Clinical trial NCT02325180: Artemisinin-based Combination Therapy for Treatment of Plasmodium Falciparum Malaria in North Sumatera, Indonesia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Malaria, Falciparum
Keywords: ACT
Plasmodium falciparum
malaria
efficacy
Indonesia
Lead sponsor: London School of Hygiene and Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Universitas Sumatera Utara
First posted: 2014-12-24
Enrollment: 338
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine
timeFrame: 42 days
Secondary outcomes:
measure: Parasite clearance times
timeFrame: 3 days
measure: Fever clearance times
timeFrame: 3 days
measure: Prevalence of molecular markers and the impact on treatment outcomes
timeFrame: 42 days
measure: Prevalence of gametocyte
timeFrame: 42 days
measure: Presence of other Plasmodium species
timeFrame: 42 days
measure: Haematological recovery
timeFrame: 28 days
Other outcomes:
Locations:
city: Kuala Langkat
country: Indonesia
facility: Primary health centres
state: North Sumatera
city: Tanjung Tiram
country: Indonesia
facility: Primary health centres
state: North Sumatera
city: Tello island
country: Indonesia
facility: Pulau-pulau Batu health centres
state: North Sumatera
Study officials:
affiliation: London School of Hygiene and Tropical Medicine
name: Colin J Sutherland, BSc PhD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Guidelines for the Treatment of Malaria. 2nd edition. Geneva: World Health Organization; 2010. Available from http://www.ncbi.nlm.nih.gov/books/NBK254223/
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citation: Fairhurst RM, Nayyar GML, Breman JG, Hallett R, Vennerstrom JL, Duong S, Ringwald P, Wellems TE, Plowe CV, Dondorp AM. Artemisinin-resistant malaria: research challenges, opportunities, and public health implications. Am J Trop Med Hyg. 2012 Aug;87(2):231-241. doi: 10.4269/ajtmh.2012.12-0025.
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citation: White NJ. Malaria: a molecular marker of artemisinin resistance. Lancet. 2014 Apr 26;383(9927):1439-1440. doi: 10.1016/S0140-6736(14)60656-5. No abstract available.
citation: Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, Kim S, Duru V, Bouchier C, Ma L, Lim P, Leang R, Duong S, Sreng S, Suon S, Chuor CM, Bout DM, Menard S, Rogers WO, Genton B, Fandeur T, Miotto O, Ringwald P, Le Bras J, Berry A, Barale JC, Fairhurst RM, Benoit-Vical F, Mercereau-Puijalon O, Menard D. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014 Jan 2;505(7481):50-5. doi: 10.1038/nature12876. Epub 2013 Dec 18.
citation: Lubis IND, Wijaya H, Lubis M, Lubis CP, Beshir KB, Staedke SG, Sutherland CJ. Recurrence of Plasmodium malariae and P. falciparum Following Treatment of Uncomplicated Malaria in North Sumatera With Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine. Open Forum Infect Dis. 2020 Apr 2;7(5):ofaa116. doi: 10.1093/ofid/ofaa116. eCollection 2020 May.