A pharmacokinetic randomised interventional study to optimise dihydroartemisinin-piperaquine dosing for malaria preventive treatment in Malawian infants (OPTIMAL Study) version 1.0
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Date
2022-09-08
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Kamuzu University of Health Sciences
Abstract
Type of study
This is an open-label randomised interventional study (with 1:1 allocation into intervention
and control groups) to optimise the dosing of an antimalarial drug, dihydroartemisininpiperaquine
(DP), administered with routine vaccinations, for malaria preventive treatment in
infants.
Problem to be studied
The World Health Organisation (WHO) recommends the use of sulphadoxine-pyrimethamine
(SP), administered with routine immunisation, for intermittent preventive treatment of malaria
in infancy (IPTi) in areas of moderate to high transmission in sub-Saharan Africa. However,
there is limited uptake of this recommendation and increasing resistance of malaria
parasites to SP. Fortunately, another antimalarial drug, DP, has shown higher protective
efficacy than SP. Nevertheless, there is a paucity of evidence to guide its optimal dosing
when administered together with routine vaccinations in infancy. The present study seeks to
define the optimal dose of DP for IPTi when administered with routine vaccinations.
Overall objective
The overall objective of this study is to define the optimal dose of DP for IPTi when
administered with routine vaccinations
Specific objectives
1. To describe age-related changes in population pharmacokinetic properties of
piperaquine following partially supervised administration of IPTi-DP at four different
routine immunization time points in infancy (i.e., at 10-, 14 weeks, 6 months, and 9
months of age).
2. To evaluate the association between piperaquine exposure and incidence of
symptomatic and asymptomatic malaria during IPTi-DP.
3. To compare the safety and tolerability of DP following supervised administration of
IPTi-DP at routine immunizations with routine immunizations alone.
4. To apply population pharmacokinetic modelling and simulation techniques to
optimise the dose of piperaquine when administered as IPTi-DP
Methodology
220 infants will be randomised, from 10 weeks of age, to receive DP with routine vaccines
(intervention group, n=110) or standard of care; routine vaccines only (control group,
n=110). They will be followed up until 12 months of age. In the intervention group, infants will
contribute capillary samples for piperaquine concentrations, at different time points after
administration of DP, and capillary samples to quantify malaria parasitaemia using
microscopy and quantitative PCR. In the control group, infants will contribute capillary blood
samples at the same time points as those in the intervention group for malaria parasitaemia
over the first year of life. Additionally, the safety and tolerability of DP for IPTi with routine
vaccinations will be monitored by comparing adverse events in the intervention and control
groups
Expected findings and their dissemination
Optimised dosing regimens of DP for IPTi will be developed by applying population
pharmacokinetic-pharmacodynamic modelling techniques on data obtained from:
1. Understanding age-related changes in piperaquine pharmacokinetics from infants in
the intervention group.
2. Evaluating the pharmacokinetics, efficacy and safety of DP for IPTi in infants in the
intervention group compared with malaria incidence and adverse events in the
control group.
This work will provide the much-needed evidence to inform DP dosing for IPTi when
administered with routine immunisation. Additionally, it will inform future work on optimal DP
dosing for malaria treatment in infants. The findings will be disseminated to study
participants, in peer-reviewed scientific journals, WHO, national malaria control programs in
malaria-endemic settings and ethics committees that will review and approve the study
(COMREC, LSTM REC and UCT HREC).
Description
Keywords
Pharmacokinetic study to optimize dosing of DHA_PQ in infants