Evaluation of the Efficacy of Artemisinin Combination Therapy in Kenya (EAPHLNP)

Artemisinin-based combination therapies (ACTs) are recommended for use against uncomplicated malaria in areas of multi-drug resistant malaria. The Ministry of Health, Division of Malaria Control (DOMC) rolled out the use of artemether-lumefantrine as the first line treatment for uncomplicated malaria in 2006.The development of the ACTs and its derivatives are the most rapidly acting of all the current antimalarial drugs and recognition of their potential role as a component of combination therapy have led to several large trials aimed at assessing different combinations of existing drugs, and to the specific development of new combination drugs.

This proposal aims to (1) evaluate the efficacy of artemisinin-based anti-malaria combination drugs in different sites across Kenya (2) elucidate the markers of resistance to ACTs through molecular genetics and in this process further strengthen capacity in the proposed study sites as well as improve links between research and control ultimately to influence malaria treatment policy and practice.

Five groups in East Africa will conduct a multi-centre, randomised, two arm trial to assess the efficacy of dihydroartemisin-piperaquine with artemether-lumefantrine as the comparative drug. The network will determine antimalarial drug efficacy using standardised protocols and collate clinical responses and adverse events. Molecular markers to artemisinin resistance will be investigated by molecular sequencing and comparison of parasite profiles in drug failure cases. Recrudescence or re-infections will be differentiated by analysis of the MSP1, MSP2 and GLURP genes and assess transmission dynamics post treatment. Data from these studies will be captured into a database developed by the network. The latter offers several advantages including

• Working towards the standardization of methodologies and common protocols as a way of comparing data across sites
• Pulling together datasets and conduct a multi-centre analysis
• Sharing and coordinating quality assurance mechanisms

Study Overview

• Status: Unknown
• Conditions: Malaria
• Intervention / Treatment: Drug: Artemether lumefantrine; Drug: Dihydroartemisinin piperaquine

• Study Type: Interventional
• Enrollment (Anticipated): 2100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Busia, Kenya
    • Busia district hospitals
  • Kisii, Kenya
    • Kisii district hospitals
  • Kitale, Kenya
    • Kitale district hospitals
  • Machakos, Kenya
    • Machakos district hospital
  • Malindi, Kenya
    • Malindi district hospitals
  • Nyando, Kenya
    • Nyando district hospital
  • Kwale
    • Msambweni, Kwale, Kenya
      • Msambweni sub-district hospital

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:

1. Age between 6 months - 5 years (in high endemic areas); 6 months to 10 years (in low endemic areas) inclusive.
2. Presence of axillary temperature > 37.5oC or rectal / tympanic temp > 38.0oC, or history of fever in the last 24 hours.
3. Monoinfection with Plasmodium falciparum with parasitaemia, asexual parasitemia between 2,000 - 200,000 p/µl (in areas of high transmission); 1,000-100,000p/ µl (in areas of low to moderate malaria transmission)
4. Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; and
5. Signed informed consent form by the parents or legal guardian.

Exclusion Criteria:

1. 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;
2. Mixed or mono-infection with another Plasmodium species detected by microscopy;
3. Presence of co-morbid infection (e.g. acute lower respiratory tract infection, severe diarrhoea with dehydration, Severe Anaemia) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases,Epilepsy, HIV/AIDS);
4. 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Artemether lumefantrine; Tablets, 1-4 tablets (weight calculated dose), BD, at hr 0, 8, 24, 36, 48 and 60.	Drug: Artemether lumefantrine; Artemether 20mg Lumefantrine 120mg; Other Names: Coartem
Experimental: Dihydroartemisinin piperaquine; Tablets, 2 paediatric tablets/1 adult tablet, OD, every 24 hours for 48 hours	Drug: Dihydroartemisinin piperaquine; Dihydroartemisinin 20mg Piperaquine 160mg; Other Names: Duocortexin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary endpoint will be the PCR-corrected and parasitological response (PCR corrected ACPR) at days 28 and 42. Change in this outcome measure will be assessed.	ACPR is defined as the absence of parasitaemia on day 42 irrespective of the temperature without previously meeting any of the criteria of early treatment failure or late clinical or parasitological failure. Patients with late asexual parasite reappearance will be considered ACPR if the CR analyses shows a new infection rather than a recrudescence (through PCR genotyping). The total treatment failure is defined according to the WHO criteria as the sum of early and late treatment failures.	Day 28 and day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Crude (PCR uncorrected) ACPR ratio at day 28 (PCR uncorrected ACPR)		Day 28
Cure ratios at day 28, 42, (PCR corrected and PCR uncorrected). Change in this outcome measure will be assessed.		Day 28 and day 42
Fever Clearance Time (FCT)	This will be defined as the time (hrs) from the start of a patient's treatment to the first consecutive axillary temp measurements below 37.5 for at least 48 hrs	0 to 48 hours
Asexual parasite clearance time (PCT)	PCT(proportion of patients remaining parasitaemic) defined as the time (in hours) from the start of a patient's treatment to 2 consecutive negative blood slides (collected at different days)	Day 0 to day 28, upto day 42
Gametocyte carrier rates and geometric mean densities (excluding negatives) will be compared on days 7, 14, 28 and 42. Change in this outcome measure will be assessed.		Day 7, 14, 28 and 42
Changes of haemoglobin (Hb) concentration from day 0 to days 28, and 42		Day 0, day 28 and day 42
Number of participants with adverse events		Up to day 42
Comparison between adverse events related to artemether lumefantrine and dihydroartemisinin piperaquine		Up to day 42
Temperature		Up to day 42
Oxygen saturation		Up to day 42
Heart rate		Up to day 42
Respiratory rate		Up to day 42

Collaborators and Investigators

• Sponsor: Sabah Ahmed Omar
• Collaborators: Kenya Medical Research Institute; World Bank
• Investigators: Principal Investigator: Sabah A Omar, PhD, KEMRI CGMR-C

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Anticipated): June 1, 2014
• Study Completion (Anticipated): July 1, 2015

Study Registration Dates

• First Submitted: April 17, 2013
• First Submitted That Met QC Criteria: July 11, 2013
• First Posted (Estimate): July 15, 2013

Study Record Updates

• Last Update Posted (Estimate): October 8, 2013
• Last Update Submitted That Met QC Criteria: October 7, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination; Piperaquine; Artenimol
• Other Study ID Numbers: KEMRI_CT_2013/0017; SSC 2276 (Other Identifier: KEMRI Scientific Steering Committee)