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Kamija Phiri1,2; Michael Esan1,2; Michael Boele van Hensbroek3; Carole Khairallah4; Brian Faragher4; Feiko O ter Kuile4 1Community Health Department, College of Medicine, University of Malawi, Blantyre, Malawi 2MLW Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi 3Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands 4Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Kamija Phiri Community Health Department, College of Medicine, University of Malawi
30% paediatric admissions 6% in-hospital mortality Complex aetiology malaria important factor
2826242220181614121086420
Months followed-up
1.0
0.9
0.8
0.7
0.6
Cum
ulat
ive
Sur
viva
l
Community controls
Hospital controls
Cases
In-hospital mortality: 6%
6 months mortality: 8%
Phiri et al,
Plos One
2008
Post-discharge mortality by 6
months was 5x higher than
hospital controls without severe
anaemia (1.6%)
recrudescence re-infection
In-hospital
Stabilize child
Blood transfusion
Parenteral quinine switch to oral ACT
Short-course antibiotics (empirical)
▪ parenteral oral
Post-discharge
No policy for follow-up or interventions
To determine if 3 months of malaria chemoprevention with IPTpd reduces the incidence of deaths or readmissions due to severe anaemia or severe malaria compared to the standard single treatment course of AL on discharge
Hb
Protection
discharge 3 months
Intermittent Preventive Therapy Post-discharge IPTpd
Design trial Multi-centre, double-blind, randomized, placebo controlled, superiority Primary endpoint: composite of death or re-admission due to severe
anaemia or severe malaria Study population Aged 4-59 months; admitted for severe anaemia Stable and able to switch to oral medication Completed blood transfusion & parenteral quinine
Interventions Group A. IPTpd with Coartem - given at 1 & 2 month post-discharge Group B. IPTpd with Placebo - given at 1 & 2 month post-discharge Both groups LA (Coartem at discharge)
Follow-up 0-6 month: Passive case detection; at 6 month: cross-sectional survey
R
E
C
R
U
I
T
E
D
Randomised
In-hospital Post-discharge
Group A
Group B
Treatment
0 IPTpd
1 IPTpd
2
At discharge 1 month 2 month 6 month
LA
LA
LA LA
PL PL
LA= lumefantrine-artemether (Coartem®) PL= Placebo
3 months chemoprevention
3 month
1 month
Eligible Children randomized
(n=1414)
Died (n=16)
Lost (n=35)
Died (n=18)
Lost (n=35)
Completed 6
month
follow-up
(n=657)
Completed 6
month
follow-up
(n=653)
Allocated to
placebo
(n=708)
Allocated to
IPTpd
(n=706)
1414 children recruited June 2006 - Aug 2009 By 6 months
Lost-to-FU 70 (5.0%)
Died 34 (2.4%)
Placebo (708) IPTpd (706)
Mean (SD) age in months 24.2 (13.3) 23.7 (13.5)
Male (%) 47.3 49.4
Bednet use 51.6 52.8
Cerebral malaria on admission (%) 4.4 6.4
Previous Blood transfusion (%) 12.3 11.2
Fever at randomisation (%) 10.6 12.7
Malaria smear+ at randomization (%) 32.8 35.6
HIV (%) Positive 6.6 9.3
Negative 81.2 77.6
Exposed/refusals 12.1 13.0
LA1
P1
LA
LA
LA2
P2 P= Placebo
LA= Lumefantrine-Artemether
Cox regression for repeated events (robust standard errors)
Cu
m H
aza
rd
Days
Period PE 95% CI P
1-6m
1-3m
4-6m
Intervention Extended FU
LA1
P1
LA
LA
LA2
P2 P= Placebo
LA= Lumefantrine-Artemether
Cox regression for repeated events (robust standard errors)
Cu
m H
aza
rd
Days
Period PE 95% CI P
1-6m
1-3m
4-6m
LA1
P1
LA
LA
LA2
P2 P= Placebo
LA= Lumefantrine-Artemether
Cox regression for repeated events (robust standard errors)
Cu
m H
aza
rd
Days
Period PE 95% CI P
1-6m 31 (5 to 50) 0.022
1-3m
4-6m
LA1
P1
LA
LA
LA2
P2 P= Placebo
LA= Lumefantrine-Artemether
Cox regression for repeated events (robust standard errors)
Cu
m H
aza
rd
Days
Period PE 95% CI P
1-6m 31 (5 to 50) 0.022
1-3m 41 (10 to 62) 0.014
4-6m
LA1
P1
LA
LA
LA2
P2 P= Placebo
LA= Lumefantrine-Artemether
Cox regression for repeated events (robust standard errors)
Cu
m H
aza
rd
Days
Period PE 95% CI P
1-6m 31 (5 to 50) 0.022
1-3m 41 (10 to 62) 0.014
4-6m 18 (-25 to 47) 0.355
1-3 Months (chemoprevention)
1-6 Month (+ extended follow-up)
Primary endpoint (Deaths or readmission due
severe anaemia/severe malaria)
41% (p=.01) 31% (p=.02)
All-cause hospitalization 38% (p=.01) 30% (p=.02)
Uncomplicated malaria 49% (p<.0001) 21% (p=.008)
No effect modification by age or ITNs (effective in all age groups, ITN users and non-users)
Investigators Kamija Phiri Michael Esan Michael Boele van Hensbroek Carol Khairallah Brian Faragher Feiko ter Kuile
Committee / monitors Sarah White (stats, Rx allocation) Victor Mwapasa (TSC) Neil French (TSC) Malcolm Molyneux (TSC) Elizabeth Molyneux (safety monitor) Geoffrey Targett (DSMB) Paul Milligan (DSMB) Enitan Carrol (DSMB)
Institutions College of Medicine University of Amsterdam Liverpool School of
Tropical Medicine (sponsor)
Funding NACCAP, Netherlands Gates Malaria Partnership UBS-Optimus Foundation
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