influenza endpoints during clinical trials · influenza endpoints during clinical trials bradford...
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Influenza endpoints during clinical trials
Bradford D. Gessner for the influenza endpoints working group
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Abdullah Baqui Punam Mangtani Richard Wunderink
Thomas Cherian Hanna Nohynek
Michael Jackson Jeff Roberts WHO: Justin Ortiz
Shabir Madhi Eoin West WHO: Marc Perut
Need for severe influenza case definition
• Severe disease of most importance for decision makers • Respiratory infection most important influenza outcome • Clinical disease
– Influenza may be present and unrelated to disease (reduced specificity) • High circulation during endemic periods • Less than 100% laboratory specificity
– Influenza may be part of causal chain and not detected at presentation (reduced sensitivity) • Bacterial superinfection • Lack of testing • Poor lab transport/processing • Less than 100% laboratory sensitivity
• Probe study to define true burden of disease – As sensitive a definition as funding allows – Let vaccine sort out what is flu/preventable flu
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WHY NOT USE EXISTING DEFINITIONS?
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Fever Core sxs Onset Hosp. No other cause
Age
WHO ILI 38C Cough Last 10 days
WHO SARI 38C or history Cough Yes
CDC ILI 37.8 Cough or sore throat
Yes
ECDC ILI Fever or feverishness or malaise or HA or myalgia
Cough or sore throat or SOB
Sudden
ECDC ARI Cough or sore throat or SOB or coryza
Sudden
WHO/IMCI URTI
Low grade Cough and coryza
WHO/IMCI pneum.
(Cough or diff breath) + tachypnea
2 mo – 5 yr
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Respiratory infection definitions
Definition will depend on purpose, goals, user groups
PURPOSE GOALS USER GROUP
Surveillance
Validity MOH
Clinical care/triage
Generalizability NITAG
Quality control
Comparability --Other studies --Nat. data
Regulatory
Basic research
Impact on burden --Any --Severe disease
Manufacturer
Clinical trial
Safety Academia/modeling
Efficacy/effectiveness International funders
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Performance of WHO outcomes: India, age<5y All pts hospitalized at least one night; RT-PCR testing; SARI pre-2012 revision
6 Bull WHO 2012;90:804-12.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
SARI(measured
fever)
SARI(reported or
measuredfever)
ILI(measured
fever)
ILI (reportedor measured
fever)
ARI Reported ormeasured
fever
Measuredfever
Cough
Sensitivity
Specificity
Performance of WHO outcomes: Kenya, age<5y All pts hospitalized with ARI; RT-PCR testing
7 Epidemiol Infect 2013;141:212-22
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
SARI ILI Cough Cough andmeasured fever
Cough and anyfever
Sensitivity
Specificity
Problem statement
• Advisory group on PPC for next-generation influenza vaccines
• Unmet need includes: “Safe and well-tolerated influenza vaccines are needed for low-resource settings that are effective at preventing important public health outcomes…”
• No consensus endpoint definition for severe influenza
• Clinical trials in LMIC need a severe suspected and confirmed influenza definition
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Goals
• Focus on clinical trial definition
• Should have – High generalizability
– Reasonable comparability
– Low cost/complexity
• Focus on – LMIC
– Severe outcomes, focus on mortality or outcomes with high risk of mortality
– Definitions of relevance for disease burden: no a priori assumption that flu is identifiable at presentation
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Is a severe disease outcome feasible?
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0
20000
40000
60000
80000
100000
120000
Baseline High Baseline High Baseline High
VE=40% VE=60% VE=80%
Sam
ple
siz
e n
eed
ed
ASIA
AFRICA
Outcome = severe ALRI with confirmed influenza (based on Nair et al) Power = 80%; Lower 95% CI = 0; drop-out = 10%; 1:1 vaccinated:control
Process
• Literature review
• Advisory group of experts
• Telephone conferences
• Ongoing: preliminary issues presented
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QUESTION 1: WHAT IS RESPIRATORY DISEASE?
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QUESTION 2: WHAT IS SEVERE DISEASE?
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What is not severity?
• Health care utilization (e.g., hospitalization)
• Bacterial infection – WHO radiologically confirmed pneumonia (alveolar
consolidation or pleural effusion)
– Positive blood culture
– Elevated WBC
– Elevated CRP
• Risk factors for severity – Malnutrition
– HIV infection
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Literature review
• Among persons with influenza: 14 scoring tools
• Among persons with CAP: 11 scoring tools
• Predict hospitalization, ICU, mechanical ventilation, death
• Children – Few evaluated tools
– Where evaluated performance poor compared to adults
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16
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
Alt
ere
d m
enta
l sta
tus
Tach
ypn
ea
Hyp
ote
nsi
on
Tach
ycar
dia
Feve
r
Sho
ck
Low
hea
rt r
ate
Dys
pn
ea
Hyp
erte
nsi
on
Nee
d f
or
mec
han
ical
ven
tila
tio
n
Deh
ydra
tio
n
Proportion of 14 severity scores using different clinical symptoms
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0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80H
ypo
xia
Aci
do
cis
Hyp
eru
rem
ia
An
emia
Hyp
on
atre
mia
Thro
mb
ocy
top
enia
Ele
vate
d c
reat
inin
e
Alk
alo
sis
Hyp
ern
atre
mia
Hyp
ergl
ycem
ia
Hyp
op
rote
inem
ia
Dec
reas
ed c
reat
inin
e
Ele
vate
d p
erip
her
ial W
BC
Dec
reas
ed p
erip
her
al W
BC
Hyp
oka
lem
ia
Hyp
erka
lem
ia
Proportion of 14 severity scores using different lab tests
Area under the curve for severity scores predicting mortality (adults with influenza)
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
PMEWS (MylesPR et al)
CAT (Myles PRet al)
CURB-65(Myles PR et al)
PSI (Riquelme Ret al)
CURB-65(Riquelme R et
al)
CRB-65(Riquelme R et
al)
A-DROP(Fujikura Y et
al)
PSI (Fujikura Yet al)
CURB-65(Fujikura Y et
al)
AU
C v
alu
e
• Subhi et al. Lancet Infect Dis 2009;9:219-27
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Nep
al
Ind
ia
Ban
glad
esh
1
Mu
lti-
cou
ntr
y
Ban
glad
esh
2
Tan
zan
ia
Ken
ya 1
Ken
ya 2
Nep
al
Ind
ia 1
Ban
glad
esh
1
Pap
ua
New
Gu
inea
Ind
on
esia
Ban
glad
esh
2
Ind
ia 2
Ban
glad
esh
3
Ken
ya 1
Ken
ya 2
Tan
zan
ia
Ken
ya 3
Severe Very severe
Pro
po
rtio
n w
ith
hyp
oxi
a Proportion of study subjects with severe or very severe pneumonia
that had associated hypoxia
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• Subhi et al. Lancet Infect Dis 2009;9:219-27
Prevalence of hypoxia in children hospitalized with pneumonia by geographic region
QUESTION 3: WHAT IS INFLUENZA? NOT ADDRESSED YET
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EXAMPLE DEFINITION OF RESPIRATORY INFECTION
• cough
AND
• fever >=38.0 OR history of objective fever OR history of subjective fever
AND
• <10 days duration
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EXAMPLE DEFINITION OF SEVERE RESPIRATORY INFECTION
• (pulse oximetry <90% at sea level OR <88% at any location) OR • (mechanical ventilation OR ICU admission) OR • (unable to drink/breastfeed OR vomiting everything OR
convulsions OR lethargy/unconscious) OR • (lower chest wall indrawing) OR • (age 18 years and above AND meets qSOFA criteria [2 of the
following: altered mental status, RR>=22/min, systolic blood pressure<=100mmHg])
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Next steps
• Gather input on proposed case definition
• Refine definition
• Publish data
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