Clinical Trial: A Pharmacokinetic/Pharmacodynamic Study of Eurartesim Dispersible Formulation in Infants With P.Falciparum Malaria
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: A Phase II, Open-label, Multicentre, Pharmacokinetic, Pharmacodynamics and Safety Study of a New Paediatric Eurartesim Dispersible Formulation and Crushed Film Coated Eurartesim Tablet, in Infant Pati
Brief Summary:
There is a need for paediatric formulations that permit accurate dosing and enhance patient compliance. However, for the treatment of malaria, scarce paediatric-friendly formulations are available on the market. Thus, a new water dispersible formulation of eurartesim has been developed for oral administration.
Aim of this study is to provide data on pharmacokinetic profile, safety and efficacy of this new paediatric formulation and compare it with the crushed film coated tablet in infant patients (6 to ≤12 months of age) suffering from uncomplicated Plasmodium falciparum malaria.
Furthermore, a Pharmacokinetic/Pharmacodynamic(PK/PD) modelling will be built up to establish PK/PD relationship in adult and paediatric populations.
Detailed Summary:
Although the significant advances made during the last decades in controlling malaria in Africa, morbidity and mortality in sub-Saharan countries remain substantial. It is estimated that around 655.000 deaths a year still occur due to malaria infection and the majority of such deaths occur among young African children.
In response to the emergence and spread of classical drug-resistant Plasmodia strains, the WHO recommends since 2004 the use of artemisinin-based combination therapies (ACTs) in the treatment of uncomplicated malaria episodes.
The artemisinin derivatives are currently the most rapidly acting and potent antimalarial drugs.
Eurartesim is a fixed-dose combination product composed of dihydroartemisinin (DHA) and piperaquine phosphate (PQP). This second compound assures the long-term efficacy of eurartesim completing the whole body cleaning from the parasites. Eurartesim appears to offer benefits over existing licensed malaria treatments and is in line with current WHO treatment policy recommendations.
Eurartesim obtained a centralized marketing authorization by the European Union as film coated tablets containing 160 mg PQP/20 mg DHA and 320 mg PQP/40 mg DHA. The drug, licensed for its use in children (above 6 months of age) and adults has been administered in infants (above 6 months) and young children by crushing the tablets and administering them with a small amount of water.
According to the Guidelines on Clinical Investigation of Medicinal Products in the Paediatric Population (EMA ICH Topic E 11), there is a need for paediatric formulations that permit accurate dosing and enhance patient compliance.
However, f
Sponsor: sigma-tau i.f.r. S.p.A.
Current Primary Outcome:
- Comparison of peak plasma concentration of Dihydroartemisinin in the two studied formulations [ Time Frame: DHA plasma samples will be collected on the first day of study drug administration at 20, 30, 40, 60, 100, 200 and 300 minutes post-dose ]
In order to minimize the blood sampling in infants, patients will be divided into 10 blood sampling groups for both the treatments (water dispersible and crushed film coated tablet) and only 2 blood draws per group will be taken within the prespecified timepoints.
Optimal sampling design was performed by using the appropriate software. The D-optimal design option was used to determine the optimal sampling design.
- Comparison of area under the plasma concentration versus time curve of Dihydroartemisinin in the two studied formulations. [ Time Frame: DHA plasma samples will be collected on the first day of study drug administration at 20, 30, 40, 60, 100, 200 and 300 minutes post-dose ]
In order to minimize the blood sampling in infants, patients will be divided into 10 blood sampling groups for both the treatments (water dispersible and crushed film coated tablet) and only 2 blood draws per group will be taken within the pre-specified timepoints.
Optimal sampling design was performed by using the appropriate software. The D-optimal design option was used to determine the optimal sampling design.
- Comparison of peak plasma concentration of Piperaquine in the two studied formulations [ Time Frame: PQP plasma samples will be collected on day
Original Primary Outcome: Same as current
Current Secondary Outcome:
- Parasite clearance time [ Time Frame: At screening and then about every 12 hours until the time of the first negative result, then confirmed by a second negative result or up to three days ]Blood film for parasite count will be read by two independent microscopists.
- Fever clearance time [ Time Frame: At screening and then about every 12 hours until the time on which body temperature falls down below 37.5 °C, or up to three days ]Body temperature will be recorded to collect information about the fever clearance time
- Change from baseline of electrocardiographic QT interval at 4-6 hours after the last study drug intake [ Time Frame: Before randomization and then at 4-6 hours after the last dose of study drug. ]
Triplicate ECGs will be undertaken on screening (before study drug administration)as well as 4-6 hours after the last drug administration.
The triplicate ECG values will be averaged in order to obtain one single value per patient and time point. These averages will be used for the statistical analysis.
From the collected values the heart rate corrected QT intervals will be derived according to Fridericia's correction (QTcF)
- Blood chemistry: proportion of patients with deterioration of parameters at day 7 respect to screening. [ Time Frame: screening and Day 7 ]The evaluated analytes are: Blood Urea Nitrogen, Creatinine, Glucose, Alanine aminotransferase, aspartate aminotransferase, Total Bilirubin, electrolytes (Na+, K+ and Cl-)
- Hematology: proportion of patients with deterioration of parameters at day 7 respect to screening [ Time Frame: screening and day 7 ]the following parameters are evaluated: Hemoglobin, hematocrit and full blood counts including Red Blood Cell and differential White Blood Cells, Platelet Count
- Adverse Events occurrence to calculate percentage of patients experiencing Adverse Events and Serious Adverse Events [ Time Frame: during all the study period from randomization and up to day 42 ]
Original Secondary Outcome: Same as current
Information By: sigma-tau i.f.r. S.p.A.
Dates:
Date Received: November 11, 2013
Date Started: November 2013
Date Completion:
Last Updated: November 4, 2016
Last Verified: November 2016
- Parasite clearance time [ Time Frame: At screening and then about every 12 hours until the time of the first negative result, then confirmed by a second negative result or up to three days ]
