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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

Tracking Information
First Submitted Date  ICMJE October 27, 2006
First Posted Date  ICMJE October 30, 2006
Last Update Posted Date February 3, 2014
Study Start Date  ICMJE July 2007
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2008)
  • PCR unadjusted treatment failure (TF28U): all treatment failures detected during the active follow up, regardless of genotyping. [ Time Frame: Day 28 ]
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 27, 2006)
  • 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.
Change History Complete list of historical versions of study NCT00393679 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2008)
  • 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 ]
  • 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 ]
  • 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); [ Time Frame: 28 days ]
  • Hb changes day 3, 7, 14 and 28 (first and second follow up); [ Time Frame: 28 days ]
  • Clinical malaria after first active follow-up; [ Time Frame: 28 Days ]
  • Clinical malaria after second active follow-up; [ Time Frame: Up to seven months ]
  • TF second clinical episode (D28 and D63); [ Time Frame: 63 days ]
  • 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. [ Time Frame: Up to seven months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2006)
  • 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).
  • Safety profiles including significant changes in relevant laboratory values.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
Official Title  ICMJE Evaluation of 4 Artemisinin-based Combinations for Treating Uncomplicated Malaria in African Children
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Fever
  • Malaria
Intervention  ICMJE
  • 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
  • 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.
  • Drug: artemether-lumefantrine (AL)
    Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine.
    Other Name: Coartem, Riamet by Novartis
  • 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.
Study Arms  ICMJE
  • Experimental: 1
    AS-AQ
    Intervention: Drug: amodiaquine-artesunate (ASAQ)
  • 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.

    Intervention: Drug: dihydroartemisinin-piperaquine (DHAPQ)
  • Experimental: 3
    AL
    Intervention: Drug: artemether-lumefantrine (AL)
  • 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.

    Intervention: Drug: Lapdap (Chlorproguanil-Dapsone) + artesunate (AS)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 4, 2009)
4112
Original Enrollment  ICMJE
 (submitted: October 27, 2006)
5100
Actual Study Completion Date  ICMJE December 2009
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 59 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Gabon,   Burkina Faso,   Mozambique,   Nigeria,   Rwanda,   Uganda,   Zambia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00393679
Other Study ID Numbers  ICMJE 4 ABC
IRB Antwerp: 6/40/187
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institute of Tropical Medicine, Belgium
Study Sponsor  ICMJE Institute of Tropical Medicine, Belgium
Collaborators  ICMJE
  • 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  ICMJE
Study Director: UmbertoC D'Alessandro, MD MsC PhD Institute of Tropical Medicine, Antwerp
PRS Account Institute of Tropical Medicine, Belgium
Verification Date January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP