ACT With Chloroquine, Amodiaquine & Sulphadoxine-pyrimethamine in Pakistan
Condition: Malaria; Falciparum Malaria; Vivax Malaria
MeSH terms: Malaria; Malaria, Falciparum; Malaria, Vivax
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): SP, chloroquine, amodiaquine, primaquine, artesunate
Intervention type(s): Drug
Intervention MeSH terms: Artesunate; Chloroquine; Primaquine; Amodiaquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single
Primary purpose: Treatment
Keywords: Falciparum; Vivax; Treatment; Asia