Electrophysiological Effects of Potential QT Prolonging Drugs
Condition: Drug-induced QT Prolongation; Pharmacokinetics; Pharmacodynamics
MeSH terms: Long QT Syndrome
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      The risk of drug-induced Torsades de Pointes (TdP), a potentially fatal ventricular
      arrhythmia, has resulted in multiple drugs worldwide being removed from the market, as well
      as over 150 drugs being listed on CredibleMeds.org for QT prolongation or TdP association. In
      response, 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. While this labeling affects physician prescribing, it
      also has the potential to limit effective therapeutic options for patients.

      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.

      Recently, the International Council on Harmonization (ICH) released a new Guideline with
      updated Questions and Answers (Q&As) to the clinical (ICH E14) and nonclinical (ICH S7B)
      Guidelines for assessing the QT prolongation and proarrhythmic risk of non-antiarrhythmic
      drugs. The Q&A provides more guidance on the use of an integrated nonclinical analysis to
      support clinical QT assessment. This includes the comparison of the hERG safety margin of the
      investigational product to the safety margin of predominant hERG (the human
      Ether-à-go-go-Related Gene) blockers with a characterization of the concentration-QTc
      relationship based on a limited set of example drugs, i.e., ondansetron, moxifloxacin and
      dofetilide.

      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.

      Part 1: Intermediate risk predominant hERG blocking drugs The FDA performed a literature
      review and identified 28 proarrhythmic drugs from available in vitro studies of cardiac ion
      channel IC50 (using HEK293 cells and the hERG 1a subunit). Two of these drugs, classified as
      intermediate risk "predominant hERG blocking" (pimozide and clarithromycin), have been
      identified as candidates for evaluation in Part 1. An aim of this study will be generating
      higher quality QT data on "intermediate risk" "predominant hERG" blocking drugs' effect on
      both electrocardiographic biomarkers, QTc and J-Tpeakc interval prolongation, at therapeutic
      and supratherapeutic exposures. These data will also be used to support assessment of the
      hERG safety margin threshold together with moxifloxacin, dofetilide, and ondansetron as
      described in the recently released ICH Q&A's.

      Part 2: Combination of hERG and multi-ion channel block Part 2 of this study will assess the
      effects of a mixed ion channel blocking drug, cobicistat, on the QTc and J-Tpeakc interval
      alone and in combination with a predominant hERG blocking drug (moxifloxacin). Clinical data
      with cobicistat, a structural analog of ritonavir used as a pharmacokinetic enhancer in
      various anti-viral regimens, has demonstrated QTc shortening and PR prolongation with
      supratherapeutic doses. Whether this is a results of late sodium block, calcium channel
      block, or other features is unclear. Additional clinical data with cobicistat alone or in
      combination with moxifloxacin will enhance our understanding of the effects of mixed ion
      channel blocking on electrocardiographic biomarkers (QTc and J-Tpeakc interval).
    

Intervention name(s): Clarithromycin; Pimozide; Placebo (Part 1); Moxifloxacin; Cobicistat; Moxifloxacin and Cobicistat; Placebo (Part 2)
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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).; Subjects receive the Pimozide intervention orally according to the following schedule:
Days 1-3: Pimozide 6 mg immediate release (IR) once per day.; Subjects receive matching placebo for treatments.; Subjects receive Moxifloxacin 800 mg orally once on day 1.; Subjects receive Cobicistat 450 mg orally once on day 1.; Subjects receive Moxifloxacin 800 mg and Cobicistat 450 mg orally once on day 1.; Subjects receive matching placebo for treatments.
Other intervention name(s): Treatment A; Treatment B; Treatment C; Treatment D; Treatment E; Treatment F; Treatment G
Intervention MeSH terms: Moxifloxacin; Clarithromycin; Cobicistat; Pimozide; Norgestimate, ethinyl estradiol drug combination
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other