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

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 (Cmax) 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.).

FIG 1

CONSORT (consolidated standards of reporting trials) flow diagram. The patients were given dihydroartemisinin-piperaquine (DP) or placebo. The trial was halted after the prespecified cardiac safety endpoint was met with 4 episodes of QTcF prolongation > 500 ms at 4- to 8-h postdose.

FIG 2

Pre- and postdosing ECG tracings for the first subject whose treatment was halted. QT-U fusion waves are denoted by red arrows.

FIG 3

Mean differences between predose QTcF intervals at baseline and at 4-h postdose intervals on days 1 and 2 of dosing during month 1 in the group that received dihydroartemisinin-piperaquine (DP) (n = 47) and the group that received placebo (n = 22). All volunteers who received at least one dose of study drug (n = 69) are shown. One subject whose treatment was halted after the first dose is not included in the postdose day 2 analysis. The center of each box represents the median, the top and bottom represent the 25th and 75th percentiles, the whiskers extend to either the lowest or highest value.

FIG 4

Peak concentrations of piperaquine (PIP) in plasma at 4 and 28 h after the first dose each month. The time of the first dose is given as follows: the month (M) and hours after the first dose (H). Each symbol represents the value for an individual subject. The mean ± standard deviation (error bar) are shown for each group. The values for the treatment-halted subjects are shown by the solid symbols.

FIG 5

Plot of the change in QTcFm from baseline versus plasma piperaquine concentration for subjects receiving dihydroartemisinin-piperaquine. The values for treatment-halted subjects are indicated by the solid orange circles. Spearman correlation analysis between concentration and QT interval prolongation was significant for subjects treated with dihydroartemisinin-piperaquine (n = 47; rho = 0.6706; P < 0.0001), with stronger correlation in the treatment-halted subjects (n = 4; rho = 0.8990; P < 0.0001).

FIG 6

Pharmacokinetic simulation of piperaquine concentration-time profiles when given as 960 mg piperaquine phosphate (PQP) for 3 days, 960 mg PQP for 5 days, and 1,440 mg PQP for 2 days.