Malaria Clinical Trial
Official title:
Studies on Adding Artesunate to Existing Antimalarial Therapies With Chloroquine, Amodiaquine & Sulphadoxine-pyrimethamine in Pakistan
Chloroquine resistant falciparum malaria in Pakistan is prevalent in every malarious area examined. Resistance to the favoured second-line treatment, sulphadoxine-pyrimethamine S/P is rising fast. To avert a repetition of the resistance catastrophe that occurred in SE Asia it is critical to preserve the effective life of SP by using it in combination with artesunate. Efficacy of ACT with artesunate in combination with chloroquine, SP or amodiaquine for treatment of malaria (falciparum or vivax) will be examined in malaria patients in Pakistan.
The incidence of falciparum malaria in Pakistan has risen 6-fold over the last 15 years and
chloroquine resistance is prevalent in every malarious area examined. Chloroquine's position
as first line treatment must be reconsidered. Resistance to the favoured second-line
treatment, sulphadoxine-pyrimethamine SP, is 10% and rising fast. It is critical to preserve
the effective life of SP by using it in combination with a non-related fast-acting
antimalarial such as artesunate (AS). It is conceivable that use of AS in combination with
chloroquine itself might even recover the latter's effectiveness and restrain the selection
of stronger levels of chloroquine resistance. To determine the tolerability and efficacy of
AS combination therapy in the subcontinent, randomized controlled trials will be conducted
by HealthNet International and government staff, with technical support from LSHTM, in
Afghan refugee camps in Pakistan against the current therapies of chloroquine, amodiaquine
and SP. Current policy is to use primaquine(PQ) as the gametocytocidal drug with CQ or SP.
It is not clear whether this has any value in the face of high levels of CQ resistance. The
efficacy of PQ in combination with CQ or SP will be examined in individual randomised trial
in comparison with CQ or SP alone.
In the past, treatment of falciparum and vivax malaria was with chloroquine. With
development of drug resistance treatment of the two species is diverging and this places
higher priority on accurate differential diagnosis which cannot always be met at peripheral
health posts. There may be advantage in harmonising treatment of the two species with ACT.
Thus the current treatment for vivax, chloroquine, shall be compared with that of ACT with
artesunate and SP, the likely ACT to be adopted for falciparum malaria.
Protocol design:
Randomised, single-blind, controlled trials comparing for falciparum malaria (1) artesunate
(AS) and chloroquine (CQ), vs CQ alone, vs CQ and primaquine (PQ); (2) AS and
sulphadoxine-pyrimethamine (SP), vs SP alone, vs SP and PQ; (3) AS and amodiaquine (AQ), vs
AQ alone.
Randomised, single-blind, controlled trial comparing for vivax malaria: AS and
sulphadoxine-pyrimethamine (SP), vs CQ alone.
Patients will be randomly assigned to one of the following treatment groups:
- CQ (day1,2,3) + placebo (day 1, 3) vs
- CQ (day 1,2,3) + PQ (day 1) + placebo (day 3) vs
- CQ (day 1,2,3) + PQ (day 3) + placebo (day 1) vs
- CQ (day 1,2,3) + AS (day 1) + placebo (day 3)
- S/P (day 1) + placebo (day 1) vs
- S/P (day 1) + AS (day 1) vs
- S/P (day 1) + PQ (day 1)
- AQ (day 1,2,3) + placebo (day 1,2,3) vs
- AQ (day 1,2,3) + AS (day 1,2,3)
To determine the viability and transmissibility of any gametocytes (and also to detect
sub-patent gametocytaemias) still present after treatment it is also proposed to carry out
mosquito feeding studies directly on patients on the 7th day after the start of combination
therapy with either CQ, CQ+AS, CQ+PQ., SP, SP+AS, SP+PQ and to incubate any midgut
infections to the oocyst stage. To determine the genetic consequences of any selection from
the different drugs (i.e. CQ, AS, or PQ), the mosquito midgut infections would be preserved
for further genetic studies in UK, as would blood samples taken from initial and
recrudescent infections.
To improve our understanding of the genetic basis of drug resistance we will genotype
parasites from blood samples of patients with treatment failure in this study. Blood samples
of 20 patients from each arm of the study who had parasitological treatment failure will be
selected randomly, together with midgut infections, and analysed for genetic markers of
resistance to chloroquine and sulphadoxine/pyrimethamine. These will be compared with
genotypes of pre-treatment infections.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind, Primary Purpose: Treatment
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