Clinical Trial: Cardio‑Safety of Dihydroartemisinin‑Piperaquine and Pharmacokinetics of Piperaquine Amongst Pregnant Women in Tanzania

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Cardio‑Safety of Dihydroartemisinin‑Piperaquine and Pharmacokinetics of Piperaquine Amongst Pregnant Women in Tanzania

Brief Summary: Sulfadoxine-pyrimethamine (SP) is currently recommended by the World Health Organization for use as intermittent preventive treatment against malaria in pregnancy (IPTp) in areas of moderate to high malaria transmission. However, in some locales malaria parasites have lost sensitivity to SP, compromising its protective effect. Dihydroartemisinin-piperaquine (DP) is a candidate replacement for SP. This trial is designed to confirm the cardio-safety of DP compared to SP amongst pregnant women in Tanzania.

Detailed Summary:

The trial hypothesis is that DP will increase the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, a phenomenon referred to as QT prolongation, in the study population. However, if QT prolongation is observed, it is expected to be time-limited and of no clinical consequence.

The QT interval, measured in milliseconds (MS) will be corrected (QTc) to account for natural heart rate (HR) extremes. The Fridericia formula will also be used to correct (QTcF) for variation in cardio-contraction. As part of the electrocardiogram (ECG), the period from the beginning of the P wave to the beginning of the QRS complex (PR interval) will be measured, as well as the ST-segment which connects the QRS complex and the T wave.

Prolongation of the QT interval will be estimated when peak drug-concentrations are most likely to be found in the peripheral blood as measured using pharmacokinetic (PK) techniques. Polymerase chain reaction (PCR) methods will be used for genetic sequencing of molecular markers (A581G) associated with malaria parasite drug resistance to SP. The rapid diagnostic test (RDT) CareStart™ will be used to screen pregnant women attending antenatal care.


Sponsor: London School of Hygiene and Tropical Medicine

Current Primary Outcome: Proportion of participants in Groups 3-4 with an absolute QTc of > 500 milliseconds [ Time Frame: Measured on day 7 post-dose ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Proportion of participants in Groups 1-2 with an absolute QTc of > 500 milliseconds [ Time Frame: Measured on day 0 ]
  • Proportion of participants in Groups 1-2 with an absolute QTc of > 480 milliseconds [ Time Frame: Measured on day 0 ]
  • Proportion of participants in Groups 1-2 with an absolute QTc of > 460 milliseconds [ Time Frame: Measured on day 0 ]
  • Proportion of participants in Groups 3-4 with an absolute QTc of > 500 milliseconds [ Time Frame: Measured on day 2 ]
  • Proportion of participants in Groups 3-4 with an absolute QTc of > 480 milliseconds [ Time Frame: Measured on day 2 ]
  • Proportion of participants in Groups 3-4 with an absolute QTc of > 450 milliseconds [ Time Frame: Measured on day 2 ]
  • Incidence of participants in Groups 1-4 with QTcF prolongation > 500 milliseconds. [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants in Groups 1-4 with QTcF deviation from baseline > 60 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants in Groups 1-4 with ventricular arrhythmia captured on ECG recording and/or suspected by a clinical event as palpitation, dizziness, syncope, convulsion, or sudden death [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with mean heart rate < 40 beats per minute [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with mean heart rate > 130 beats per minute [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with PR interval > 210 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with PR interval > 220 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with QRS interval > 110 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with QRS interval > 120 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with change in QTcF from baseline > 60 milliseconds + Absolute QTc > 480 milliseconds (QTcF refers to the QT interval that has been corrected using the Fridericia formula) [ Time Frame: Measured on days 2 and 7 ]
  • Proportion of participants in Groups 1-4 with QTcF > 480 milliseconds and > 500 milliseconds (QTcF refers to the QT interval that has been corrected using the Fridericia formula) [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 3-4 with change in QTcF between day 0 pre-dose, day 2 post dose at peak > 60 milliseconds, and day 7 (QTcF refers to the QT interval that has been corrected using the Fridericia formula) [ Time Frame: Measured on days 0, 2 and 7 ]
  • Proportion of participants in Groups 1-4 with arrhythmias [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants in Groups 3-4 with sinus pause / arrest > 3.0 seconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants in Groups 3-4 with 2nd degree atrioventricular block (Mobitz 2) [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants in Groups 3-4 with 3rd degree atrioventricular block [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants with ventricular tachycardia [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants with torsades de pointes [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants with ventricular fibrillation [ Time Frame: Measured on days 0, 2 and 7 ]
  • Mean piperaquine absorption at maximum observed concentrations (Cmax) in Groups 3-4 [ Time Frame: Measured on day 2 ]
  • Incidence of participants who experience myocardial ischemia defined as: • ST-segment deviations ≥ 1 millimetre 80 millisecond after J-point, or • New Q-waves, or T-wave inversion [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants who experience morphological changes of the T-wave [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants who experience pathological U-wave [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants who experience sinus pause or arrest > 3.0 seconds [ Time Frame: Measured on days 0, 2 and 7 ]
  • Incidence of participants who experience 2nd degree atriovent

    Original Secondary Outcome: Same as current

    Information By: London School of Hygiene and Tropical Medicine

    Dates:
    Date Received: September 5, 2016
    Date Started: September 2016
    Date Completion: September 2017
    Last Updated: September 19, 2016
    Last Verified: June 2016