Have Malaria Infections in Kenya Become Less Responsive to Artemisinin Treatment? (CATMAP)

Confirmation of Artemisinin Tolerance in Malaria Parasites Trial in Kilifi

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

Study Overview

• Status: Unknown
• Conditions: Malaria
• Intervention / Treatment: Drug: Artesunate

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.

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 4

Contacts and Locations

Study Locations

• Kenya
  • Kilifi, Kenya
    • Junju Dispensary
  • Kilifi, Kenya
    • Pingilikani Dispensary
  • Kilifi
    • Kadzinuni, Kilifi, Kenya
      • Kadzinuni Dispensary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Artesunate; Confirmation of artemisinin tolerance	Drug: Artesunate; Oral, once daily, 7-day regimen of artesunate 2mg/kg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary endpoint of this study will be the re-infection-adjusted day 28 failure rate	Cure is defined as clearance of asexual P. falciparum parasitemia until day 7 and no recrudescence of asexual P. falciparum parasitemia until day 28. Re-infections are defined by genetic fingerprinting methods as newly emerging parasite clones during follow-up.	Day 0-28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of patients with positive malaria smears	The number of patients still having parasites at these time points divided by the total treated will give an estimate of early cure rates or estimates of early treatment failure rates as a percentage.	24hr, 48hr, 72hr
The percentage reduction of parasitaemia from baseline	These results will be used to compute the percentage of uncleared parasites so as to evaluate cases of early treatment failure according to the WHO criteria.	24hr, 48hr, 72hr
The mean time to parasite clearance	Estimated by parametric survival analysis will give an estimate of how long the drug takes to clear parasites from the time of first dosing till the time of the first negative smear.	Up to day 7
The mean time to fever clearance	Estimated by parametric survival analysis mean time to fever clearance will be estimated to reflect the time it takes the the temperature to settle down consistently for at least 24 hours.	Up to day 7
To estimate the rates for late clinical and parasitological failure rates	We will estimate the cumulative incidence of success and failure rates at days 28 and 42, by both PCR-uncorrected and PCR-corrected for recrudescence	Days 28 and 42

Collaborators and Investigators

• Sponsor: KEMRI-Wellcome Trust Collaborative Research Program
• Collaborators: University of Oxford; Heidelberg University
• Investigators: Principal Investigator: Roma Chilengi, KEMRI Centre for Geographic Medicine Research (Coast), University of Oxford, England; Principal Investigator: Steffen Borrmann, KEMRI Centre for Geographic Medicine Research (Coast), Heidelberg University of Medicine, Germany

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): November 1, 2011
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: August 24, 2010
• First Submitted That Met QC Criteria: August 26, 2010
• First Posted (Estimate): August 27, 2010

Study Record Updates

• Last Update Posted (Actual): February 23, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Artemisinin tolerance
• 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; Artesunate
• Other Study ID Numbers: KEMRI_CT_2010/0013; SSC 1821 (Other Identifier: KEMRI Scientific Steering Committee)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No