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

4

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?

10

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

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0.10

0.20

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0.40

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0.60

0.70

0.80

0.90

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Proportion of 14 severity scores using different clinical symptoms

17

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ypo

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Dec

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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

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0.2

0.3

0.4

0.5

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0.7

0.8

0.9

1

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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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