Trial Outcomes & Findings for Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening (NCT NCT01929083)

NCT ID: NCT01929083

Last Updated: 2015-10-30

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 19 participants
• Primary outcome timeframe: After 7 days of progesterone or placebo, prior to receiving IV ibutilide
• Results posted on: 2015-10-30

Participant Flow

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

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

Participant milestones

Measure	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	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
Intervention 1 STARTED	10	9
Intervention 1 Returned for 1st Ibutilide Administratio	7	9
Intervention 1 COMPLETED	7	9
Intervention 1 NOT COMPLETED	3	0
Intervention 2 STARTED	7	9
Intervention 2 Returned for 2nd Ibutilide Administratio	7	8
Intervention 2 COMPLETED	7	8
Intervention 2 NOT COMPLETED	0	1

Reasons for withdrawal

Measure	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	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
Intervention 1 Lost to Follow-up	2	0
Intervention 1 Nonadherent to study medications	1	0
Intervention 2 Adverse Event	0	1

Baseline Characteristics

Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

Baseline characteristics by cohort

Measure	Entire Study Population n=15 Participants n=15 subjects who completed the study
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	15 Participants n=93 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants
Age, Continuous	29 years STANDARD_DEVIATION 5 • n=93 Participants
Sex: Female, Male Female	15 Participants n=93 Participants
Sex: Female, Male Male	0 Participants n=93 Participants
Region of Enrollment United States	15 participants n=93 Participants

PRIMARY outcome

Timeframe: After 7 days of progesterone or placebo, prior to receiving IV ibutilide

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Baseline (Pre-Ibutilide) QTcI Intervals	412 ms Standard Deviation 15	419 ms Standard Deviation 14

PRIMARY outcome

Timeframe: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration

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.

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Maximum Individual-corrected QT Interval (QTcI)	443 ms Standard Deviation 17	458 ms Standard Deviation 19

PRIMARY outcome

Timeframe: After 7 days of progesterone or placebo

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration	7.5 percentage change from baseline value Standard Deviation 2.4	9.3 percentage change from baseline value Standard Deviation 3.4

PRIMARY outcome

Timeframe: From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Area Under the QTcI - Time Curve (AUEC)	497 ms*hr Standard Deviation 13	510 ms*hr Standard Deviation 16

SECONDARY outcome

Timeframe: During 7 days of treatment with oral progesterone or placebo

Outcome measures

Measure	Progesterone n=16 Participants 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	Placebo n=17 Participants 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
Incidence of Progesterone-associated Adverse Effects Compared to Placebo Fatigue/general malaise	38 percentage of participants	6 percentage of participants
Incidence of Progesterone-associated Adverse Effects Compared to Placebo Headache	13 percentage of participants	6 percentage of participants
Incidence of Progesterone-associated Adverse Effects Compared to Placebo Mood changes	13 percentage of participants	0 percentage of participants
Incidence of Progesterone-associated Adverse Effects Compared to Placebo Breast tenderness	13 percentage of participants	0 percentage of participants
Incidence of Progesterone-associated Adverse Effects Compared to Placebo Hypotension	6 percentage of participants	0 percentage of participants
Incidence of Progesterone-associated Adverse Effects Compared to Placebo Vertigo requiring discontinuation	6 percentage of participants	0 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Within 8 hours following ibutilide administration

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=17 Participants 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
Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases Bradycardia (HR < 60 bpm)	20 percentage of participants	12 percentage of participants
Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases Burning at infusion site	7 percentage of participants	6 percentage of participants
Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases Transient QTc interval > 500 ms	0 percentage of participants	6 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.)

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases	1247 pg/mL Standard Deviation 770	1172 pg/mL Standard Deviation 709

OTHER_PRE_SPECIFIED outcome

Timeframe: Following 7 days of progesterone or placebo

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Serum Estradiol Concentrations During the Progesterone and Placebo Phases	89.3 pg/mL Standard Deviation 62.8	71.8 pg/mL Standard Deviation 31.7

OTHER_PRE_SPECIFIED outcome

Timeframe: After 7 days of progesterone or placebo

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Serum Progesterone Concentrations During Progesterone and Placebo Phases	16.2 ng/mL Standard Deviation 11.0	1.2 ng/mL Standard Deviation 1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: After 7 days of progesterone or placebo

Outcome measures

Measure	Progesterone n=15 Participants 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	Placebo n=15 Participants 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
Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases	205 Ratio Standard Deviation 40	18 Ratio Standard Deviation 16

Adverse Events

Progesterone

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	Progesterone n=16 participants at risk 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	Placebo n=17 participants at risk 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
Ear and labyrinth disorders Vertigo requiring discontinuation of therapy	6.2% 1/16 • Number of events 1 • During 7 days of therapy with progesterone or placebo	0.00% 0/17 • During 7 days of therapy with progesterone or placebo

Other adverse events

Measure	Progesterone n=16 participants at risk 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	Placebo n=17 participants at risk 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
General disorders Fatigue/general malaise	37.5% 6/16 • Number of events 6 • During 7 days of therapy with progesterone or placebo	5.9% 1/17 • Number of events 1 • During 7 days of therapy with progesterone or placebo
General disorders Headache	12.5% 2/16 • Number of events 2 • During 7 days of therapy with progesterone or placebo	5.9% 1/17 • Number of events 1 • During 7 days of therapy with progesterone or placebo
General disorders Mood changes	12.5% 2/16 • Number of events 2 • During 7 days of therapy with progesterone or placebo	0.00% 0/17 • During 7 days of therapy with progesterone or placebo
Endocrine disorders Breast tenderness	12.5% 2/16 • Number of events 2 • During 7 days of therapy with progesterone or placebo	0.00% 0/17 • During 7 days of therapy with progesterone or placebo
General disorders Hypotension	6.2% 1/16 • Number of events 1 • During 7 days of therapy with progesterone or placebo	0.00% 0/17 • During 7 days of therapy with progesterone or placebo

Additional Information

Dr. James E Tisdale

Indiana University

Phone: 317-880-5418

Email: jtisdale@purdue.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place