Study of the Effect of GS-6615 in Subjects With LQT-3

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Gilead Sciences
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT01849003
First received: May 6, 2013
Last updated: October 6, 2014
Last verified: October 2014
  Purpose

This mechanism of action study is to evaluate the effect of oral GS-6615 on the QTc interval in participants with Long QT-3 syndrome. This study will be performed in six cohorts of participants in a sequential manner, four single-dose cohorts followed by two multiple-dose cohorts. Duration of treatment for the single-dose cohorts and multiple-dose cohorts will be 1 day and 7 days, respectively. Participants will be confined at the study center from check-in until completion of assessments at discharge.

Participants will be continuously monitored using real-time telemetry throughout the in-clinic confinement. Physical examinations including vital signs, laboratory analysis, electrocardiograms (ECGs), Holter recordings and echocardiography (ECHO) will be performed at defined time points throughout the study period. Assessment of adverse events and concomitant medications will continue throughout the duration of the study.


Condition Intervention Phase
Long QT Syndrome
Drug: GS-6615
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label Study to Evaluate the Effect of Single Dose GS-6615 on QT, Safety and Tolerability in Subjects With Long QT-3 Syndrome

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Changes in QTc intervals (Fridericia formula) [ Time Frame: Baseline through Day 7 ] [ Designated as safety issue: No ]

    Changes in QTc intervals (Fridericia formula; QTcF) from the time-matched ECG in the primary lead V5. In case QT cannot be measured in lead V5, lead II will be designated as the primary lead

    • Change from the time-matched ECG on Day -1 to Day 1 for Cohorts 1-4
    • Change from the time-matched ECG average of Day -1 and Day -2 to Days 1-7 for Cohort 5 and 6


Secondary Outcome Measures:
  • Incidence of Adverse Events (AEs) [ Time Frame: Baseline through Day 22 ] [ Designated as safety issue: No ]
  • Changes in ECHO parameters [ Time Frame: Baseline through Day 7 ] [ Designated as safety issue: No ]
    ECHO parameters relevant for measurement of diastolic function will be assessed.

  • Area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration of GS-6615 [ Time Frame: Baseline through Day 12 ] [ Designated as safety issue: No ]
  • Maximum observed plasma concentration (Cmax) of GS-6615 [ Time Frame: Baseline through Day 12 ] [ Designated as safety issue: No ]
  • Time to maximum observed concentration (Tmax) of GS-6615 [ Time Frame: Baseline through Day 12 ] [ Designated as safety issue: No ]
  • Changes in ECG parameters [ Time Frame: Baseline through Day 12 ] [ Designated as safety issue: No ]

    ECG parameters assessed will include PR, RR, QRS, and QT.

    • PR: electrocardiographic interval occurring between the onset of the P wave and the QRS complex representing time for atrial and ventricular depolarization, respectively
    • RR: electrocardiographic interval representing the time measurement between the R wave of one heartbeat and the R wave of the preceding heartbeat
    • QRS: electrocardiographic deflection between the beginning of the Q wave and termination of the S wave representing time for ventricular depolarization
    • QT: electrocardiographic interval between the beginning of the Q wave and termination of the T wave representing the time for both ventricular depolarization and repolarization to occur

  • Changes in QTc interval (Bazett [QTcB]) [ Time Frame: Baseline through Day 7 ] [ Designated as safety issue: No ]

    Changes in QTcB from the time-matched ECG in the primary lead V5. In case QT cannot be measured in lead V5, lead II will be designated as the primary lead

    • Change from the time-matched ECG on Day -1 to Day 1 for Cohorts 1-4
    • Change from the time-matched ECG average of Day -1 and Day -2 to Days 1-7 for Cohort 5 and 6


Estimated Enrollment: 34
Study Start Date: May 2013
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Participants will receive a single 10 mg dose of GS-6615.
Drug: GS-6615
GS-6615 tablet(s) administered orally
Experimental: Cohort 2
Participants will receive a single 20 mg dose of GS-6615.
Drug: GS-6615
GS-6615 tablet(s) administered orally
Experimental: Cohort 3
Participants will receive a single 30 mg dose of GS-6615.
Drug: GS-6615
GS-6615 tablet(s) administered orally
Experimental: Cohort 4
Participants will receive a single 60 mg dose of GS-6615.
Drug: GS-6615
GS-6615 tablet(s) administered orally
Experimental: Cohort 5

Participants will receive single doses of GS-6615 as follows:

  • Day 1: 20 mg (loading dose)
  • Day 2: 40 mg (loading dose)
  • Days 3-7: 6 mg (maintenance dose) once daily

If a participant has a QTcF value of ≤ 420 msec on 2 consecutive time points after the 20 mg dose on Day 1, the participant will receive the maintenance dose of 6 mg on Day 2.

Drug: GS-6615
GS-6615 tablet(s) administered orally
Experimental: Cohort 6

Participants will receive single doses of GS-6615 as follows:

  • Day 1: 50 mg (loading dose)
  • Day 2-3: 10 mg once daily
  • Days 4-7: 20 mg once daily
Drug: GS-6615
GS-6615 tablet(s) administered orally

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females between ages 18-65 years (inclusive) at time of screening
  2. Documented LQT-3 genotype with one of the following mutations: delta KPQ, R1623Q, N1325S, E1784K, S1787N, D1790G, G1631D, 1795insD, delF1617, R1644H, L409P, F2004L, I1768V, T1304M, A1330T, or F1596I3.
  3. QTc > 480 msec in lead V5 at screening
  4. Weight of at least 50 kg with body mass index (BMI) between 18 and 30 kg/m^2 (inclusive)
  5. Females of childbearing potential must have a negative serum pregnancy test at screening and check-in
  6. Females of childbearing potential must agree to utilize protocol recommended highly effective contraception methods from three weeks prior to the single dose of study drug and for 30 days following the single dose of study drug

    a. Females who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least 3 months prior to study dosing

  7. Males must agree to utilize a protocol recommended highly effective method of contraception during heterosexual intercourse throughout the study period and for 90 days following last dose of study drug. Periodic abstinence and withdrawal are not acceptable methods of contraception
  8. Males must refrain from sperm donation from Day -2 through completion of the study and continuing for at least 90 days from the date of last dose of study drug
  9. Willing and able to comply with the requirements of the protocol and directions from the clinic staff
  10. Willing to avoid consumption of grapefruit, grapefruit juice and Seville oranges within 2 weeks prior to the single dose of study drug until discharge from the clinic
  11. Willing to avoid consumption of nicotine (including nicotine gum) and alcoholic beverages within 2 weeks prior to the single dose of study drug until discharge from the clinic
  12. Understand and willing to sign informed consent

Exclusion Criteria:

  1. Ongoing or history of any medical or surgical condition that, in the judgment of the Investigator, might jeopardize the individual's safety or interfere with the absorption, distribution, metabolism or excretion of the study drug
  2. History of meningitis or encephalitis, seizures, migraines, tremors, myoclonic jerks, sleep disorder, anxiety, syncope, head injuries or a family history of seizures
  3. Any abnormal electrocardiographic (ECG) findings (except QTc > 460 msec) at screening judged to be clinically significant by the investigator
  4. Any abnormal laboratory value or physical examination finding at screening or check-in that is judged by the investigator as clinically significant
  5. History of positive serology test for HIV, or hepatitis B or C
  6. Positive urine drug test for ethanol, barbiturates, cocaine, opiates, or amphetamines at screening or check-in
  7. Positive urine cotinine test at check-in
  8. Current treatment with drugs affecting the QT interval
  9. Current treatment with sodium-channel blockers, eg, flecainide and mexiletine
  10. Current treatment with strong or moderate inhibitors or inducers of cytochrome P450 (CYP)3A4 and 1A2
  11. Prior treatment with ranolazine within 7 days prior to study drug administration
  12. Use of systemic prescription medications or over-the-counter (OTC) medication, including multivitamins, and dietary and herbal supplement within 2 weeks or 5 times the terminal half-lives of the medication (whichever is longer) prior to the single dose of study drug, and for the duration of the study
  13. Use of any experimental or investigational drug or device within 30 days prior to the single dose of study drug or 5 half-lives of the drug, whichever is longer
  14. Females who are pregnant or lactating
  15. History of drug or alcohol abuse within 12 months prior to initial dosing of study drug
  16. Psychosocial or addictive disorders that would interfere with ability to give informed consent or could compromise compliance with the protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01849003

Locations
United States, New York
University of Rochester Medical Center/Strong Memorial Hospital Recruiting
Rochester, New York, United States, 14620
Contact: David J Pinto, RN, BSN    585-273-4460    DavidJ_Pinto@urmc.rochester.edu   
Contact: Colleen Patterson    585-273-5247    colleen_patterson@urmc.rochester.edu   
Principal Investigator: Spencer Z Rosero, MD         
Principal Investigator: Wojciech Zareba, MD, PhD         
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Elizabeth Layug, MD Gilead Sciences
  More Information

No publications provided

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01849003     History of Changes
Other Study ID Numbers: GS-US-279-0110
Study First Received: May 6, 2013
Last Updated: October 6, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Gilead Sciences:
Long QT Syndrome
LQTS
Long QT-3 Syndrome
LQT-3
prolonged QT interval
GS-6615
late sodium current inhibitor

Additional relevant MeSH terms:
Long QT Syndrome
Syndrome
Arrhythmias, Cardiac
Cardiovascular Abnormalities
Cardiovascular Diseases
Congenital Abnormalities
Disease
Heart Defects, Congenital
Heart Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on October 23, 2014