Electrophysiological Effects of Potential QT Prolonging Drugs

Summary

Since 2005, FDA has required almost all new drugs be tested for their ability to prolong the QT interval through clinical studies. This requirement stems from the increased TdP risk QT interval prolongation can cause. However, the QT interval is an imperfect biomarker, as there are multiple drugs that can prolong the QT interval, without causing increased TdP occurrence. As such, numerous drugs labeled as causing QT prolongation, may in fact have no impact on TdP occurrence.

To address this problem, FDA, in collaboration with multiple external partners, has led an initiative to combine novel preclinical in vitro experiments within silico modeling and simulation followed by pharmacodynamic electrocardiographic (ECG) biomarkers. The goal is to use these novel computational and analytical tools to better predict TdP risk (beyond just the QT interval) by focusing on understanding the underlying mechanisms and applying an integrated biological systems approach.

This clinical study consists of 2 parts: a 3-arm, 22-subject crossover study (Part 1) and a 4-arm, 22-subject crossover study (Part 2). These parts are included in the same protocol and study due to the similarity of the inclusion and exclusion criteria, similar procedures, and similar primary goals.

Conditions

• Drug-induced QT Prolongation
• Pharmacokinetics
• Pharmacodynamics

Interventions

DRUG

Clarithromycin

Subjects receive the Clarithromycin intervention orally according to the following schedule: Day 1: 1 Clarithromycin 500 mg immediate release (IR) tablet twice (Clarithromycin 500 mg BID). Day 2: 2 Clarithromycin 500 mg immediate release (IR) tablets twice (Clarithromycin 1000 mg BID). Day 3: 2 Clarithromycin 500 mg immediate release (IR) tablets once (Clarithromycin 1000 mg QD).

DRUG

Pimozide

Subjects receive the Pimozide intervention orally according to the following schedule: Days 1-3: Pimozide 6 mg immediate release (IR) once per day.

DRUG

Placebo (Part 1)

Subjects receive matching placebo for treatments.

DRUG

Moxifloxacin

Subjects receive Moxifloxacin 800 mg orally once on day 1.

DRUG

Cobicistat

Subjects receive Cobicistat 450 mg orally once on day 1.

DRUG

Moxifloxacin and Cobicistat

Subjects receive Moxifloxacin 800 mg and Cobicistat 450 mg orally once on day 1.

DRUG

Placebo (Part 2)

Subjects receive matching placebo for treatments.

Sponsors & Collaborators

• Spaulding Clinical Research LLC

  collaborator OTHER

• Food and Drug Administration (FDA)

  lead FED

Principal Investigators

• Jennifer Boston, MSN, APNP · Spaulding Clinical Research LLC

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

QUADRUPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

50 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2023-03-21

Primary Completion

2023-06-13

Completion

2023-06-13

FDA Drug

Yes

Countries

• United States

Study Locations