beyond the primary phase iii efficacy & safety results · 2012. 10. 23. · saes including is...
TRANSCRIPT
1
RotaTeq®: The of the Story
Beyond the Primary Phase III Efficacy & Safety Results
Penny M. Heaton, MDMerck Research Laboratories
7th International Rotavirus SymposiumJune 12-13, 2006
2
Objectives
Rationale for development of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine
Characteristics of RotaTeq®
Design of Rotavirus Efficacy and Safety Trial (REST) and other Phase III studies
Results of Phase III studies– Efficacy– Safety
Current environment and future studies of RotaTeq®
3
Basis for Developing a Pentavalent Rotavirus Vaccine
Infants and young children have multiple rotavirus infections in the first few years of life
Wild-type rotavirus infection induces immunity against subsequent rotavirus (RV) gastroenteritis
Natural immunity is largely serotype-specific, particularly with a child’s first infection
– A second illness caused by the same G-serotype is uncommon
Velazquez et al, N Engl J Med 1996;335:1022-8.
Any
77 (60, 88)
83 (64, 92)
92 (44, 99)
Mod. to severe
87 (55, 96)
100
---
# of previousRV infections
1
2
3
% efficacy (95% CI) by disease severity
4
Basis for Developing a Pentavalent Rotavirus Vaccine (Cont.)
Antibody responses broaden with repeated infections – Broadening of immune response to different G types most likely due
to common P type
Homotypic response to VP7 (G) typically of greater magnitude than heterotypic response mediated by VP4 (P)
Merck Phase II Study*
We developed a pentavalent vaccine containing the most prevalent G serotypes for comprehensive protection of young infants
– Included P1[8] for protection against non G1-4 strains
*Vesikari et al, Vaccine 2006; 24:4821-9.
Quad (G1-4)270
74 (40, 90)
100 (25, 100)
Mono (P1[8])327
43 (-2, 63)
88 (11, 100)
RV disease severityN
Any severity
Severe disease
% efficacy (95% CI)
5
Development of the Human-Bovine (WC3) Reassortants
RotaTeq® contains 5 human-bovine (WC3) reassortants
WC3 bovine rotavirus strain isolated in 1981
Animal studies showed that WC3 was naturally attenuated for non-bovine species (e.g., poor replication in mice and rabbits)
Clinical trials indicated WC3 was naturally attenuated for human infants
– Well tolerated in >700 infants who received at least one dose– Efficacy was variable
Human-bovine reassortants were developed to improve efficacy
– Human surface VP7/VP4 (G/P) induce immunity– WC3 strain preserves tolerability
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Bovine Rotavirus
WC3
Human-Bovine Reassortant Rotavirus Vaccine Strains
G1 (P7) G2 (P7) G3 (P7) G4 (P7) P1 (G6)
Human Rotaviruses G1-4, P1[8]
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Characteristics of RotaTeq®Oral vaccine suspended in a liquid buffer/stabilizer
– Protected from gastric acid– Stored refrigerated with 24-month shelf life
Ready-to-use, administered directly from tube– No reconstitution required
3-dose regimen: First dose at age 6 to 12 weeks and subsequent doses at 1- to 2-month intervals
– Integrates into existing immunization schedules• 2-, 3-, 4-month• 2-, 4-, 6-month• 6-, 10-, 14-week
– Provides coverage before peak age of rotavirus hospitalizations
8
RotaTeq® Packaging and Container
9
Developmentof RotaTeq®
Proof-of-concept study (G1-3,
P1) (002)
Study to establish dose
and reassortant composition
(pentavalent; G1-4, P1) (005)
1993 1997 1998 2001 2002 200320001999
Reports ofIS with RRV-TV
Large-Scale Trial(Rotavirus Efficacy and
Safety Trial ; REST) (006)
Dose Confirmation
Efficacy(007)
2004 2005
Consist-ency Lots
Study (009)
Phase III (RotaTeq™)
Clinical study ofdifferent buffers (G1-2) (003)
FDA ACMfor REST
2006
10
Analyses of Data from REST and Other Phase III Studies
Efficacy – Rotavirus acute gastroenteritis (RV AGE) caused by
serotypes in the vaccine (G1-4, P1[8])• First and second RV seasons postvaccination
– Reduction in health care encounters for RV AGE• Hospitalizations, emergency department visits, and
office visits• First and second years of life• Serotype-specific• By region (EU, US, Latin American/Caribbean)
Safety– Serious adverse events including intussusception (IS)– Other adverse events (AEs) including AEs of special
clinical interest
11
Design of REST and Other Phase III Studies
Sample size: 71,799 (36,203 RotaTeq® : 35,596 Placebo)
Age: 6 to 12 weeks at first dose
Regimen: 3 oral doses, 1 every 4 to 10 wks
Sites: Areas with good standard of care for intussusception
Duration: January 2001 to October 2005
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71,799 Subjects in 11 Countries 36,203 in RotaTeq® Group35,596 in Placebo Group
GermanyGermanyBelgiumBelgium
FinlandFinland
USUSPuerto RicoPuerto RicoJamaicaJamaica
Native Native American American NationsNations
SwedenSweden
TaiwanTaiwanMMééxicoxico
GuatemalaGuatemalaCosta RicaCosta Rica
ItalyItaly
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71,799 Subjects in 11 Countries 36,203 in RotaTeq® Group35,596 in Placebo Group
US ~35,100US ~35,100
Latin America/Latin America/CaribbeanCaribbean
~5300~5300
EU ~31,100EU ~31,100
Asia: ~200Asia: ~200
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Efficacy Evaluations in the Phase IIIStudies
All Subjects in REST• Efficacy against hospitalizations and emergency department visits for rotavirus acute gastroenteritis (RV AGE)
• Efficacy against all RV AGE (severity classified by scoring system)
• Efficacy against office visitsfor RV AGE (REST only)
Substudy in REST and All Subjects
in 007
REST, Protocol 007
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Efficacy EvaluationCase definition for RV AGE
– >3 loose stools and/or vomiting– RV-positive stool by EIA; serotype by PCR
In efficacy substudy, severity of cases designated with a 24-pt scoring system
– Based on intensity and duration of vomiting, diarrhea, fever, and behavioral changes (parent reported)
Scoring system validated in a Phase II study– Strongly correlates with physician assessment of severity– Also correlates with intensity of care required for RV AGE
MildModerate-and-Severe
Severe
Severity1 – 8
>8 and ≤16>16
Score
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Surveillance for Acute Gastroenteritis (AGE)
Monitoring for hospitalizations and emergency visits for AGE
– Parents contacted wks 1, 2, and 6 after each dose– After dose 3, contacts continued every 6 weeks for up to 2
years
Monitoring for all AGE– Parents contacted every 2 weeks during rotavirus season
Subjects were enrolled year-round– If enrolled during the RV season, followed for the rest of that
season and another RV season
A subset of infants in REST were followed for a second rotavirus season postvaccination
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14 days PD 3
Duration of Efficacy Follow-up For Subjects Who Received Dose 3 Before
Start of Rotavirus Season
* If enrolled early enough into the study, surveillance was also conducted for a second season.
Subject A*Completes
1st Full RV Season 2nd Full RV Season
SeasonBegins
SeasonEnds
SeasonBegins
SeasonEnds
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Duration of Efficacy Follow-up For Subjects Who Received Dose 3 After
Start of Rotavirus Season
SeasonBegins
1st Partial RV Season
14 days PD 3
1st Full RV Season
Subject B*Completes
SeasonEnds
SeasonBegins
SeasonEnds
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Efficacy Results
20
Cumulative Number of G1-4 RV AGE Cases by Day of Follow-up and Treatment Group
Integrated Data – REST and Protocol 007
1 50 100 150 200 250 300 350 400 450 Day of Follow-up
0
50
100
150
200
250
300
350
Cum
ulat
ive
Num
ber o
f Cas
es RotaTeq™Placebo
Days of Follow-up
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REST Efficacy Substudy and Protocol 007(For the First Rotavirus Season Postvaccination)
Efficacy of RotaTeq® Against G1-4 RV AGE
N=number vaccinated.
DiseaseSeverityAnySevere
% Efficacy7498
95% CI67,7990,100
Number of Cases
971
Vaccine(N=3484)
36957
Placebo(N=3499)
22* Adjusted for multiplicity.
Summary of Efficacy ResultsFrom Phase II and III Studies
N Vaccinated
Any Severity% Efficacy (95% CI)
Severe% Efficacy (95% CI)
Severity of RV AGE(G1-G4)
Phase II
439
75 (50,88)
100 (44,100)
002
G1-3, P1~5.9×107
PFU/dose650
74 (38,91)*
100 (35,100)
005(Middle-dose)
G1-4, P1~7.9×106
PFU/dose
Phase III
1310
73 (51,86)
100 (13,100)
007(Expiry)
G1-4, P1~1.1×107
IU/dose5673
74 (67,80)
98 (88,100)
REST(Release)
G1-4, P1~6.7 to 12.4×107
IU/dose
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Efficacy of RotaTeq® During the Second Rotavirus Season Postvaccination
REST
First Season Second Season0
20
40
60
80
100
Effi
cacy
(%)
(36V:88P) (2V:17P)(1V:51P)(82V:315P)
AnySevere
(74%)
(98%)
(63%)
(88%)
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Efficacy of RotaTeq® Against Hospitalizations, Emergency Department
Visits & Office Visits for G1-4 RV AGE
† N=34,035 vaccinated in vaccine group and 34,003 vaccinated in placebo group.‡ N=2834 vaccinated in vaccine group and 2839 vaccinated in placebo group.
Type of HealthCare Encounter
Hospitalizations†
Emerg. Dept. Visits†
Office Visits‡
% RateReduction
969486
95% CI91, 98 89, 9774, 93
Number of Cases
61313
Vaccine138191
98
Placebo
REST
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Efficacy of RotaTeq® Against Hospitalizations and Emergency
Department Visits for G1-4 RV AGE by Year of Age
Age StrataLess than 1 Yr Old*1-2 Years of Age†
% RateReduction
9497
95% CI91,9782,100
Number of Cases
191
Vaccine33732
Placebo
REST
*N=34,035 RotaTeq®/ 34,003 Placebo†N=1219 RotaTeq®/ 1283 Placebo
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Serotype-Specific Efficacy of RotaTeq®Against Hospitalizations and Emergency
Department Visits for RV AGEREST
Serotype % Efficacy95889389
100
Number of Cases
161120
Vaccine(N=34,035)
3288
151813
Placebo(N=34,003) 95% CI
92,97<0,9949,9952,9867,100
G1P1a*G2P1bG3P1aG4P1aG9P1a
* Representative subset of samples with VP4 testing.N=number vaccinated.
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Serotype-Specific Efficacy of RotaTeq® Against Hospitalizations and Emergency Department
Visits for RV AGE:ITT Population (Subjects Who Received At Least One Dose)
Serotype % Efficacy9292859092
Number of Cases
321322
Vaccine(N=34,035)
41412202025
Placebo(N=34,003) 95% CI
88,9535,9950,9657,9866,98
G1P1a*G2P1bG3P1aG4P1aG9P1a
* Representative subset of samples with VP4 testing.N=number vaccinated.
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Efficacy of RotaTeq® Against Hospitalizations and Emergency Department Visits for G1-4 RV
AGE by Region
RegionEurope*
US¶
Native AmericanNations†
Latin America/Caribbean‡
% RateReduction
95
96
93
90
95% CI91,97
77,100
76,99
29,100
Number of Cases
16
1
2
1
Vaccine301
27
31
10
Placebo
REST
*N = 14,018 RotaTeq®/ 13,984 Placebo¶N = 11,990 RotaTeq®/ 11,892 Placebo†N = 294 RotaTeq®/ 287 Placebo‡N = 2252 RotaTeq®/ 2237 Placebo.
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Efficacy of RotaTeq® Against Hospitalizations and Emergency Department Visits for RV AGE
Regardless of Serotype by Region ITT Population (Subjects Who Received At Least One Dose)
Region% Rate
Reduction92
77
82
80
95% CI88,95
51,89
63,92
29,96
Number of Cases
31
15
9
3
Vaccine387
66
54
15
PlaceboEurope*
US¶
Native AmericanNations†
Latin America/Caribbean‡
*N = 14,831 RotaTeq®/ 14,734 Placebo¶N = 15,261 RotaTeq®/ 15,218 Placebo†N = 326 RotaTeq®/ 343 Placebo‡N = 2651 RotaTeq®/ 2630 Placebo.
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Safety Evaluationsin Phase III Studies
Substudy in RESTand All Subjects in
Protocol 007 andProtocol 009
All serious adverse events (SAEs) including intussusception (IS)
All adverse events (AEs)
All Subjects in REST,Protocol 007, and
Protocol 009
• Fecal vaccine-strain shedding was evaluated in 2 ways– Pre-specified time interval– All rotavirus-positive potential acute gastroenteritis cases
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Safety Monitoring
Case definition for intussusception (IS) required radiographic, surgical, autopsy diagnosis
Contacted parents of all subjects and asked about SAEs including IS weeks 1, 2, and 6 after each dose
– Continued every 6 weeks after the third dose for up to one year after the first dose
Continuous monitoring by independent DSMB as each case occurred
Of 71,799 subjects enrolled in the Phase III studies, follow-up for 6 weeks after the last dose was completed in:
– 99.8% in the RotaTeq® group– 99.7% in the placebo group
32
REST Intussusception Results
No intussusception cases in Protocols 007 and 009
35 Investigator-DiagnosedIntussusception Cases
0V:2P
11 caseswithin
42 daysof a dose
4 casesreported after studycompleted
17 cases>42 daysof a doseand ≤1 yrof dose 1
0V:4P6V:5P 7V:10P
32 positively-adjudicatedcases
2 negatively-adjudicated
cases
1 unadjudicatedcase
0V:1P
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AEs Occurring at a Statistically Significant Different Rate in the RotaTeq® vs. Placebo Groups for All 3
Phase III StudiesDifferences are only evident when data are combined across the 3 Phase III studies
– N=11,722 [6143 RotaTeq®/5579 Placebo]
AE of crying was reported at a higher rate in placebo recipients than vaccine recipients (3.6% vs. 4.4%)
AEs within 42 days after any dose reported at a higher rate among vaccine recipients than placebo recipients:
– Diarrhea (24% vs. 21%)– Vomiting (15% vs. 14%)– Nasopharyngitis (7% vs. 6%)– Otitis media (15% vs. 13%)– Bronchospasm (1.1% vs. 0.7%)
34
Fecal Shedding of Vaccine-Virus Strains in REST and Protocol 007
OneTwoThree
Dose Number32/360 (8.9)0/249 (0)1/385 (0.3)
RotaTeq®
Number of Shedders/Number Tested (%)
• Shedding peaks 4 to 6 days postvaccination (Phase II)• Latest shedding in Phase III was 15 days from dose 1• One subject shed 4 days from dose 3• Low quantities (5×101 to 1.88×104 PFU/mL)
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Percent of Infants with Fever Within Week of First Dose by Day after Dose and
Vaccination Group
0
5
10
15
20
25
1 2 3 4 5 6 7Days Postdose 1
% o
f Sub
ject
s
RotaTeq™ Placebo
N=11,722 (6143 RotaTeq®/5579 Placebo)
Fever = temperatures ≥100.5°F, rectal equivalent
36
0
5
10
15
20
25
1 2 3 4 5 6 7
Percent of Infants with Vomiting and/or Diarrhea Within Week of First Dose by Day after Dose
and Vaccination Group
0
5
10
15
20
25
1 2 3 4 5 6 7Days Postdose 1
RotaTeq™ Placebo
Percent of Subjects
Vomiting
Diarrhea
37
Overall Assessment and Conclusions
RotaTeq® was well tolerated with respect to all adverse events including IS
RotaTeq® prevented RV AGE– 74% efficacy against any severity– 98% efficacy against severe disease– 95% reduction in RV-related hospitalizations
RotaTeq® reduced RV-related hospitalizations and emergency department visits caused by strains G1P[8], G2P[4], G3P[8], G4[P8], and G9[P8]
The reduction in RV-related hospitalizations and emergency department visits appeared similar by region (EU, US, Native American Nations, Latin America/Caribbean)
38
Study to establish dose
and reassortant composition
(pentavalent; G1-4, P1) (005)
1997 1998 2001 2002 200320001999
Reports ofIS with RRV-TV
Large-Scale Trial(Rotavirus Efficacy and
Safety Trial ; REST) (006)
Dose Confirmation
Efficacy(007)
2004 2005
Consist-ency Lots
Study (009)
Filed for licensure
Phase III (RotaTeq™)
Clinical study ofdifferent buffers (G1-2) (003)
FDA ACMfor REST
2006
FDA ACM US
Approval
Positive CHMP
Opinion
ACIPUniversal
Recommendation
39
Current EnvironmentSince February, over half a million doses of RotaTeq®distributed in the US
Intussusception is a naturally-occurring illness; therefore, cases are expected to occur
Post-licensure studies in place to monitor safety– Prospective population-based study to assess IS
and general safety– Enhanced passive surveillance
Coordinating with regulatory and public health agencies
40
Developing World Program for RotaTeq®
Ongoing study of concomitant use of OPV and RotaTeq® in Latin America
Rotavirus disease surveillance and an effectiveness study of RotaTeq® in Latin America
41
Developing World Program for RotaTeq®
Efficacy and safety studies in Africa and Asia
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Thank You