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

Malaria, Falciparum Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02325180
• Other study ID #: QA620
• Status: Completed
• Phase: Phase 4
• First received: December 19, 2014
• Last updated: September 1, 2015
• Start date: January 2015
• Est. completion date: June 2015

Study information

• Verified date: September 2015
• Source: London School of Hygiene and Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: Indonesia: Departement Kesehatan (Department of Health)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 338
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum

Intervention

Drug:
• Dihydroartemisinin-Piperaquine

• Artemether-lumefantrine

Locations

Country	Name	City	State
Indonesia	Primary health centres	Kuala Langkat	North Sumatera
Indonesia	Primary health centres	Tanjung Tiram	North Sumatera
Indonesia	Pulau-pulau Batu health centres	Tello island	North Sumatera

Sponsors (2)

Lead Sponsor	Collaborator
London School of Hygiene and Tropical Medicine	University of Sumatera Utara

Country where clinical trial is conducted

Indonesia, 

References & Publications (7)

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, Ménard 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, Ménard 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. — View Citation

Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009 Jul 30;361(5):455-67. doi: 10.1056/NEJMoa0808859. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. — View Citation

Fairhurst RM, Nayyar GM, 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):231-41. Review. — View Citation

Guidelines for the Treatment of Malaria. 2nd edition. Geneva: World Health Organization; 2010. — View Citation

Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM; Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008 Dec 11;359(24):2619-20. doi: 10.1056/NEJMc0805011. Epub 2008 Dec 8. — View Citation

White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet. 2014 Feb 22;383(9918):723-35. doi: 10.1016/S0140-6736(13)60024-0. Epub 2013 Aug 15. Review. — View Citation

White NJ. Malaria: a molecular marker of artemisinin resistance. Lancet. 2014 Apr 26;383(9927):1439-40. doi: 10.1016/S0140-6736(14)60656-5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Parasite clearance times	Parasite reduction ratio, parasite clearance half-life	3 days	No
Secondary	Fever clearance times		3 days	No
Secondary	Prevalence of molecular markers and the impact on treatment outcomes	Pfcrt, Pfmdr1, Pfk13 and any other important molecular markers	42 days	No
Secondary	Prevalence of gametocyte	Proportion of patients with gametocyte	42 days	No
Secondary	Presence of other Plasmodium species	Plasmodium vivax, Plasmodium malariae, Plasmodium ovale spp, Plasmodium knowlesi	42 days	No
Secondary	Haematological recovery	Haemoglobin	28 days	No