Artemisinin-based Combination Therapy for Treatment of Plasmodium Falciparum Malaria in North Sumatera, Indonesia

Study Overview
=================
Brief Summary
-----------------
This is a prospective, open label, randomised controlled trial to assess the safety and efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria infection. Molecular markers for antimalarial resistance will also be assessed and the presence of molecular markers in the parasites will be associated with treatment outcomes.

Detailed Description
-----------------
Artemisinin-based combination therapy (ACT) is the current recommended treatment by WHO for uncomplicated falciparum malaria. It is highly effective with few adverse effects. The artemisinin component is combined with a partner drug with a longer half-life to ensure the clearance of the remaining parasites after rapid reduction by artemisinin. ACT is used as first-line treatment for uncomplicated P. falciparum infection in Indonesia since 2004. There are 3 combinations available in the country including artesunate-amodiaquine (AS-AQ), dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL). Studies at different sites across Indonesia have shown various efficacy. Yet, there is an increased concern of reduced susceptibility of P. falciparum to artemisinin in neighbouring countries. Therefore, there is a need to evaluate and monitor the efficacies of these combinations in Indonesia. Molecular markers are an important tool for detecting and monitoring the presence of antimalarial resistance. Their significant implication is to geographically map the extent of resistant-parasites, thus enabling strategies for their control and elimination to be applied before the inevitably increase in the disease burden occurs. Different markers have been used to identify antimalarial resistance and recently a molecular marker for artemisinin susceptibility in P. falciparum has also been proposed. The presence of these markers in parasites from our study will also be investigated.

Official Title
-----------------
Clinical Efficacy of Artemisinin-based Combination Therapy for Treatment of Uncomplicated Plasmodium Falciparum Malaria in North Sumatera, Indonesia and the Association of Molecular Markers With Treatment Outcomes

Conditions
-----------------
Malaria, Falciparum

Intervention / Treatment
-----------------
* Drug: Dihydroartemisinin-Piperaquine
* Drug: Artemether-lumefantrine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female All patients per 6 months of age Fever as defined by axillary temperature > 37.5 C or history of fever during the 48 hours before recruitment Infection with P. falciparum detected by microscopy Parasitaemia > 250 /uL blood Ability to swallow oral medication Ability and willingness to comply with the protocol for the duration of the study and to comply with the study visit schedule Informed consent from the patient or from a parent or guardian in the case of children Absence of history to hypersensitive reactions or contraindication to antimalarial drugs Not currently consuming antibiotic with antimalarial activity (such as cotrimoxazole, macrolides, tetracycline or doxycycline) Exclusion Criteria: Presence of general danger signs in children under 5 years or signs of severe falciparum malaria according to the definitions of WHO (2000) Presence of severe malnutrition according to WHO child growth standards Presence of febrile conditions caused by diseases other than malaria Presence of severe anemia (Hemoglobin < 7 gr/dL) Received any of the study drugs within the past 4 weeks Received any antimalarial within the last 2 weeks Recurrent vomiting )necessitating more than a single repeat dose) Pregnant (demonstrated by positive result of b-HCG in women of childbearing age Lactating mother

Ages Eligible for Study
-----------------
Minimum Age: 6 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DHA-PQ<br>One tablet of dihydroartemisinin-piperaquine consists of 40 mg of dihydroartemisinin and 320 mg of piperaquine. DHA-PQ is administered once daily for 3 days (at enrolment, hour 24 and you 48). Dosing should be given based on body weight. Daily dose for dihydroartemisinin is 2.25 mg/kg (total 6.75 mg/kg) and for piperaquine is 18 mg/kg (total 54 mg/kg). | Drug: Dihydroartemisinin-Piperaquine<br> <br> * Other names: Artekin;|
| Active Comparator: AL<br>Half a tablet of artemether-lumefantrine consists of 20 mg of artemether and 120 mg of lumefantrine is given per 5 kg body weight. AL is administered as 6-dose regimens given twice daily for 3 days (at enrolment, hour 8, hour 24, hour 36, hour 48 and hour 60). | Drug: Artemether-lumefantrine<br> <br> * Other names: Coartem;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine | Early treatment failure, late treatment failure, adequate clinical and parasitological response Proportion of participants with Adequate Clinical and Parasitological Response | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite clearance times | Parasite reduction ratio, parasite clearance half-life | 3 days | 
| Fever clearance times |  | 3 days | 
| Prevalence of molecular markers and the impact on treatment outcomes | Pfcrt, Pfmdr1, Pfk13 and any other important molecular markers | 42 days | 
| Prevalence of gametocyte | Proportion of patients with gametocyte | 42 days | 
| Presence of other Plasmodium species | Plasmodium vivax, Plasmodium malariae, Plasmodium ovale spp, Plasmodium knowlesi | 42 days | 
| Haematological recovery | Haemoglobin | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ACT, Plasmodium falciparum, malaria, efficacy, Indonesia