Clinical trial NCT03834883
Conditions: Long QT Syndrome Abnormalities, Drug-Induced
Sponsor: Indiana University
Start date: 2019-03-26; Completion date: 2024-05-23
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days arm 2: Subjects will receive oral placebo, two capsules once daily every evening for 7 days arm 3: Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days arm 4: Subjects will receive oral placebo, two capsules once daily every evening for 7 days
Interventions: intervention 1: Progesterone intervention 2: Ibutilide
Intervention descriptions: intervention 1: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days intervention 2: Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
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Novel Approaches for Minimizing Drug-
Induced QT Interval Lengthening: 
Reducing the Risk of Drug-Induced QT Interval 
Lengthening in Women 
 
James E Tisdale PharmD, FCCP, FAPhA, FNAP, FAHA, FACC 
Professor  
Department of Pharmacy Practice 
College of Pharmacy 
Purdue University 
Adjunct Professor 
School of Medicine 
Indiana University 
640 Eskenazi Avenue 
Indianapolis, IN 46202 
317-880-5418 
317-880-0568 
jtisdale@purdue.edu 
 
 
Funding: American Heart Association #18TPA34170523 
 
Co-Investigators: 
 
Heather A W Jaynes, MSN, RN 
Research Nurse/Project Coordinator 
Department of Pharmacy Practice 
College of Pharmacy 
Purdue University 
 
Brian Overholser, PharmD, Associate Professor 
Department of Pharmacy Practice 
College of Pharmacy 
Purdue University 
Adjunct Associate Professor 
School of Medicine 
Indiana University 
 
Kevin Sowinski, PharmD, Professor 
Department of Pharmacy Practice 
College of Pharmacy 
Purdue University 
Adjunct Professor 
School of Medicine 


 
2 
Revised: 01/31/2020 
Indiana University 
 
Richard Kovacs MD, Professor 
Cardiologist 
Krannert Institute of Cardiology 
Indiana University School of Medicine 
Dr. Kovacs has been a collaborator of Dr. Tisdale’s for 16 years. His role on this project 
is: contributed to hypothesis development; contributed to development of protocol and 
AHA grant; will contribute to data analysis and interpretation; provides expertise related 
to ECG interpretation and QT interval measurement and analysis 
 
Elena Tomaselli Muensterman, PharmD 
Graduate Student 
Department of Pharmacy Practice 
College of Pharmacy 
Purdue University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Revised: 01/31/2020 
 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Follow-up and Record Retention 
 
 


 
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1.0 
Background 
 
Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia associated with 
heart rate-corrected QT (QTc) interval prolongation, which can be caused by > 150 
commonly prescribed drugs. TdP risk is higher in women than men, and is modulated by 
progesterone, which shortens the QTc interval, and estradiol, which lengthens it. The 
higher the serum progesterone and the progesterone:estradiol ratio, the lower the risk 
of QTc interval prolongation and TdP. The TdP risk in women increases with age, likely 
due to declining postmenopausal serum progesterone concentrations. Methods to 
reduce TdP risk in older women requiring therapy with QTc interval-prolonging drugs 
have not been developed. In addition, differential effects of progesterone on drug-
induced lengthening of early vs late ventricular repolarization in humans are unknown.  
 
nnn  Drug-Induced QTc Interval Prolongation and Torsades de Pointes (TdP). 
QTc interval prolongation may result in TdP, which is associated with sudden cardiac 
death.1 We propose to investigate a novel approach to minimizing drug-induced QTc 
interval lengthening in postmenopausal women: oral progesterone administration. Over 
150 available drugs may cause TdP,2 including antimicrobials, antidepressants, 
antipsychotics, antiarrhythmics, methadone, and others. Many QTc interval -prolonging 
drugs are among the top 200 drugs prescribed in the U.S. and millions of patients are 
exposed annually to drugs that cause TdP.3 Methods to reduce the TdP risk in high-risk 
patients have not been developed; risk reduction strategies are critically needed. The 
investigation described herein will determine the efficacy of a novel therapeutic 
approach to attenuate drug-induced QTc lengthening in postmenopausal women.  
 
nnn  Female Sex as a Risk Factor for QTc Interval Prolongation/TdP. Women 
are at higher risk of drug-induced TdP, in part due to testosterone production in males 
beginning at puberty. However, estrogen lengthens the QTc interval,4 which is shorter 
during the luteal phase of the menstrual cycle (when serum progesterone is highest) 
than in the follicular phase.5 Progesterone has an androgen structure similar to 
testosterone and is a testosterone precursor in testicular Leydig cells. In women with 
long QT syndrome (LQTS), TdP risk is low during pregnancy, but increases post-partum, 
when serum progesterone declines.6 Progesterone-induced shortening of ventricular 
action potential duration (APD) is reversed by progesterone receptor inhibition.7 In a 
transgenic rabbit LQTS type 2 model, progesterone reduced the incidence of 
spontaneous polymorphic ventricular tachycardia (PVT) or sudden cardiac death (SCD) 
and ventricular early afterdepolarizations.8 Older age is a risk factor for TdP in women, 
likely due to the decline in serum progesterone concentrations after menopause. Overall, 
data indicate that progesterone shortens ventricular repolarization and protects against 
drug-induced ventricular APD lengthening and arrhythmias.  
 
We conducted a prospective, double-blind “proof-of concept” study, assessing the effect 
of oral progesterone on drug-induced QT interval lengthening in young women.10 We 
randomized n=19 healthy women 21-40 years of age to receive 7 days of therapy with 
oral progesterone 400 mg once daily or matching placebo. After a washout period, 
subjects were crossed over to the alternate therapy. Women were studied during the 
menses phase, to minimize the influence of endogenous sex hormones. Following 7 days 
of treatment, subjects received intravenous ibutilide 0.003 mg/kg and QTc interval 


 
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response was determined. Pre-ibutilide QTc intervals were significantly shorter during 
the progesterone phase. In addition, both the mean maximum QTc interval and 
maximum % change in QTc interval from pre-ibutilide value were significantly shorter 
during the progesterone phase.10 On the basis of this “proof-of-concept” study, we now 
propose to investigate the effects of oral progesterone administration on drug-induced 
QTc interval lengthening in a target population of interest: postmenopausal women, who 
have low serum progesterone concentrations.  
 
nnn  Influence of Estradiol on Progesterone-Associated Attenuation of Drug-
Induced Lengthening of Ventricular Repolarization. Estradiol lengthens the QTc 
interval.4,11-13 In the transgenic LQTS type 2 model,8 estradiol increased the incidence of 
PVT and SCD. Some data suggest that the protective effects of progesterone against 
drug-induced lengthening of ventricular repolarization may be lessened by estradiol. Our 
group showed that the effect of progesterone on attenuation of quinidine-associated 
lengthening of ventricular APD90 was diminished by concomitant administration of 
estradiol in ovariectomized rabbits.14 In young, healthy women, ibutilide-induced QTc 
interval prolongation was greatest during menses and ovulation, when the mean serum 
progesterone:estradiol concentration ratios are low (16 and 31, respectively), and least 
during the luteal phase, when the ratio is highest (82).9 This raises the possibility that 
protective effects of progesterone against drug-induced QTc interval lengthening may be 
diminished in the presence of higher serum estradiol concentrations.  
 
In contrast, however, patients receiving hormone replacement therapy show a 
significantly smaller degree of QTc interval prolongation among those taking both 
estrogen and progesterone compared with those taking estrogen alone, indicating a 
protective effect of progesterone despite concomitant estrogen therapy.4-11-13,15 
Therefore, whether progesterone administered to premenopausal women remains 
protective against drug-induced QTc interval lengthening during menstrual cycle phases 
with higher estradiol concentrations than in the menses phase remains unknown. Before 
initiating clinical trials of progesterone for attenuation of drug-induced QTc interval 
lengthening in broader populations of women at risk, it is critical to determine if the 
protective effects of progesterone persist in premenopausal women with high serum 
estradiol concentrations. Based on our previous study discussed above,10 in which oral 
progesterone 400 mg once daily achieved a mean serum progesterone concentration of 
16.2±11.0 ng/mL, we hypothesize that, in premenopausal women in the ovulation or 
luteal phase, this dose will achieve progesterone:estradiol ratios of roughly 164 and 214, 
respectively,9,10 which will be sufficiently high to attenuate drug-induced QTc 
lengthening.  
 
nnn  Influence of Progesterone on Early and/or Late Repolarization. 
Progesterone enhances IKs current (influencing late phase repolarization)7 and decreases 
ICa,L density in rabbit cardiomyocytes16 (early repolarization). Progesterone may also 
activate the (PI3K/AKT) signaling pathway,17 inhibiting late sodium current (early 
repolarization). However, the effects of progesterone on drug-induced lengthening of 
specific phases of ventricular repolarization in humans are unknown, though this 
information carries important clinical significance. If progesterone attenuates drug-
induced lengthening of both early and late repolarization, then it can be anticipated to 
attenuate QTc lengthening induced by drugs that lengthen early or late repolarization 
(or both). However, if progesterone is effective for attenuation of drug-induced 
lengthening of only early or late repolarization, but not both, then progesterone may be 
effective for attenuation of QTc lengthening induced by drugs that inhibit only early 


 
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repolarization (late sodium activating agents, PI3K inhibitors) or late repolarization (IKr 
inhibitors). We will assess progesterone’s influence on early and late repolarization by 
measuring its effect on ibutilide-associated lengthening of J-Tpeak and Tpeak-Tend in both 
proposed clinical studies.  
 
nnn  Feasibility and Potential Clinical Application of Progesterone to 
Attenuate Drug-Induced QTc Lengthening in High Risk Women. Upon 
completion of these investigations, large clinical studies will be conducted to determine 
feasibility, efficacy and safety of concomitant therapy with oral progesterone for 
reducing risk of drug-induced QTc prolongation in postmenopausal women with 
additional TdP risk factors who require short or longer-term therapy with QTc-prolonging 
drugs. Clinical applications for concomitant therapy with oral progesterone in women 
with TdP risk factors could include patients requiring: a short course of therapy with QTc 
interval-prolonging antimicrobial agents, such as fluoroquinolones, macrolides, or 
antifungal agents; QTc-prolonging antidepressants and/or antipsychotic agents; 
methadone for narcotic addiction or pain control; QTc interval-prolonging anticancer 
agents. Progesterone 400 mg orally daily was associated with no reported adverse 
effects.18 In our study,10 the only adverse effects associated with progesterone with a 
signficantly greater frequency than placebo were fatigue/malaise, though one subject 
withdrew due to progesterone-associated vertigo. Therefore, risks associated with oral 
progesterone appear minimal. 
 
nnn  Summary. Women are at increased risk of drug-induced QTc prolongation and 
TdP. While we have established in our previous study that oral progesterone attenuates 
drug-induced QTc interval lengthening in young women during menses, when serum 
estradiol concentrations are at their lowest, it is important to establish that oral 
progesterone remains effective in premenopausal women with higher serum estradiol 
concentrations prior to initiating larger clinical studies. In addition, age is a risk factor for 
drug-induced QTc interval prolongation and TdP in women, likely due to declining serum 
progesterone concentrations. Prior to initiating larger clinical trials in postmenopausal 
women, it is important to establish the efficacy of oral progesterone administration in 
this population. We hypothesize that drug-induced QTc interval lengthening is 
attenuated by administration of oral progesterone in premenopausal women during 
menstrual cycle phases with higher serum estradiol concentrations and in 
postmenopausal women.  
 
Establishing the influence of progesterone administration as a preventive method to 
reduce the risk of TdP will lead to important advances in proarrhythmia risk reduction. 
Pre- and postmenopausal women at high risk of drug-induced TdP who require therapy 
with a QTc interval-prolonging drug could be pre- or concomitantly treated with oral 
progesterone. This will represent a significant advance in arrhythmia prevention and 
medication safety.  
 
 
2.0 
Rationale and Specific Aims 
 
Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia associated with 
corrected QT (QTc) interval prolongation, which can be provoked by commonly 
prescribed drugs. TdP risk is higher in women and is modulated by the ratio of serum 
progesterone and estradiol; progesterone shortens the QTc interval, while estradiol 


 
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lengthens it. The higher the serum progesterone and the progesterone:estradiol ratio, 
the lower the risk of QTc interval prolongation and TdP, and vice versa. TdP risk 
increases with age, likely due to declining postmenopausal serum progesterone. 
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. Evidence by our group, presented in the Background and 
Significance section and supported by our preliminary data, suggests: 1) Oral 
progesterone attenuates QTc interval lengthening in young women during the menses 
phase, when serum estradiol is low, and 2) Progesterone reduces the risk of drug-
induced TdP. 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 lengthening in older, postmenopausal women is also unknown. 
Identifying effective means of attenuating drug-induced QTc interval lengthening will 
improve medication safety in women requiring therapy with QTc prolonging drugs. 
 
Our long-term goal is to determine mechanisms by which drugs cause arrhythmias and 
identify safe and effective methods of prevention and management of drug-induced 
arrhythmias. The objective in this application is to evaluate the efficacy of a novel 
therapeutic approach to reduce the degree of drug-induced QTc interval lengthening in 
women. Our central hypothesis is that acquired QTc interval lengthening is attenuated 
by exogenous progesterone administration in women. To test this hypothesis, we 
propose the following specific aim:  
 
Specific Aim 1: Determine the efficacy of oral progesterone as a preventive 
method to diminish drug-induced QT interval lengthening in postmenopausal 
women. Hypothesis: Oral progesterone attenuates drug-induced QTc interval response 
in postmenopausal women. Postmenopausal women will receive progesterone in a 
prospective, randomized, double-blind, placebo-controlled 2-way crossover study. QTc 
interval response to ibutilide will be assessed.  
 
Specific Aim 2: Determine the influence of oral progesterone on drug-induced 
lengthening of early versus late ventricular repolarization in postmenopausal 
women. Hypothesis: Based on preclinical data reporting effects of progesterone on the 
slow delayed rectifier potassium (IKs), and L-type calcium (ICa,L) current, progesterone 
attenuates drug-induced lengthening of both early (represented by measurement of J-
Tpeak) and late (represented by measurement of Tpeak-Tend) 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. Hypothesis: Despite higher serum estradiol, oral progesterone achieves a 
sufficiently high progesterone: estradiol ratio to attenuate drug-induced QTc interval 
response in premenopausal women during the ovulation phase.  
 
Specific Aim 4: Determine the influence of oral progesterone on drug-induced 
lengthening of early versus late ventricular repolarization in premenopausal 


 
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women during the ovulation phase of the menstrual cycle, when serum 
estradiol concentrations are high. Hypothesis: Based on preclinical data reporting 
effects of progesterone on the slow delayed rectifier potassium (IKs), and L-type calcium 
(ICa,L) current, progesterone attenuates drug-induced lengthening of both early 
(represented by measurement of J-Tpeak) and late (represented by measurement of 
Tpeak-Tend) ventricular repolarization in premenopausal women during the ovulation 
phase. 
 
This work will establish the efficacy of progesterone administration for attenuation of 
drug-induced QTc interval lengthening in older women and in premenopausal women 
during the ovulation phase, when serum estradiol concentrations are high. Our expected 
outcome is that this novel preventive strategy will be effective, and these data will lead 
to large clinical trials investigating the efficacy of short- and longer-term administration 
of oral progesterone for reducing risk of drug-induced QTc interval prolongation in 
women with multiple TdP risk factors who require therapy with QTc interval-prolonging 
drugs, such as specific antibiotics, antifungal drugs, anti-depressants, antipsychotics, 
methadone, cancer chemotherapy and others. Due to catastrophic outcomes associated 
with TdP, there is a critical need to identify strategies to reduce the risk of drug-induced 
QTc interval prolongation in high-risk patients. The results of this proposed work will 
improve patient outcomes and change clinical practice. 
 
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
     Specific Aims 1&2: Postmenopausal women, based on the following criteria: 
o Age > 50 years AND 
o No menstrual periods for > 365 days 
 
Specific Aims 3&4: Premenopausal women, 21-40 years of age 
 
Exclusion Criteria (apply to all specific aims): 
- 
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: 
o Pitting edema > 2+ 
o Crackles or rales on lung auscultation 
o S3 or S4 heart sounds 
o Unable to climb ³ 2 flights of stairs without becoming short of breath 
- 
Current ECG rhythm of atrial fibrillation or other tachyarrhythmia 


 
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- 
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) 
- 
Peanut allergy 
- 
We will exclude subjects who are currently taking medications that induce or are 
moderate or strong inhibitors CYP 2B6/3A4/3A5 metabolism : 
Carbamazepine 
(tegretol) 
Phenytoin 
Phenobarbital 
Plioglitazone 
(actos) 
Refabutin 
Rifampin 
St Johns Wort 
Troglitazone 
(rezulin) 
 
 
 
Clopidogrel 
(Plavix) 
Ticlopidine 
Voriconazole 
HIV antiviral 
meds 
Verapamil 
Diltiazem 
Suboxone 
Aprepitant 
 
 
 
 
4.0 
Enrollment/Randomization 
 
Subject Recruitment: 
 
Forty volunteer subjects (n=20 postmenopausal women, n=20 premenopausal women) 
will be recruited through 2 methods: 
 
• 
Potential subjects will be recruited through the use of a recruitment database 
maintained through the CTSI InResearch Volunteer research database. Potential 
volunteers who meet inclusion criteria will be contacted via email and will be 
offered the opportunity to participate in this study. 
 
• 
Advertisements will be placed in public locations throughout the IUPUI campus. 
Purdue University Research volunteers website, publications targeted at seniors 
and on the IU Health website asking for volunteers.  Potential subjects will call or 
Email the PI or research coordinator if interested in participating in the study.   
 
During the initial phone call with the potential subject, the investigator will explain the 
purpose of the study, study procedures and risks associated with the study.  If the 
potential subject is interested in participating, the investigator will then ask the potential 
subject specifically about inclusion and exclusion criteria.  If the subject meets all inclusion 
criteria and had no exclusion criteria, the screening visit will be scheduled. A letter will be 
Emailed or sent via US mail to the subject containing the following information: 
• 
Location of the Clinical Research Center  
• 
Brief explanation of the CRC setting and study activities that will take place there 
• 
What subjects should bring with them (their current medications) 
• 
Directions to IU Health University Hospital and to the CRC and where to park 
• 
That they will be given lunch and that their parking will be reimbursed 


 
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• 
A copy of the informed consent form for them to review 
 
Prior to Visit 1, the screening visit, an investigator will telephone, Email or text the subject 
(whichever the subject prefers) to remind them of their visit, review the consent form, 
and answer any questions they may have. This does not constitute the official review ofn 
the consent form with the subject but provides an opportunity to answer questions that 
the subject may have prior to them appearing for the screening visit. 
 
 
 
5.0 
Study Procedures 
 
This study will be performed using a crossover design. Each subject will act as her own 
control.  Subjects will be randomized to the order that they receive either the study 
medication or the placebo.  A random number generator will be used to determine the 
order of randomization.  Subjects will be randomized during their first visit to the 
Indiana Clinical Research Center (ICRC) after informed consent has been obtained. 
 
This study will be conducted at the ICRC. All subjects will undergo a screening visit (visit 
1) that will include obtaining of a 12-lead ECG, performance of a history and physical 
examination, obtaining height and weight, and bloodwork. Using a two-way crossover 
design, each subject will be studied two times, serving as her own control. During each 
phase, subjects will receive a single IV dose of ibutilide 0.003 mg/kg, which will be 
administered by an ICRC nurse.9,10 Each subject will take oral progesterone 400 mg 
orally once daily in the evening, or use matching placebo daily in the evening for 7 
days. The crossover order will be randomized. The study design is summarized below in 
Figure 1: 
 
 
Figure 1. Study design 
 
This study will be conducted with 3 visits: visit one is a screening visit; visits 2 and 3 
includes 7 days of medication self-administration followed by a 10 hour ICRC visit. There 
will be a minimum 14-day washout period between visits 2 and 3. In premenopausal 
women, during each phase, subjects will be studied during the ovulation phase of the 
menstrual cycle.  The ovulation phase is selected for this study rather than the luteal 
phase because, while serum estradiol is similar in the two phases, the natural 
progesterone:estradiol ratio is lower in the ovulation phase.9 In order to time the 
administration of ibutilide and measurement of on-drug QT intervals to the ovulation 
phase, premenopausal women with a typical 28-day menstrual cycle will begin taking 
their study medication on the 5th day of their menstrual period (see Figure 2). For 
women who typically have longer menstrual cycles (30-35 days), study drug therapy will 
be initiated on the 6th or 7th day of their menstrual periods (Figure 2). 
 


 
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Figure 2. Hormone fluctuation during the menstrual cycle. 
 
Visit 1 (Screening visit):  
Subjects will be asked to come to the ICRC at IU Health University Hospital. An 
investigator will review the procedures and risks of the study in detail and obtain written 
informed consent. After written informed consent is obtained, subjects will undergo a 
screening history and physical examination performed by an investigator. Three 12-lead 
ECGs one minute apart (QTc will be averaged across ECGs to determine eligibility), 
height, weight and blood work will be obtained at this time to determine serum 
potassium, magnesium,  liver enzymes, hematocrit. Premenopausal women will undergo 
a urine human chorionic gonadotropin (HCG) test to rule out pregnancy.  
 
Once laboratory results are obtained and the physical is completed and the subject has 
met inclusion criteria and has no exclusion criteria, the subject will be enrolled in the 
study.  If the subject meets any exclusion criteria, they will not be allowed to proceed in 
the study. This process will take approximately 1 hour. 
 
Immediately following the screening history and physical examination, subjects will be 
randomly assigned to two groups:  
 
Group A: (n= 20 subjects) 
Each subject will take two placebo capsules once daily in the evening for 7 days. 
 
Group B: (n= 20 subjects) 
Each subject will take oral progesterone 400 mg orally once daily (two x 200 mg capsules) 
in the evening for 7 days. 
 
Subjects will be sent home with one week’s supply of the study medication to which they 
are initially randomized and a medication diary with which to keep track of when they take 
the medication, any adverse effects they may experience, and any changes in their own 


 
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concurrent medications. They will receive written and verbal instructions about the study 
medication and dates will be established for Visit 2.  
 
Visit 2:  
Prior to the visit subjects will be NPO and remain NPO until 4 hours after the end of the 
ibutilide dosing.  Subjects may drink non-caloric drinks during this period such as coffee, 
tea, diet soda, water ect.  If the serum potassium concentration is low as defined 
previously in the protocol, then the subject may have orange juice or a banana as 
previously defined in the protocol.26,27,28 
 
Two indwelling intravenous catheters will be placed, one in each arm. Blood will be drawn 
to determine serum progesterone, estradiol, and pre-ibutilide potassium and ibutilide 
concentrations. Blood for a serum ibutilide concentration will be obtained prior to 
administration of ibutilide (and therefore will have no detectable ibutilide) will be obtained 
because sometimes the assay lab uses a “blank” serum sample in validation of the assay.  
If any subjects are found to have hypokalemia as defined in the exclusion criteria: 
• 
They will be offered a glass of orange juice and/or a banana. After consuming the 
potassium-containing food, another blood sample for serum potassium 
concentration will be obtained and sent to the laboratory OR 
• 
The subject’s visit will be rescheduled 
If the subject chooses to drink a glass of orange juice and/or eat a banana, and the follow-
up serum potassium concentration is still < 3.6 mEq/L, the subject’s visit will be 
rescheduled, or the subject can withdraw from the study, whichever of those options they 
prefer 
 
Pre-menopausal women will also undergo a urine HCG test to rule out pregnancy prior to 
ibutilide administration. Pre-menopausal women with a positive HCG urine test will be 
withdrawn from the study.  
 
All subjects will receive a single intravenous (IV) dose of ibutilide 0.003 mg/kg, which will 
be administered by an ICRC nurse. The ibutilide dose will be calculated based on the 
subject’s weight during their screening visit. However, subjects will be weighed upon 
arrival at the CRC; if their weight is > 10% different than the weight recorded during their 
screening visit, the weight recorded upon arrival for this visit will be used to calculate the 
ibutilide dose. An MD (Dr. Munro Peacock or his designee) will be notified regarding the 
scheduled time of ibutilide administration. 
 
Continuous ECG monitoring will be initiated prior to ibutilide administration and will 
continue until the post-ibutilide Bazett’s-corrected QT interval is < 450 ms, which generally 
occurs within 2 hours following administration of this low, subtherapeutic dose of ibutilide. 
Three 12 lead ECGs approximately one minute apart (three ECGs within a total of 5 
minutes) will be selected for QT interval measurement before ibutilide administration and 
after ibutilide at: at 5 minutes during infusion, end of infusion, 5, 10, 15, 20, 30 and 45 
minutes and 1, 2, 4, 6, and 8 hours. Blood (6 mL) for determination of ibutilide 
concentrations will be obtained from the indwelling catheter in the arm contralateral to 
that into which ibutilide was infused at approximately the following times (within 5 minutes 
of the times listed) 5 minutes during infusion, the end of infusion, and 5, 10, 15, 20, 30 
& 45 minutes, and 1, 2, 4, 6, and 8 hours following end of infusion. An 8-hour data 


 
13 
Revised: 01/31/2020 
collection and monitoring period is sufficient, as QTc intervals return to baseline within 2-
6 hours.9,10  
 
At the end of this visit, and after a minimum 14-day washout period, subjects will take 
another of the study drugs as follows: 
 
Group A: (n= 20 subjects) 
Each subject will take oral progesterone 400 mg orally once daily (two x 200 mg capsules) 
in the evening for 7 days.   
 
Group B: (n= 20 subjects) 
Each subject will take two placebo capsules once daily in the evening for 7 days. 
 
Subjects will be sent home with one week’s supply of the study medication to which they 
are randomized for this phase and a medication diary with which to keep track of when 
they take the medication, any adverse effects they may experience, and any changes in 
their own concurrent medications. They will receive written and verbal instructions about 
the study medication and dates will be established for Visit 3.  
 
At 3-7 days following the study visit, subjects will be called/texted or emailed based on 
preference to assess for any potential adverse events related to study medications or 
procedures. 
 
Visit 3: 
Prior to the visit subjects will be NPO and remain NPO until 4 hours after the end of the 
ibutilide dosing.  Subjects may drink non-caloric drinks during this period such as coffee, 
tea, diet soda, water ect.  If the serum potassium concentration is low as defined 
previously in the protocol, then the subject may have orange juice or a banana as 
previously defined in the protocol.26,27,28 
 
Two indwelling intravenous catheters will be placed, one in each arm. Blood will be drawn 
to determine serum progesterone, estradiol, and pre-ibutilide potassium and ibutilide 
concentrations. Blood for a serum ibutilide concentration will be obtained prior to 
administration of ibutilide (and therefore will have no detectable ibutilide) will be obtained 
because sometimes the assay lab uses a “blank” serum sample in validation of the assay.  
If any subjects are found to have hypokalemia as defined in the exclusion criteria: 
• 
They will be offered a glass of orange juice and/or a banana. After consuming the 
potassium-containing food, another blood sample for serum potassium 
concentration will be obtained and sent to the laboratory OR 
• 
The subject’s visit will be rescheduled 
If the subject chooses to drink a glass of orange juice and/or eat a banana, and the follow-
up serum potassium concentration is still < 3.6 mEq/L, the subject’s visit will be 
rescheduled, or the subject can withdraw from the study, whichever of those options they 
prefer 
 
Pre-menopausal women will also undergo a urine HCG test to rule out pregnancy prior to 
ibutilide administration. Pre-menopausal women with a positive HCG urine test will be 
withdrawn from the study.  


 
14 
Revised: 01/31/2020 
 
All subjects will receive a single intravenous (IV) dose of ibutilide 0.003 mg/kg, which will 
be administered by an ICRC nurse. The ibutilide dose will be calculated based on the 
subject’s weight during their screening visit. However, subjects will be weighed upon 
arrival at the CRC; if their weight is > 10% different than the weight recorded during their 
screening visit, the weight recorded upon arrival for this visit will be used to calculate the 
ibutilide dose. An MD (Dr. Munro Peacock or his designee) will be notified regarding the 
scheduled time of ibutilide administration. 
 
Continuous ECG monitoring will be initiated 30 minutes prior to ibutilide and will continue 
until the post-ibutilide Bazett’s-corrected QT interval is < 450 ms, which generally occurs 
within 2 hours following administration of this low, subtherapeutic dose of ibutilide. Three 
12 lead ECGs approximately one minute apart (three ECGs within a total of 5 minutes) will 
be selected for QT interval measurement before (time 0) and after ibutilide at: at 5 
minutes during infusion,  end of infusion, 5, 10, 15, 20, 30 and 45 minutes and 1, 2, 4, 6, 
and 8 hours. Blood (6 mL) for determination of ibutilide concentrations will be obtained 
from the indwelling catheter in the arm contralateral to that into which ibutilide infused 
was approximately the following times (within 5 minutes of the times listed)  5 minutes 
during infusion, at the end of infusion, and 5, 10, 15, 20, 30 & 45 minutes, and 1, 2, 4, 6, 
and 8 hours following end of infusion. An 8-hour data collection and monitoring period is 
sufficient, as QTc intervals return to baseline within 2-6 hours.9,10  
 
In addition, blood will be drawn to determine serum progesterone, estradiol, and 
potassium concentrations at the same time as the time 0 ibutilide concentration is drawn.  
If the subjects is found to have hypokalemia as defined in the exclusion criteria, then they 
will be withdrawn from the study.  
 
At 3-7 days following the study visit, subjects will be called/texted or emailed based on 
preference to assess for any potential adverse events related to study medications or 
procedures. 
 
 
Following visit 3, subjects’ participation in the study will be complete. 
 
Serum ibutilide concentrations will be performed in the CPAC Laboratory9,20 and serum 
estradiol and progesterone concentrations will be performed in the IU Health Pathology 
Laboratory.21 In each of the two groups of subjects (postmenopausal women and 
premenopausal women), peak serum ibutilide concentrations and area under the serum 
ibutilide concentration:time curves from 0-1 hours (AUC0-1) be compared across the 
groups to assure no differences that could influence QT intervals. QT intervals will be 
measured by an investigator with vast training and experience in QT interval 
measurement, and who will be blinded to subjects’ assigned treatment groups. Area under 
the effect (AUEC; effect = QT interval) vs time curves from 0-1 hour following ibutilide 
administration (AUEC0-1.17, accounting for the 10-minute ibutilide infusion) and from 0-8 
hours following ibutilide (AUEC0-8.17), indices of QTc interval exposure, will be calculated 
using the linear trapezoidal rule.  
 


 
15 
Revised: 01/31/2020 
In summary, this study will take a total of 15 days to complete, excluding the washout 
periods.  The total study period will take place over a minimum of 15 days.  Each subject 
will need to complete 3 visits, and take a medication for 7 days prior to visits 2 and 3.  The 
first visits involves no drug administration, but simply involves a 1 hour stay in the ICRC 
and includes a screening visit. Then subjects will begin self-administration of study 
medications for 7 days. Visit 2 begins the day after the 7th day of medication 
administration.  During visit 2, the subjects will undergo an approximate 10 hour stay in 
the ICRC. After a minimum of a 14 day washout period, subjects will self-administer study 
medications for 7 days.  Visit 3 begins on the day after the 7th day of medication 
administration.  During visit 3, the subjects will undergo an approximate 10 hour stay in 
the ICRC.  
 
 
Genetic testing: 
Subjects have the option of consenting to a single 10ml blood draw at the time of another 
scheduled blood draw in the study.  This sample with be used for genetic testing. Subjects 
will be genotyped for polymorphisms for an array of relevant genes, including those that 
encode for cytochrome P (CYP) 450 3A5, which is a major contributor to progesterone 
metabolism;3 other CYP enzymes contributing to progesterone metabolism, including 
2C19, 2C9, and 3A4;4 progesterone receptors;5 estrogen receptors; potassium current, 
including hERG and KCNQ1; and calcium current. 
 
Process of obtaining written informed consent: 
 
We will either provide prospective subjects with the informed consent document during 
recruitment or we will send it via Email or regular mail, and we will establish a time to 
review the informed consent document with the subject. Written informed consent will 
be obtained at the beginning of Visit #1, immediately prior to the baseline assessment, 
in a private room at the CRC by the PI or co-investigator prior to the screening exam 
and blood work. 
 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others;  
 
Ibutilide is an antiarrhythmic drug used to terminate atrial fibrillation and flutter.22 
Ibutilide prolongs QTc interval dose-dependently, with a rapid onset and return to 
baseline in 2-6 hours .9,10 Serum ibutilide concentrations decline rapidly, and there are 
no active metabolites. Ibutilide prolongs QT interval via inhibition of IKr and activation of 
slow inward sodium current.23,24 The proposed ibutilide dose (0.003 mg/kg) is 
approximately 20% of the lowest therapeutic dose (1.0 mg), and approximately 10% of 
the highest therapeutic dose (2.0 mg). Ibutilide has been administered safely at this 
dose healthy volunteers (n=58) with no episodes of TdP (Table).9 Further, we recently 
completed a study in premenopausal female volunteers during which n=15 subjects 
safely received this ibutilide dose, each on two separate occasions.10 In addition, 
substantially higher doses of ibutilide (0.7 – 1.0 mg) have been administered to healthy 
volunteers (n=253), with no episodes of TdP (Table).18 
 


 
16 
Revised: 01/31/2020 
The risks associated with this investigation will be minimized by the administration of a 
subtherapeutic dose of ibutilide (0.003 mg/kg, approximately 20% of the lowest 
therapeutic dose, approximately 10% of the highest therapeutic dose). In addition, risks 
will be minimized, in large part, by the exclusion criteria employed, which will allow us to 
exclude patients that are at risk for experiencing excessive QT interval prolongation 
associated with a subtherapeutic dose of ibutilide. Subjects with specific risk factors for 
TdP will be excluded – these risk factors include hypokalemia, hypomagnesemia, 
pretreatment QTc interval > 450 ms, liver disease, NYHA class IV HF, LVEF < 20%, 
history of TdP, and taking other QT interval-prolonging drugs. During the day on which 
ibutilide will be administered, patients will be maintained on continuous ECG telemetry 
monitors until the post-ibutilide Bazett’s-corrected QT interval is < 450 ms, which 
generally occurs within 2 hours following administration of this low, subtherapeutic dose 
of ibutilide. Ibutilide will be administered in the ICRC which is housed within University 
Hospital and has full medical services if needed in the case of an emergency.  There is a 
cardiac arrest (code) cart in the CRC that includes magnesium sulfate. A physician 
investigator (or his designee) will be notified regarding the planned time of 
administration of ibutilide administration.  Subjects will not be discharged from the ICRC 
if they have a QTc interval of > 450ms after treatment.  They will be monitored until the 
QTc interval is below 450ms. This study has a DSMB to periodically monitor the safety 
and any adverse events which may occur.  
 
In all of the published literature, the overall incidence of TdP associated with ibutilide is 
2.0%. TdP has never been reported at the dose that we propose to administer in this 
study. The lowest dose of ibutilide that has ever been associated with TdP in the 
published literature is 0.5 mg, and there has only been one reported case at this dose. 
That is more than double the dose that we propose to administer. In order to achieve 
this dose in our study, a patient would have to weight 166 kg (based on our dose of 
0.003 mg/kg). No subject in this study will receive a dose as high as 0.5 mg, because 
we have an upper weight exclusion of 135 kg. Therefore, this risk of TdP in our 
volunteer subjects, at a low dose of 0.003 mg/kg (roughly 20% of the lowest clinical 
dose), is extremely low, and again, TdP has never been reported at this low dose. 
 
 
 
Oral progesterone 400 mg once daily is the dose that was effective for attenuating drug-
associated QTcI interval response in premenopausal women. Oral progesterone 400 mg 
daily has been administered to pre-menopausal women with minimal adverse events 
including abdominal cramping, nausea, vomiting, mood disturbances and menstrual 
spotting or bleeding following withdrawl of the medication.  Subjects will be monitored 
via phone calls throughout the dosing period and advised to discontinue the medication 
if adverse events become intolerable. 
 
Risks related to the blood draws and intravenous catheter placement will be minimized 
through the use of experienced staff placing the intravenous catheter.  Subjects will be 
evaluated for anemia prior to inclusion in order to minimize the risk of anemia due to 
blood draws. 
 
 


 
17 
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Safety Monitoring 
 
 
Any serious or unexpected adverse event will be reported to the Research and 
Sponsored Programs Committee on the IUPUI campus within 3 working days of 
notification of the event.  A written report of the adverse event will also be submitted.  
Any Serious Adverse Event (SAE) that is observed during the study or within 30 days 
after administration of ibutilide will be recorded and reported to the SAE contact 
investigator. The SAE contact investigator will serve as the chair for the Data and Safety 
Monitoring Board (DSMB).   
 
A Data Safety & Monitoring Board (DSMB) has been established for this study. The 
DSMB will be chaired by Sara Quinney, PharmD, PhD, Assistant Professor of Obstetrics & 
Gynecology, School of Medicine, Indiana University. The other members of the DSMB 
are: 
• Noll Campbell, PharmD, Assistant Professor, College of Pharmacy, Purdue 
University, and Faculty Associate, Center on Aging and Life Course. Dr. Campbell 
has substantial experience in clinical research studies, and was recently awarded 
an NIH R01 as principal investigator for a large clinical investigation 
• John Hertig, PharmD, Associate Professor, College of Pharmacy and Health 
Sciences, Butler University. Dr. Hertig previously was Associate Director of the 
Center for Medication Safety Advancement at Purdue University, and has 
extensive experience in assessing patient safety. 
. The designated DSMB will be responsible for notifying the Sponsored Programs 
Committee in the time specific time allotted from above. 
 
 
Study/Data Monitoring 
 
The following documents will be on file in the primary investigators office before patient 
enrollment: 
 
Copy of the IU IRB/Ethics Committee approval of the protocol and consent; 
 
Copy of the IRB approved informed consent; 
 
A pre-study start meeting will take place to ensure that investigators and other essential 
personnel are aware of the protocol requirements for ibutilide administration and data 
collection.   
 
The DSMB will meet after 1/4 (n=10) of the study subjects have completed the study, 
after ½ of the study subjects have completed the study (n=20), and after ¾ (n=30) of 
the study subjects have completed the study. The DSMB will monitor subject 
recruitment, accrual, retention, adverse event data, results of related studies that may 
impact subject safety, and procedures designed to protect the privacy of subjects. The 
DSMB will analyze and interpret data submitted by the principal investigator. In the 
unlikely event that a subject experiences an ibutilide-associated arrhythmia, the DSMB 
will determine whether the study should continue or should be suspended. 
 
Data from the study will be monitored continuously throughout the study and will be 
reviewed at each DSMB meeting. 


 
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Revised: 01/31/2020 
Definitions (ICH Guideline on Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting and FDA Regulation 21 CFR 312.32, Final Rule 
October 7,1997) 
• 
Adverse Event: Any untoward event, which occurs regardless of its 
causality, including and side effect, injury, toxicity or sensitivity reaction 
during testing of protocol treatments (whether or not considered drug-
related), will be designated as an adverse clinical event. 
• 
Serious Adverse Event: An event that is fatal, life-threatening, or leads to 
persistent or significant disability; one that requires or prolongs 
hospitalization; or one that results in a congenital anomaly, or significant 
medical event. 
• 
Unexpected Adverse Event: Any adverse event not identified in nature, 
severity, or frequency in current package label for ibutilide or product 
information. 
• 
Adverse events will be defined as any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure that may or may 
not be considered related to the medical treatment or procedure. (NCI 
definition). The level of severity of an adverse event will be based on a 
grading scale which is adopted from the NCI Common Terminology Criteria 
for Adverse Events: Grade 1, Mild AE; Grade 2, Moderate AE; Grade 3, 
Severe AE; Grade 4, Life threatening or disabling AE; Grade 5, death related 
to AE. For prolonged QTc interval Grade 1, QTc>0.48-0.50 seconds; Grade 2, 
QTc >0.50 seconds and/or increase in QTc ³0.06 seconds above baseline; 
Grade 3, QTc >0.55 seconds; Grade 4, QTc >0.60 seconds and/or life-
threatening signs or symptoms (e.g., arrhythmia, CHF, hypotension, shock, 
syncope) and/or torsades de pointes; Grade  
5, Death. 
 
Ethical Aspects of the Proposed Research 
 
The minimum possible number of subjects is proposed, based on sample size 
calculations. Progesterone 400 mg orally daily was associated with no reported adverse 
effects.18 In our study,10 adverse effects associated with progesterone were primarily 
fatigue/malaise. Therefore, risks associated with oral progesterone appear minimal. 
Subjects will be carefully screened and a through physical examination will be performed 
prior to initiation of the protocol. Extensive exclusion criteria have been included to 
minimize the risk of adverse effects to subjects enrolled in the study.   
 
Safety measures have been put into place to minimize the potential risks in this study, 
and the results of this study may provide benefit to society by enhancing patient safety. 
 
DSMB Safety Monitoring 
 
A Data Safety & Monitoring Committee (DSMB) has been established for this study.  
The DSMB will monitor subject recruitment, accrual, retention, adverse event data, 
results of related studies that may impact subject safety, and procedures designed to 
protect the privacy of subjects. The DSMB will analyze and interpret data submitted by 


 
19 
Revised: 01/31/2020 
the principal investigator. In the unlikely event that a subject experiences an ibutilide-
associated arrhythmia, the DSMB will determine whether the study should continue or 
should be suspended. During the anticipated two and a half-year duration of the study, 
the DSMB will meet after 1/4 (n=10) of the study subjects have completed the study, 
after ½ of the study subjects have completed the study (n=20), and after ¾ (n=30) of 
the study subjects have completed the study. 
 
The IRB will receive information regarding frequency and dates of monitoring, summary 
of cumulative adverse events, assessment of external factors, including scientific 
reports, therapeutic developments, & results of related studies that could impact subject 
safety, summaries of subject privacy and research data confidentiality outcomes, and 
any changes to the risk: benefit ratio. 
 
7.0 
Study Withdrawal/Discontinuation 
 
Subjects may withdraw from the study at anytime during the study.  If a subject wishes 
to withdraw from the study, he/she may call the principal investigator and withdraw 
himself/herself from the study. The subject will receive compensation for their time up 
to the period of withdrawal.  
 
The principal investigator may withdraw a subject from the study for the following 
reasons: a change in the subject’ medical condition resulting in an increased risk profile, 
change in any inclusion or exclusion criteria for the subject, or subject unwilling or 
unable to complete part of the protocol as stated.  If the PI determines that a subject 
needs to be withdrawn from the study, he will contact the subject by phone and also in 
writing.  The subject will receive compensation for any part of the study that he/she has 
completed.   
 
8.0 
Statistical Considerations 
 
Statistical analysis will be performed separately for the two subject populations: 
• 
Postmenopausal women (progesterone vs placebo) 
• 
Premenopausal women (progesterone vs placebo) 
 
QT intervals will be corrected for heart rate using two correction methods, the Fridericia 
(QTF) and Framingham (QTFra) methods.  
 
Study Endpoints:  Comparison of progesterone and placebo phases for: 1) Baseline (pre-
ibutilide) maximum QTF & QTFra 2) Ibutilide effect on maximum QTF & QTFra, 3) Ibutilide 
effect on maximum % change in QTF & QTFra, and 4) Ibutilide effect on AUEC0-1.17 and 
AUEC0-8.17. Endpoints will be correlated with progesterone concentrations. 5)  
 
Statistical analyses: Means (standard deviations) or medians (interquartile range) will be 
presented for continuous variables. Distribution normality will be assessed using the 
Kolmogorov-Smirnov test. Paired t-test (if normality holds) or signed-rank rest (if 
normality does not hold) will be used to compare outcome measures between the two 
treatment phases; 95% confidence intervals will be calculated. SAS 9.4 (Cary, NC) will be 


 
20 
Revised: 01/31/2020 
used. Correlations between the primary endpoints and serum progesterone concentrations 
will be performed using Pearson’s correlation coefficient.  
 
Anticipated Outcomes: During the progesterone phase, the following outcome measures 
will be significantly lower than vs placebo: 1) Pre-ibutilide QTF and QTFra; 2) Post-
ibutilide maximum QTF and QTFra; 3) AUEC 1 hour and 8 hours after ibutilide; 4) Post-
ibutilide % change in maximum QTF and QTFra, 5) J-Tpeak and Tpeak-Tend. 
 
Sample Size Calculation:  In this 2-way crossover study, at a two-sided α level of 0.05 and 
a power of 0.80, a sample size of 20 subjects in the postmenopausal population and n=20 
subjects in the premenopausal population will be sufficient to detect a difference in 
maximum QTF and QTFra of 15 ms, assuming a QTF and QTFra interval prolongation of 
24±12 ms associated with ibutilide in the absence of progesterone.  
 
9.0 
Privacy/Confidentiality Issues 
 
All ECGs will be collected using a standard ECG machine, on which the ECG data are 
collected on paper. This information will not contain the patients’ names, just an unique 
identifier.  Blood samples will be collected and maintained in a locked laboratory freezer, 
they will not contain the patients’ names, just an unique identifier.  Medical information, 
such as laboratory and echocardiogram information will be stored on a password protected 
computer database containing only an unique identifier.  All information linking the 
patient’s name and health information to the unique identifier will be stored in a locked 
cabinet in the study coordinator’s office. All this information will not be stored 
electronically. Information on the password protected computer database will only be 
accessed by the investigators.  All information with unique identifiers will be locked in the 
study coordinator’s office or laboratory, or on a password protected computer.  To assure 
study coordinator’s office is physically secure, it is located on the 3th floor of the FTB 
Faculty Office Building at Eskenazi Medical Center, which requires authorized entry. 
Furthermore, the study coordinator’s office remains locked and any information that can 
be used to identify patients will be kept in a locked cabinet and not stored electronically. 
All study documentation will be stored for a minimum of seven years after completion of 
the study.  All paper documentation will be shredded and electronic files deleted.  
 
There will be paper copies of spreadsheet for the purpose of statistical analysis, 
pharmacokinetic and pharmacodynamic analysis shared with the co-investigators involved 
in the analysis, however, the unique identifier will be the only information that is available 
on the spreadsheets.  The information linking the unique identifier to the patient will be 
kelp in a locked cabinet in the study coordinator’s office.  
 
 
Safeguards used to protect the confidentiality and security of health 
information 
 
Any information that is gathered about these patients will be kept confidential and any 
information that is generated on a patient will does not ultimately participate in the 
study will be destroyed immediately. 
 


 
21 
Revised: 01/31/2020 
All ECGs will be collected using digital ECG recordings. Information entered will not 
contain the patients’ names, just a unique identifier.  Blood samples will be collected and 
maintained in a locked laboratory freezer, they will not contain the patients’ names, just 
a unique identifier.  Medical information, such as laboratory information will be stored on 
a password protected computer database containing only a unique identifier.  All 
information linking the patient’s name and health information to the unique identifier will 
be stored in a locked cabinet in Dr. Tisdale’s office. All this information will not be stored 
electronically. Information on the password protected computer database will only be 
accessed by the investigators.  All information with unique identifiers will be locked in 
the study coordinator’s office or laboratory, or on a password protected computer.  To 
assure the study coordinator’s office is physically secure, it is located on the 3th floor of 
the FTB Faculty Office Building at Eskenazi Medical Center, which requires authorized 
entry. Furthermore, the study coordinator’s office remains locked and any information 
that can be used to identify patients will be kept in a locked cabinet and not stored 
electronically. All study documentation will be stored for a minimum of seven years after 
completion of the study.  All paper documentation will be shredded and electronic files 
deleted.  
 
 
There will be paper copies of spreadsheet for the purpose of statistical analysis and will 
be shared with the co-investigators involved in the analysis, however, the unique 
identifier will be the only information that is available on the spreadsheets.  The 
information linking the unique identifier to the patient will be kelp in a locked cabinet in 
the study coordinator’s office.  
 
Discuss the methods for ensuring participant privacy, and the methods for protecting 
privacy and confidentiality. 
 
10.0 
Follow-up and Record Retention 
 
The estimated time frame for completion of this study is 24 months.  All identifiable data 
(informed consents) will be stored in a locked filing cabinet in the PI or study 
coordinator’s office behind a locked door with limited access.  All electronic data will be 
stored on a password protected computer in the same location.  Data will be stored a 
minimum of 7 years per Indiana State Law.  All ECGs, clinical assessment data, 
laboratory data and blood samples will be de-identified at the time of data collection.  
List the duration of the study.  List the duration of record retention and the method for 
destruction or the possibility of indefinite archiving of information. 
 
 
 
 
 


 
22 
Revised: 01/31/2020 
 
 
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2017-0054. 
 
 
 
 
 
 


 
26 
Revised: 01/31/2020 
 
Appendix. Incidence of Ibutilide-Associated Torsades de Pointes in Published Literature 
Paper 
n 
Population 
Ibutilide 
0.003 mg/kg 
Dose for our 
study – 0.21 
mg in a 70 
kg person 
Ibutilide 
0.25 mg 
Ibutilide 
0.5 mg 
Ibutilide 
0.005 
mg/kg 
Ibutilide 
0.7 mg 
Ibutilide 
1.0 mg x 1 
Ibutilide 
1.0 mg x 1 
then 0.5 
mg x 1 
Ibutilide 
0.025 
mg/kg 
Ibutilide 
1.0 mg x 
2 
Total 
incidence, 
all doses 
combined 
Guo, J Am 
Coll Cardiol 
1996 
n=8 ibutilide 
two x 1 mg 
n=4 ibutilide 
1 x 1.0 mg 
then 1 x 0.5 
mg 
n=13 
ibutilide 1.0 
mg 
n=10 placebo 
Spontaneous 
sustained 
a.flutter 
-- 
-- 
-- 
 
 
0/13 
0/4 
 
0/8 
 
Stambler Am 
J Cardiol 
1996 
N=18 
ibutilide 
N= 11 
placebo 
Patients with 
atrial flutter 
 
 
 
0/2 
0/1 
0/2 
0/4 
0/3 
0/3 
 
Ellenbogen J 
Am Coll 
Cardiol 1996 
N=157, dose-
ranging 
N=41 
placebo 
Patients with 
AF or atrial 
flutter 
-- 
 
1/42 
(2.4%) 
(n=1)¶ 
 
2/39 
(5.1%)§ 
1/39 
(2.6)% 
 
1/39 
(2.6%) 
 
 
Stambler 
Circulation 
1996 
N=79, 
ibutilide 1.0 
mg then 0.5 
mg 
N=82, 
ibutilide 1.0 
mg then 1.0 
mg 
N=81, 
placebo 
Patients with 
AF or a. flutter 
-- 
-- 
-- 
 
-- 
11/161 
(6.8%) 
2/144 
(1.4%) 
 
2/144 
(1.3%) 
 


 
27 
Revised: 01/31/2020 
Vanderlugt 
Circulation 
1999 
2.0 mg – 70 
1.0 mg – 73 
0.5 mg – 75 
Placebo - 84 
Post-CABG 
AF conversion 
-- 
0 
0 
 
 
2/70 
(2.9%)* 
 
 
2/70 
(2.9%)* 
 
Stambler Am 
J Cardiol 
1997 
Ibutilide 1 
mg - 12 
Ibutilide 2 
mg - 12 
Placebo - 12 
Patients with 
or without HF 
-- 
-- 
-- 
 
 
 
 
 
0/12 – 
no HF 
1/12 
(8.5%) – 
with HF 
 
Oral NEJM 
1999 
N = 64, 
Ibutilide 
N=36, 
placebo 
Patients with 
AF undergoing 
DCC 
-- 
-- 
-- 
 
-- 
2/64 
(3.1%)‡ 
-- 
 
-- 
 
Glatter 
Circulation 
2001 
n=70 
Elective 
conversion of 
AF – also on 
amio 
-- 
-- 
-- 
 
 
-- 
 
 
1/70 
(1.4%) 
 
Rodriguez 
JAMA 2001 
n=58 
Young healthy 
volunteers (38 
men, 20 
women) – 
received 3 
doses in 
crossover 
fashion 
0/58 
-- 
-- 
 
 
-- 
 
 
-- 
 
Gowda Am J 
Ther 2003 
n=52 – two x 
1 mg  
n =6 – 1 x 1 
mg 
Patients with 
new-onset AF 
or a.flutter 
-- 
-- 
-- 
 
 
0/6 
 
 
4/52 
(7.7%) 
 
Giudici, J 
Cardiovasc 
Nurs 2008 
n=238, 
retrospective 
study 
 
-- 
-- 
-- 
 
 
4/238 
(1.7%) 
 
 
-- 
 
Kannankeril, 
Heart 
Rhythm 
2011 
N=253  
Ibutilide 10 
mcg/kg up to 
total dose of 
1 mg 
Healthy 
volunteers 
aged 18-40 
-- 
-- 
0 
 
-- 
0/253 
 
 
-- 
 


 
28 
Revised: 01/31/2020 
 
 
*patients with torsades had reduced LVEF 
 ¶This patient had NYHA class II HF with decreased LVEF 
§These 2 patients had NYHA class III HF with LVEF 45% and NYHA class II HF with LVEF 30% 
Tisdale, J 
Clin 
Pharmacol 
2012 
N=15 
Patients with 
AF  
N=6 had 
decreased 
LVEF 
-- 
-- 
-- 
 
 
0/6 
 
 
-- 
 
Tisdale JE et 
al, JACC 
Clin EP 
2016;2:765-
774 
N=19, 
randomized 
crossover 
(n=31 doses 
of ibutilide 
0.003 mg/kg) 
Healthy 
premenopausal 
female 
volunteers 
during menses 
phase 
0/31 
 
 
 
 
 
 
 
 
 
Muensterm
an 
Tomaselli E, 
Tisdale JE, 
et al. 
Circulation 
2018 
(anstract: in 
press) 
n=14, 
randomized 
3-way 
crossover 
(n=42 doses 
of ibutilide 
0.003 mg/kg) 
Men ³ 65 
years of age 
0/42 
 
 
 
 
 
 
 
 
 
Tisdale JE, 
et al. 
Circulation 
2018 
(abstract; in 
press) 
n=20, 
randomized 
parallel 
(n=20 doses 
of ibutilide 
0.003 mg/kg) 
n=10 subjects 
with HFpEF 
n=10 matched 
control 
subjects 
0/20 
 
 
 
 
 
 
 
 
 
Total in all 
studies 
 
 
0/151 
0% 
incidence at 
dose used in 
our studies 
0/252 
1/42 
0/2 
2/40 
20/852 
(2.3%) 
2/152  
(1.3%) 
1/42 
(2.4%) 
10/371 
(2.7%) 
36/1,904 
(1.9%) 


 
29 
Revised: 01/31/2020 
‡both patients had LVEF < 20% 
Other data: 
Gowda, et al - Am J Ther 2002 – 4 cases of ibutilide-induced TdP – two doses of 1.0 mg (n=3), one dose of 1.0 mg (n=1) 
 
 
 


 
30 
Revised: 01/31/2020 
Investigators’ Experience Administering Intravenous (IV) Ibutilide 0.003 mg/kg 
 
In our studies to date, we have administered n=118 doses of IV ibutilide 0.003 mg/kg to study volunteers. This has resulted in: 
 
• n=0 occurrences of torsades de pointes 
• n= 0 occurrences of ventricular tachyarrhythmias of any kind 
• n=2 (1.7%) instances of transient QTc interval > 500 ms. In both cases, the QTc interval declined to < 500 ms within a couple 
of minutes, and rapidly declined to < 450 ms shortly thereafter