Treatment Efficacy and Malaria TRANSmission After Artemisinin Combination Therapy 2 (TRANSACT2)

Study Overview
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Brief Summary
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Artemisinin combination therapy (ACT) with artemether lumefantrine (AL) is currently the first line treatment policy in Kenya. AL is an efficacious drug that also has the capacity to reduce malaria transmission to mosquitoes. Nevertheless, there is concern about the development of parasite resistance against AL. Clinical trials in Asia showed that mefloquine-artesunate (MQ-AS) may be more efficacious than AL and may have a more pronounced beneficial effect on post-treatment malaria transmission. MQ-AS is registered and used in Kenya but there have been no reported direct comparisons of AL and MQ-AS with clinical and transmission endpoints (i.e. adequately clearing parasites and preventing transmission to mosquitoes). Screening for molecular markers that are related to parasite susceptibility to ACT drugs and to post-ACT treatment malaria transmission can assist strategies to prevent the development and spread of ACT resistance. In the current study, we compare AL and MQ-AS for the treatment of uncomplicated malaria. Our endpoints are i) clinical efficacy, ii) post-treatment gametocytaemia by molecular techniques. In the current study, the investigators compare AL and MQ-AS for the treatment of uncomplicated malaria. The investigators endpoints are clinical efficacy post-treatment gametocytaemia by molecular techniques

Detailed Description
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Accurate diagnosis followed by prompt and efficacious treatment is the backbone of any malaria control programme. However, malaria treatment has been facing huge challenges in recent years. A number of affordable antimalarial drugs have been used to cure malaria since the 1940s: these include chloroquine (CQ), sulphadoxine-pyrimethamine (SP; Fansidar®), mefloquine (MQ), amodiaquine (AQ) and quinine. The emergence and spread of resistance to these commonly-used drugs has been largely responsible for the worsening of the malaria situation observed in the past decades. Across the African continent, guidelines have recently been changed. The World Health Organization (WHO) recommends for falciparum malaria the use of combination therapies, preferably those containing artemisinin derivatives (ACT, artemisinin-based combination therapy). Artemisinin derivatives, e.g. artesunate, artemether and dihydroartemisinin, being extremely potent antimalarial agents are the ideal partners in combinations with other antimalarials. ACTs have three demonstrable advantages over conventional therapy, they i) are efficacious in clearing asexual parasites, ii) substantially reduce post-treatment gametocyte carriage and iii) protect the partner drug from selecting resistant parasites. In Kenya, both CQ and SP have lost clinical efficacy. CQ was replaced by SP in 1998 and in the year 2006, SP was effectively replaced by Artemether-Lumefantrine (AL: Coartem®). The policy change to the artemisinin-based drug AL is in line with the WHO recommendations to shift to ACT as first line antimalarial treatment.The most efficacious ACT, however, needs local comparisons in terms of treatment efficacy and transmission-reducing activity.

Official Title
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Treatment Efficacy and Malaria TRANSmission After Artemisinin Combination Therapy 2 (TRANSACT2)

Conditions
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Malaria

Intervention / Treatment
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* Drug: Mefloquine - Artesunate
* Drug: Artemether-lumefantrine combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6 months - 10 years Residents of research area (5 km around the clinic) Willingness to come for complete scheduled follow-up. Uncomplicated malaria with P. falciparum mono-infection Parasitaemia of 1000-200,000 parasites/ul Temperature > 37.5°C and < 39.5°C, or history of fever in previous 24 hours. No history of adverse reactions to AL Understanding of the procedures of the study by parent or guardian and willing to participate by signing informed consent forms. Exclusion Criteria: General signs of severe malaria Haemoglobin concentration < 5g/dl Presence of disease other than malaria causing febrile conditions Mixed infection with P. malariae or other non-falciparum malaria species Unwilling to participate and sign informed consent forms.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Artemether- Lumefantrine<br>Treatment with artemether-lumefantrine (AL; Coartem; Novartis Pharma), administered as half a tablet (20 mg of artemether and 120 mg of lumefantrine) per 5 kg of body weight in a 6-dose regimen (at enrolment and 8, 20, 32, 44, and 56 h [+/-90 min] after the initiation of treatment). AL is currently the first line treatment in Tanzania Other Name: Coartem; | Drug: Artemether-lumefantrine combination<br> <br> * Other names: Coartem;|
| Active Comparator: Drug: Mefloquine-Artesunate, an alternative ACT<br>Treatment with the paediatric fixed dose combination Mefloquine-Artesunate (MQ-AS; Artequin; Mepha, Aesch, Basel, Switzerland, artesunate (50 mg/day) and mefloquine (125 mg/day) fixed dose formulation (stick pack) once daily for 3 consecutive days, given in three daily doses. The weight range of enrolled children is chosen to be recommended for this fixed dose combination. MQ-AS is available in Kenya as Artequin and has been extensively tested in uncomplicated malaria in children. | Drug: Mefloquine - Artesunate<br> <br> * Other names: Artequin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of participants with clinical and parasitological treatment failure after treatment artemether-lumefantrine (AL) and mefloquine-artesunate MQ-AS | Parasite prevalence will be determined by microscopy and molecular methods on days 3-42 after intitiation of treatment. Clinical (fever+parasitological failure) and parasitological efficacy will be determined in relation to treatment arm and parasite clearance dynamics | 42 day follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of individuals with gametocytes after treatment with AL or MQ-AS | gametocyte carriage will be determined by microscopy and molecular QT-NASBA to generate gametocyte prevalence estimates on follow-up days and the mean duration of gametocyte carriage in days. | 42 days follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria treatment efficacy, Malaria transmission