Source: tdr-scientists@who.ch
Chorproguanil/dapsone (LAPDAP) multicentre phase III
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clinical trial under way in Africa
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A potential new treatment for uncomplicated Plasmodium falciparum ma-
laria
In March 2000, the pivotal Phase III clinical trial of chlorprogua-
nil/dapsone (LAPDAP) for the treatment of uncomplicated Plasmodium
falciparum malaria was initiated in five African clinical trial
sites.
The goal is to develop a 'new' safe and effective alternative to
chloroquine and sulphadoxine/pyrimethamine (S/P) for the treatment of
falciparum malaria in Africa. Chloroquine has been the principal drug
for decades, but it no longer achieves adequate cure rates across
much of the continent. However, it remains the first line drug in
many national malaria control programmes. Some African countries,
such as Malawi, have replaced chloroquine with S/P, but unfortunately
this compound has the drawback of rapidly selecting resistant organ-
isms, due to its slow elimination from the body and simple molecular
mechanism of resistance. This was the case in Thailand where S/P had
a useful lifetime of less than 10 years.
This double blind Phase III trial is designed to measure the safety
and efficacy of LAPDAP for 3 days as compared to treatment with a
single dose (the standard course) of S/P. The trial will randomize -
in a 4:1 ratio of LAPDAP:S/P - 2000 African children aged 12-120
months. The trial sites are in Gabon, Kenya, Malawi, Nigeria and
United Republic of Tanzania.
Both chlorproguanil and dapsone, which work by inhibition of folate
metabolism, are agents with a long history of safe and efficacious
use for malaria and leprosy, respectively. The hypothesis that these
two agents in combination would be effective against falciparum ma-
laria, was proven by Watkins, Winstanley and colleagues at the Well-
come Trust laboratories in Nairobi. It has been proposed that LAPDAP
may have the following significant advantages over the existing S/P
treatment regimen: more rapid elimination of chlorproguanil, chlor-
cycloguanil (its active metabolite), and dapsone; and retention of
activity of chlorcycloguanil against certain pyrimethamine resistant
parasites.
The LAPDAP development project is a public/private sector collabora-
tion between WHO/TDR, the UK Department for International Develop-
ment, and SmithKline Beecham.
http://www.who.int/tdr/publications/tdrnews/news62/lapdap.htm
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