FinOM-rokotetutkimuksen tulosten esitys FDA:n asiantuntijakokouksessa
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FinOM-rokotetutkimuksen tulosten esitys FDA:n asiantuntijakokouksessa

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Terhi Kilpi, Rokotusten ja immuunisuojan osasto, THL

Terhi Kilpi, Rokotusten ja immuunisuojan osasto, THL
ADVISORY COMMITTEE -kokous
21.5.2002, Maryland, Yhdysvallat

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FinOM-rokotetutkimuksen tulosten esitys FDA:n asiantuntijakokouksessa FinOM-rokotetutkimuksen tulosten esitys FDA:n asiantuntijakokouksessa Presentation Transcript

  • FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine Terhi Kilpi National Public Health Institute (KTL) Finland
  • FinOM Vaccine Trial 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 2 P Helena Mäkelä
  • 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 3
  • FinOM Vaccine Trial 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 4
  • FinOM Studies 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 5
  • FinOM Studies 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 6
  • FinOM Vaccine Trial 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 7
  • FinOM Vaccine Trial 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 8
  • FinOM Vaccine Trial Disposition of subjects PncCRM Control Total 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 Enrolled 9
  • Primary analysis FinOM Vaccine Trial All AOM episodes due to vaccine serotypes Per protocol follow-up from 6.5 to 24 months of age PncCRM Control Total Number of episodes 107 250 357 Rate/person-year 0.09 0.21 Vaccine efficacy: 57% (95% CI: 44% to 67%) 10
  • FinOM Vaccine Trial Secondary analysis First and subsequent AOM episodes due to vaccine serotypes Per protocol follow-up PncCRM HBV Vaccine efficacy % 95 % lower CL 95 % upper CL 89 177 52 39 63 0.08 0.17 18 73 45 5 69 0.25 0.47 First N Rate* Subsequent N Rate* *Per person-year 11
  • FinOM Vaccine Trial Acute Otitis Media Summary of efficacy results Per protocol follow-up from 6.5 to 24 months of age Endpoint AOM due to vaccine serotypes Pneumococcal AOM (culture+) Pneumococcal AOM (culture and/or PCR+) Any AOM Recurrent AOM Episodes PncCRM HBV Vaccine efficacy % 95 % lower CL 95 % upper CL 107 250 57 44 64 271 414 34 21 45 548 687 20 7 31 1251 1345 6 -4 16 123 149 16 -6 35 12
  • FinOM Vaccine Trial Acute Otitis Media Summary of efficacy results Intention to treat follow-up from 2 to 24 months of age Endpoint AOM due to vaccine serotypes Pneumococcal AOM (culture+) Pneumococcal AOM (culture and/or PCR+) Any AOM Recurrent AOM Episodes PncCRM HBV Vaccine efficacy % 95 % lower CL 95 % upper CL 135 292 54 41 64 322 467 32 19 42 642 775 18 5 29 1474 1532 4 -7 14 158 174 9 -12 27 13
  • FinOM Vaccine Trial Acute Otitis Media Pneumococcal AOM episodes Per protocol follow-up from 6.5 to 24 months of age Endpoint Pneumococcal AOM (culture+) Pneumococcal AOM (culture+ and/or PCR+) Pneumococcal AOM (culture– and PCR+) Episodes PncCRM HBV Vaccine efficacy % 95 % lower CL 95 % upper CL 271 414 34 21 45 548 687 20 7 31 310 326 4 -15 19 14
  • FinOM Vaccine Trial PCR counts* in MEF of Pnc Ply PCR positive AOM * GM (95% CI) PCR counts 600000 500000 400000 300000 200000 100000 0 PncCRM HBV Pnc culture negative PncCRM HBV Pnc culture positive 15
  • FinOM Vaccine Trial Acute Otitis Media Individual vaccine serotypes Per protocol follow-up Serotype 23F 19F 6B 14 18C 9V 4 Episodes PncCRM HBV 33 82 43 58 9 56 8 26 7 17 5 11 2 4 Vaccine efficacy % 59 25 84 69 58 54 49 95 % lower CL 35 -14 62 20 -4 -48 -176 95 % upper CL 75 51 93 88 83 86 91 16
  • FinOM Vaccine Trial Acute Otitis Media Vaccine, vaccine-related and other serotypes Per protocol follow-up Serotypes Episodes 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 17
  • FinOM Vaccine Trial Acute Otitis Media Vaccine-related serotypes Per protocol follow-up Serotype Episodes 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 18
  • FinOM Vaccine Trial Conclusions 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%) 19
  • FinOM Vaccine Trial Extended follow-up
  • FinOM Follow-up Study 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 21
  • FinOM Follow-up Study 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 22
  • FinOM Follow-up Study Inclusion criteria PncCRM Control Total % Enrolled in the FinOM Vaccine 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 23
  • FinOM Vaccine Trial and Follow-up Study Study flow 65 dropped out during the trial Children, N 107 moved out of Tampere Area 1662 1490 1597 Hospital Eligible children tympanostomy data = Analysis population 2 available 756 Fully evaluated children Complete tympanostomy data = Analysis population 1 available 0 10 20 30 40 Start of long-term follow-up 50 60 Age, months 24
  • FinOM Follow-up Study 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 25
  • FinOM Studies 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 26
  • FinOM Studies 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% 27
  • Incidence of tube placement / 100 person-years 14 12 10 8 FinOM control group * * Finland overall 6 4 2 0 <2 2-4 Age, years * National hospital discharge register and national sick insurance reimbursement 28 database
  • FinOM Vaccine Trial and Follow-up Study Study flow 65 dropped out during the trial Children, N 107 moved out of Tampere Area 1662 1490 1597 Eligible children = Analysis population 2 756 Fully evaluated children = Analysis population 1 0 10 20 30 40 Start of long-term follow-up 50 60 Age, months 29
  • FinOM Vaccine Trial and Follow-up Study Tympanostomy tube placement in fully evaluated children* Intention to treat follow-up PncCRM N=403 2 months to 2 years % with events Rate of events* 2 years to 4-5 years % with events Rate of events* *Analysis population 1 HBV N=353 Vaccine efficacy 95% CI 20.3 12.9 23.8 14.8 12% (-1734) 8.2 3.5 13.0 5.7 39% (461) *Per 100 person-years 30
  • FinOM Vaccine Trial and Follow-up Study Tympanostomy tube placement in all eligible children* Intention to treat follow-up PncCRM 2 months to 2 years % with events Rate of events* 2 years to 4-5 years % with events Rate of events* *Analysis population 2 HBV N=831 18.4 12.0 N=831 19.3 12.7 N=746 6.2 2.4 N=744 9.5 4.1 Vaccine efficacy 95% CI 4% (-1923) 44% (1962) *Per 100 person-years 31
  • FinOM Vaccine Trial and Follow-up Study Cumulative hazard of tympanostomy tube placement Cumulative 0,45 hazard 0,40 HBV 0,35 PncCRM 0,30 0,25 Fully evaluated children 0,20 0,15 0,10 0,05 0,00 0 10 20 30 40 50 Start of long-term follow-up 60 70 Age,months 32
  • FinOM Vaccine Trial and Follow-up Study Cumulative hazard of tympanostomy tube placement Cumulative 0,40 hazard HBV 0,35 0,30 PncCRM 0,25 0,20 All eligible children 0,15 0,10 0,05 0,00 0 10 20 30 40 50 Start of long-term follow-up 60 70 Age,months 33
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-23F g/ml 10 PncCRM 1 HBV 0,1 0,01 0 10 20 30 40 Start of long-term follow-up 50 60 34
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-19F g/ml 10 PncCRM HBV 1 0,1 0,01 0 10 20 30 40 Start of long-term follow-up 50 60 35
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-6B g/ml 10 PncCRM 1 HBV 0,1 0,01 0 10 20 30 40 Start of long-term follow-up 50 60 36
  • FinOM Follow-up Study Long-term effect on otitis media and carriage PncCRM N 403 HBV N 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 37
  • FinOM Follow-up Study Conclusions PncCRM • PncCRM reduces tube placement due to OM • Vaccine efficacy against OM persists for several years 38
  • Back-up slides
  • FinOM Vaccine Trial Acute Otitis Media Vaccine-related serotypes Per protocol follow-up Serotype 9V Episodes PncCRM HBV 5 11 Vaccine efficacy % 54 95 % lower CL -48 95 % upper CL 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 40
  • FinOM Vaccine Trial Acute Otitis Media Vaccine-related serotypes Per protocol follow-up Serotype 6A Episodes PncCRM HBV 19 45 Vaccine efficacy % 57 95 % lower CL 24 95 % upper CL 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 41
  • FinOM Vaccine Trial Vaccine efficacy by dose Intention to treat analysis Interval from dose to dose 1 2 Vaccine efficacy 95 % lower CL % 95 % upper CL 22 -74 65 2 3 46 -4 72 3 4 57 36 71 4 end 55 39 67 42
  • FinOM Vaccine Trial Efficacy of PncCRM with subsequent episodes due to same serotypes excluded Vaccine efficacy % AOM episodes (95% CI) All episodes *due to a given serotype 55 (4365) 34 34 (21-45) any Pnc 57 (4467) due to vaccine serotypes First episodes* (2144) 43
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-14 g/ml 10 PncCRM 1 HBV 0,1 0,01 0 10 20 30 40 Start of long-term follow-up 50 60 44
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-18C g/ml 10 1 PncCRM HBV 0,1 0,01 0 10 20 30 40 Start of long-term follow-up 50 60 45
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-9V g/ml 10 PncCRM 1 HBV 0,1 0 10 20 30 40 Start of long-term follow-up 50 60 46
  • FinOM Vaccine Trial and Follow-up Study Kinetics of anti-4 g/ml 10 1 PncCRM HBV 0,1 0,01 0 10 20 30 40 Start of long-term follow-up 50 60 47
  • FinOM Vaccine Trial Efficacy of PncCRM and PncOMPC Vaccine efficacy % AOM episodes due to (95% CI) PncCRM* *Eskola et al. N Engl J Med J 2001;344:403-9 (5889) 25 37 (159) 59 52 (3575) 23F 79 (-1451) 19F 84 (6293) 6B PncOMPC** (2868) ** Kilpi et al. ICAAC 48 2000
  • FinOM Vaccine Trial Nasopharyngeal carriage of any Pnc % 30 25 20 15 10 5 0 PncCRM Control 12 mo 18 mo 4-5 yrs Age 49
  • FinOM Vaccine Trial Nasopharyngeal carriage of Pnc serotypes 12 months of age % 15 10 PncCRM Control 5 0 Vaccine Cross-reactive Other 50
  • FinOM Vaccine Trial Nasopharyngeal carriage of Pnc serotypes % P<0.001 18 months of age P=0.02 15 10 PncCRM Control 5 0 Vaccine Cross-reactive Other 51
  • FinOM Vaccine Trial Nasopharyngeal carriage of Pnc serotypes % P=0.05 4-5 years of age 15 10 PncCRM Control 5 0 Vaccine Cross-reactive Other 52
  • FinOM Vaccine Trial Relative risk of Pnc AOM in PncCRM vs. control group Vaccine serotypes RR Per-protocol follow-up 0,8 0,6 0,4 0,2 0 6.5 -11 mo 12 -17 mo 18 -24 mo 53
  • FinOM Vaccine Trial Relative risk of Pnc AOM and carriage in PncCRM vs. control group RR Vaccine serotypes Per-protocol follow-up 0,8 0,6 0,4 0,2 0 AOM Carriage AOM Carriage AOM Carriage 6.5 -11 mo 12 mo 12 -17 mo 18 mo 18 -24 mo 4-5 yrs 54
  • FinOM Vaccine Trial Relative risk of Pnc AOM and carriage in PncCRM vs. control group RR 1,2 1 0,8 0,6 0,4 0,2 0 Type 6B Per-protocol follow-up AOM Carriage AOM Carriage AOM Carriage 6.5 -11 mo 12 mo 12 -17 mo 18 mo 18 -24 mo 4-5 yrs 55
  • FinOM Vaccine Trial Relative risk of Pnc AOM and carriage in PncCRM vs. control group Type 6A RR Per-protocol follow-up 2 1,5 1 0,5 0 AOM Carriage AOM Carriage AOM Carriage 6.5 -11mo 12 mo 12 -17 mo 18 mo 4-5 yrs 56
  • Efficacy for first and subsequent episodes: Vaccine specific serotypes PncCRM Proportion at risk for first episode 0.9  Control 0.8 VE  Rate of AOM for first episode 0.08 + Proportion at risk for subsequent episode 0.1  0.17 + 0.2 52%  Rate of Over-all AOM for rate of AOM subsequent episode 0.25 = 0.09 0.47 = 0.21 45% 57% 57
  • FinOM Follow-up Study Rate of tympanostomy tube placement before the date of unblinding* *1 Oct 1999 Per-protocol follow-up Fully evaluated children >2 years / 100 person-years 10 PncCRM HBV 5 0 Before unblinding Total 58
  • FinOM Follow-up Study Rate of tympanostomy tube placement *1 Oct 1999 before the date of unblinding* Per-protocol follow-up All eligible children >2 years / 100 person-years 10 PncCRM HBV 5 0 Before unblinding Total 59