CiPA Phase 1 ECG Biomarker Validation Study

Phase 1

Completed

Conditions: Pharmacodynamics
Drug-induced QT Prolongation
Pharmacokinetics

Interventions: Drug: Ranolazine
Drug: Lopinavir / Ritonavir
Drug: Placebo
Drug: Dofetilide and Diltiazem
Drug: Verapamil
Drug: Chloroquine

Registration Number: NCT03070470

Lead Sponsor: Food and Drug Administration (FDA)

Brief 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ranolazine	Ranolazine	Ranolazine 1500 mg two times per day for 2.5 days
Lopinavir / Ritonavir	Lopinavir / Ritonavir	Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days
Placebo	Placebo	Placebo capsules
Dofetilide and Diltiazem	Dofetilide and Diltiazem	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.
Verapamil	Verapamil	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
Chloroquine	Chloroquine	Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3

Primary Outcome Measures

Name	Time	Method
Change From Baseline QTc With "Predominant hERG" Blocking Drug (Chloroquine)	3 days	The primary outcome measure for the "predominant hERG" drug (chloroquine) is for the upper bound of the 2-sided 90% CI to be ≥10 msec for the projected placebo-corrected change from baseline QTc effect at the peak plasma level on Day 1 using a linear mixed-effects exposure response model
Change From Baseline J-Tpeakc With "Balanced Ion Channel" Drugs (Ranolazine, Verapamil, Lopinavir / Ritonavir)	3 days	The primary outcome measure for the "balanced ion channel" drugs (ranolazine, verapamil, lopinavir / ritonavir) is for the upper bound of the 2-sided 90% confidence interval (CI) to be \<10 msec for the projected placebo-corrected change from baseline J-Tpeakc effect at the peak plasma level on Day 3 using a linear mixed-effects exposure response model. Placebo drug concentration was set to 0 (see SAP).
QTc Shortening From Calcium Block (Diltiazem) in the Presence of hERG Block (Dofetilide)	3 days	* It will be assessed whether the projected QTc effect of dofetilide alone is significantly greater (i.e., p\<0.05) than the projected QTc effect of the combination of dofetilide + diltiazem. This will be assessed at the dofetilide peak plasma level on Day 3 (computed from the combination of dofetilide + diltiazem) on the pooled dofetilide alone, diltiazem alone, and dofetilide + diltiazem data using a linear mixed effects model. * Subsequently, and if the test is significant for QTc, the same test will be performed to assess calcium block (diltiazem) effects on J-Tpeakc.