Influenza endpoints during clinical trials

Transcription

1 Influenza endpoints during clinical trials Bradford D. Gessner for the influenza endpoints working group Abdullah Baqui Punam Mangtani Richard Wunderink Thomas Cherian Hanna Nohynek Michael Jackson Jeff Roberts WHO: Justin Ortiz Shabir Madhi Eoin West WHO: Marc Perut 1

2 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 2

3 WHY NOT USE EXISTING DEFINITIONS? 3

4 Respiratory infection definitions Fever Core sxs Onset Hosp. No other cause WHO ILI 38C Cough Last 10 days WHO SARI 38C or history Cough Yes CDC ILI 37.8 Cough or sore throat ECDC ILI ECDC ARI WHO/IMCI URTI WHO/IMCI pneum. Fever or feverishness or malaise or HA or myalgia Low grade Cough or sore throat or SOB Cough or sore throat or SOB or coryza Cough and coryza (Cough or diff breath) + tachypnea Sudden Sudden Yes Age 2 mo 5 yr 4

5 Definition will depend on purpose, goals, user groups PURPOSE GOALS USER GROUP Surveillance Validity MOH Clinical care/triage Generalizability NITAG Quality control Basic research Comparability --Other studies --Nat. data Impact on burden --Any --Severe disease Regulatory Manufacturer Clinical trial Safety Academia/modeling Efficacy/effectiveness International funders 5

6 Performance of WHO outcomes: India, age<5y All pts hospitalized at least one night; RT-PCR testing; SARI pre-2012 revision 100% 90% 80% 70% 60% Sensitivity Specificity 50% 40% 30% 20% 10% 0% SARI (measured fever) SARI (reported or measured fever) ILI (measured fever) ILI (reported or measured fever) ARI Reported or measured fever Measured fever Cough Bull WHO 2012;90:

7 Performance of WHO outcomes: Kenya, age<5y All pts hospitalized with ARI; RT-PCR testing 100% 90% 80% 70% 60% 50% 40% 30% Sensitivity Specificity 20% 10% 0% SARI ILI Cough Cough and measured fever Cough and any fever Epidemiol Infect 2013;141:

8 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 8

9 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 9

10 Sample size needed Is a severe disease outcome feasible? ASIA AFRICA Baseline High Baseline High Baseline High VE=40% VE=60% VE=80% Outcome = severe ALRI with confirmed influenza (based on Nair et al) Power = 80%; Lower 95% CI = 0; drop-out = 10%; 1:1 vaccinated:control 10

11 Process Literature review Advisory group of experts Telephone conferences Ongoing: preliminary issues presented 11

12 QUESTION 1: WHAT IS RESPIRATORY DISEASE? 12

13 QUESTION 2: WHAT IS SEVERE DISEASE? 13

14 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 14

15 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 15

16 Altered mental status Tachypnea Hypotension Tachycardia Fever Shock Low heart rate Dyspnea Hypertension Need for mechanical ventilation Dehydration 0.90 Proportion of 14 severity scores using different clinical symptoms

17 Hypoxia Acidocis Hyperuremia Anemia Hyponatremia Thrombocytopenia Elevated creatinine Alkalosis Hypernatremia Hyperglycemia Hypoproteinemia Decreased creatinine Elevated peripherial WBC Decreased peripheral WBC Hypokalemia Hyperkalemia 0.80 Proportion of 14 severity scores using different lab tests

18 AUC value Area under the curve for severity scores predicting mortality (adults with influenza) PMEWS (Myles PR et al) CAT (Myles PR et al) CURB-65 PSI (Riquelme R (Myles PR et al) et al) CURB-65 (Riquelme R et al) CRB-65 (Riquelme R et al) A-DROP (Fujikura Y et al) PSI (Fujikura Y et al) CURB-65 (Fujikura Y et al) 18

19 Nepal India Bangladesh 1 Multi-country Bangladesh 2 Tanzania Kenya 1 Kenya 2 Nepal India 1 Bangladesh 1 Papua New Guinea Indonesia Bangladesh 2 India 2 Bangladesh 3 Kenya 1 Kenya 2 Tanzania Kenya 3 Proportion with hypoxia Proportion of study subjects with severe or very severe pneumonia that had associated hypoxia Severe Very severe Subhi et al. Lancet Infect Dis 2009;9:

20 Prevalence of hypoxia in children hospitalized with pneumonia by geographic region Subhi et al. Lancet Infect Dis 2009;9:

21 QUESTION 3: WHAT IS INFLUENZA? NOT ADDRESSED YET 21

22 cough AND EXAMPLE DEFINITION OF RESPIRATORY INFECTION fever >=38.0 OR history of objective fever OR history of subjective fever AND <10 days duration 22

23 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]) 23

24 Next steps Gather input on proposed case definition Refine definition Publish data 24