Simplified management of infections in neonates and young infants for use in outpatient and community settings A multicentre randomised

controlled trial in DR Congo, Kenya and Nigeria

Elizabeth Mason On behalf of the African Neonatal Sepsis Trial (AFRINEST) Group Johannesburg, April 2013

Department of Maternal, Newborn, Child and Adolescent Health

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AFRINEST Investigator Group

Democratic Republic of Congo (DRC)
Prof. Antoinette Kitoto Tshefu, University of Kinshasa, School of Public Health

Kenya
Prof. Fabian Esamai, Moi University School of Medicine, Child Health and Paediatrics.

Nigeria
Dr Adejumoke Ayede, University of Ibadan, College of Medicine Prof. Ebunoluwa A. Adejuyigbe, Obafemi Awolowo University Ile-Ife, Paediatrics. Prof. Robinson D. Wammanda, Ahmadu Bello University, Zaria, Paediatrics

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Study Sites
DRC Kenya Nigeria

Site

Equateur Province 300,000 2 districts 12,000 2000

Western province 350,000 8 districts 12500 2000

Ibadan, IleIfe, Zaria 600,000 5 LGAs* 25,000 3000

Gemena, DRC

Study population Expected Births/year Expected sick infants/year

*LGA: Local government authority

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Primary Objective

To evaluate simple, safe and effective antibiotic regimens for use at first level facilities and in the community for young infants with possible serious bacterial infection whose families do not accept or cannot access referral level care.

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Context: Research in programme setting

1: Facility based care
Facility births

2: Home based care

Home births CHWs
Find births Make home visits to: identify signs of illness empower families to identify signs of illness and promote care seeking

Home care
No illness

3: IMCI
Normal or mild illness (treated)

Sick young infants seen by trained health workers IMCI assessment and management

Possible Severe Bacterial Infection (PSBI)

Referral to hospital accepted

Referral not accepted

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Study Design: Randomized trial

Open-label equivalence with two strata

4: Current research

Referral not accepted

Outpatient management

Critically ill

Clinical severe infection

Fast breathing only

Not enrolled
Offered simplified antibiotic regimen

Consent given and enrolled

Treated with simplified antibiotic regimens on outpatient basis

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Inclusion and exclusion criteria

Inclusion criteria
Study I: Clinical severe infection
One or more of the following signs: stopped feeding well movement only when stimulated severe chest in-drawing Temperature >38.0oC or <35.5oC

Exclusion criteria
Study 1: Clinical severe infection
Signs of critical illness

Study 2: Fast breathing

Signs of clinical severe infection Critically ill infants

Study 2: Fast breathing

Respiratory rate 60 or more per minute

For both studies

Previous inclusion in the study Hospitalization in the last 2 weeks

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Treatment regimens
Control arm for both studies
A (reference treatment): IM gentamicin and procaine penicillin once daily for 7 days 14 injections

Experimental interventions
Clinical severe infection B: IM gentamicin once daily and oral amoxicillin twice daily for 7 days 7 injections C: IM gentamicin and procaine penicillin once daily for 2 days, thereafter oral amoxicillin twice daily for 5 days 4 injections
D: IM gentamicin once daily and oral amoxicillin twice daily for 2 days, thereafter oral amoxicillin twice daily for 5 days 2 injections Fast breathing E: oral amoxicillin twice daily for 7 days
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No injections

Outcomes
Primary outcome
Treatment failure within 7 days of randomization (includes death)

Secondary outcomes
Death between 8-15 days of enrolment Relapse of signs/symptoms present at enrolment Compliance to study therapy Adverse effects due to study drugs

Independent outcome assessment

Scheduled on days 4, 8, 11 and 15 Additionally when treatment health workers feels the need

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Treatment Failure - Clinical Severe Infection

IN THE FIRST WEEK AFTER RANDOMIZATION Death Hospitalization

Serious adverse effect of the study antibiotics

Clinical deterioration defined as emergence of any sign of critical illness or a new sign of severe infection

No improvement by day 4
Re-emergence of any presenting sign after disappearance on day 4 Persistence of a presenting sign on day 8

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Treatment Failure - Fast Breathing

IN THE FIRST WEEK AFTER RANDOMIZATION Death Hospitalization Serious adverse effect of the study antibiotics Clinical deterioration defined as emergence of any sign of critical illness or a new sign of severe infection No improvement in respiratory rate by day 4 Persistence of fast breathing on day 8

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Sample size
Clinical severe infection - 3600 in 3 countries Fast Breathing - 2300 in 3 countries Duration of study: 30 months

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Current status of study

Surveillance Births identified Infants identified by CHW to have any sign of infection Infants assessed by nurses to have signs of Possible Serious Bacterial Infection Infants not enrolled because of critical illness Number 77,589 11,625 6918 467

Infants not enrolled because of another reason

Infants with clinical severe infection enrolled in the study Infants with fast breathing enrolled in the study

985
3335 2131

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Policy implications
Simplest safe and effective regimens for outpatient treatment of clinical severe infection, where referral is not possible Simplest safe and effective treatment of fast breathing Role of CHWs in identifying signs of infection at home, and taking infants for treatment to nearest health facility

Health system requirements planning, human resources, commodities, supervision and monitoring for outpatient treatment of severe infections

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Next Steps
Complete enrolment of the study Complete follow-up & data collection Data entry completion and cleaning Data analysis and report writing Dissemination of the results May 2013 June 2013 July to August 2013 September 2013 November 2013

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Other members of Study Group

Democratic Republic of Congo
Dr. Cyril Engmann Dr Adrien L. Longombe

Nigeria Ibadan
Prof. A. Falade Prof. A. Sowunmi Prof. E.A. Bamgboye Mr. K. A. Ogedengbe

Kenya
Dr. Peter Gisore Prof. Edward Liechty Dr. Sherri Bucher

Ile Ife
Prof. A. Odebiyi Dr. O. Esimai Dr H.C Anyabolu Prof. W. Ogala Dr Clara Ejembi

Data Management: London School of Hygiene and Tropical Medicine, London (Lu Gram and Simon Cousens) Zaria

Technical Support and Coordination: Department of Maternal, Newborn, Child & Adolescent Health, WHO Geneva (S. Qazi, R. Bahl, N. Rollins, S. Yoshida)
Funding: Bill and Melinda Gates Foundation through WHO

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