Electrophysiological Effects of Potential QT Prolonging Drugs

NCT05716854 | Completed Phase 1 FDA Drug

• 1 other identifier: SCR-014
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief 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

Outcome Measures

Primary Outcomes (2)

• Part 1: Plasma concentration of pimozide and clarithromycin associated with ΔΔQTc prolongation of 10 ms based on concentration-QTc analysis.

  1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours

• Part 2: ΔΔJ-TpeakC between cobicistat and moxifloxacin compared to moxifloxacin based on ECG timepoint analysis.

  -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours

Secondary Outcomes (6)

• Part 1: ΔΔQTc for pimozide and clarithromycin at maximum drug concentration on day 3 based on concentration-QTc analysis.

  1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours

• Part 1: ΔΔJ-TpeakC for pimozide and clarithromycin at maximum drug concentration on day 3 based on concentration-QTc analysis.

  1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours

• Part 1: The margin (ratio) between hERG IC50 and free plasma concentration causing 10 ms QTc prolongation.

  1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours

• Part 2: ΔΔQTc between cobicistat and moxifloxacin compared to moxifloxacin based on ECG timepoint analysis.

  -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours

• Part 2: ΔΔQTc for moxifloxacin, cobicistat, and moxifloxacin + cobicistat compared to placebo based on ECG timepoint analysis.

  -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours

Study Arms (7)

Part 1: Clarithromycin Administration Only

ACTIVE COMPARATOR

Subjects in this arm will be administered Clarithromycin only over 3 days of dosing.

Drug: Clarithromycin

Part 1: Pimozide Administration Only

ACTIVE COMPARATOR

Subjects in this arm will be administered Pimozide only over 3 days of dosing.

Drug: Pimozide

Part 1: Placebo

PLACEBO COMPARATOR

Subjects in this arm will not be administered any drug. Will serve as placebo comparator arm.

Drug: Placebo (Part 1)

Part 2: Moxifloxacin Administration Only

ACTIVE COMPARATOR

Subjects in this arm will be administered Moxifloxacin only for 1 day of dosing.

Drug: Moxifloxacin

Part 2: Cobicistat Administration Only

ACTIVE COMPARATOR

Subjects in this arm will be administered Cobicistat only for 1 day of dosing.

Drug: Cobicistat

Part 2: Moxifloxacin and Cobicistat Administration

ACTIVE COMPARATOR

Subjects in this arm will be administered both Cobicistat and Moxifloxacin for 1 day of dosing.

Drug: Moxifloxacin and Cobicistat

Part 2: Placebo

PLACEBO COMPARATOR

Subjects in this arm will not be administered any drug. Will serve as placebo comparator arm.

Drug: Placebo (Part 2)

Interventions

Clarithromycin DRUG

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).

Also known as: Treatment A

Part 1: Clarithromycin Administration Only

Pimozide DRUG

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

Also known as: Treatment B

Part 1: Pimozide Administration Only

Placebo (Part 1) DRUG

Subjects receive matching placebo for treatments.

Also known as: Treatment C

Part 1: Placebo

Moxifloxacin DRUG

Subjects receive Moxifloxacin 800 mg orally once on day 1.

Also known as: Treatment D

Part 2: Moxifloxacin Administration Only

Cobicistat DRUG

Subjects receive Cobicistat 450 mg orally once on day 1.

Also known as: Treatment E

Part 2: Cobicistat Administration Only

Moxifloxacin and Cobicistat DRUG

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

Also known as: Treatment F

Part 2: Moxifloxacin and Cobicistat Administration

Placebo (Part 2) DRUG

Subjects receive matching placebo for treatments.

Also known as: Treatment G

Part 2: Placebo

Eligibility Criteria

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

You may qualify if:

• Subject has signed an IRB approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
• Subject is a healthy non-smoker who weighs at least 50 kg (110 lbs) and has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening.
• Subject has normal medical history findings, clinical laboratory results, vital sign measurements, pulse oximetry, 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).
• Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in days.
• Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in for all study periods.
• Female subjects must be of non-childbearing potential (confirmed with follicle-stimulating hormone levels \> 40 mIU/mL) or, if they are of childbearing potential, they must: 1) have negative serum HCG at screening and check-in 2) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 3) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month after the end of the study.
• Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) from at least 1 month before check-in (Day -1) until at least 3 months 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 12-lead safety ECG result at Screening or check-in (Day -1) with evidence of any of the following abnormalities:
• QT corrected interval (QTc) using Fridericia correction (QTcF) \>430 milliseconds (ms)
• PR interval \>220 ms or \<120 ms
• QRS duration \>110 ms
• 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 ms)
• Ventricular pre-excitation
• 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 shall 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 used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug. This includes prescription or nonprescription ophthalmic drugs. Note the only two drugs permitted are oral contraceptives and acetaminophen.
• Subject is currently participating in another clinical study of an investigational drug or has been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of dosing for this study.
• Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must refrain from using these throughout the study.
• Subject has consumed alcohol, xanthine-containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 24 hrs of check-in. Subjects must refrain from ingesting these throughout the study.
• Subject is unable to tolerate a controlled, quiet study conduct environment, including avoidance of music, television, movies, games, and activities that may cause excitement, emotional tension, or arousal during the prespecified time points (e.g., before and during ECG extraction windows).

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 (17)

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• Dutta S, Chang KC, Beattie KA, Sheng J, Tran PN, Wu WW, Wu M, Strauss DG, Colatsky T, Li Z. Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment. Front Physiol. 2017 Aug 23;8:616. doi: 10.3389/fphys.2017.00616. eCollection 2017.

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MeSH Terms

Interventions

Clarithromycin; Pimozide; Moxifloxacin; Cobicistat

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Carbamates; Acids, Acyclic; Carboxylic Acids; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Jennifer Boston, MSN, APNP

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be double-blind, and the blind will be maintained through a randomization schedule held by the dispensing pharmacist. Treatments will be over-encapsulated. The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 27, 2023
• First Posted: February 8, 2023
• Study Start: March 21, 2023
• Primary Completion: June 13, 2023
• Study Completion: June 13, 2023
• Last Updated: June 22, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

US (1)