A Multicenter Equivalence Study of Oral Amoxicillin versus Injectable Penicillin in Children Aged 3 to 59 Months with Severe Pneumonia Amoxicillin Penicillin Pneumonia International Study (APPIS) Group Colombia, Ghana, India, Mexico, Pakistan, South Africa, Vietnam, Zambia Center for International Health, SPH, Boston University Department of Child and Adolescent Health & Development, WHO

2 Background Estimated 2.1 million ARI deaths in children every yearEstimated 2.1 million ARI deaths in children every year WHO-defined severe pneumonia: admission & treatment with injectable penicillin / ampicillinWHO-defined severe pneumonia: admission & treatment with injectable penicillin / ampicillin Drawbacks of hospitalization and injectable therapy:Drawbacks of hospitalization and injectable therapy: –Side effects: local and needle-borne infections –Costs: dispensing drugs, hospitalization Amoxicillin Penicillin Pneumonia International Study (APPIS)

3 Research Questions Primary: Is treatment failure at 48 h among children aged 3-59 months with WHO- defined severe pneumonia treated with oral amoxicillin equivalent to that with injectable penicillinPrimary: Is treatment failure at 48 h among children aged 3-59 months with WHO- defined severe pneumonia treated with oral amoxicillin equivalent to that with injectable penicillin? Secondary: Do the two treatments remain clinically equivalent through follow-up on days 5 and 14?Secondary: Do the two treatments remain clinically equivalent through follow-up on days 5 and 14? Amoxicillin Penicillin Pneumonia International Study (APPIS)

4 Study design and setting Non-blinded, equivalency randomized clinical trialNon-blinded, equivalency randomized clinical trial Nine tertiary care centers in eight low & middle income countries in three continents:Nine tertiary care centers in eight low & middle income countries in three continents: -Colombia -Ghana -India -Mexico -Pakistan (2 sites) -South Africa -Vietnam -Zambia Amoxicillin Penicillin Pneumonia International Study (APPIS)

5 Inclusion Criteria  Children aged 3 to 59 months with WHO-defined severe pneumonia (lower chest indrawing in children with cough and/or difficult breathing) WHO-defined severe pneumonia (lower chest indrawing in children with cough and/or difficult breathing)  Informed consent by a legal guardian Amoxicillin Penicillin Pneumonia International Study (APPIS)

6 Exclusion Criteria Very severe disease (severe malnutrition)Very severe disease (severe malnutrition) Chronic or congenital conditionsChronic or congenital conditions Antibiotics for more than 48 hrsAntibiotics for more than 48 hrs Hospitalization in prior two weeksHospitalization in prior two weeks Bronchial asthma or wheeze whose LCI improved with inhaled salbutamolBronchial asthma or wheeze whose LCI improved with inhaled salbutamol Measles in the last one monthMeasles in the last one month Oxygen saturation < 80%/75% in room airOxygen saturation < 80%/75% in room air Clinical evidence of HIV infection (clinical category B or C, CDC-defined)Clinical evidence of HIV infection (clinical category B or C, CDC-defined) Known penicillin allergyKnown penicillin allergy Previous inclusion in studyPrevious inclusion in study Living outside study areaLiving outside study area Amoxicillin Penicillin Pneumonia International Study (APPIS)

7 Trial Entry and Interventions Clinical baseline and naso - pharyngeal sampling for RSV and routine microbiologyClinical baseline and naso - pharyngeal sampling for RSV and routine microbiology Randomization:Randomization: –Computer generated at coordinating center (WHO) –Opaque, sealed and numbered envelopes Interventions:Interventions: –Injectable penicillin G 200,000 IU/kg/day in four doses –Oral amoxicillin 45 mg/kg/day in three doses Amoxicillin Penicillin Pneumonia International Study (APPIS)

8 Follow up In hospital: every 6 h for at least 48 hIn hospital: every 6 h for at least 48 h Outpatient clinic: 5 and 14 daysOutpatient clinic: 5 and 14 days Data collected by trained observers:Data collected by trained observers: –Vital signs –Presence of danger signs –Lower chest indrawing –Oxygen saturation by pulse oximetry –Adverse events Amoxicillin Penicillin Pneumonia International Study (APPIS)

9 Outcomes Primary: failure at 48 hours:Primary: failure at 48 hours: –Persistence of severe pneumonia (LCI) –Danger signs (very severe disease) –Death –Severe hypoxemia (< 80%/75%) –Life-threatening or serious adverse drug reaction –Received another antibiotic –Newly diagnosed condition –Voluntary withdrawal Secondary: failure at 5 and 14 days:Secondary: failure at 5 and 14 days: –As for failure at 48 h –Recurrence of LCI or hypoxemia (<90%/88%) –Non-severe pneumonia on day 14 Amoxicillin Penicillin Pneumonia International Study (APPIS)

10 Sample size and analysis Sample size: Equivalence trial:Sample size: Equivalence trial: –Expected failure rate with penicillin: 10% –Equivalence: rate amoxicillin = penicillin  5% –Alpha 0.05 (one side), power 90% –Loss to follow-up at 48 h: 1% –Three interim and one final analyses –861 children per group (1,722) Analysis:Analysis: –Failure rates difference and 95%CI –Intention to treat and per protocol analysis Amoxicillin Penicillin Pneumonia International Study (APPIS)

11 Ethical issues Review and approval by the Institutional Review Board in all participating and coordinating centersReview and approval by the Institutional Review Board in all participating and coordinating centers Monitoring by an independent Data Safety Monitoring Board three times along the studyMonitoring by an independent Data Safety Monitoring Board three times along the study Second interim analysis: trend to increased early deaths at sites with high prevalence of HIV = exclusion of children under one year with oral thrush, hepatosplenomegaly or parent known to be HIV-infectedSecond interim analysis: trend to increased early deaths at sites with high prevalence of HIV = exclusion of children under one year with oral thrush, hepatosplenomegaly or parent known to be HIV-infected Amoxicillin Penicillin Pneumonia International Study (APPIS)

12 Baseline comparison Amoxicillin Penicillin Pneumonia International Study (APPIS)

13 Study profile

14 Treatment failures Amoxicillin Penicillin Pneumonia International Study (APPIS)

15 Reasons for failure at 48 hours Amoxicillin Penicillin Pneumonia International Study (APPIS)

16 Baseline risk factors for failure at 48 h Amoxicillin Penicillin Pneumonia International Study (APPIS)

17 Cost-minimization Study Conducted at Indira Gandhi Medical College, Nagpur, India (Dr. A. Patel)Conducted at Indira Gandhi Medical College, Nagpur, India (Dr. A. Patel) Amoxicillin therapy is associated with significant reductions in:Amoxicillin therapy is associated with significant reductions in: –Medication costs –Direct medical costs –Total costs Amoxicillin Penicillin Pneumonia International Study (APPIS)

18 Discussion Main finding: oral amoxicillin and injectable penicillin are equally effective in terms of treatment failures and clinical relapse ratesMain finding: oral amoxicillin and injectable penicillin are equally effective in terms of treatment failures and clinical relapse rates Treatment failure rates higher than expected:Treatment failure rates higher than expected: –Strict but non validated criteria –High incidence of wheeze associated with lower chest indrawing at 48 h –HIV – infected children with newly diagnosed conditions –Hypoxemia associated with high altitude Clinical efficacy of amoxicillin and penicillin is equivalent to other more expensive antibioticsClinical efficacy of amoxicillin and penicillin is equivalent to other more expensive antibiotics Amoxicillin Penicillin Pneumonia International Study (APPIS)

19 Conclusions Oral amoxicillin and injectable penicillin are equally effective in hospitalized children with severe pneumoniaOral amoxicillin and injectable penicillin are equally effective in hospitalized children with severe pneumonia Use of oral amoxicillin reduces the costs associated with treatmentUse of oral amoxicillin reduces the costs associated with treatment Caution is needed for using these findings in high HIV prevalence areasCaution is needed for using these findings in high HIV prevalence areas Amoxicillin Penicillin Pneumonia International Study (APPIS)

20 Acknowledgements Participating children and their parentsParticipating children and their parents Sponsors:Sponsors: –Department of Child and Adolescent Health & Development, WHO –ARCH Project Data Safety Monitoring Board membersData Safety Monitoring Board members Staff at research centersStaff at research centers Amoxicillin Penicillin Pneumonia International Study (APPIS)

A Multicenter Equivalence Study of Oral Amoxicillin versus Injectable Penicillin in Children Aged 3 to 59 Months with Severe Pneumonia Amoxicillin Penicillin Pneumonia International Study (APPIS) Group Colombia, Ghana, India, Mexico, Pakistan, South Africa, Vietnam, Zambia Center for International Health, SPH, Boston University Department of Child and Adolescent Health & Development, WHO

23 Some Potential Policy Implications Practical benefits of switching-over to oral amoxicillin:Practical benefits of switching-over to oral amoxicillin: –Simpler treatment –Reduction in direct costs –Health workers can start therapy at primary facilities –Treatment option for severe pneumonia when referral is not feasible / desirable Amoxicillin Penicillin Pneumonia International Study (APPIS)

24 Some Limitations of Data for Policy RCT conducted in controlled environment (close monitoring)RCT conducted in controlled environment (close monitoring) Safety of treating severe pneumonia in communities is unknownSafety of treating severe pneumonia in communities is unknown Children with severe pneumonia are admitted to hospital due to several reasons:Children with severe pneumonia are admitted to hospital due to several reasons: –Administration of injectable antibiotics –Identification and treatment of associated hypoxemia –Ensuring compliance with treatment –Need for additional observation  APPIS data do not address home treatment of severe pneumonia Amoxicillin Penicillin Pneumonia International Study (APPIS)

25 How to move on? Further analysis of APPIS data:Further analysis of APPIS data: –Features that predict severe hypoxemia –Relationship between hypoxemia and therapy failure –Further look of children screened but excluded Need to collect information from hospitals in LMIC about:Need to collect information from hospitals in LMIC about: –Availability of oxygen for treating severe pneumonia –Current prevalent practices for oxygen administration Home vs. hospital treatment of severe pneumonia:Home vs. hospital treatment of severe pneumonia: –RCT of outpatient management of severe pneumonia –Carefully conducted descriptive studies Amoxicillin Penicillin Pneumonia International Study (APPIS)