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

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ClinicalTrials.gov Identifier: NCT00393679
Recruitment Status : Completed
First Posted : October 30, 2006
Last Update Posted : February 3, 2014
Sponsor:
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
Information provided by (Responsible Party):
Institute of Tropical Medicine, Belgium

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.


Condition or disease Intervention/treatment Phase
Fever Malaria Drug: amodiaquine-artesunate (ASAQ) Drug: dihydroartemisinin-piperaquine (DHAPQ) Drug: artemether-lumefantrine (AL) Drug: Lapdap (Chlorproguanil-Dapsone) + artesunate (AS) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
Study Start Date : July 2007
Actual Primary Completion Date : December 2009
Actual Study Completion Date : December 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: 1
AS-AQ
Drug: amodiaquine-artesunate (ASAQ)
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
Other Name: Coarsucam by Sanofi-Aventis

Experimental: 2

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.

Drug: dihydroartemisinin-piperaquine (DHAPQ)
DHAPQ tablets contain either 20/160mg or 40/320mg of dihydroartemisinin (DHA) and piperaquine phosphate (PQ) respectively.
Other Names:
  • Artekin, Eurartekin by Sigma Tau
  • NOTE: batches expire on 31Oct08. Due to unavailability of new batches, recruitment in this arm was discontinued on 30Oct08.

Experimental: 3
AL
Drug: artemether-lumefantrine (AL)
Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine.
Other Name: Coartem, Riamet by Novartis

Experimental: 4

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.

Drug: Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)

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.

Other Names:
  • Lapdap by GSK.
  • Arsumax by Sanofi and Guilin.




Primary Outcome Measures :
  1. PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping. [ Time Frame: Day 28 ]
  2. 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 Measures :
  1. 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 ]
  2. 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 ]
  3. Fever clearance time.
  4. Asexual parasite clearance time.
  5. Gametocytaemia (prevalence and density) at day 7, 14, 21 and 28 after treatment (for both active follow-ups); [ Time Frame: 28 days ]
  6. Hb changes day 3, 7, 14 and 28 (first and second follow up); [ Time Frame: 28 days ]
  7. Clinical malaria after first active follow-up; [ Time Frame: 28 Days ]
  8. Clinical malaria after second active follow-up; [ Time Frame: Up to seven months ]
  9. TF second clinical episode (D28 and D63); [ Time Frame: 63 days ]
  10. 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).
  11. Safety profiles including significant changes in relevant laboratory values. [ Time Frame: Up to seven months ]


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Ages Eligible for Study:   6 Months to 59 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00393679


Locations
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Burkina Faso
Centre Muraz/IRSS
Bobo-Dioulasso, Burkina Faso
Gabon
Albert Schweitzer Hospital
Lambaréné, Gabon
Mozambique
Manhiça Health Research Center
Manhica, Mozambique
Nigeria
Hospital
Calabar, Nigeria
Rwanda
Mashshesha and Rukara
Kigali, Rwanda
Uganda
Jinja and Tororo
Kampala, Uganda
Mbarara,
Mbarara, Uganda
Zambia
Tropical Diseases Research Centre, P O Box 71769,
Ndola, Zambia
Sponsors and Collaborators
Institute of Tropical Medicine, Belgium
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
Investigators
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Study Director: UmbertoC D'Alessandro, MD MsC PhD Institute of Tropical Medicine, Antwerp

Publications of Results:
Other Publications:
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Responsible Party: Institute of Tropical Medicine, Belgium
ClinicalTrials.gov Identifier: NCT00393679     History of Changes
Other Study ID Numbers: 4 ABC
IRB Antwerp: 6/40/187
First Posted: October 30, 2006    Key Record Dates
Last Update Posted: February 3, 2014
Last Verified: January 2014
Keywords provided by Institute of Tropical Medicine, Belgium:
Children 6-59 months
P.falciparum
Haemoglobin
Informed consent
ACT
Additional relevant MeSH terms:
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Malaria
Protozoan Infections
Parasitic Diseases
Artesunate
Lumefantrine
Artemether
Piperaquine
Artemether, Lumefantrine Drug Combination
Amodiaquine
Dihydroartemisinin
Artemisinins
Dapsone
Chlorproguanil
Proguanil
Artemisinine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leprostatic Agents
Anti-Bacterial Agents
Antimetabolites