumolysin PCR
• AOM episode defined to start at diagnosis and to last
for 30 days
FinOM Studies
7
Efficacy of PncCRM against AOM
• Primary
– All AOM episodes due to vaccine serotypes
• Secondary
– First and subsequent AOM episodes due to vaccine serotypes
• Other
– All Pnc AOM episodes
– All AOM episodes
– Recurrent AOM
FinOM Vaccine Trial
8
Efficacy of PncCRM against AOM
• Post Hoc
– AOM episodes due to vaccine related serotypes (6A, 9N, 18B, 19A,
23A)
– AOM episodes due to serotypes unrelated to vaccine types
– AOM episodes due to individual serotypes
FinOM Vaccine Trial
9
Disposition of subjects
PncCRM Control Total
Enrolled 831 831 1662
Excluded from PP analysis 20 10 30
Early temination of PP f-up 25 27 52
Withdrawn permanently 33 32 65
Completed as PP 786 794 1580
Completed ITT follow-up 798 799 1597
FinOM Vaccine Trial
10
All AOM episodes due to vaccine serotypes FinOM Vaccine Trial
PncCRM Control Total
Number of episodes 107 250 357
Rate/person-year 0.09 0.21
Primary analysis
Vaccine efficacy: 57% (95% CI: 44% to 67%)
Per protocol follow-up from 6.5 to 24 months of age
11
First and subsequent AOM episodes due
to vaccine serotypes
PncCRM HBVVaccine efficacy
%95 %
lower CL95 %
upper CL
First
N 89 177
Rate* 0.08 0.17
52 39 63
Subsequent
N 18 73
Rate* 0.25 0.47
45 5 69
FinOM Vaccine Trial
Per protocol follow-up
Secondary analysis
*Per person-year
12
Summary of efficacy results
EpisodesEndpoint
PncCRM HBVVaccine efficacy
%95 %
lower CL95 %
upper CL
AOM due to vaccineserotypes
107 250 57 44 64
Pneumococcal AOM(culture+)
271 414 34 21 45
Pneumococcal AOM(culture and/or PCR+)
548 687 20 7 31
Any AOM 1251 1345 6 -4 16
Recurrent AOM 123 149 16 -6 35
FinOM Vaccine Trial
Per protocol follow-up from 6.5 to 24 months of age
Acute Otitis Media
13
Summary of efficacy results
EpisodesEndpoint
PncCRM HBVVaccine efficacy
%95 %
lower CL95 %
upper CL
AOM due to vaccineserotypes
135 292 54 41 64
Pneumococcal AOM(culture+)
322 467 32 19 42
Pneumococcal AOM(culture and/or PCR+)
642 775 18 5 29
Any AOM 1474 1532 4 -7 14
Recurrent AOM 158 174 9 -12 27
FinOM Vaccine Trial
Intention to treat follow-up from 2 to 24 months of age
Acute Otitis Media
14
Pneumococcal AOM episodes
EpisodesEndpoint
PncCRM HBVVaccine efficacy
%
95 %lowerCL
95 %upper CL
Pneumococcal AOM(culture+)
271 414 34 21 45
Pneumococcal AOM(culture+ and/or PCR+)
548 687 20 7 31
Pneumococcal AOM(culture– and PCR+)
310 326 4 -15 19
FinOM Vaccine Trial
Per protocol follow-up from 6.5 to 24 months of age
Acute Otitis Media
15
PCR counts* in MEF of
Pnc Ply PCR positive AOM
0
100000
200000
300000
400000
500000
600000
PncCRM HBV PncCRM HBV
PCR counts
Pnc culture negative Pnc culture positive
* GM (95% CI)
FinOM Vaccine Trial
16
Individual vaccine serotypes
EpisodesSerotype
PncCRM HBVVaccine efficacy
%95 %
lower CL95 %
upper CL
23F 33 82 59 35 75
19F 43 58 25 -14 51
6B 9 56 84 62 93
14 8 26 69 20 88
18C 7 17 58 -4 83
9V 5 11 54 -48 86
4 2 4 49 -176 91
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
17
Vaccine, vaccine-related and other serotypes
EpisodesSerotypes
PncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
Vaccine 107 250 57 44 67
Vaccine-related 41 84 51 27 67
Other 125 95 -33 -80 1
Pnc AOM(culture+)
271 414 34 21 45
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
18
Vaccine-related serotypes
EpisodesSerotype
PncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
6B 9 56 84 62 93
6A 19 45 57 24 76
19F 43 58 25 -14 51
19A 17 26 34 -26 65
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
19
PncCRM
• is efficacious against
– culture-confirmed, vaccine serotype specific AOM
(VE: 57%)
– culture-confirmed AOM due to vaccine-related
serotypes (VE: 51%)
– culture-confirmed pneumococcal AOM (VE: 34%)
FinOM Vaccine Trial Conclusions
Extended follow-up
FinOM Vaccine Trial
21
Objectives
• To assess long-term effects of PncCRM on
– pneumococcal carriage
– antibody persistence
– surgery due to OM in the routine practice after
the Vaccine Trial
FinOM Follow-up Study
22
Methods
• Single follow-up visit at the age of 4 to 5 years in spring
2001
• Collection of data
– Parental interview
– Pneumatic otoscopy
– Medical records
– Nasopharyngeal, blood and saliva samples
FinOM Follow-up Study
23
Inclusion criteria
PncCRM Control Total %
Enrolled in the FinOMVaccine Trial
831 831 1662 100
Completed ITT follow-up 798 799 1597 96
Still living in the area 746 744 1490 90
Informed consent for the Follow-up Study
403 353 756 45
FinOM Follow-up Study
24
0 10 20 30 40 50 60
1597
Study flow
Start of long-term follow-up
Children, N
FinOM Vaccine Trial and Follow-up Study
65 dropped out
during the trial
1662
756
1490
107 moved out of
Tampere Area
Age, months
Fully evaluated children
= Analysis population 1
Eligible children
= Analysis population 2
Complete tympanostomy data
available
Hospital
tympanostomy data
available
25
Case ascertainment for tube placement
• Fully evaluated children (Analysis population 1)
– Parental interview
– Hospital records from Tampere University Hospital, three
district hospitals (78%)
– Medical records from private physician offices for verification
(22%)
• Eligible children (Analysis population 2)
– Hospital records from Tampere University Hospital, three
district hospitals
FinOM Follow-up Study
26
Tube placement during the Vaccine Trial
• Included in the study services
• Close follow-up in the study clinics, active treatment
strategy, specific criteria for referral in the SOP
• Tampere University Hospital
• Free of charge
• Within 4 to 8 weeks of referral
FinOM Studies
27
Tube placement after the Vaccine Trial
• Public hospitals
– Nominal charge
– Waiting time 3 to 4 months
– 78%
• Private medical centers and hospitals
– Charge 10 x public sector charge
– No waiting time
– 22%
FinOM Studies
28
0
2
4
6
8
10
12
14
<2 2 - 4
FinOM control group
Finland overall
Incidence of tube placement
*
* National hospital discharge register and national sick insurance reimbursement
database
/ 100 person-years
*
Age, years
29
0 10 20 30 40 50 60
1597
Study flow
Start of long-term follow-up
Children, N
FinOM Vaccine Trial and Follow-up Study
65 dropped out
during the trial
1662
756
1490
107 moved out of
Tampere Area
Age, months
Fully evaluated children
= Analysis population 1
Eligible children
= Analysis population 2
30
Tympanostomy tube placement
in fully evaluated children*
PncCRMN=403
HBVN=353
Vaccineefficacy
95% CI
2 months to 2 years
% with events 20.3 23.8
Rate of events* 12.9 14.812% (-1734)
2 years to 4-5 years
% with events 8.2 13.0
Rate of events* 3.5 5.739% (461)
FinOM Vaccine Trial and Follow-up Study
Intention to treat follow-up
*Per 100 person-years *Analysis population 1
31
Tympanostomy tube placement
in all eligible children*
PncCRM HBV Vaccineefficacy
95% CI
2 months to 2 years N=831 N=831
% with events 18.4 19.3
Rate of events* 12.0 12.74% (-1923)
2 years to 4-5 years N=746 N=744
% with events 6.2 9.5
Rate of events* 2.4 4.144% (1962)
Intention to treat follow-up
*Per 100 person-years
FinOM Vaccine Trial and Follow-up Study
*Analysis population 2
32
0,00
0,05
0,10
0,15
0,20
0,25
0,30
0,35
0,40
0,45
0 10 20 30 40 50 60 70
Age,months
Cumulative hazard of tympanostomy
tube placement
Start of long-term follow-up
Cumulative
hazard
FinOM Vaccine Trial and Follow-up Study
Fully evaluated
children
HBV
PncCRM
33
0,00
0,05
0,10
0,15
0,20
0,25
0,30
0,35
0,40
0 10 20 30 40 50 60 70
Age,months
Cumulative hazard of tympanostomy
tube placement
Start of long-term follow-up
Cumulative
hazard
FinOM Vaccine Trial and Follow-up Study
All eligible
children
HBV
PncCRM
34
0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-23F
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
HBV
PncCRM
35
0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-19F
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
36
0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-6B
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
37
Long-term effect on otitis media and carriage
FinOM Follow-up Study
PncCRMN 403
HBVN 353
Children with AOM after 24 mo of age,% 67.3 72.7
Diagnosed with OM at the Follow-up visit,% 11.4 12.5
Vaccine type Pnc carriage, % 8.5 13.6 P=0.05
38
PncCRM
• PncCRM reduces tube placement due to OM
• Vaccine efficacy against OM persists for several years
FinOM Follow-up Study Conclusions
Back-up slides
40
Vaccine-related serotypes
EpisodesSerotype
PncCRM HBVVaccine efficacy
%95 %
lower CL95 %
upper CL
9V 5 11 54 -48 86
9N 2 8 75 -24 95
18C 7 17 58 -4 83
18B 2 1 -103 -213 82
23F 33 82 59 35 75
23A 1 4 75 -24 95
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
41
Vaccine-related serotypes
EpisodesSerotype
PncCRM HBVVaccine efficacy
%95 %
lower CL95 %
upper CL
6A 19 45 57 24 76
9N 2 8 75 -24 95
18B 2 1 -103 -213 82
19A 17 26 34 -26 65
23A 1 4 75 -24 95
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
42
Vaccine efficacy by dose
Interval
from dose to doseVaccine efficacy
%95 % lower CL 95 % upper CL
1 2 22 -74 65
2 3 46 -4 72
3 4 57 36 71
4 end 55 39 67
FinOM Vaccine Trial
Intention to treat analysis
43
Efficacy of PncCRM with subsequent
episodes due to same serotypes excluded
Vaccine efficacy %(95% CI)AOM episodes
All episodes First episodes*
due to vaccine serotypes 57 55
(4467) (4365)
any Pnc 34 34
(21-45) (2144)
FinOM Vaccine Trial
*due to a given serotype
44
0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-14
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
45
0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-18C
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
46
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-9V
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
47
0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-4
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
48
Efficacy of PncCRM and PncOMPC
Vaccine efficacy %(95% CI)AOM episodes due to
PncCRM* PncOMPC**
6B 84 79
(6293) (5889)
19F 25 37
(-1451) (159)
23F 59 52
(3575) (2868)
FinOM Vaccine Trial
*Eskola et al. N Engl J Med J 2001;344:403-9 ** Kilpi et al. ICAAC 2000
49
Nasopharyngeal carriage of any Pnc
0
5
10
15
20
25
30
12 mo 18 mo 4-5 yrs
PncCRM
Control
%
FinOM Vaccine Trial
Age
50
Nasopharyngeal carriage of Pnc serotypes
0
5
10
15
Vaccine Cross-reactive Other
PncCRM
Control
%
FinOM Vaccine Trial
12 months of age
51
Nasopharyngeal carriage of Pnc serotypes
0
5
10
15
Vaccine Cross-reactive Other
PncCRM
Control
%
FinOM Vaccine Trial
18 months of age
P<0.001 P=0.02
52
Nasopharyngeal carriage of Pnc serotypes
0
5
10
15
Vaccine Cross-reactive Other
PncCRM
Control
%
FinOM Vaccine Trial
4-5 years of age
P=0.05
53
Relative risk of Pnc AOM in PncCRM vs.
control group
0
0,2
0,4
0,6
0,8
RR
FinOM Vaccine Trial
Vaccine serotypes
6.5 -11 mo 12 -17 mo 18 -24 mo
Per-protocol follow-up
54
Relative risk of Pnc AOM and carriage
in PncCRM vs. control group
0
0,2
0,4
0,6
0,8
AOM Carriage AOM Carriage AOM Carriage
RR
FinOM Vaccine Trial
Vaccine serotypes
6.5 -11 mo 12 mo 12 -17 mo 18 mo 18 -24 mo 4-5 yrs
Per-protocol follow-up
55
Relative risk of Pnc AOM and carriage
in PncCRM vs. control group
0
0,2
0,4
0,6
0,8
1
1,2
AOM Carriage AOM Carriage AOM Carriage
RR
FinOM Vaccine Trial
Type 6B Per-protocol follow-up
6.5 -11 mo 12 mo 12 -17 mo 18 mo 18 -24 mo 4-5 yrs
56
Relative risk of Pnc AOM and carriage
in PncCRM vs. control group
0
0,5
1
1,5
2
AOM Carriage AOM Carriage AOM Carriage
RR
FinOM Vaccine Trial
Type 6A
6.5 -11mo 12 mo 12 -17 mo 18 mo 4-5 yrs
Per-protocol follow-up
57
Efficacy for first and subsequent
episodes: Vaccine specific serotypes
Proportionat risk forfirstepisode
Rate ofAOM forfirstepisode
Proportionat risk forsubsequentepisode
Rate ofAOM forsubsequentepisode
Over-allrate of AOM
PncCRM 0.9 0.08 + 0.1 0.25 = 0.09
Control 0.8 0.17 + 0.2 0.47 = 0.21
VE 52% 45% 57%
58
Rate of tympanostomy tube placement
before the date of unblinding*
0
5
10
Before unblinding Total
PncCRM
HBV
FinOM Follow-up Study
Per-protocol follow-up Fully evaluated
children >2 years
*1 Oct 1999
/ 100 person-years
59
Rate of tympanostomy tube placement
before the date of unblinding*
0
5
10
Before unblinding Total
PncCRM
HBV
FinOM Follow-up Study
Per-protocol follow-up All eligible
children >2 years
*1 Oct 1999
/ 100 person-years