Clinical trial NCT01190371: Have Malaria Infections in Kenya Become Less Responsive to Artemisinin Treatment?
Official title: Confirmation of Artemisinin Tolerance in Malaria Parasites Trial in Kilifi
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Malaria
Keywords: Artemisinin tolerance
Lead sponsor: KEMRI-Wellcome Trust Collaborative Research Program
Sponsor class: OTHER
Collaborators: name: University of Oxford
name: Heidelberg University
First posted: 2010-08-27
Enrollment: 175
Sex: ALL
Minimum age (years): 6
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether P. falciparum infections in Kilifi District have developed tolerance to the artemisinin class of drugs.

Detailed description: Artemisinin-based combination therapies (ACT) are the treatment of choice for episodes of uncomplicated P. falciparum malaria in all endemic countries. Rapid clearance of pathogenic blood stage malaria parasites by artemisinins is associated with swift recovery from mild malaria and reduced mortality from severe forms of the disease. In Kenya, and most malaria endemic sub-saharan Africa, artemether-lumefantrine has been introduced as first-line treatment in the public health care sector in 2006. Alarmingly, despite the short time since the introduction of ACTs artemisinin-resistant P. falciparum malaria has already emerged in South-East Asia, an area that has historically been the cradle of global spreads of drug-resistant malaria parasites.

In a previous study in Kilifi we have observed a significant drop in early response rates to treatment with two ACTs from 2005 to 2008. Conventional markers of potential changes in anti-parasitic host immunity, drug exposure, or baseline parasite biomass could not account for the observed time-dependent change in response rates.

This protocol aims to establish with reasonable confidence whether P. falciparum infections in Kilifi District have developed tolerance to the artemisinin class of drugs. We propose to study treatment response rates to an established 7-day regimen of artesunate alone in the treatment of uncomplicated P. falciparum malaria in children aged 6 months to 10 years, at the KEMRI study site in Pingilikani, Kilifi District, Kenya. The study will also assess (i) pharmacokinetic parameters of artesunate; (ii) ex vivo and in vitro chemosensitivity of parasite isolates to DHA; (iii) genetic determinants of altered in vivo and in vitro responses to DHA; and (iv) ex vivo expression profiles in normally vs. slowly responding P. falciparum infections before and during treatment.

Eligibility criteria: Inclusion Criteria:

* aged between 6 months to 10 years, inclusive
* mono-infection with P. falciparum detected by microscopy;
* parasitaemia of 10,000-300,000/µl asexual forms;
* presence of axillary temperature ≥ 37.5 °C or history of fever during the past 24 h;
* ability to swallow oral medication;
* ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; and
* informed consent from a parent or guardian.

Exclusion Criteria:

* presence of clinical danger signs: not able to drink or breast-feed, vomiting (\>twice in 24 hours), recent history of convulsions (\>1 in 24h), unconscious state, unable to sit or stand;
* mixed or mono-infection with another Plasmodium species detected by microscopy;
* presence of severe acute malnutrition defined as weight for height \<70% of the median NCHS/WHO (Appendix 2);
* presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS);
* regular medication, which may interfere with antimalarial pharmacokinetics or pharmacodynamic assessments (e.g., antibiotics with known antimalarial activity); and
* history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s).

Primary outcomes:
measure: The primary endpoint of this study will be the re-infection-adjusted day 28 failure rate
timeFrame: Day 0-28
Secondary outcomes:
measure: The proportion of patients with positive malaria smears
timeFrame: 24hr, 48hr, 72hr
measure: The percentage reduction of parasitaemia from baseline
timeFrame: 24hr, 48hr, 72hr
measure: The mean time to parasite clearance
timeFrame: Up to day 7
measure: The mean time to fever clearance
timeFrame: Up to day 7
measure: To estimate the rates for late clinical and parasitological failure rates
timeFrame: Days 28 and 42
Other outcomes:
Locations:
city: Kadzinuni
country: Kenya
facility: Kadzinuni Dispensary
state: Kilifi
city: Kilifi
country: Kenya
facility: Junju Dispensary
city: Kilifi
country: Kenya
facility: Pingilikani Dispensary
Study officials:
affiliation: KEMRI Centre for Geographic Medicine Research (Coast), University of Oxford, England
name: Roma Chilengi
role: PRINCIPAL_INVESTIGATOR
affiliation: KEMRI Centre for Geographic Medicine Research (Coast), Heidelberg University of Medicine, Germany
name: Steffen Borrmann
role: PRINCIPAL_INVESTIGATOR
References: