title: The prospective IQ-CSRC trial: A prototype early clinical proarrhythmia assessment investigation for replacing the ICH E14 thorough QTc (TQT) study.
abstract: BACKGROUND
  Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA).
  
  
  OBJECTIVE
  The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT). Designed in accordance with the results of a simulation study by the FDA QT Interdisciplinary Review Team (IRT), it succeeded in correctly categorizing 5/5 established QTc-prolonging agents free of notable heart rate effects (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and the QTc-negative drug, levocetirizine.
  
  
  CONCLUSIONS
  The positive results obtained with the IQ-CSRC study require additional confirmation with threshold QTc-positive and negative drugs and established QTc prolongers producing both increases and decreases in heart rate. In the future, similar studies should also adopt and validate innovative proarrhythmic metrics, in addition to, or instead of, the traditional proarrhythmic surrogate of QTc, to assess the proarrhythmic safety of candidate drugs.
authors.affiliation: 54 Rue de la Glacière, 75013 Paris, France. Electronic address: iciliocavero@outlook.com.
authors.forename: Icilio
authors.initials: I
authors.lastname: Cavero
authors.affiliation: 13765 Seabiscuit Drive, Reno, NV, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Holzgrefe
authors.affiliation: GE Healthcare Life Sciences, Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7YT, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Clements
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology*; D004562:Electrocardiography / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D011446:Prospective Studies; D012107:Research Design; D014481:United States; D014486:United States Food and Drug Administration
keywords: ECG restitution; Exposure-response relationship analysis; IQ-CSRC prospective study; Intensive early phase I ECG study; Positive and negative QTc-prolongers; Proarrhythmic metrics; Thorough QT study (TQT)