Paediatric formulations of artemisinin-based combination therapies for treating uncomplicated malaria in children

Sabine Bélard, Michael Ramharter, Florian Kurth, Sabine Bélard, Michael Ramharter, Florian Kurth

Abstract

Background: In endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.

Objectives: To evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.

Selection criteria: We included randomised controlled clinical trials (RCTs) of paediatric versus non-paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.

Data collection and analysis: Two authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non-paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.

Main results: Three trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ), and one trial assessed artemether-lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub-Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia). In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)-adjusted treatment failure rates of < 10% on day 28 in the per-protocol (PP) population. For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR-adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low-certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR-adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study). We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low-certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study). In the dispersible ACT arms, drug-related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA-PQ study. In the control arms, drug-related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA-PQ study. Drug-related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate-certainty evidence). There was no detected difference in the rate of drug-related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study). Drug-related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low-certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered. No study assessed acceptability.

Authors' conclusions: Trials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug-related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.

Trial registration: ClinicalTrials.gov NCT00386763 NCT01992900 NCT00529867.

Conflict of interest statement

SB participated as investigator in the clinical development of artesunate–mefloquine (sponsored by Mepha, Aesch, Switzerland) between 2005 and 2006, and pyronaridine–artesunate (sponsored by Medicines for Malaria Venture, Geneva, Switzerland) between 2006 and 2008.

MR has participated as investigator in the clinical development of pyronaridine‐artesunate (sponsored by Medicines for Malaria Venture, Geneva, Switzerland) in 2005‐2020, artesunate‐mefloquine (sponsored by Mepha, Aesch, Switzerland) between 2005‐2006, and artemether‐lumefantrine in 2006‐2008. He has received consulting fees from Medicines for Malaria Venture.

FK participated as investigator in the clinical development of artesunate–mefloquine (sponsored by Mepha, Aesch, Switzerland) between 2005 and 2006, and pyronaridine–artesunate (sponsored by Medicines for Malaria Venture, Geneva, Switzerland) between 2006 and 2008.

Figures

2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Red = high risk; green = low risk; and yellow = unclear risk.

**1.1. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 1: Day 28 PCR‐adjusted treatment failure PP

**1.2. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 2: Day 28 PCR‐adjusted treatment failure ITT

**1.3. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 3: Day 28 PCR‐unadjusted treatment failure PP

**1.4. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 4: Day 28 PCR‐unadjusted treatment failure ITT

**1.5. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 5: PCR‐adjusted treatment failure last day of observation (D42) PP

**1.6. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 6: PCR‐adjusted treatment failure last day of observation (D42) ITT

**1.7. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 7: PCR‐unadjusted treatment failure last day of observation (D42) PP

**1.8. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 8: PCR‐unadjusted treatment failure last day of observation (D42) ITT

**1.9. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 9: Serious adverse events

**1.10. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 10: Drug‐related adverse events

**1.11. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 11: Drug‐related vomiting

**1.12. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 12: Drug‐related gastrointestinal disorders

**1.13. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 13: Drug‐related vomiting and gastrointestinal disorders

**1.14. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 14: Adverse events

**1.15. Analysis**
Comparison 1: ACT dispersible tablet versus ACT crushed tablet, Outcome 15: Drug‐related serious adverse events

**2.1. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 1: Day 28 PCR‐adjusted treatment failure PP

**2.2. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 2: Day 28 PCR‐adjusted treatment failure ITT

**2.3. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 3: Day 28 PCR‐unadjusted treatment failure PP

**2.4. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 4: Day 28 PCR‐unadjusted treatment failure ITT

**2.5. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 5: Serious adverse events

**2.6. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 6: Drug‐related adverse events

**2.7. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 7: Drug‐related vomiting

**2.8. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 8: Drug‐related gastrointestinal disorders

**2.9. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 9: Drug‐related vomiting and gastrointestinal disorders

**2.10. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 10: Fever clearance time

**2.11. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 11: Parasite clearance time

**2.12. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 12: Adverse events

**2.13. Analysis**
Comparison 2: ACT suspension versus ACT crushed tablet, Outcome 13: Drug‐related serious adverse events

References

References to studies included in this review Abdulla 2008 {published data only}

1. Abdulla S, Sagara I, Borrmann S, D'Alessandro U, González R, Hamel M, et al. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet 2008;372(9652):1819-27. [DOI: 10.1016/S0140-6736(08)61492-0]
1. Bassat Q, González R, Machevo S, Nahum A, Lyimo J, Maiga H, et al. Similar efficacy and safety of artemether-lumefantrine (Coartem®) in African infants and children with uncomplicated falciparum malaria across different body weight ranges. Malaria Journal 2011;10:369. [DOI: 10.1186/1475-2875-10-369]
1. Djimde AA, Tekete M, Abdulla S, Lyimo J, Bassat Q, Mandomando I, et al. Pharmacokinetic and pharmacodynamic characteristics of a new pediatric formulation of artemether-lumefantrine in African children with uncomplicated Plasmodium falciparum malaria. Antimicrobial Agents and Chemotherapy 2011;55(9):3994–9. [DOI: 10.1128/AAC.01115-10]

Gargano 2018 {published data only}

1. Gargano N, Madrid L, Valentini G, D’Alessandro U, Halidou T, Sirima S, et al. Efficacy and tolerability outcomes of a phase II, randomized, open-label, multicenter study of a new water-dispersible pediatric formulation of dihydroartemisinin-piperaquine for the treatment of uncomplicated plasmodium falciparum malaria in African infants. Antimicrobial Agents and Chemotherapy 2018;62(1):e00596-17. [DOI: 10.1128/AAC.00596-17]

Juma 2008 {published data only}

1. Juma EA, Obonyo CO, Akhwale WS, Ogutu BR. A randomized, open-label, comparative efficacy trial of artemether-lumefantrine suspension versus artemether-lumefantrine tablets for treatment of uncomplicated Plasmodium falciparum malaria in children in western Kenya. Malaria Journal 2008;7:262. [DOI: 10.1186/1475-2875-7-262]

References to studies excluded from this review Banek 2018 {published data only}

1. Banek K, Webb EL, Smith SJ, Chandramohan D, Staedke SG. Adherence to treatment with artemether-lumefantrine or amodiaquine-artesunate for uncomplicated malaria in children in Sierra Leone: a randomized trial. Malaria Journal 2018;17(1):222.

Dama 2018 {published data only}

1. Dama S, Niangaly H, Djimde M, Sagara I, Guindo CO, Zeguime A, et al. A randomized trial of dihydroartemisinin-piperaquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. Malaria Journal 2018;17(1):347.

Faye 2010 {published data only}

1. Faye B, Ndiaye JL, Tine R, Sylla K, Gueye A, Lo AC, et al. A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children. American Journal of Tropical Medicine and Hygiene 2010;82(1):140-4.

Faye 2012 {published data only}

1. Faye B, Kuete T, Kiki-Barro CP, Tine RC, Nkoa T, Ndiaye JL, et al. Multicentre study evaluating the non-inferiority of the new paediatric formulation of artesunate/amodiaquine versus artemether/lumefantrine for the management of uncomplicated Plasmodium falciparum malaria in children in Cameroon, Ivory Coast and Senegal. Malaria Journal 2012;11:433.

Kayentao 2012 {published data only}

1. Kayentao K, Doumbo OK, Penali LK, Offianan AT, Bhatt KM, Kimani J, et al. Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malaria Journal 2012;11(1):364.

Ogutu 2014 {published data only}

1. Ogutu BR, Onyango KO, Koskei N, Omondi EK, Ongecha JM, Otieno GA, et al. Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children aged less than five years: results of an open-label, randomized, single-centre study. Malaria Journal 2014;13:33. [DOI: 10.1186/1475-2875-13-33]

Paczkowski 2016 {published data only}

1. Paczkowski M, Mwandama D, Marthey D, Luka M, Makuta G, Sande J, et al. In vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine for uncomplicated Plasmodium falciparum malaria in Malawi. Malaria Journal 2016;15:236.

Roth 2018 {published data only}

1. Roth JM, Sawa P, Makio N, Omweri G, Osoti V, Okach S, et al. Pyronaridine-artesunate and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a randomized controlled non-inferiority trial. Malaria Journal 2018;17(1):199.

Sagara 2018 {published data only}

1. Sagara I, Beavogui AH, Zongo I, Soulama I, Borghini-Fuhrer I, Fofana B, et al. Pyronaridine–artesunate or dihydroartemisinin–piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet 2018;391(10128):1378-90.

Sirima 2016 {published data only}

1. Sirima SB, Ogutu B, Lusingu JP, Mtoro A, Mrango Z, Ouedraogo A, et al. Comparison of artesunate-mefloquine and artemether-lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial. Lancet Infectious Diseases 2016;16(10):1123-33.

Tahar 2014 {published data only}

1. Tahar R, Almelli T, Debue C, Foumane NV, Djaman AJ, Whegang YS, et al. Randomized trial of artesunate-amodiaquine, atovaquone-proguanil, and artesunate-atovaquone-proguanil for the treatment of uncomplicated falciparum malaria in children. Journal of Infectious Diseases 2014;210(12):1962-71.

Toure 2011 {published data only}

1. Toure OA, Kouame MG, Didier YJ, Berenger AA, Djerea K, Genevieve GO, et al. Artesunate/mefloquine paediatric formulation vs. artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Anonkoua koute, Cote d'Ivoire. Tropical Medicine & International Health 2011;16(3):290-7.

Additional references GRADEpro GDT [Computer program]

1. McMaster University (developed by Evidence Prime) GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), accessed November 2019. Available at .

Higgins 2017

1. Higgins JP, Altman DG, Sterne JA, editor(s). Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Churchill R, Chandler J, Cumpston MS, editor(s), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017). The Cochrane Collaboration, 2017. Available from .

ICH 2016

1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). Available at: 2016.

Kurth 2010

1. Kurth F, Bélard S, Adegnika AA, Gaye O, Kremsner PG, Ramharter M. Do paediatric drug formulations of artemisinin combination therapies improve the treatment of children with malaria? A systematic review and meta-analysis. Lancet Infectious Diseases 2010;10(2):125-32.

Ranmal 2018

1. Ranmal SR, O'Brien F, Lopez F, Ruiz F, Orlu M, Tuleu C, et al. Methodologies for assessing the acceptability of oral formulations among children and older adults: a systematic review. Drug Discovery Today 2018;23(4):830-47.

Review Manager 2020 [Computer program]

1. Nordic Cochrane Centre, The Cochrane Collaboration Review Manager 5 (RevMan 5). Version 5.4. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2020.

Thabet 2018

1. Thabet Y, Klingmann V, Breitkreutz J. Drug formulations: standards and novel strategies for drug administration in pediatrics. Journal of Clinical Pharmacology 2018;58(Suppl 10):26-35.

WHO 2009

1. World Health Organization. Methods for surveillance of antimalarial drug efficacy. WHO Library 2009 2009. [ISBN 978 92 4 159753 1]

WHO 2015

1. World Health Organization. Guidelines for the treatment of malaria - 3rd edition. 2015. [ISBN 978 92 4 154912 7]

WHO 2019

1. World Health Organization. World malaria report 2019. 2019. [ISBN 978-92-4-156572-1]

References to other published versions of this review Bélard 2012

1. Bélard S, Kurth F, Ramharter M. Paediatric formulations of artemisinin-combination therapies for treating uncomplicated malaria in children. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No: CD009568. [DOI: 10.1002/14651858.CD009568]

Source: PubMed

Paediatric formulations of artemisinin-based combination therapies for treating uncomplicated malaria in children

Abstract

Conflict of interest statement

Figures

References

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas