The study group call for contributors opened in June 2016 with a first scoping meeting held in July. Data collection is planned to close by end of 2016, with analysis due at the end of 2017.

Quinoline antimalarials, and structurally related drugs, are known to have cardiovascular effects (for detailed review see [1]). One of the more recently developed synthetic quinolones is piperaquine. Dihydroartemisinin-piperaquine is recommended for the treatment of uncomplicated falciparum malaria and is being explored as intermittent preventive treatment and mass drug administration. Widespread use of an antimalarial among unselected populations that include asymptomatic and uninfected individuals requires a drug with a wide therapeutic dose range and excellent safety profile.

Recent pharmacokinetic studies [2] and WWARN’s pooled meta-analysis of individual patient data on the effect of mg/kg dose on therapeutic efficacy [3] have raised concerns about potential under-dosing of young children with the manufacturers’ recommended weight-based dosing regimens and advocated higher dosing regimens in this vulnerable population. However, piperaquine has a relatively narrow, poorly defined therapeutic dose range which poses dosing challenges. The World Health Organization (WHO) recently amended their treatment guidelines for dihydroartemisinin-piperaquine in young children weighing less than 25 kg [4], recommending a narrow dose range of 24–32 mg/kg piperaquine per day. This maintains piperaquine as the antimalarial with the most narrow recommended dose range, resulting in dosing recommendations with eight weight bands [4], and consequently posing substantial challenges to implementation of dihydroartemisinin-piperaquine by national malaria control programmes.

The key concern with piperaquine is the remaining uncertainty around the cardiac safety in different subgroups, as piperaquine is known to prolong the QT interval in a concentration-dependent manner. While the European Medicines Agency has approved the drug, it has called for more data to substantiate the cardiac safety of dihydroartemisinin-piperaquine and its effect on QTc intervals, particularly in children [5]. Although other widely used quinolines have also been shown to prolong the QT interval, the concentration-dependent association, and its relationship to dose and other determinants (including malaria disease severity and electrolyte disturbances) have not been defined sufficiently to inform the upper mg/kg dose threshold.

In addition, whilst dosing guidelines are usually set at the same level for all patients, this does not take into account subgroups of patients, such as human immunodeficiency virus (HIV) positive patients, who may be at higher risk of harms related to antimalarials, due to having different pharmacokinetics, potential drug interactions, and other HIV-related risk factors. Data on piperaquine-ARV interactions is scarce, and whilst dihydroartemisinin-piperaquine has been used safely in HIV positive children [6, 7], a lack of systematically collected, standardised safety data in this population limits the ability to use this data to inform optimal dosing in this group of vulnerable patients.

The Piperaquine Safety Study Group’s aim is to establish the evidence-base and safety profile to inform decision-making on the use and optimal dosing of dihydroartemisinin-piperaquine in all key target populations. To achieve these important goals, we aim to pool individual patient data to better define the cardiac risk of piperaquine, and other key adverse events of special interest. Such analyses should help to identify patient factors that lead to an increased risk of these adverse events. One of the key tasks of the Piperaquine Safety Study Group will also be to propose procedures on how to analyse and report electrocardiogram (ECG) data from antimalarial efficacy and safety studies so that results can be compared between studies.

The proposed work will provide evidences to further refine dihydroartemisinin-piperaquine dosing regimens. Beyond dihydroartemisinin-piperaquine, it will demonstrate the importance of identifying global research priorities for targeted antimalarial safety studies and the role of integrating pooled individual level safety analyses into WWARN’s global efficacy data platform. Linking efficacy and safety data offers a powerful standardized process for dose optimization that is applicable across a range of drugs.

The specific objectives are:

• Characterise the cardiac safety profile of piperaquine across subgroups
• Identify determinants associated with changes in QTc intervals or other relevant cardiac adverse events and estimate the relative cardiac risks, including:

1. Distinguish between disease (severity) effects and drug effects on cardiac safety, i.e. differentiate disease-dependent, dose-dependent, concentration-dependent, and other patient risk factor-dependent effects on QT interval and other cardiac safety parameters
2. Define the effect of HIV disease and co-administration of widely-used ARVs on dihydroartemisinin-piperaquine safety and compare this to other anti-malarials to allow comparison of safety profiles

• Update the lower and upper dose threshold for piperaquine and develop optimal weight-based, and if feasible age-based, dosing regimens
• Propose procedures on how to analyse and report ECG data specifically for antimalarial studies

• Clinical studies in patients with OR people at risk of falciparum malaria (either alone or mixed infections) OR healthy volunteers (both-HIV infected or uninfected)
• Treatment or chemoprevention with any dihydroartemisinin-piperaquine (including single dose in healthy volunteers) or piperaquine monotherapy; for the ARV/HIV interaction analysis, treatment of chemoprevention with any other anti-malarial

• Dosing regimen
• Baseline data on patient demographics
• ECG data with day of recording, and review procedures, type of equipment AND/OR safety data such as serious and non-serious adverse events during follow up

• Treatment details:

-          manufacturer,

-          food intake instructions / measurements,

-          supervision of drug doses,

-          timing of drug intake

• Drug concentration measurements including sample time(s), sample matrix, assay method 
• Any predisposing factors (e.g. electrolyte disturbances, co-medication, co-morbidity)
• Height of patient
• Other ECG parameters and cardiotoxicity data
• Relevant medical history including any serious and non-serious adverse events 

Once uploaded into the WWARN Data Repository, datasets will be standardised according to the WWARN Clinical (and, if applicable, Pharmacology) Data Management and Statistical Analysis Plan. Data sets will be pooled into a single database of quality-assured individual patient data. A full Statistical Analysis Plan will be developed collaboratively and approved by the Study Group prior to the analysis. 

The Study Group comprises investigators who contribute relevant data sets to the pooled analysis and invited technical experts. Data sets remain the property of the investigator. More details about sharing data with WWARN and how WWARN will use data are available on the WWARN website.

The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. Dr Eva Maria Hodel (EvaMaria.Hodel@LSTMed.ac.uk) leads the Study Group, Cheryl Pace (Cheryl.Pace@LSTMed.ac.uk) leads data curation, and Dr Georgina Humphreys is the Scientific Coordinator for the Study Group (georgina.humphreys@wwarn.org).

For further information, email Eva Maria Hodel (EvaMaria.Hodel@LSTMed.ac.uk) and/or Georgina Humphreys (georgina.humphreys@wwarn.org). 

1. White NJ: Cardiotoxicity of antimalarial drugs.Lancet Infect Dis 2007, 7:549-558.
2. Tarning J, Zongo I, Some FA, Rouamba N, Parikh S, Rosenthal PJ, Hanpithakpong W, Jongrak N, Day NP, White NJ, et al: Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria.Clin Pharmacol Ther 2012, 91:497-505.
3. WorldWide Antimalarial Resistance Network DP Study Group: The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data.PLoS Med 2013, 10:e1001564.
4. World Health Organization: Guidelines for the treatment of malaria – 3^rd edition. 3rd edn. Geneva: World Health Organization; 2015.
5. Eurartesim: European public assessment reports - Product Information
6. Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, Talisuna AO, Greenhouse B, Nosten F, Rosenthal PJ, et al: Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial.PLOS Clin Trial 2007, 2:e20.
7. Katrak S, Gasasira A, Arinaitwe E, Kakuru A, Wanzira H, Bigira V, Sandison TG, Homsy J, Tappero JW, Kamya MR, Dorsey G: Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children.Malar J 2009, 8:272