Community-Acquired Pneumonia Immunization Trial in Adults — CAPiTA

M. Bonten 1 , M. Bolkenbaas 1 , S. Huijts 1 , C. Webber 2 , S. Gault 2 , W. Gruber 3 , D. Grobbee 1,4 , for the CAPiTA study team 1 Julius Center for Health Sciences and Primary Care, UMC Utrecht, the Netherlands 2 Pfizer Vaccine Clinical Research, Maidenhead, UK 3 Pfizer Vaccine Clinical Research, Pearl River, NY, USA 4 Julius Clinical, Zeist, the Netherlands

Disclaimer

This study was sponsored by Wyeth, which was acquired by Pfizer Inc in October 2009.

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Background

• Effectiveness of pneumococcal polysaccharide vaccines against community-acquired pneumonia (CAP) is uncertain 1,2 • Pneumococcal conjugate-vaccines are effective in preventing IPD and pneumonia in children, but efficacy in preventing pneumococcal pneumonia or IPD in adults over 65 has not been investigated.

3 • Establishing efficacy of pneumococcal vaccine for preventing pneumonia has been hampered by the lack of a specific and sensitive test for identification of causative S. pneumoniae serotypes.

1. Moberley S, Holden J et al. Cochrane Database of Systematic Reviews 2013, Issue 1.

2. Huss A, Scott P et al. CMAJ 2009; 180: 48-58 3. Grijalva CG, Pelton SI. Curr Opin Pediatr. 2011 Feb;23(1):98-104.

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The Serotype-Specific Urinary Antigen Detection (UAD) Assay

• • • Developed by Pfizer specifically for the CAPiTA study A multiplex antigen-binding assay for detection of PCV13-type capsular polysaccharide Enables accurate testing of urine for the presence of PCV13 serotypes: 97% sensitivity and 100% specificity in adults with pneumonia Pride MW et al.

Clin. Vaccine Immunol

. 2012;19(8):1131-1141 Huijts et al.,

Eur Resp Journal.

2013; 42(5):1283-90 4

Key Points

Need Purpose A clear medical need exists among adults for an effective vaccine to prevent pneumococcal disease, including pneumococcal community acquired pneumonia (CAP) The primary outcome of CAPiTA is to establish in adults aged 65 years and older the efficacy of PCV13 to prevent a first episode of confirmed vaccine-serotype pneumococcal CAP (VT-CAP) Design CAPiTA is a randomized, placebo-controlled clinical trial that is one of the largest prospective vaccine efficacy trials ever conducted in adults Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383.

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•

Why CAPiTA was Conducted in the Netherlands

The Netherlands does not have a generalized, age-based recommendation for 23-valent pneumococcal polysaccharide vaccine (PPSV23) – – The Netherlands Health Council recommends that PPSV23 be provided to only very high-risk individuals, and recommended a placebo-controlled study.

Adults aged 65 years and older are generally PPSV23-naïve.

• All subjects are linked to a single General Practitioner (GP) – Allowing identification of eligible study candidates and follow-up for relevant endpoints for safety and efficacy • Antibiotic prescription is restricted to physicians, either the GP or in a hospital, facilitating case identification.

• The infrastructure of GP-based antibiotic prescription and hospital referral allowed for implementing a standardized approach to detect study subjects hospitalised with CAP in the catchment areas of participating GPs.

Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383.

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Clinical Trial Design

Screening and recruitment 84,496 volunteers

Aged ≥ 65 years

R

Placebo Accrual of VT-CAP Cases Review of Primary and Secondary Outcome Data PCV13

CAPiTA was an event-driven trial dependent on accrual of sufficient number of cases of VT-CAP Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383.

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Inclusion/Exclusion Criteria

Inclusion Criteria

• ≥65 years • Registered with the GP referring subjects to study • Able to fulfill study requirements

Exclusion Criteria

• Previous pneumococcal vaccination • Use of investigational vaccine or medication in past 30 days • Resident in nursing home/long-term care facility • Immune deficiency or suppression* • History of severe adverse reaction to a vaccine or component • Contraindication to influenza vaccination, if influenza vaccine is to be administered at same time • Contraindication to PCV13 * Immunocompetent subjects with co-morbid conditions were included e.g. chronic heart disease, diabetes mellitus, chronic pulmonary disease 8 Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383.

Primary and Secondary Efficacy Objectives

Demonstrate the Efficacy of PCV13 in the Prevention of a First Episode of:

1. Vaccine-serotype (VT) Pneumococcal CAP 2. VT Non-Bacteremic Non-Invasive (NB/NI) Pneumococcal CAP VT Invasive Pneumococcal Disease (IPD) Analyses populations are per protocol and modified intention-to-treat.

Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383.

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Selected Exploratory Efficacy Objectives

Demonstrate the Efficacy of PCV13 in the Prevention of:

• • • First episode of confirmed pneumococcal CAP First episode of confirmed NB/NI pneumococcal CAP First episode of IPD Analyses are per protocol.

Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383.

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How Were Cases of VT-CAP Identified?

Standardized approach for identifying study subjects presenting with a clinical suspicion of CAP at the ER of any of the 58 sentinel hospitals.

Diagnostic work-up included chest X-ray, blood culture and urine sample for Binax testing according to standard care practice, plus protocol defined collection of urine for SSUAD.

Definition of CAP based on protocol defined clinical criteria AND X-ray findings consistent with pneumonia.

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CAP Case Capture flow

Patient presents at a sentinel center with suspected pneumonia >14 days post vaccination Independent Committee Independent Committee Radiological assessment: Is Chest X-Ray consistent with CAP?

And ≥2 Clinical Criteria positive Yes Microbiological Assessment: S pneumoniae by microscopy, culture, Binax or SSUAD No Yes Immune Status review: Is the patient immunocompromised?

Yes No Pneumococcal CAP Case Per Protocol population Not pneumococcal CAP Inclusion in immuno-compromised subgroup of modified ITT population

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Microbiological Definitions for Primary and Secondary Endpoints

Endpoint Definition Confirmed VT pneumococcal CAP Confirmed NB/NI VT pneumococcal CAP VT-IPD

(1) Presence of 2 or more specified clinical findings consistent with CAP AND (2) Chest x-ray consistent with CAP AND (3) Culture of VT

S pneumoniae

from blood, pleural fluid or other sterile site and/or positive VT SSUAD Confirmed VT pneumococcal CAP for which a blood culture result is available and is negative and for which any other culture results from pleural fluid or other sterile site are negative for

S pneumoniae

VT

S pneumoniae

in blood, pleural fluid or other sterile site , If no serotype was determined from the

S pneumoniae

culture isolate and a serotype was determined by SSUAD for the same case, the SSUAD serotype was assigned to the case.

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Timelines

Sep 13, 2008 Jan 31, 2010 Aug 28, 2013 14

CAPiTA Recruitment by Region

North Holland: 14,901 South Holland: 6,140 Zeeland: 50

Total Recruitment: 84,496 in all regions of the Netherlands

Groningen: 3,155 Friesland: 1,005 Drenthe: 2,799 Flevoland: 1,521 Overijssel: 6,716 Gelderland: 10,852 Utrecht: 8,239 North Brabant: 17,573 Limburg: 11,545 15

Baseline Characteristics

Characteristic Age (mean, SD) PCV13 n=42,237 72.8 (5.7) Male (%) Female (%) Asthma (%) Diabetes mellitus: Insulin Use (%) Diabetes mellitus: No Insulin Use (%) Heart disease (%) Liver disease (%) Lung disease (%) Splenectomy (%) 55.5

44.5

4.8

3.3

9.1

25.3

0.5

10.1

<0.1

Placebo n=42,255 72.8 (5.6) 56.3

43.7

5.0

3.2

9.4

25.4

0.5

10.3

<0.1

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Primary and Secondary Objectives: Per Protocol

Efficacy Endpoint

First episode of confirmed VT pneumococcal CAP First episode of confirmed NB/NI VT pneumococcal CAP

Vaccine Group

PCV13 (n=42,240) Placebo (n=42,256)

VE (%) 95.2% CI p-Value

First episode of VT-IPD

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Primary and Secondary Objectives: Per Protocol

Efficacy Endpoint

First episode of confirmed VT pneumococcal CAP First episode of confirmed NB/NI VT pneumococcal CAP

Vaccine Group

PCV13 (n=42,240) Placebo (n=42,256)

VE (%)

49 90 45.56

95.2% CI p-Value

(21.82,62.49) 0.0006

First episode of VT-IPD

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Primary and Secondary Objectives: Per Protocol

Efficacy Endpoint

First episode of confirmed VT pneumococcal CAP First episode of confirmed NB/NI VT pneumococcal CAP

Vaccine Group

PCV13 (n=42,240) Placebo (n=42,256)

VE (%)

49 90 45.56

95.2% CI p-Value

(21.82,62.49) 0.0006

33 60 45.00

(14.21, 65.31) 0.0067

First episode of VT-IPD

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Primary and Secondary Objectives: Per Protocol

Efficacy Endpoint

First episode of confirmed VT pneumococcal CAP First episode of confirmed NB/NI VT pneumococcal CAP

Vaccine Group

PCV13 (n=42,240) Placebo (n=42,256)

VE (%)

49 90 45.56

95.2% CI p-Value

(21.82,62.49) 0.0006

33 60 45.00

(14.21, 65.31) 0.0067

First episode of VT-IPD 7 28 75.00

(41.43, 90.78)* 0.0005

* 95% Confidence Intervals 20

Cumulative Case Counts

60 1st Episode VT-CAP 30 1st Episode VT-IPD 60 Days since vaccination 1st Episode NB/NI VT-CAP Days since vaccination Days since vaccination

Interim analyses (1 st episode VT-CAP, n=74)

PCV13 Placebo VE 99.48% CI p-Value 25 49 49.0

-2.4 , 75.9

Final analyses (1 st episode VT-CAP, n=139)

0.007

95.2% CI 49 90 45.56

21.82,62.49

0.0006

Days since vaccination plots from post hoc analysis 21

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Serotype Distribution

First episode VT-CAP PCV13 vs. Placebo by Serotype

10 5 20 15 0 1 3 4 5 6A 6B PCV13 7F Placebo 9V 14 18C 19A 19F 23F 22

10 8 2 0 6 4 16 14 12 1

Serotype Distribution

First episode VT-NB/NI CAP PCV13 vs. Placebo by Serotype

3 4 5 6A 6B PCV13 7F Placebo 9V 14 18C 19A 19F 23F 23

8 7 6 1 0 3 2 5 4 1

Serotype Distribution

First Episode VT-IPD PCV13 vs. Placebo by Serotype

3 4 5 14 6A 13vPnC 6B Placebo 7F 9V 18C 19A 19F 24

Primary and Secondary Objectives: mITT

Efficacy Endpoint

First episode of confirmed VT pneumococcal CAP Immunocompetent Immunodeficient/suppressed

Vaccine Group

PCV13 (n=42,240) Placebo (n=42,256)

VE (%)

66 106 37.74

95% CI p-Value

(14.31, 55.05) 0.0028

51 14 93 11 First episode of confirmed NB/NI VT pneumococcal CAP Immunocompetent Immunodeficient/suppressed 43 35 7 73 63 10 41.10

(12.70, 60.70) 0.0068

First episode of VT-IPD Immunocompetent 8 7 33 28 75.76

(46.47, 90.33) Immunodeficient/suppressed 1 3

3 patients were not assessed by Immune Status Committee (2 in Placebo, 1 in Prevenar13) 25

0.0001

Selected Exploratory Efficay Endpoints: Per Protocol

Efficacy Endpoint

First episode of Confirmed Pneumococcal CAP (VT + N-VT + untypeable)

Vaccine Group

PCV13 (n=42,240) Placebo (n=42,256)

VE (%) 95.2% CI p-Value

100 144 30.56

(9.75, 46.74) 0.0058

First episode of Confirmed NB/NI Pneumococcal CAP First episode of IPD 66 27 87 56 24.14

51.79

(-5.68, 45.76) (22.38, 70.72) 0.1056

0.0039

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Safety

Safety Outcome Serious Adverse Events ≤28 days Cardiac disorders General disorders and administration site conditions Deaths PCV 13 n=42,279 327 (0.8%) 72 (0.2%) 23 (0.1%%) Placebo n=42,255 314 (0.7%) 74 (0.2%) 7 (<0.1%) p-Value 0.606

0.934

0.003

3,006 (7.1%) 3,005 (7.1%) 0.979

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Reactogenicity

Safety Outcome, in immunogenicity subset Any local reaction Redness: any severe 1 Swelling: any severe 1 Pain: any severe 2 Limitation of arm movement: any severe 3 PCV13 352 (38.4%) N 916 43 (4.9%) 886 4 (0.5%) 60 (6.8%) 1 (0.1%) 330 (36.1%) 3 (0.3%) 881 888 881 914 881 126 (14.1%) 891 11 (1.2%) 882 Placebo N 73 (8.4%) 867 10 (1.2%) 859 1 (0.1%) 10 (1.2%) 1 (0.1%) 53 (6.1%) 1 (0.1%) 859 859 859 863 860 28 (3.2%) 865 6 (0.7%) 861

Severe = >10.0 cm ( 1 ); prevents daily activity ( 2 ); unable to move arm above shoulder ( 3 )

p-Value <0.001

<0.001

0.374

<0.001

>0.99

<0.001

0.625

<0.001

0.331

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Systemic Reactions

Safety Outcome in immunogenicity subset Any systemic event Fever Fatigue Headache Chills Rash Vomiting Decreased Appetite Diarrhea New Generalized Muscle Pain Aggravated Generalized Muscle Pain New Generalized Joint Pain Aggravated Generalized Joint Pain PCV13 363 (39.5%) N 918 26 (2.9%) 168 (18.8%) 142 (15.9%) 84 (9.4%) 29 (3.3%) 3 (0.3%) 47 (5.3%) 51 (5.7%) 165 (18.4%) 81 (9.1%) 66 (7.4%) 46 (5.2%) 885 895 892 891 882 881 886 887 896 889 886 884 Placebo 315 (34.7%) N 907 11 (1.3%) 130 (14.8%) 130 (14.8%) 73 (8.4%) 7 (0.8%) 8 (0.9%) 32 (3.7%) 76 (8.7%) 73 (8.4%) 38 (4.4%) 47 (5.4%) 36 (4.2%) 860 876 878 886 860 862 865 873 868 866 866 865

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p-Value 0.037

0.019

0.031

0.553

0.504

<0.001

0.141

0.109

0.017

<0.001

<0.001

0.098

0.311

Conclusions

Vaccine efficacy of PCV13 was:  45.56% (95.2% CI 21.82%-62.49%; p=0.0006) for preventing the first episode of VT-CAP  45.00% (95.2% CI 14.21%-65.31%; p=0.0067) for preventing the first episode of NB/NI VT-CAP  75.00% (95% CI 41.43%-90.78%; p=0.0005) for preventing the first episode of VT-IPD Safety profile was satisfactory and consistent with prior adult experience 30

Other Findings

All 13 serotypes were circulating - PCV7 NIP in children started in 2006, - PCV10 introduced in March 2011 Most prominent effects on serotypes 3, 7F, 19A Effectiveness seemed to remain stable over the period of observation (mean 3.97 years).

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• • • • • • • • •

Acknowledgements

Julius Clinical 2,260 GPs Sub-investigators and research nurses in 58 sentinel hospitals Drs. Vos, Lely, van Leersum, Coche (Adjudication Committee) Drs. Van Paasen, Ellerbroek, Cohen Tervaert, Dam (Immune Status Committee) Drs. Springer, Lughtmeier, van der Schuur, Lamers (Mortality Assessment Committee) Dr. Van de Ende (National Reference Center, AMC) Dr. Coenjaerts (Dept of Med Microbiology UMCU) Linnaeusinstituut , Spaarneziekenhuis Haarlem (Substudy) • • Dr. M. Peeters, Tilburg (June 6th, 2010) Dr. R. Veenhoven, Haarlem (October 6th, 2013) 32

Backups

Subset Analysis

Immunogenicity and Nasopharyngeal Carriage

Blood Nasopharyngeal Sample Swab

P P • • •

Subset of study subjects

– n=2000 (1000 each from PCV13 and placebo groups)

Immunogenicity Nasopharyngeal Carriage

– Pneumococcal carriage of PCV13 and non-PCV13 serotypes plus other organisms Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383 Data on File. CAPiTA Study Protocol 6115A1-3006-NL 34

How Are Cases of VT-CAP Confirmed?

Possible CAP By Protocol Defined Clinical Criteria

+

X-Ray Consistent with Pneumonia

+

Microbiological Criteria to Confirm Pneumococcal CAP and VT/NVT Case definition of confirmed vaccine-type (VT) pneumococcal CAP Clinical features of CAP, AND X-ray consistent with pneumonia, AND Evidence of vaccine-serotype pneumococcal infection Blood culture or other normally sterile sites (per clinical practice) AND / OR Non-culture methods (serotype-specific urinary antigen detection assay)

Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383 35

Analysis Populations

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Patient Selection

• • • General Practitioner selects eligibles >65 jaar, not meeting exclusion criteria “Eligible candidate” receives invitation letter + study information on behalf of their own GP “Eligible candidate” return card if interested in study participation • • • • • “Eligible candidates” are invited by study team to come to vaccination facility “Eligible candidates” receive detailed study information by study physician Informed consent is obtained Demographic data are collected and presence of exclusion criteria are checked Study participant receives pneumococcal vaccination (or placebo) • • GP reports Serious Adverse Events occurring within the first 28 days after vaccination GP reports death and loss to follow-up until end of study 37

Analysis Populations

Safety population:

All vaccinated subjects who were followed for safety

mITT population: All CAP Immunocompetent pneumococcal CAP & IPD Per protocol:

• Eligible for study • Identified as a case • Not immunocompromised • No protocol violations

Immunodeficient*

* At time of episode 38