In Vivo and In Vitro Efficacy of Artemisinin Combination Therapy

In Vivo and In Vitro Efficacy of Artemisinin Combination Therapy in Kisumu County, Western Kenya

This study aims to assess the degree of artemisinin resistance in adult and pediatric subjects presenting with uncomplicated falciparum malaria in Western Kenya. The study treatments will be Artemether Lumefantrine (AL) and Artesunate Mefloquine (ASMQ).

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: Artesunate; Drug: Artemether Lumefantrine; Drug: Mefloquine

Detailed Description

Data generated by this study will provide a snapshot of the current situation regarding P. falciparum sensitivity to ACTs in Western Kenya. By having subjects in one of the study arms receive artesunate and then the partner drug after completion of the artemisinin phase will enable the accurate evaluation of the artemisinin derivative without the confounding influence of the partner drug. Sequential administration of the components of an ACT drug is recognized by the WHO as one of the ways in which ACTs can be administered. There will be close follow-up of the subjects throughout the duration of the study, and as such, subjects who fail to respond adequately will receive prompt rescue treatment. Since it is largely expected that most subjects in Western Kenya will have satisfactory responses to ACTs, data from this study will provide baseline information regarding parasite characteristics when compared to data from Thailand, an area that has reported resistance to ACTs. This, in turn, will potentially enable the identification of key markers, both in the host and the parasite, that may assist in the early detection of resistance, and also to better understand the development of resistance to ACTs. As such, the data generated from this study, both on its own and when compared to and pooled with data from similar studies that will be conducted in Peru and Thailand, will potentially inform both local and international policy regarding ACT use for the treatment of uncomplicated P. falciparum malaria.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 4

Contacts and Locations

Study Locations

• Kenya
  • Kisumu, Kenya
    • Walter Reed Project, Kombewa Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult/child aged between 6 months and 65 years inclusive (minimum weight 11kg), presenting with a measured temperature of ≥37.5 C, or history of fever within 24 hours prior to presentation
• Mono-infection with Plasmodium falciparum
• Baseline parasitemia of 2000 - 200,000 asexual parasites/µl
• Ability to provide informed consent
• Willingness and ability to comply with the study protocol for the duration of the study
• Willingness to remain in the hospital for 3 days

Exclusion Criteria:

• Presence of signs of severe malaria as defined by WHO
• Presence of severe anemia, defined as hemoglobin level below 6 g/dl
• Presence of mixed Plasmodium infection, or mono-infection of non-falciparum Plasmodium
• Inability to take oral medication
• History of allergy or contraindications to the study treatments
• Lactating or pregnant females
• Any condition that the investigator feels will result in an unfavorable outcome should the potential subject participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: AS/MQ; Treatment of P.falciparum mono-infection with 4 mg/kg of Artesunate daily for three days followed by 25mg/kg of Mefloquine split over two days.	Drug: Artesunate; Other Names: AS; Drug: Mefloquine; Other Names: MQ
ACTIVE_COMPARATOR: AL; Treatment of P. falciparum mono-infection with Artemether Lumefantrine administered at the standard dosage according to pre-defined weight bands (5-14 kg: 1 tablet; 15-24 kg: 2 tablets; 25-34 kg: 3 tablets; and > 34 kg: 4 tablets) given twice a day for 3 days.	Drug: Artemether Lumefantrine; Other Names: AL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasitological clearance rates by microscopy	Clearance rates for the first 72 hour period after first ACT dose in patients with uncomplicated P. falciparum malaria	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasitological clearance rates by quantitative Polymerase Chain Reaction (PCR)	PCR adjusted clearance rates for the first 72 hours after first ACT dose in patients with uncomplicated P. falciparum malaria	72 hours
PCR-adjusted treatment efficacy of AL and AS/MQ		42 days
Antimalarial drug sensitivity responses and molecular genotyping	Correlate clinical outcomes with results of above tests	42 days
Identify common specific genetic determinants of artemisinin resistance derived from parasite populations		42 days
Gametocyte carriage in patients with uncomplicated malaria after treatment		42 days
Catalog parasite samples	Correlated to clinical datasets to longitudinally track resistance trends	42 days
Pharmacokinetic parameters associated with ACT failure		42 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite clearance rates and immune response in semi-immune population	To assess the role of pre-existing semi-immunity against malaria in parasite clearance rates and immune response to acute infection	42 days
Production of microbiocidal molecules	To determine if stimulation of Peripheral Blood Mononuclear Cells (PBMC) (with MSP-1 or CSP antigens) elicit production of microbiocidal molecules (to be pursued only in if pre-existing immunity is shown to affect rate of clearance)	42 days
Acute cytokine response	To determine associations between the acute cytokine response with parasitemia clearance rates and immunologic responses	42 days

Collaborators and Investigators

• Sponsor: Global Emerging Infections Surveillance and Response System
• Collaborators: Walter Reed Army Institute of Research (WRAIR); United States Army Medical Unit - Kenya
• Investigators: Study Chair: James F Cummings, MD, GEIS; Principal Investigator: Ben Andagalu, MD, Kenya Medical Research Institute/Walter Reed Project

Publications and helpful links

General Publications

• Odhiambo G, Bergmann-Leitner E, Maraka M, Wanjala CNL, Duncan E, Waitumbi J, Andagalu B, Jura WGZO, Dutta S, Angov E, Ogutu BR, Kamau E, Ochiel D. Correlation Between Malaria-Specific Antibody Profiles and Responses to Artemisinin Combination Therapy for Treatment of Uncomplicated Malaria in Western Kenya. J Infect Dis. 2019 May 24;219(12):1969-1979. doi: 10.1093/infdis/jiz027.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: October 25, 2013
• First Submitted That Met QC Criteria: October 30, 2013
• First Posted (ESTIMATE): November 6, 2013

Study Record Updates

• Last Update Posted (ACTUAL): May 11, 2017
• Last Update Submitted That Met QC Criteria: May 10, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Malaria; P. falciparum mono infection; Early Treatment Failure; Late Treatment Failure
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Lumefantrine; Artemether; Artesunate; Artemether, Lumefantrine Drug Combination; Mefloquine
• Other Study ID Numbers: WRAIR1935

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED