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Artemether/ Lumefantrine: A Study of the Effect of Local Food on Pharmacokinetics and Population Pharmacokinetics

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ClinicalTrials.gov Identifier: NCT01944189
Recruitment Status : Unknown
Verified May 2014 by College of Health Sciences, Makerere University.
Recruitment status was:  Recruiting
First Posted : September 17, 2013
Last Update Posted : May 28, 2014
Sponsor:
Collaborators:
Karolinska Institutet
Swedish International Development Cooperation Agency (SIDA)
Information provided by (Responsible Party):
College of Health Sciences, Makerere University

Brief Summary:

Despite preventive programs, effective case management is still the cornerstone in malaria control.

This study is as a strategy towards improved recommendations in resource limited countries during artemether -lumefantrine (AL) treatment in order to maximize the public health benefits.

This is observational population pharmacokinetics study with a nested comparative bioavailability study.The study is intended to describe the variability in lumefantrine blood levels among under five year old Ugandan children with uncomplicated falciparum malaria receiving current standard artemether-lumefantrine dose regimens. Findings will form a basis for development of rational dosage recommendations. The nested comparative bioavailability study will explore effect of profiled local food intake (maize porridge plus vegetable oil versus milk) on lumefantrine uptake. As a strategy towards improved recommendations in resource limited countries during AL treatment in order to maximize the public health benefits. As a secondary objective we will correlate the variability in lumefantrine uptake to malaria treatment outcome and safety profile in this population.

Research hypotheses

  1. The population pharmacokinetic profile of lumefantrine among under five year old children in Uganda with uncomplicated falciparum malaria is not affected by demographic factors.
  2. There is no difference in the bioavailability of lumefantrine when artemether-lumefantrine is received with maize porridge plus vegetable oil versus milk among under five year old Ugandan children treated for uncomplicated falciparum malaria.

Condition or disease Intervention/treatment Phase
Malaria, Falciparum Dietary Supplement: Food Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Artemether/ Lumefantrine: A Study of the Effect of Local Food on Pharmacokinetics of Lumefantrine and Population Pharmacokinetics of Lumefantrine Among Ugandan Children
Study Start Date : September 2013
Estimated Primary Completion Date : September 2014
Estimated Study Completion Date : March 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: Food Supplement

Population PK Study will enroll 70 children receiving standard AL dose at 0, 8, 24, 36, 48, 60 hour with recommended milk or maize porridge plus oil. Both foods contain sufficient fat therefore will contribute to pool evaluations as a single cohort.

A subset, 48 children will have participated in nested comparative bio-availability study as follows Standard arm children receiving single dose with milk (12) Standard arm children receiving double dose with milk (12) Experimental arm children receiving single dose with maize porridge plus oil (12) Experimental arm children receiving double dose with maize porridge plus oil (12) The rest, 22 children will have participated exclusively in PPK, receiving appropriate single or double dose with milk similar to those in standard arm

Dietary Supplement: Food

Nested comparative bioavailability study: 48 out of 70 children randomized to 2 food arms under 2 dose groups of artemether lumefantrine (20mg /120 mg) treatment according to standard care weight based dose groups (> 5 to >15 kg receive 1 tablet and 15 to > 25 kg receive 2 tablets)

Food arms:

Standard arm = Milk

Experimental arm = maize porridge plus oil

Groups include Single dose group= 1 tablet of artemether lumefantrine (20/120 mg) and Double dose group= 2 tablet of artemether lumefantrine (20/120 mg)

Standard arm children receiving milk and single dose(12) Standard arm children receiving milk and double dose(12) Experimental arm children receiving maize porridge plus oil and single dose(12) Experimental arm children receiving maize porridge plus oil and double dose (12)

Other Names:
  • Coartem Dispersible 20/120 mg
  • NAFDAC REG.NO.: A4-1680

Experimental: Food Supplement Arm

Population PK Study will enroll 70 children receiving standard AL dose at 0, 8, 24, 36, 48, 60 hour with recommended milk or maize porridge plus oil. Both foods contain sufficient fat therefore will contribute to pool evaluations as a single cohort.

A subset, 48 children will have participated in nested comparative bio-availability study as follows Standard arm children receiving single dose with milk (12) Standard arm children receiving double dose with milk (12) Experimental arm children receiving single dose with maize porridge plus oil (12) Experimental arm children receiving double dose with maize porridge plus oil (12) The rest, 22 children will have participated exclusively in PPK, receiving appropriate single or double dose with milk similar to those in standard arm

Dietary Supplement: Food

Nested comparative bioavailability study: 48 out of 70 children randomized to 2 food arms under 2 dose groups of artemether lumefantrine (20mg /120 mg) treatment according to standard care weight based dose groups (> 5 to >15 kg receive 1 tablet and 15 to > 25 kg receive 2 tablets)

Food arms:

Standard arm = Milk

Experimental arm = maize porridge plus oil

Groups include Single dose group= 1 tablet of artemether lumefantrine (20/120 mg) and Double dose group= 2 tablet of artemether lumefantrine (20/120 mg)

Standard arm children receiving milk and single dose(12) Standard arm children receiving milk and double dose(12) Experimental arm children receiving maize porridge plus oil and single dose(12) Experimental arm children receiving maize porridge plus oil and double dose (12)

Other Names:
  • Coartem Dispersible 20/120 mg
  • NAFDAC REG.NO.: A4-1680




Primary Outcome Measures :
  1. Pharmacokinetic (PK) exposure parameters of lumefantrine [ Time Frame: 28 days ]
    Sparse pharmacokinetic data will be pooled for evaluation of both individual and population PK parameter estimates of lumefantrine using Non linear mixed effect model. Pharmacokinetic exposure will be depicted principally by area under the concentration-time curves following the last dose through to 28 days of follow up (AUC0-28). Other PK parameters portraying exposure will also be assessed alongside. These include half life (t1/2), peak concentrations (Cmax) and time to reach Cmax (Tmax), apparent clearance and volumes of distribution.


Secondary Outcome Measures :
  1. Relative Oral Bioavailability of lumefantrine [ Time Frame: 8 h after the first dose ]

    Nested Randomized Comparative Bioavailability study: Relative oral bioavailability between the two food arms will be assessed using lumefantrine pharmacokinetic exposure outcomes at 8 h after first dose. Parameters to be considered will be attained peak concentrations (Cmax ) and area under concentration-time curve up to 8h after the first dose (AUC0-8h).

    Peak concentrations (Cmax) and AUC0-8h will be used for relative bioavailability evaluations using confidence interval approach for average bioequivalence.



Other Outcome Measures:
  1. Malaria treatment outcome (clinical and parasitological response) [ Time Frame: 28 days ]
    Correlation of overall lumefantrine exposure (AUC0-28d and AUC0-∞) to clinical and parasitological response to artemether lumefantrine treatment will be explored.

  2. Adverse events [ Time Frame: 28 days ]
    To assess the relationship between drug exposure over the time and the safety profile in particular clinical parameters



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 5 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Diagnosis of uncomplicated falciparum malaria
  • Age ≥ 6 months to ≤5 years.
  • For nested comparative bioavailability study, age >1 to ≤5 years of age, to avoid intense blood draws from younger children
  • Weight ≥5 kg.
  • For nested comparative bioavailability study, restrict evaluation to 2 weight/dose groups >5 to < 15kg and 15 to < 25kg
  • Within 10 km radius from recruitment site
  • Informed consent from parent or guardian
  • Willingness to adherence to study procedures

Exclusion criteria:

  • Severe or complicated malaria "Danger signs"
  • Mixed plasmodial infection
  • Hemoglobin < 5 mg/dl
  • Weight < 5kg
  • Allergy to study medication or milk
  • Medication which known to inhibit or induce CYP3A4/5 examples ketoconazole, erythromycin, steroids, antidepressants, anticonvulsants, antiretroviral drugs.
  • Receipt of artemisinin containing compounds in the past 7 days or lumefantrine in the past 28 days

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): NCT01944189


Contacts
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Contact: Norah Mwebaza, MBChB M Sc +256 711589889 mwebno@yahoo.com
Contact: Paul Waako, PhD +256 772468458 pwaako@chs.mak.ac.ug

Locations
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Uganda
Department of Pharmacology & Therapeutics, MakCHS, Mulago Hospital Complex Recruiting
Kampala, Uganda, 256
Contact: Norah Mwebaza, MBChB M Sc    +256 711589889    mwebno@yahoo.com   
Contact: Paul Waako, PhD    +256 772468458    pwaako@chs.mak.ac.ug   
Principal Investigator: Norah Mwebaza, MBChB M Sc         
Sponsors and Collaborators
Makerere University
Karolinska Institutet
Swedish International Development Cooperation Agency (SIDA)
Investigators
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Principal Investigator: Norah Mwebaza, MBChB M Sc • Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences (MakCHS), Uganda
Study Chair: Urban Hellgren, MD PhD Div Infectious Diseases, Karolinska Institutet (KI) , Sweden
Study Chair: Lars L Gustaffson, MD PhD Dep Lab Medicine, Div Clinical Pharmacology, KI
Study Chair: Paul Waako, PhD Department of Pharmacology and Therapeutics, MakCHS, Kampala, Uganda
Study Chair: Celestino Obua, PhD Department of Pharmacology and Therapeutics, MakCHS, Kampala, Uganda

Publications:
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Responsible Party: College of Health Sciences, Dr Norah Mwebaza, Makerere University
ClinicalTrials.gov Identifier: NCT01944189     History of Changes
Other Study ID Numbers: HS 567
2009/054 ( Other Identifier: Makerere University Research Ethics Committee )
First Posted: September 17, 2013    Key Record Dates
Last Update Posted: May 28, 2014
Last Verified: May 2014

Keywords provided by College of Health Sciences, Makerere University:
lumefantrine pharmacokinetics & bioavailability

Additional relevant MeSH terms:
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Malaria, Falciparum
Malaria
Protozoan Infections
Parasitic Diseases
Lumefantrine
Artemether
Artemether, Lumefantrine Drug Combination
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents