Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults

Study Overview
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Brief Summary
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This study will evaluate the effect of oral GS-6615 on QTc interval in healthy adults with dofetilide-induced QTc prolongation.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Subjects

Conditions
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Long QT Syndrome

Intervention / Treatment
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* Drug: GS-6615
* Drug: Placebo to match GS-6615
* Drug: Placebo to match dofetilide
* Drug: Dofetilide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs Have a calculated body mass index (BMI) from 18 to 30 kg/m^2, inclusive, at study screening Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant and which do not interfere with the ability to interpret the QT interval in the opinion of the investigator in consultation with the medical monitor Exclusion Criteria: History of meningitis or encephalitis, epilepsy, seizures (known or suspected), migraines, tremors, myoclonic jerks, sleep disorder, anxiety, syncope, head injuries, or a family history of seizures Have any serious or active medical or psychiatric illness (including depression) which, in the opinion of the investigator, would interfere with treatment, assessment, or compliance with the protocol. This would include renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment. Presence or history of cardiovascular disease, including structural heart disease, myocardial infarction (by ECG and/or clinical history), history of ventricular tachycardia or torsade de pointes, heart failure or cardiomyopathy (by clinical history and/or left ventricular ejection fraction < 40%), presence of cardiac conduction abnormalities, a family history of Long QT or Brugada Syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years Additional cardiovascular-specific exclusion criteria include findings on screening ECG of: QTcF interval > 430 msec PR interval > 220 msec QRS duration > 110 msec Second- or third-degree atrioventricular block Complete left or right bundle branch block or incomplete right bundle branch block Resting heart rate < 40 or > 100 beats per minute (bpm) Pathological Q waves (defined as Q wave > 40 msec) Ventricular pre-excitation More than 2 ectopic beats Syncope, palpitations, or unexplained dizziness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo to match GS-6615<br>Placebo to match GS-6615 + dofetilide or placebo to match dofetilide twice daily | Drug: Placebo to match GS-6615<br>* Placebo to match GS-6615 tablets administered orally<br>Drug: Placebo to match dofetilide<br>* Placebo to match dofetilide capsules administered orally<br>Drug: Dofetilide<br>* Dofetilide 500 μg capsules administered orally according to the current prescribing information<br>|
| Experimental: GS-6615<br>GS-6615 or placebo to match GS-6615 + dofetilide or placebo to match dofetilide twice daily | Drug: GS-6615<br>* GS-6615 tablets administered orally<br>Drug: Placebo to match GS-6615<br>* Placebo to match GS-6615 tablets administered orally<br>Drug: Placebo to match dofetilide<br>* Placebo to match dofetilide capsules administered orally<br>Drug: Dofetilide<br>* Dofetilide 500 μg capsules administered orally according to the current prescribing information<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in daytime QT interval corrected for heart rate using the Fridericia formula (QTcF) |  | Up to 6 days | 
| Pharmacokinetic (PK) profiles of GS-6615 and dofetilide | This endpoint will measure the plasma PK profiles of GS-6615 and dofetilide. PK parameters that will be measured include Cmax, Tmax, AUC_0-24, and AUC_0-tlast. | Predose and postdose on Days -2 through Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events, clinical laboratory test results, vital sign measurements, and electrocardiogram (ECG) data | This endpoint will measure the safety and tolerability profile of GS-6615. | Up to 6 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug-induced long QT syndrome, DILQTS, prolonged QT