Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Two-Day Regimen of Dihydroartemisinin-Piperaquine for Malaria Prevention Halted for Concern over Prolonged Corrected QT Interval

Abstract

f Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (C max ) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.)

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia

“…This finding supports the general recommendation for a 3-h fast before and after dosing. The slope estimate (0.05 ms per ng/ml, or an increase of 5 ms for every 100 ng/ml piperaquine) of the piperaquine exposure-QT interval response from the pooled analysis is similar to that described in recent publications (3,13). The QT-lengthening effects of piperaquine have been observed in clinical studies for more than a decade.…”

“…In 2012, a follow-on randomized, double-blind, placebo-controlled study evaluating a 2-day DP regimen as a monthly malaria prevention therapy was halted after 4 out of 69 volunteers met prespecified criteria to stop the study because of individual cardiac safety endpoints with a QTcF prolongation of Ͼ500 ms. An unblind review by the Data Safety Monitoring Board (DSMB) revealed a 46-ms mean QTcF prolongation over that achieved with placebo at the time of the maximum plasma concentration (C max ) of piperaquine on day 2. A moderate, statistically significant correlation between the piperaquine concentration and the QTcF increase over the baseline was observed, and a strong correlation was observed for the four volunteers whose findings precipitated the cessation of the study (3). Lastly, in 2013 there was a moderate correlation between the piperaquine concentration and corrected QT interval (QTc) interval changes when DP was used as a 3-day regimen for the treatment of P. falciparum infection, though the effect was less pronounced than that found in the previous studies (5).…”

“…The average of the three QT and RR intervals was recorded manually using calipers. Details of the EKG measurements and the criteria used to halt the studies were reported previously (3,4). Final decisions regarding subject disposition and the grading of adverse events were made by the principal investigators with concurrence from the DSMB on the basis of manual QTcF (QTcF m ) measurements.…”

“…Those randomized to 2-day regimens received 4.5 tablets daily, with 3 tablets daily being given for the 3-day regimen. The study designs of and the participants in the three clinical trials have been described previously (3,4,31). Briefly, the 3 trials were (i) WR1737, which was an evaluation of the efficacy and safety of the 2DP regimen versus those of the 3DP regimen in Cambodian military personnel at risk for P. falciparum and P. vivax malaria conducted from September 2010 to March 2011 (referred to hereafter as the 2010 study); (ii) WR1849, which was performed to determine the protective efficacy of a monthly 2DP regimen in healthy volunteers (referred to hereafter as the 2012 study); and (iii) WR1877, which was an evaluation of the efficacy of the 3DP regimen with or without a single dose of 45 mg of primaquine for the treatment of uncomplicated P. falciparum or mixed P. falciparum-P. vivax malaria (referred to hereafter as the 2013 study).…”

“…While the clinical significance remains poorly defined, piperaquine is known to inhibit a slow-rectifier potassium channel expressed by the human ether-a-go-go gene, known as IK r or the hERG channel. While piperaquine is a lipophilic drug with a large volume of distribution and long half-life, peak plasma levels decline rapidly and clinically significant QT interval prolongation typically occurs in the first 4 to 8 h after dosing, resolving over 24 h (3). As is the case with chloroquine, the risks of clinically significant events are thought to be relatively low, and DP is widely used in Cambodia and elsewhere, even though limited or no ability to monitor cardiac safety is available in those regions.…”