What is the problem/background?

The first-line drugs world-wide to treat malaria are artemisinin-based combination therapies (ACTs).  Resistance to artemisinins and their partner drugs has now been noted, and the resulting treatment failure now severely threatens treatment of falciparum malaria in the South-East Asia.  A spread of artemisinin and partner drug resistance to Sub-Saharan-Africa would have devastating consequences.  We urgently need new combinations of drugs which will reduce the threat of resistance. The drug arterolane used in combination with piperaquine under the brand name Synriam®, is a promising new antimalarial drug combination to treat artemisinin resistant falciparum malaria.  It is produced in India and is likely to be an affordable treatment in Sub Saharan Africa.  Furthermore, the use of multiple drugs with different modes of action has the potential to reduce emergence of drug resistance and is common practice in a range of human diseases, including HIV and tuberculosis. We are therefore considering triple drug combinations, and propose a randomized controlled trial to compare the effect and safety of such combinations.

What questions are we trying to answer?

This study aims to evaluate two alternative combination treatments for malaria in the setting of uncomplicated Plasmodium falciparum infections in children in Kenya.

Where is the study taking place, how many people does it involve and how are they selected?

The study will be recruiting children from Pingilikani dispensary and Kilifi County Hospital. All children will be admitted in the Kilifi County Hospital for the duration of treatment. We will recruit 219 children in this study after being identified from the outpatient facility or at admission as a child with mild malaria (not ordinarily needing admission).

What does the study involve for those who are in it?

Children with febrile malaria will be eligible to participate.  Instead of being treated as an outpatient they will be admitted to Kilifi Hospital andwill be randomized either to standard care or to a new treatment regimen. .A number of blood tests will be done during the 3 days they spend in hospital and they will also be followed-up as outpatients for 6 further occasions.

What are the benefits and risks/costs of the study for those involved?        How will the study benefit society?     

Although most children with uncomplicated malaria can be successfully treated without admission, a few will experience complications requiring inpatient treatment. The main benefit to the individual involved in the trial will be closely supervised treatment for malaria.  There are risks of side effects from anti-malarial drugs, which are mitigated by the previous experience with these drugs, where minimal side effects have been seen, and by the close medical supervision.  The costs will include the inconvenience of a hospital stay for research purposes and frequent outpatient visits, and the discomfort associated with additional blood tests.

When does the study start and finish?

The study will start upon receipt of ethical clearance. Data collection, analysis and write up will take place over 18 months.

Resistance to artemisinins and their partner drugs resulting in high treatment failure with artemisinin-based combination therapies (ACTs) severely threatens treatment of falciparum malaria. A spread of artemisinin and partner drug resistance to Sub-Saharan-Africa would have devastating consequences. Currently, there is no good alternative to ACTs for the treatment of uncomplicated falciparum malaria. This study aims to evaluate two alternative treatments with existing antimalarials for the treatment of uncomplicated Plasmodium falciparum infections in children in Kenya. The synthetic trioxolane arterolane maleate (OZ277), marketed in combination with piperaquine (PPQ) under the brand name Synriam®, is a promising new antimalarial drug combination to treat artemisinin resistant falciparum malaria. It is produced in India by the company Ranbaxy and is likely to be affordable in Lower Middle Income Countries. The use of multiple drugs with independent mechanisms of action aims to reduce emergence of drug resistance and is common practice in a range of human diseases, including HIV and tuberculosis. The triple combination dihydroartemisinin-piperaquine (available in Sub-Saharan Africa as Artekin) with mefloquine (now off-patent) has been shown to be as tolerable and safe as the more usual double combination dihydroartemisinin- piperaquine). The combination arterolane-piperaquine with mefloquine (where the DHA is replaced by arterolane) might be a very valuable addition to the potential future arsenal of combination drugs. TACT (i.e. triple artemisinin combination therapy), rather than double therapies with ACTs, might become the new standard treatment to prevent spread of resistance. We propose a randomised controlled clinical trial comparing the safety, tolerability, therapeutic efficacy and pharmacokinetics and pharmacodynamics of arterolane-piperaquine, arterolane-piperaquine plus mefloquine versus artemether-lumefantrine.in children with uncomplicated falciparum malaria in Kilifi, Kenya. This study will also provide an up to date insight on the current presence of antimalarial resistance in this site. In addition, all children will be treated with a single low dose of primaquine according to WHO guidelines, in order to prevent onward transmission of parasites to mosquitoes. We will recruit 219 patients aged 2 years to 12 years with acute uncomplicated falciparum malaria in Kilifi County Hospital. The primary endpoint will be day 42, PCR corrected assessments of adequate clinical and parasitological response (ACPR). In addition, we will collect data on parasite clearance during treatment, on adverse events, and on drug levels.