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| Name | Class |
|---|---|
| American Heart Association | OTHER |
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Female sex is an independent risk factor for the potentially fatal drug-induced arrhythmia (irregular heartbeat) known as torsades de pointes (TdP), which is associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram (ECG). Mechanisms for this increased risk in women are not well-understood. QTc interval duration has been shown to fluctuate throughout the phases of the menstrual cycle. Evidence indicates that the QTc interval response to drugs that may cause TdP is greater during the menses and ovulation phases of the menstrual cycle, during which serum progesterone concentrations are lowest, and lesser during the luteal phase, during which serum progesterone concentrations are highest. Additional evidence from our laboratory suggests that progesterone may be protective against TdP. Specific Aim 1: Establish the influence of oral progesterone administration as a preventive method by which to diminish the degree of drug-induced QT interval prolongation in women. Working hypothesis: Oral progesterone administration effectively attenuates enhanced drug-induced QT interval response in women. To test this hypothesis, progesterone or placebo will be administered in a crossover fashion to women during the menses phase of the menstrual cycle. QTc interval response to low-dose ibutilide, a drug known to lengthen the QT interval, will be assessed. The primary endpoint will be individually-corrected QT interval (QTcI) response to ibutilide, in the presence and absence of progesterone, which will be assessed by: 1) Effect on maximum change in QTcI, and 2) Area under the QTcI interval-time curves (AUEC). At the conclusion of this study, we will have established that oral progesterone administration is a safe and effective method of attenuating drug-induced QT interval prolongation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Progesterone | Experimental | Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days |
|
| Placebo | Placebo Comparator | Subjects will receive oral placebo, two capsules once daily every evening for 7 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Progesterone | Drug | Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Baseline (Pre-Ibutilide) QTcI Intervals | After 7 days of progesterone or placebo, prior to receiving IV ibutilide | |
| Maximum Individual-corrected QT Interval (QTcI) | QT intervals will be corrected as follows: Prior to randomization, subjects will come to the Indiana Clinical Research Center for a 12-hour stay, during which three ECGs, one minute apart, will be obtained at the following times: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours. Subjects will be discharged, and then return then next morning for the 24 hour ECG. QT and RR intervals will be used to determine each subject's individual rate-corrected QT interval (QTcI) using the parabolic model QT = β•RRα, where RR is the interval between adjacent QRS complexes, and α and β are subject-specific correction factors. | 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration |
| Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration | After 7 days of progesterone or placebo | |
| Area Under the QTcI - Time Curve (AUEC) | From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Progesterone-associated Adverse Effects Compared to Placebo | During 7 days of treatment with oral progesterone or placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Within 8 hours following ibutilide administration | |
| Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases | Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.) |
Inclusion Criteria:
Exclusion Criteria:
Serum potassium ,< 3.6 meq/l
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| Name | Affiliation | Role |
|---|---|---|
| James E Tisdale, BSc, PharmD | Purdue University & Indiana University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Indiana Clinical Research Center | Indianapolis | Indiana | 46202 | United States | ||
| Purdue University |
n=333 subjects assessed for eligibility; n=27 consented, n=306 excluded (n=108 did not meet inclusion criteria, n=198 declined to participate); of n=27 consented, n=19 enrolled, n=8 excluded because they met one or more exclusion criteria
Subjects recruited from a) INResearch database, maintained by Indiana Clinical Translational Research Institute (CTSI), and b) Hard copy and electronic advertisements on the IUPUI and Purdue University campuses Participants were recruited between October 2012 and February 2014
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| ID | Title | Description |
|---|---|---|
| FG000 | Progesterone First, Then Placebo | Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days |
| FG001 | Placebo First, Then Progesterone | Subjects will receive oral placebo, two capsules once daily every evening for 7 days Placebo: Subjects will receive oral placebo two capsules once daily every evening for 7 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention 1 |
|
| ||||||||||||||||||||||||
| Intervention 2 |
|
Includes n=15 subjects included in the final analysis. Includes subjects randomized to receive progesterone first and patients randomized to receive placebo first
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | n=15 subjects who completed the study |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Baseline (Pre-Ibutilide) QTcI Intervals | Posted | Mean | Standard Deviation | ms | After 7 days of progesterone or placebo, prior to receiving IV ibutilide |
|
During 7 days of therapy with progesterone or placebo
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Progesterone | Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days Progesterone: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vertigo requiring discontinuation of therapy | Ear and labyrinth disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue/general malaise | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. James E Tisdale | Indiana University | 317-880-5418 | jtisdale@purdue.edu |
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| ID | Term |
|---|---|
| D029593 | Jervell-Lange Nielsen Syndrome |
| D016171 | Torsades de Pointes |
| D040242 | Risk Reduction Behavior |
| ID | Term |
|---|---|
| D008133 | Long QT Syndrome |
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D011374 | Progesterone |
| C067192 | ibutilide |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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| Placebo | Drug | Subjects will receive oral placebo two capsules once daily every evening for 7 days |
|
| Ibutilide | Drug | Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval |
|
| Serum Estradiol Concentrations During the Progesterone and Placebo Phases | Following 7 days of progesterone or placebo |
| Serum Progesterone Concentrations During Progesterone and Placebo Phases | After 7 days of progesterone or placebo |
| Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases | After 7 days of progesterone or placebo |
| Indianapolis |
| Indiana |
| 46202 |
| United States |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Primary | Maximum Individual-corrected QT Interval (QTcI) | QT intervals will be corrected as follows: Prior to randomization, subjects will come to the Indiana Clinical Research Center for a 12-hour stay, during which three ECGs, one minute apart, will be obtained at the following times: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours. Subjects will be discharged, and then return then next morning for the 24 hour ECG. QT and RR intervals will be used to determine each subject's individual rate-corrected QT interval (QTcI) using the parabolic model QT = β•RRα, where RR is the interval between adjacent QRS complexes, and α and β are subject-specific correction factors. | Posted | Mean | Standard Deviation | ms | 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration |
|
|
|
|
| Secondary | Incidence of Progesterone-associated Adverse Effects Compared to Placebo | Posted | Number | percentage of participants | During 7 days of treatment with oral progesterone or placebo |
|
|
|
|
| Primary | Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration | Posted | Mean | Standard Deviation | percentage change from baseline value | After 7 days of progesterone or placebo |
|
|
|
|
| Primary | Area Under the QTcI - Time Curve (AUEC) | Posted | Mean | Standard Deviation | ms*hr | From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion |
|
|
|
|
| Other Pre-specified | Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases | Posted | Number | percentage of participants | Within 8 hours following ibutilide administration |
|
|
|
|
| Other Pre-specified | Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases | Posted | Mean | Standard Deviation | pg/mL | Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.) |
|
|
|
|
| Other Pre-specified | Serum Estradiol Concentrations During the Progesterone and Placebo Phases | Posted | Mean | Standard Deviation | pg/mL | Following 7 days of progesterone or placebo |
|
|
|
|
| Other Pre-specified | Serum Progesterone Concentrations During Progesterone and Placebo Phases | Posted | Mean | Standard Deviation | ng/mL | After 7 days of progesterone or placebo |
|
|
|
|
| Other Pre-specified | Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases | Posted | Mean | Standard Deviation | Ratio | After 7 days of progesterone or placebo |
|
|
|
|
| 1 |
| 16 |
| 9 |
| 16 |
| EG001 | Placebo | Subjects will receive oral placebo, two capsules once daily every evening for 7 days Placebo: Subjects will receive oral placebo two capsules once daily every evening for 7 days | 0 | 17 | 2 | 17 |
| Headache | General disorders | Systematic Assessment |
|
| Mood changes | General disorders | Systematic Assessment |
|
| Breast tenderness | Endocrine disorders | Systematic Assessment |
|
| Hypotension | General disorders | Systematic Assessment |
|
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| D000075224 |
| Cardiac Conduction System Disease |
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D017180 | Tachycardia, Ventricular |
| D013610 | Tachycardia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001519 | Behavior |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D003339 | Corpus Luteum Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045167 | Progesterone Congeners |
| D012739 | Gonadal Steroid Hormones |
| Mood changes |
|
| Breast tenderness |
|
| Hypotension |
|
| Vertigo requiring discontinuation |
|
| 0.60 |
p values for incidence of headache |
| 2-Sided |
| No |
| Superiority or Other |
| Fisher Exact | 0.23 | p value for incidence of mood changes | 2-Sided | No | Superiority or Other |
| Fisher Exact | 0.23 | p value for incidence of breast tenderness | 2-Sided | No | Superiority or Other |
| Fisher Exact | 0.48 | p value for incidence of hypotension | 2-Sided | No | Superiority or Other |
| Fisher Exact | 0.48 | p value for incidence of vertigo requiring discontinuation of therapy | 2-Sided | No | Superiority or Other |
| Transient QTc interval > 500 ms |
|
p value for burning at infusion site |
| 2-Sided |
| No |
| Superiority or Other |
| Fisher Exact | > 0.99 | p value for transient QTc interval > 500 ms | 2-Sided | No | Superiority or Other |