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Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

Primary Purpose

Long QT Syndrome, Abnormalities, Drug-Induced

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Progesterone
Ibutilide
Sponsored by
Indiana University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Long QT Syndrome

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

Postmenopausal women:

  • 50 years of age or older
  • No menstrual periods for 365 days or longer

Premenopausal women:

- 21-40 years of age

Exclusion Criteria:

  • History of breast, uterine or ovarian cancer
  • History of hysterectomy and/or ovariectomy
  • Weight > 135 kg
  • Serum K+ < 3.6 mEq/L;
  • Serum Mg2+ < 1.8 mg/dL;
  • Hematocrit < 26%;
  • Hepatic transaminases > 3x upper limit of normal;
  • Baseline Bazett's-corrected QT interval > 450 ms
  • Taking hormone replacement therapy
  • Diagnosis of heart failure
  • Symptoms associated with heart failure:

    • Pitting edema > 2+
    • Crackles or rales on lung auscultation
    • S3 or S4 heart sounds
    • Unable to climb at least 2 flights of stairs without becoming short of breath
  • Current ECG rhythm of atrial fibrillation or other tachyarrhythmia
  • Family or personal history of long-QT syndrome or sudden cardiac death not associated with acute myocardial infarction
  • Concomitant use of any QTc interval-prolonging drug.
  • Permanently paced ventricular rhythm
  • Pregnancy
  • Using any hormonal contraceptives [oral contraceptives, hormone-secreting intrauterine devices (IUDs), hormonal implants]

Sites / Locations

  • Indiana UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Postmenopausal women: Progesterone

Postmenopausal women: Placebo

Premenopausal women: Progesterone

Premenopausal women: Placebo

Arm Description

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Outcomes

Primary Outcome Measures

Baseline (pre-ibutilide) QT-F and QT-Fram intervals
QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
Maximum post-ibutilide QT-F and QT-Fram intervals
Maximum post-ibutilide QT-F and QT-Fram intervals
% change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
% change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
Area under the QT-F and QT-Fram versus time curves during and for 1 hour following ibutilide infusion
Area under the QT-F and QT-Fram versus time curves during and for 1 hour
Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion

Secondary Outcome Measures

Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Maximum post-ibutilide J-Tpeakc intervals
Maximum post-ibutilide J-Tpeakc intervals
% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion
Area under the J-Tpeakc versus time curve during and for 1 hour following
Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion
Area under the J-Tpeakc versus time curve during and for 8 hours following
Baseline (pre-ibutilide) Tpeak-Tend intervals
Baseline (pre-ibutilide) Tpeak-Tend intervals
Maximum post-ibutilide Tpeak-Tend intervals
Maximum post-ibutilide Tpeak-Tend intervals
% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion

Full Information

First Posted
February 6, 2019
Last Updated
June 30, 2023
Sponsor
Indiana University
Collaborators
American Heart Association, Purdue University
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1. Study Identification

Unique Protocol Identification Number
NCT03834883
Brief Title
Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
Official Title
Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 26, 2019 (Actual)
Primary Completion Date
January 15, 2024 (Anticipated)
Study Completion Date
January 22, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Indiana University
Collaborators
American Heart Association, Purdue University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research will determine if oral progesterone attenuates drug-induced QT interval lengthening in a) Postmenopausal women 50 years of age or older, and b) Premenopausal women studied during the ovulation phase of the menstrual cycle. This investigation will consist of two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design studies in a) Postmenopausal women, and b) Premenopausal women. Each subject will take progesterone or placebo capsules for 1 week. After a two-week "washout" (no progesterone or placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1 week. After 7 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be compared
Detailed Description
Torsades de pointes (TdP) is a catastrophic arrhythmia associated with corrected QT (QTc) interval prolongation, which can be induced by > 150 commonly prescribed drugs. TdP risk is higher in women and is modulated by the ratio of serum progesterone and estradiol; the higher the serum progesterone and progesterone:estradiol ratio, the lower the risk, and vice-versa. TdP risk increases with age, likely due to declining postmenopausal progesterone concentrations. Methods to reduce TdP risk in postmenopausal women requiring therapy with QTc interval-prolonging drugs have not been developed. In addition, the differential effects of progesterone on drug-induced lengthening of early vs late ventricular repolarization in humans are unknown. The investigators have previously shown that oral progesterone attenuates QTc interval lengthening in young women during the menses phase when serum estradiol concentrations are low. However, whether oral progesterone remains effective for attenuating drug-induced QTc interval lengthening during menstrual cycle phases with higher serum estradiol concentrations is unknown. The efficacy of oral progesterone for attenuating drug-induced QTc interval lengthening in postmenopausal women is also unknown. Specific Aim1: Determine the efficacy of oral progesterone as a preventive method to diminish drug-induced QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the influence of oral progesterone on drug-induced lengthening of early versus late ventricular repolarization in postmenopausal women. Specific Aim 3: Determine the efficacy of oral progesterone to diminish drug-induced QTc interval lengthening in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high. Specific Aim 4: Specific Aim 4: Determine the influence of oral progesterone on drug-induced lengthening of early versus late ventricular repolarization in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high. Concurrent prospective, randomized, double-blind, placebo-controlled two-way crossover-design studies will be conducted in a) Postmenopausal women > 50 years of age (n=20) and b) Premenopausal women 21-40 years of age (n=20) who will be studied during the ovulation phase of the menstural cycle. QTc interval response to low-dose ibutilide will be assessed. Subjects will receive, in randomized order (with a minimum two-week washout phase) oral progesterone 400 mg or placebo once daily for 7 days. On the morning after the 7th dose, subjects will present to the Indiana Clinical Research Center to receive one dose of the QT interval-lengthening drug ibutilide 0.003 mg/kg, after which ECGs and blood for determination of serum ibutilide concentrations will be obtained serially for 8 hours. Primary outcome measures: 1) Baseline (pre-ibutilide) Fridericia (QTFrid) and Framingham (QTFram)-corrected QT intervals, 2) Maximum QTFrid and QTFram intervals following ibutilide, 3) Maximum % change in QTFrid and QTFram intervals following ibutilide, 4) Area under the QTFrid and QTFram interval-time curves from 0-1 and 0-8 hours. Secondary outcome measures: 1) J-Tpeak interval, 2) Tpeak-Tend interval, and 5) Incidence of progesterone and ibutilide adverse effects. These studies will establish oral progesterone as a safe and effective method of attenuating drug-induced QTc interval lengthening in postmenopausal women.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Long QT Syndrome, Abnormalities, Drug-Induced

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Postmenopausal women: Progesterone
Arm Type
Experimental
Arm Description
Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
Arm Title
Postmenopausal women: Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects will receive oral placebo, two capsules once daily every evening for 7 days
Arm Title
Premenopausal women: Progesterone
Arm Type
Experimental
Arm Description
Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
Arm Title
Premenopausal women: Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects will receive oral placebo, two capsules once daily every evening for 7 days
Intervention Type
Drug
Intervention Name(s)
Progesterone
Intervention Description
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Intervention Type
Drug
Intervention Name(s)
Ibutilide
Other Intervention Name(s)
Corvert
Intervention Description
Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval
Primary Outcome Measure Information:
Title
Baseline (pre-ibutilide) QT-F and QT-Fram intervals
Description
QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
Time Frame
After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
Title
Maximum post-ibutilide QT-F and QT-Fram intervals
Description
Maximum post-ibutilide QT-F and QT-Fram intervals
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
% change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
Description
% change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
Area under the QT-F and QT-Fram versus time curves during and for 1 hour following ibutilide infusion
Description
Area under the QT-F and QT-Fram versus time curves during and for 1 hour
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion
Title
Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
Description
Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Secondary Outcome Measure Information:
Title
Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Description
Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Time Frame
After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
Title
Maximum post-ibutilide J-Tpeakc intervals
Description
Maximum post-ibutilide J-Tpeakc intervals
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
Description
% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion
Description
Area under the J-Tpeakc versus time curve during and for 1 hour following
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion
Title
Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion
Description
Area under the J-Tpeakc versus time curve during and for 8 hours following
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
Baseline (pre-ibutilide) Tpeak-Tend intervals
Description
Baseline (pre-ibutilide) Tpeak-Tend intervals
Time Frame
After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
Title
Maximum post-ibutilide Tpeak-Tend intervals
Description
Maximum post-ibutilide Tpeak-Tend intervals
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
Description
% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Title
Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
Description
Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion
Title
Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
Description
Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
Time Frame
Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
Other Pre-specified Outcome Measures:
Title
Adverse effects
Description
Adverse effects fo progesterone, placebo and ibutilide will be assessed
Time Frame
During the 7 days of treatment with progesterone/placebo and at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Postmenopausal - 50 years of age or older and no menstrual period for 365 days or longer Premenopausal - 21-40 years of age
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Postmenopausal women: 50 years of age or older No menstrual periods for 365 days or longer Premenopausal women: - 21-40 years of age Exclusion Criteria: History of breast, uterine or ovarian cancer History of hysterectomy and/or ovariectomy Weight > 135 kg Serum K+ < 3.6 mEq/L; Serum Mg2+ < 1.8 mg/dL; Hematocrit < 26%; Hepatic transaminases > 3x upper limit of normal; Baseline Bazett's-corrected QT interval > 450 ms Taking hormone replacement therapy Diagnosis of heart failure Symptoms associated with heart failure: Pitting edema > 2+ Crackles or rales on lung auscultation S3 or S4 heart sounds Unable to climb at least 2 flights of stairs without becoming short of breath Current ECG rhythm of atrial fibrillation or other tachyarrhythmia Family or personal history of long-QT syndrome or sudden cardiac death not associated with acute myocardial infarction Concomitant use of any QTc interval-prolonging drug. Permanently paced ventricular rhythm Pregnancy Using any hormonal contraceptives [oral contraceptives, hormone-secreting intrauterine devices (IUDs), hormonal implants]
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
James E Tisdale, PharmD
Phone
317-880-5418
Email
jtisdale@purdue.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Heather Jaynes, MSN
Phone
317-880-5410
Email
hwroblew@iu.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James E Tisdale, PharmD
Organizational Affiliation
Purdue University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
James E Tisdale, PharmD
Phone
317-880-5418
Email
jtisdale@purdue.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

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