Cardiac Safety of Repeated Doses of Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns
Cardiac Safety of Repeated Doses of Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns
Mass drug administration with antimalarial treatment is a tool that can potentially reduce or
 totally eliminate malaria parasite infections from a population.
 Dihydroartemisinin-piperaquine (DHA/PPQ) given monthly for 3 months to the entire population
 might be a good candidate for mass drug administration because the long acting PPQ exerts a
 long post-treatment prophylactic effect against reinfection and relapse. The use of a
 repeated dose of DHA/PPQ could lead to increased PPQ plasma concentrations and increased
 cardiotoxicity. However, there is no data on a second course of treatment or on safety of the
 drug administered in repeated monthly doses. The proposed project is a clinical trial to
 assess the electrocardiographic safety of monthly DHA/PPQ (for 3 days at a time) for 3
 months. The investigators aim to assess the safety of the drug to be used monthly in mass
 treatment campaigns. Recommendations issued from this study will benefit health authorities
 on Lihir-Island by setting the stage for a possible subsequent campaign to completely
 eliminate malaria from the whole island. This study could be a crucial step to inform the
 feasibility of drug-based strategies for eliminating malaria elsewhere in PNG, other
 Melanesian countries and throughout the world.
Given the absence of regulatory data related to the safety of repeated dosing, the European
 Medicines Agency has set a conservatively long 2-month "wash-out" period before
 administration of subsequent courses can be recommended. Unfortunately such a recommendation
 would make it impossible to implement effective mass drug administration with PPQ as this
 probably requires a maximum interval of one month between doses (in order to ensure that drug
 levels remain high enough to prevent infections occurring between doses). Therefore it is
 important that a formal evaluation is performed to regulatory standards that can conclusively
 document the safety of repeated monthly doses of PPQ. The extensive previous experience from
 monthly PPQ administration in China suggests that such a study would pose minimal risks to
 study participants.

 Various studies have looked at the potential of DHA/PPQ to cause prolongation of corrected QT
 interval (QTc) intervals in humans. In a study of 62 adults and children, in Cambodia,
 electrocardiographic (ECG) findings after DHA/PPQ treatment showed a lengthening of the mean
 QTc by 11 ms. In two randomized controlled trials in Thailand, the mean QTc prolongation of
 56 patients was 14 ms after the last dose of DHA/PPQ. The degree of QT prolongation observed
 in these studies was therefore similar to that seen with other anti-malarial drugs (including
 lumefantrine, and chloroquine) generally considered to have no cardiotoxicity in conventional
 dosing, and substantially less than with others such as halofantrine.and quinidine that have
 been associated with cardiotoxicity. Study-DM09-006 compared QTc data of healthy subjects
 that received DHA/PPQ with respective placebo groups and found maximum mean QT Fridericia's
 correction (QTcF) prolongation of 45.2 ms if co-administered with high fat, and 21.0 ms if
 fasting (EMEA/H/C/119). Of total of 96 participants given DHA/PPQ in the three studies
 mentioned above, no subjects showed QTc > 500ms post-treatment or prolongations (after- vs
 pre-dose) >60ms.

 The proposed project is a pharmacovigilance study for electrocardiographic safety evaluation
 of monthly DHA/PPQ (administered as a conventional 3-day course repeated monthly for 3
 months). The investigators aim to assess the safety of the drug to be used monthly in mass
 treatment campaigns.
Inclusion Criteria:

 1. Male or female ≥3 years to ≤50 years

 2. Good general health by medical history physical examination, baseline
 electrocardiographs and laboratory tests.

 3. No clinically relevant abnormalities in blood pressure and heart rate

 4. No clinically relevant abnormalities in 12-lead ECG results*

 *Patients with a QTcB or QTcF greater than 450 ms or clinically significant
 abnormalities of rhythm at Screening are not eligible. Patients with a pre-dose
 baseline value > 450 ms should be withdrawn from the study prior to dosing.

 Exclusion Criteria:

 5. A history of additional risk factors for Torsades-des-Pointes (e.g., heart failure,
 hypokalemia, family history of Long QT Syndrome);

 6. The use of concomitant medications that prolong the QT/QTc interval;

 7. Any condition requiring regular concomitant medication, including herbal products and
 over-the-counter (OTC) medication or predicted need of any concomitant medication
 during the study;

 8. History of relevant clinical allergic reactions of any origin;

 9. Any other condition that in the opinion of the Investigator would interfere with the
 evaluation of the results or constitute a health risk for the subject;

 10. Patients who are not willing to give informed consent (patient and/or parent/legal
 representative), or who withdraw consent.

 11. Pregnant women in the 1st trimester of pregnancy.