A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)

This study is an open-label randomised trial comparing standard ACT treatment with matching triple artemisinin-based combination therapies (TACTs), evaluating efficacy in safety and tolerability. The estimated total sample size is 2040 patients from 16 sites in Asia and 1 site in Africa. There are 2 arm study groups that have 2 treatment arms each.

Study group A:

A.1: Artemether-lumefantrine for 3 days. versus: A.2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days.

Study group B:

B.1: Dihydroartemisinin-piperaquine for 3 days. versus: B.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.

Study group C:

C.1: Artesunate-mefloquine for 3 days versus: C.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.

According to the WHO guideline, all patients except for children under the age of 1 year or a weight below 10 kilograms will also be treated with a single dose of low dose primaquine.

In Laos, Myanmar, Bangladesh, India and DRC, the following two combinations will be used:

1. Artemether-lumefantrine combined with amodiaquine (TACT arm) or
2. Artemether-lumefantrine (ACT arm)

In Myanmar and Vietnam the following two combinations will be used:

1. Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or
2. Dihydroartemisinin-piperaquine (ACT arm)

In Cambodia and Thailand the following two combinations will be used:

1. Dihydroartemisinin-piperaquine plus Mefloquine hydrochloride (TACT arm) or
2. Artesunate-mefloquine (ACT arm)

Eligibility Criteria:
Inclusion Criteria:

* Male or female, aged from 6 months to 65 years old
* Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
* Asexual P. falciparum parasitaemia: 5,000 to 200,000/uL, de-termined on a thin or thick blood film (In Cambodia patients with a parasitaemia of 16 to 200,000/uL are eligible. In DRC patients with a parasitaemia of 10,000 to 250,000/ul are eligi-ble)
* Fever defined as \>/= 37.5°C tympanic temperature or a history of fever within the last 24 hours
* Written informed consent (by parent/guardian in case of children)
* Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

* Signs of severe/complicated malaria
* Haematocrit \< 25% or Hb \< 5 g/dL at screening (DRC: Hct\<15% and Hb \<5 g/dL due to high prevalence of anemia).
* Acute illness other than malaria requiring treatment
* For females: pregnancy, breast feeding
* Patients who have received artemisinin or a derivative or an artemisinin containing combination therapy (ACT) within the previous 7 days
* Treatment with mefloquine in the 2 months prior to presentation will be an exclusion criteria in the DHA-P+MQ sites
* History of allergy or known contraindication to artemisinins, or to the ACT or TACT to be used at the site e.g. neuropsychiatric disorders will be a contraindication for the use of mefloquine.
* Previous splenectomy
* QTc-interval \> 450 milliseconds at moment of presentation
* Documented or claimed history of cardiac conduction problems
* Earlier participation within the TRACII trial or another trial in the previous 3 months.