CiPA Phase 1 ECG Biomarker Validation Study

NCT03070470 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16-086DSCR-004
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Drug-induced QT Prolongation; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (3)

• Change From Baseline J-Tpeakc With "Balanced Ion Channel" Drugs (Ranolazine, Verapamil, Lopinavir / Ritonavir)

  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).

  3 days

• Change From Baseline QTc With "Predominant hERG" Blocking Drug (Chloroquine)

  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

  3 days

• QTc Shortening From Calcium Block (Diltiazem) in the Presence of hERG Block (Dofetilide)

  * 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.

  3 days

Study Arms (6)

Ranolazine

ACTIVE COMPARATOR

Ranolazine 1500 mg two times per day for 2.5 days

Drug: Ranolazine

Verapamil

ACTIVE COMPARATOR

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

Drug: Verapamil

Lopinavir / Ritonavir

ACTIVE COMPARATOR

Lopinavir / Ritonavir 800 mg / 200 mg two times per day for 2.5 days

Drug: Lopinavir / Ritonavir

Chloroquine

ACTIVE COMPARATOR

Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3

Drug: Chloroquine

Placebo

PLACEBO COMPARATOR

Placebo capsules

Drug: Placebo

Dofetilide and Diltiazem

ACTIVE COMPARATOR

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.

Drug: Dofetilide and Diltiazem

Interventions

Ranolazine DRUG

Ranolazine 1500 mg orally two times per day for 2.5 days

Ranolazine

Verapamil DRUG

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)

Verapamil

Lopinavir / Ritonavir DRUG

Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days

Lopinavir / Ritonavir

Chloroquine DRUG

Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses)

Chloroquine

Placebo DRUG

Placebo (administered orally)

Placebo

Dofetilide and Diltiazem DRUG

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.

Dofetilide and Diltiazem

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject signs an institutional review board (IRB) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] authorization) before any study related procedures are performed.
• Subject is a healthy man or woman, 18 to 50 years of age, inclusive, who weighs at least 50 kg (110 pounds) and has a body mass index of 18 to 30 kg/m2, inclusive, at Screening.
• Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead ECG results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
• Female subjects will be at least 2 years postmenopausal, surgically sterile, or practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique).
• Female subjects must not be pregnant or lactating before enrollment in the study.
• Male or female subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from Screening until 30 days after the last dose of study drug.
• Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

You may not qualify if:

• Subject has a safety 12 lead ECG result at Screening or Check in with evidence of any of the following abnormalities:
• QTc using Fridericia correction (QTcF) \>430 msec
• PR interval \>220 msec or \<120 msec
• QRS duration \>110 msec
• Second- or third-degree atrioventricular block
• Complete left or right bundle branch block or incomplete right bundle branch block
• Heart rate \<50 or \>90 beats per minute
• Pathological Q-waves (defined as Q wave \>40 msec)
• Ventricular pre-excitation
• Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.
• Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsade de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome.
• Subject has a history or current evidence of any clinically significant (as determined by the investigator) cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy (excluding nonmelanoma skin cancer). The investigator may allow exceptions to these criteria (e.g., cholecystectomy, childhood asthma) following discussion with the medical monitor.
• Subject has a history of thoracic surgery.
• Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).
• Subject has a skin condition likely to compromise ECG electrode placement.

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

Related Publications (3)

• 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. Epub 2017 Nov 16.

  PMID: 28986934 BACKGROUND

• Vicente J. Update on the ECG component of the CiPA initiative. J Electrocardiol. 2018 Nov-Dec;51(6S):S98-S102. doi: 10.1016/j.jelectrocard.2018.08.003. Epub 2018 Aug 7.

  PMID: 30121123 BACKGROUND

• Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason JW, Sanabria C, Kemp S, Sager PT, 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. 2019 Apr;105(4):943-953. doi: 10.1002/cpt.1303. Epub 2019 Jan 18.

  PMID: 30447156 RESULT

MeSH Terms

Interventions

Ranolazine; Verapamil; Lopinavir; Chloroquine; dofetilide; Diltiazem

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenethylamines; Ethylamines; Pyrimidinones; Pyrimidines; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines

Results Point of Contact

• Title: Jose Vicente, PhD
• Organization: U.S. Food and Drug Administration

Jose.VicenteRuiz@fda.hhs.gov

301-796-8442

Study Officials

• Carlos Sanabria, MD

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 27, 2017
• First Posted: March 3, 2017
• Study Start: March 14, 2017
• Primary Completion: June 26, 2017
• Study Completion: June 26, 2017
• Last Updated: January 18, 2020
• Results First Posted: January 18, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: January 2018: Study protocol and SAP (doi: 10.1002/cpt.896). August 2018: ECG analysis plan (doi: 10.1016/j.jelectrocard.2018.08.003). December 2018: Annotated ECG waveforms and clinical data database (https://physionet.org/physiobank/database/ecgcipa/) December 2018: Study results report published (doi: 10.1002/cpt.1303)
• Access Criteria: Open access

Locations

US (1)