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London School of Hygiene & Tropical Medicine Malaria Centre

LSHTM and partners launch cardio-safety trial in Tanzania

14 October 2016
A multi-national team have launched a trial to investigate the cardio-safety trial of dihydroartemisinin-piperaquine amongst pregnant women and pharmacokinetics of piperaquine.

A research team from the London School of Hygiene & Tropical Medicine, Kilimanjaro Christian Medical College (KCMC), Tanzania’s National Institute for Medical Research (NIMR), Banook Group, and Medicines for Malaria Venture has launched a clinical trial at the Handeni District Hospital in north-western Tanzania.  The team will measure the cardio-safety of dihydroartemisinin-piperaquine (DP) and the pharmacokinetics of piperaquine in pregnancy women, as well as the prevalence of the genetic mutation amongst malaria parasites located at codon 581 in the same population. 

Representatives from LSHTM, MMV, and Banook meet with local officials in Handeni to explain the importance of the trial and to secure their support

Representatives from LSHTM, MMV, and Banook meet with local officials in Handeni to explain the importance of the trial and to secure their support

 

Since 2004, the World Health Organization has recommended the provision of SP during antenatal visits in areas of moderate to high malaria transmission [1].  However, a study published by the London School last year found that two or more doses of IPTp-SP no longer protects against the incidence of low birth weight in areas where the prevalence of the 581 mutation in malaria parasites is greater than 10.1% [2].  The team chose the Handeni District Hospital for this trial because prior research by the London School, KCMC, and NIMR in the same area of Tanzania found that 55% of malaria parasites expressed the 581 mutation [3].  An alternative to SP is urgently needed. 

 A pregnant women has vital signs recorded as part of the cardio-safety trial in Tanzania.

A pregnant women has vital signs recorded as part of the cardio-safety trial in Tanzania. 

 

Dihydroartemisinin-piperaquine is the leading candidate to replace SP in IPTp [4].  The combination is well-tolerated and has a suitable half-life for chemoprevention.  Although dihydroartemisinin is quickly eliminated within 12 hours, piperaquine has a terminal half-life between 4 to 5 weeks [5], meaning that pregnant women may be shielded from the adverse consequences of malaria infection between monthly antenatal visits.  Piperaquine, however, may alter the natural contraction cycle of the heart, prolonging the QTc interval [6].  Malaria infection itself can have the same effect [7].  Prolongation associated with piperaquine use has been shown to be time-limited and of no clinical consequence among children and non-pregnant adults [6].  This needs to be confirmed among pregnant women before DP can be recommended for broader use in IPTp.  Pregnancy is known to alter the absorption, distribution, metabolism, and excretion of medication.  Similar changes can occur in pregnant women with the macro- and micro-nutrients from food. 

 

 

 A nurse at the Handei District Hospital in Tanzania participates in cardio-safety training

A male nurse at the Handei District Hospital in Tanzania participates in cardio-safety training

 

To understand the absorption of DP and potential effect on cardio-function, hospital staff draw blood from women who are receiving DP before the first dose, again before the third (final) dose, and then at hours 4, 5, and 6 following the third dose.  This will allow researchers to pin-point when the peak concentration of piperaquine has been absorbed and relate this maximum drug exposure to the electro-cardiograph and Holter-device measurements that are being collected at the same time to see what, if any, differences occurred in cardio-functioning between women (with and without parasites) given DP versus women (with and without parasites) given SP.  In total, 200 pregnant women will participant in the trial.  Each woman will give birth at the District Hospital and be visited by trial staff at their homes 28 days later to confirm the health and wellbeing of mother and child.  While other research is underway to consider the possible role of DP as a substitute for SP in IPTp, this study is the first to propose a detailed safety analysis based on frequent monitoring of cardiac signals throughout the drug’s administration.  Result of the trial will be available in late 2017.   

 

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This trial has been approved by ethics committees of LSHTM and the National Institute of Medical Research in Tanzania, as well as the Tanzanian Food and Drug Authority.  An independent data safety monitoring committee will review interim results and have the authority to suspend the trial at any time for reasons of patient safety.  More details can be found in the trial registry and results database maintained by the U.S. National Institutes of Health at http://www.ClinicalTrials.gov using the Identifier: NCT02909712.  Additional information is also available from Matthew Chico, Assistant Professor in the Department of Disease Control at the London School of Hygiene & Tropical Medicine: matthew [dot] chico [at] lshtm [dot] ac [dot] uk

 

References

 

1.         World Health Organization, A Strategic Framework for Malaria Prevention and Control During Pregnancy in the Africa Region. Vol. AFR/MAL/04/01. 2004: World Health Organization Regional Office for Africa.

2.         Chico, R.M., et al., Influence of malaria transmission intensity and the 581G mutation on the efficacy of intermittent preventive treatment in pregnancy: systematic review and meta-analysis. Trop Med Int Health, 2015. 20(12): p. 1621-33.

3.         Gesase, S., et al., High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581. PLoS One, 2009. 4(2): p. e4569.

4.         Chico, R.M. and W.J. Moss, Prevention of malaria in pregnancy: a fork in the road? The Lancet, 2015.

5.         Valecha, N., et al., An open-label, randomised study of dihydroartemisinin-piperaquine versus artesunate-mefloquine for falciparum malaria in Asia. PLoS One, 2010. 5(7): p. e11880.

6.         Zani, B., et al., Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev, 2014(1): p. Cd010927.

7.         vn Seidlein, L., S. Jaffar, and B. Greenwood, Prolongation of the QTc interval in African children treated for falciparum malaria. Am J Trop Med Hyg, 1997. 56(5): p. 494-7.