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Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children

Primary Purpose

Fever, Malaria

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
amodiaquine-artesunate (ASAQ)
dihydroartemisinin-piperaquine (DHAPQ)
artemether-lumefantrine (AL)
Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)
Sponsored by
Institute of Tropical Medicine, Belgium
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fever focused on measuring Children 6-59 months, P.falciparum, Haemoglobin, Informed consent, ACT

Eligibility Criteria

6 Months - 59 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Males and Females aged between 6 months and 59 months inclusive. In the sites where CDA is tested all recruited children will be aged between 12 months and 59 months inclusive (this arm was discontinued on 17th February 2008). This criterion applies only for the recruitment in the first follow up. For the second follow up, children having been included in the first follow up are eligible, regardless of their age.
  • Body weight of 5 Kg and above.
  • Microscopically confirmed, monoinfection of Plasmodium falciparum (parasitaemia ≥ 2,000/μL to 200,000/μL).
  • Fever (axillary temperature at ≥ 37.5°C) or history of fever in the previous 24 hours.
  • Haemoglobin value ≥ 7.0 g/dl;
  • Signed (or thumb-printed whenever parents/guardians are illiterate) informed consent by the parents or guardians. Note the informed consent will be asked only at recruitment and will cover the whole period of the study, including second active follow up and passive case detection.
  • Parents' or guardians' willingness and ability to comply with the study protocol for the duration of the trial.

Exclusion Criteria:

  • Participation in any other investigational drug study (antimalarial or others) during the previous 30 days.
  • Known hypersensitivity to the study drugs.
  • Severe malaria.
  • Danger signs: not able to drink or breast-feed, vomiting (> twice in 24hours), recent history of convulsions (>1 in 24h), unconscious state, unable to sit or stand.
  • Presence of intercurrent illness or any condition (cardiac, renal, hepatic diseases) which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study, including known G6PD deficiency.
  • Severe malnutrition (defined as weight for height <70% of the median NCHS/WHO reference).
  • Ongoing prophylaxis with drugs having antimalarial activity such as cotrimoxazole for the prevention of Pneumocystis carinii pneumonia in children born to HIV+ women.

Sites / Locations

  • Centre Muraz/IRSS
  • Albert Schweitzer Hospital
  • Manhiça Health Research Center
  • Hospital
  • Mashshesha and Rukara
  • Jinja and Tororo
  • Mbarara,
  • Tropical Diseases Research Centre, P O Box 71769,

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

1

2

3

4

Arm Description

AS-AQ

DHAPQ TO BE NOTED: since the batches of the study drug DHAPQ expire at the end of October 2008, and because of the unavailability of a new batch of DHAPQ from the manufacturer, the recruitment in the DHAPQ arm had to be discontinued on 30th October 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.

AL

Lapdap + AS TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.The leading EC approval was obtained on 2nd June 2008.

Outcomes

Primary Outcome Measures

PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping.
PCR adjusted treatment failure up to day 28 (TF28A): all early failures before day 14 plus the recurrent parasitaemias detected at day 14 or later and classified by genotyping as recrudescence.

Secondary Outcome Measures

PCR unadjusted treatment failure up to day 63 (TF63U): TF28U plus all cases of recurrent parasitaemia (symptomatic or asymptomatic) detected between day 29 and day 63 by passive follow up, regardless of genotyping
PCR adjusted treatment failure for the whole period of passive surveillance (TFAPS): TF28A plus all episodes of recurrent parasitaemia identified as recrudescence by genotyping.
Fever clearance time.
Asexual parasite clearance time.
Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups);
Hb changes day 3, 7, 14 and 28 (first and second follow up);
Clinical malaria after first active follow-up;
Clinical malaria after second active follow-up;
TF second clinical episode (D28 and D63);
Changes in the frequency of mutations in the dihydrofolate reductase (DHFR) gene at day 0 first follow-up and day re-appearance of parasitaemia (for patients treated with CDA - NOTE that CDA arm was discontinued on 17.02.2008).
Safety profiles including significant changes in relevant laboratory values.

Full Information

First Posted
October 27, 2006
Last Updated
January 31, 2014
Sponsor
Institute of Tropical Medicine, Belgium
Collaborators
Liverpool School of Tropical Medicine, East African Network for Monitoring Antimalarial Treatment, Centre Muraz, University of Calabar, Tropical Diseases Research Centre, Zambia, University Hospital Tuebingen, Albert Schweitzer Hospital, Uganda Malaria Surveillance Project, Mbarara University of Science and Technology, Ministry of Health, Rwanda, University of Barcelona, Centro de Investigacao em Saude de Manhica
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1. Study Identification

Unique Protocol Identification Number
NCT00393679
Brief Title
Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
Official Title
Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
Study Type
Interventional

2. Study Status

Record Verification Date
January 2014
Overall Recruitment Status
Completed
Study Start Date
July 2007 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
December 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institute of Tropical Medicine, Belgium
Collaborators
Liverpool School of Tropical Medicine, East African Network for Monitoring Antimalarial Treatment, Centre Muraz, University of Calabar, Tropical Diseases Research Centre, Zambia, University Hospital Tuebingen, Albert Schweitzer Hospital, Uganda Malaria Surveillance Project, Mbarara University of Science and Technology, Ministry of Health, Rwanda, University of Barcelona, Centro de Investigacao em Saude de Manhica

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The main objective is to compare the safety and efficacy of 4 artemisinin-based combinations (ACT) [amodiaquine-artesunate (AQ+AS), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) and chlorproguanil/dapsone plus artesunate] for single and repeat treatments of uncomplicated malaria in children. Safety will be determined by registering adverse events and grading, laboratory, and vital signs evaluations. Their incidence will be compared between the different study arms. TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities. The leading EC approved the amendment on 2nd June 2008. TO BE NOTED: since the batches of the study drug DHAPQ expire at the end of October 2008, and because of the unavailability of a new batch of DHAPQ from the manufacturer, the recruitment in the DHAPQ arm had to be discontinued on 30th October 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fever, Malaria
Keywords
Children 6-59 months, P.falciparum, Haemoglobin, Informed consent, ACT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
4112 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
AS-AQ
Arm Title
2
Arm Type
Experimental
Arm Description
DHAPQ TO BE NOTED: since the batches of the study drug DHAPQ expire at the end of October 2008, and because of the unavailability of a new batch of DHAPQ from the manufacturer, the recruitment in the DHAPQ arm had to be discontinued on 30th October 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.
Arm Title
3
Arm Type
Experimental
Arm Description
AL
Arm Title
4
Arm Type
Experimental
Arm Description
Lapdap + AS TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.The leading EC approval was obtained on 2nd June 2008.
Intervention Type
Drug
Intervention Name(s)
amodiaquine-artesunate (ASAQ)
Other Intervention Name(s)
Coarsucam by Sanofi-Aventis
Intervention Description
A fix-dose combination tablet containing artesunate-amodiaquine in three different dosages, to be used according to patient age and weight: 25mg/67.5mg; 50mg/135mg; 100mg/270mg
Intervention Type
Drug
Intervention Name(s)
dihydroartemisinin-piperaquine (DHAPQ)
Other Intervention Name(s)
Artekin, Eurartekin by Sigma Tau, NOTE: batches expire on 31Oct08. Due to unavailability of new batches, recruitment in this arm was discontinued on 30Oct08.
Intervention Description
DHAPQ tablets contain either 20/160mg or 40/320mg of dihydroartemisinin (DHA) and piperaquine phosphate (PQ) respectively.
Intervention Type
Drug
Intervention Name(s)
artemether-lumefantrine (AL)
Other Intervention Name(s)
Coartem, Riamet by Novartis
Intervention Description
Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine.
Intervention Type
Drug
Intervention Name(s)
Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)
Other Intervention Name(s)
Lapdap by GSK., Arsumax by Sanofi and Guilin.
Intervention Description
Lapdap tablets contain 15/18.75mg or 80/100mg of Chlorproguanil Hydrochloride and Dapsone, respectively. Arsumax® tablets contain 50mg Artesunate. TO BE NOTED: following GlaxoSmithKline decision to discontinue the clinical development of the fixed-doses combination of Lapdap (Chlorproguanil-Dapsone) and artesunate, the Lapdap plus Artesunate arm was immediately discontinued in this study, on 17th February 2008. A formal amendment has been submitted to all the concerned ECs and competent authorities.The leading EC approval was obtained on 2nd June 2008.
Primary Outcome Measure Information:
Title
PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping.
Time Frame
Day 28
Title
PCR adjusted treatment failure up to day 28 (TF28A): all early failures before day 14 plus the recurrent parasitaemias detected at day 14 or later and classified by genotyping as recrudescence.
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
PCR unadjusted treatment failure up to day 63 (TF63U): TF28U plus all cases of recurrent parasitaemia (symptomatic or asymptomatic) detected between day 29 and day 63 by passive follow up, regardless of genotyping
Time Frame
Day 63
Title
PCR adjusted treatment failure for the whole period of passive surveillance (TFAPS): TF28A plus all episodes of recurrent parasitaemia identified as recrudescence by genotyping.
Time Frame
Day 28
Title
Fever clearance time.
Title
Asexual parasite clearance time.
Title
Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups);
Time Frame
28 days
Title
Hb changes day 3, 7, 14 and 28 (first and second follow up);
Time Frame
28 days
Title
Clinical malaria after first active follow-up;
Time Frame
28 Days
Title
Clinical malaria after second active follow-up;
Time Frame
Up to seven months
Title
TF second clinical episode (D28 and D63);
Time Frame
63 days
Title
Changes in the frequency of mutations in the dihydrofolate reductase (DHFR) gene at day 0 first follow-up and day re-appearance of parasitaemia (for patients treated with CDA - NOTE that CDA arm was discontinued on 17.02.2008).
Title
Safety profiles including significant changes in relevant laboratory values.
Time Frame
Up to seven months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
59 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and Females aged between 6 months and 59 months inclusive. In the sites where CDA is tested all recruited children will be aged between 12 months and 59 months inclusive (this arm was discontinued on 17th February 2008). This criterion applies only for the recruitment in the first follow up. For the second follow up, children having been included in the first follow up are eligible, regardless of their age. Body weight of 5 Kg and above. Microscopically confirmed, monoinfection of Plasmodium falciparum (parasitaemia ≥ 2,000/μL to 200,000/μL). Fever (axillary temperature at ≥ 37.5°C) or history of fever in the previous 24 hours. Haemoglobin value ≥ 7.0 g/dl; Signed (or thumb-printed whenever parents/guardians are illiterate) informed consent by the parents or guardians. Note the informed consent will be asked only at recruitment and will cover the whole period of the study, including second active follow up and passive case detection. Parents' or guardians' willingness and ability to comply with the study protocol for the duration of the trial. Exclusion Criteria: Participation in any other investigational drug study (antimalarial or others) during the previous 30 days. Known hypersensitivity to the study drugs. Severe malaria. Danger signs: not able to drink or breast-feed, vomiting (> twice in 24hours), recent history of convulsions (>1 in 24h), unconscious state, unable to sit or stand. Presence of intercurrent illness or any condition (cardiac, renal, hepatic diseases) which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study, including known G6PD deficiency. Severe malnutrition (defined as weight for height <70% of the median NCHS/WHO reference). Ongoing prophylaxis with drugs having antimalarial activity such as cotrimoxazole for the prevention of Pneumocystis carinii pneumonia in children born to HIV+ women.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
UmbertoC D'Alessandro, MD MsC PhD
Organizational Affiliation
Institute of Tropical Medicine Antwerp
Official's Role
Study Director
Facility Information:
Facility Name
Centre Muraz/IRSS
City
Bobo-Dioulasso
Country
Burkina Faso
Facility Name
Albert Schweitzer Hospital
City
Lambaréné
Country
Gabon
Facility Name
Manhiça Health Research Center
City
Manhica
Country
Mozambique
Facility Name
Hospital
City
Calabar
Country
Nigeria
Facility Name
Mashshesha and Rukara
City
Kigali
Country
Rwanda
Facility Name
Jinja and Tororo
City
Kampala
Country
Uganda
Facility Name
Mbarara,
City
Mbarara
Country
Uganda
Facility Name
Tropical Diseases Research Centre, P O Box 71769,
City
Ndola
Country
Zambia

12. IPD Sharing Statement

Citations:
PubMed Identifier
23217117
Citation
Ravinetto RM, Talisuna A, De Crop M, van Loen H, Menten J, Van Overmeir C, Tinto H, Gonzalez R, Meremikwu M, Nabasuma C, Ngoma GM, Karema C, Adoke Y, Chaponda M, Van Geertruyden JP, D'Alessandro U. Challenges of non-commercial multicentre North-South collaborative clinical trials. Trop Med Int Health. 2013 Feb;18(2):237-41. doi: 10.1111/tmi.12036. Epub 2012 Dec 10.
Results Reference
background
PubMed Identifier
22087077
Citation
Four Artemisinin-Based Combinations (4ABC) Study Group. A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial. PLoS Med. 2011 Nov;8(11):e1001119. doi: 10.1371/journal.pmed.1001119. Epub 2011 Nov 8.
Results Reference
result

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Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children

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