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.
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 , which includes the study protocol and statistical analysis plan in the on-line supplement. Detailed ECG methods are described in . Finally, study results are available in .
ClinicalTrials.gov identifier: NCT03070470 (https://clinicaltrials.gov/ct2/show/NCT03070470)
- 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.
- 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
- 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
- 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
When using this resource, please cite the original publication:
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.
Please include the standard citation for PhysioNet: (show more options)
Goldberger, A., Amaral, L., Glass, L., Hausdorff, J., Ivanov, P. C., Mark, R., ... & Stanley, H. E. (2000). PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals. Circulation [Online]. 101 (23), pp. e215–e220.