Compare the Effectiveness Between Existing Treatment and New Treatment
Status:
Completed
Trial end date:
2017-03-30
Target enrollment:
Participant gender:
Summary
In camps for displaced persons located along the Thai-Myanmar border, mefloquine and
artesunate combination therapy has been used since 1992. In vivo efficacy of a 3 day regimen
of mefloquine + artesunate (MAS3) has been monitored regularly since its introduction in
1992. In 2009 Carrara et al summarised the in vivo PCR-adjusted cure rates at Day 42 and Day
63 in patients treated with MAS3 between 1995 and 2005, as well as the in-vitro parasite
susceptibility to MAS3 during that same period, and the changes in pfmdr1 copy numbers.The
proportion of patients with parasitaemia persisting on day-2 increased significantly from
4.5% before 2001 to 21.9% after 2002 (p<0.001). Delayed parasite clearance was associated
with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002).
MAS3 efficacy declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19,
p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI,
91.0-98.7). The proportion of infections caused by parasites with increased pfmdr1 copy
number rose from 30% (12/40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend).
Evidence of reduced susceptibility to artemisinins in Western Cambodia was first reported in
January 2007. Artemisinin resistance was manifest by a marked slowing of parasite clearance.
A more recent analysis of parasite clearance data collected prospectively in patients with
uncomplicated hyperparasitaemic malaria has shown a progressive decline in parasite clearance
rates over the last decade suggesting a decline following the same trajectory as in Western
Cambodia but with a time lag of a few years.
Surveillance data collected in 2011 have shown a dramatic and worrying decline in efficacy of
MAS3, albeit in a small number of patients. This decline in efficacy of mefloquine +
artesunate is likely to be attributable to reduced parasite susceptibility to mefloquine. The
other fixed dose combinations available dihydroartemisinin-piperaquine (DP) is the best
option to replace mefloquine-artesunate since it is thought that it remains effective in the
presence of high pfmdr1 copy numbers. In addition DP is administered once daily and needs no
special dietary modification to ensure adequate absorption.
In this study it is hypothesised that efficacy of DP (estimated to be 95%) will be
significantly higher than that of MAS3 (estimated to be 65%), therefore the investigators
propose to conduct a randomised controlled trial between DP and MAS3 for the treatment of
P.falciparum.