CiPA Phase 1 ECG Biomarker Validation Study
Condition: Drug-induced QT Prolongation; Pharmacokinetics; Pharmacodynamics
MeSH terms: Long QT Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will assess whether exposure response analysis of the electrocardiographic QTc and
      J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that drugs
      that predominantly block the potassium channel encoded by the human ether-à-go-go-related
      gene (hERG) with approximately equipotent late sodium and/or calcium block ("balanced ion
      channel" drugs) do not cause J-Tpeakc prolongation and that drugs that predominantly block
      hERG without late sodium or L-type calcium current block ("predominant hERG" drugs) cause QTc
      prolongation.
    

Detailed description: 
      This study will assess whether exposure response analysis of the electrocardiographic QTc and
      J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that
      "balanced ion channel" drugs do not cause J-Tpeakc prolongation and that "predominant hERG"
      drugs cause QTc prolongation. This clinical study consists of 2 parts: a 50-subject parallel
      part (Part 1) and a 10-subject crossover part (Part 2). Up to 74 healthy subjects will be
      enrolled (including 14 potential replacement subjects).

      Part 1 will be a double-blind, randomized, placebo-controlled, 1 period parallel design to
      assess the effect of 4 marketed drugs and 1 placebo on the QTc and J-Tpeakc intervals in 50
      healthy subjects. A parallel design similar to a single or multiple ascending dose (SAD/MAD)
      Phase 1 study will be used that will result in each study drug being administered to 10
      subjects, and placebo to 10 subjects, in 1 period of 3 consecutive days to achieve low and
      high drug exposure.

      Part 2 will be a double-blind, randomized, 2-period crossover design to assess the effect of
      hERG block (dofetilide) versus calcium block (diltiazem) on the QTc and J-Tpeakc intervals in
      10 healthy subjects on Days 1, 2, and 3 (Period 1) and Days 8, 9, and 10 (Period 2).
    

Intervention name(s): Ranolazine; Verapamil; Lopinavir / Ritonavir; Chloroquine; Placebo; Dofetilide and Diltiazem
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Ranolazine 1500 mg orally two times per day for 2.5 days; Verapamil 120 mg immediate release (IR) morning and afternoon doses on Days 1 and 2, 240 mg extended release (ER) evening dose on Days 1 and 2, and 120 mg IR morning dose on Day 3 (all oral doses); Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days; Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses); Placebo (administered orally); In one period subjects receive Dofetilide 0.125 mg on Day 1, 0.375 mg on Day 3.
In a second period (randomized cross-over) subject receive Diltiazem 120 mg IR morning dose on Day 8, 240 mg ER evening dose on Days 8 and 9, and 120 mg IR on Day 10 with coadministration of 0.25 mg dofetilide on Day 10.
Intervention MeSH terms: Ritonavir; Lopinavir; Chloroquine; Verapamil; Dofetilide; Diltiazem; Ranolazine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This clinical study consists of 2 parts:
50 subjects in Part 1 will be randomized to receive one of four drugs (ranolazine, verapamil, lopinavir / ritonavir, chloroquine) or placebo over 3 days.
10 subjects in Part 2 will be randomized to receive one of two treatment sequences (1. dofetilide or 2. diltiazem combined with dofetilide) over 3 days, then after washout, the subjects will receive the other treatment sequence over 3 days. Thus, Part 2 will have a cross-over component.
A maximum of 14 additional replacement subjects may be enrolled.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other