CiPA ECG Validation Study

Introduction

ECG effects of ranolazine, verapamil, lopinavir+ritonavir, chloroquine, dofetilide, diltiazem, and dofetilide+diltiazem in a small sample size clinical study. The ECGCIPA database contains multi-channel ECG recordings of 60 subjects participating in the CiPA ECG validation study.

Experimental Method

This study assessed 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-a-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.

This clinical study consists of 2 parts: a 50-subject parallel part (Part 1) and a 10-subject crossover part (Part 2).

• Part 1 was a double-blind, randomized, placebo-controlled, 1 period parallel designed to assess the effect of 4 marketed drugs (ranolazine, verapamil, lopinavir+ritonavir, and chloroquine) 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 was used and resulted 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. Subjects 1001-1050 participated in part 1 of the study.
• Part 2 was 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). Subjects 2001-2010 participated in part 2 of the study.

More details about the rationale and study design are described in [1], which includes the study protocol and statistical analysis plan in the on-line supplement. Detailed ECG methods are described in [2]. Finally, study results are available in [3].

ClinicalTrials.gov identifier: NCT03070470 (https://clinicaltrials.gov/ct2/show/NCT03070470)

Files

• raw (5749 records, no annotations): original extracted 10-second 12-lead ECG segments organized in subdirectories named after the subject identifier or USUBJID in the clinical data sets.
• medians (5749 annotated records):
  • derived representative median beats of the raw ECG segments.
  • semi-automatic annotations of each median beat in the vector magnitude lead: P onset, QRS onset, QRS offset, T peak, secondary T peak (if present]) and T offset. The annotations are stored in standard MIT annotation format, with annotator extension .atr.
• The file ecgcipa_metadata.docx describes the columns of the clinical data sets:
  • ADEG (adeg.csv): This is a one record per subject per parameter per analysis period per analysis visit per analysis time point data set that contains a comprehensive set of variables pertaining to the subject and their quantitative measures in the electrocardiogram (ECG).
  • ADPC (adpc.csv): This is a one record per subject per pharmacokinetic (PK) parameter per analysis period per analysis visit per analysis time point data set that contains a comprehensive set of variables pertaining to the subject and their quantitative pharmacokinetic measures.
  • ADSL (adsl.csv): Subject-level analysis dataset containing one record per subject.
  • ADDM (addm.csv): This is a one record per subject per parameter data set with additional demographic and vital signs information collected at check-in.

The ecgcipa.zip file contains all of the WFDB ecg signal and annotation files.

References

1. Vicente J, Zusterzeel R, Johannesen L, Mason J, Sager P, Patel V, Matta MK, Li Z, Liu J, Garnett C, Stockbridge N, Zineh I, Strauss DG. Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the CiPA Initiative and Design of a Prospective Clinical Validation Study. Clin Pharmacol Ther 2018 Jan; 103(1):54-66. doi: 10.1002/cpt.896
2. Vicente J. Update on the ECG Component of the CiPA Initiative. J Electrocardiol 2018 Nov; 51(6): S98-S12. doi: 10.1016/j.jelectrocard.2018.08.003
3. Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason J, Sanabria C, Kemp S, Sager P, Patel V, Matta MK, Liu J, Florian J, Garnett C, Stockbridge N, Strauss DG. Assessment of Multi-Ion Channel Block in a Phase-I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study. Clin Pharmacol Ther. doi: 10.1002/cpt.1303