Conditions: Long QT Syndrome
Keywords: Torsades de pointes Testosterone Progesterone Clinical trial Risk reduction Electrocardiography
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 14
Healthy volunteers: yes

Brief summary:
Torsades de pointes (TdP) is a potentially fatal ventricular arrhythmia associated with corrected QT (QTc) interval prolongation. More than 50 commonly used drugs available on the US market may cause QTc interval prolongation and TdP. While TdP occurs more commonly in women, 33-45% of all cases of TdP have occurred in men. Older age is a risk factor for drug-induced TdP in men, possibly due to declining serum testosterone concentrations. Available evidence shows an inverse relationship between QTc intervals and serum testosterone concentrations. In addition, experimental data, including those from the investigators' laboratory, suggest that both exogenous testosterone or progesterone administration may be protective against prolongation of ventricular repolarization and TdP. Specific Aim: Establish the influence of transdermal testosterone administration and oral progesterone administration as preventive methods by which to diminish the degree of drug-induced QT interval prolongation in men 65 years of age or older. Hypothesis: Transdermal testosterone administration and oral progesterone administration both effectively attenuate drug-induced QT interval response in older men. To test this hypothesis, transdermal testosterone, oral progesterone or placebo will be administered in a 3-way crossover study to men 65 years of age or older. QTc interval response to low-dose ibutilide will be assessed. The primary endpoints will be Fridericia-corrected QT interval (QTF) response to ibutilide, in the presence and absence of testosterone, and in the presence or absence of progesterone: 1) Effect on pre-ibutilide QTF, 2) Effect on maximum post-ibutilide QTF, 3) Effect on % change in post-ibutilide QTF, and 2) Area under the QTF interval-time curves.

Detailed description:

Arms:
arm 1: Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days arm 2: Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo ( 2 capsules) once daily every morning x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. arm 3: Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days arm 4: Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. arm 5: Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. arm 6: Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days. After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days. After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.

Interventions: intervention 1: Testosterone intervention 2: Progesterone intervention 3: Placebo intervention 4: Ibutilide
Intervention descriptions: intervention 1: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days intervention 2: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days intervention 3: Subjects will receive placebo transdermal gel and placebo (lactose) capsules intervention 4: Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

Protocol document:
Prot_SAP_001.pdf: 
1 
 
Influence of Testosterone Administration On 
Drug-Induced QT Interval Prolongation and 
Torsades de Pointes 
 
James E Tisdale PharmD, FCCP, FAPhA, FAHA 
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 
 
 
IRB-approved on July 10, 2017 
 
NCT#02513940 
 
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 
 
Indiana University 
 
David Flockhart, MD, PhD,  
Professor and Head 
Division of Clinical Pharmacology 
Indiana University School of Medicine 
 
Richard Kovacs MD, Professor 
Cardiologist 
Krannert Institute of Cardiology 
Indiana University School of Medicine 
 
Elena Tomaselli Muensterman, PharmD 
Graduate Student 
Department of Pharmacy Practice 
College of Pharmacy 
Purdue University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
 
 
 
 
 
 
 
 
 
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 
 
 


4 
 
1.0 
Background 
 
Torsades de pointes (TdP) is a ventricular arrhythmia associated with corrected QT (QTc) 
interval prolongation. Acquired TdP is most commonly cause by drugs, and over 50 FDA-
approved medications may cause this adverse event. TdP results in catastrophic 
outcomes, including sudden cardiac death. The risk of drug-induced TdP is lower in men 
than in women, due largely to the protective effect of testosterone. However, 29-46% of 
all reported cases of drug-induced TdP have occurred in men. Older age is an independent 
risk factor for TdP in men, likely as a result of declining testosterone concentrations. 
Methods to reduce the TdP risk in older men requiring therapy with QTc interval-prolonging 
drugs have not been developed. Evidence by our group suggests: 1) Testosterone 
administration may be protective against TdP, and 2) Oral progesterone attenuates drug-
induced QTc interval lengthening in premenopausal women. The efficacy of exogenous 
testosterone or progesterone for attenuating drug-induced QTc interval lengthening in 
older men has not been studied. Identifying effective means of attenuating drug-induced 
QTc interval lengthening will improve medication safety in older men requiring therapy 
with QTc prolonging drugs. 
 
The risk of drug-induced QTc interval prolongation and torsade de points is lower in men 
than women.1-7 Ventricular repolarization occurs more rapidly in men, manifested by 
shorter QTc intervals.8 This difference in QTc intervals becomes apparent only after 
puberty,9 suggesting that changes in serum sex hormone concentrations are responsible. 
Post-pubertal differences in QTc intervals may be largely due to reduction in QTc intervals 
in males as a result of testosterone production. In isolated perfused heart models, 
including work by our group, DHT shortens ventricular APD and attenuates the QTc interval 
prolonging effects of quinidine.10,11  
 
However, while female sex is a risk factor for drug-induced TdP, 29-46% of all reported 
cases have occurred in men. In reports of erythromycin-associated cardiac arrhythmias 
from 1970-1996, 32% of the cases occurred in men.3 In an analysis of all published cases 
of TdP associated with noncardiac drugs, 29% occurred in men.12 Of 100 cases of 
cisapride-associated TdP reported to the FDA, for which patient sex was specified, 30% 
occurred in men.13 Nearly half (46%) of reported cases of azimilide-induced TdP occurred 
in men,14 while 40% of cases of terfenadine-associated TdP occurred in men.4 Similar 
percentages have been reported regarding TdP associated with halofantrine (40% of 
cases in men)15 and quinidine (34% in men).1 Therefore, a substantial proportion of drug-
induced TdP cases occur in men.  
 
The risk of drug-induced TdP in men 55-65 years of age is > 3x higher than in those 45-
55 years, and increases in subsequent decades of age.14 Our group and others have shown 
that older age is an independent risk factor for QTc interval prolongation and TdP in both 
sexes.16-20 In men, this may be partly due to declining serum testosterone/DHT 
concentrations.21,22 There is an inverse relationship between serum testosterone 
concentrations and QT intervals.22 Testosterone is associated with reducing QT 
intervals23,24 and protects against QTc interval prolongation induced by inhibition of 
potassium (K+) conductance.10,11,25 DHT administration attenuates dofetilide-associated 
ventricular APD lengthening and inhibits early afterdepolarizations.26 Declining serum 
testosterone, therefore, may be responsible for the increase in risk of drug-induced TdP 


5 
 
in older men.  However, the influence of testosterone/DHT on the incidence of drug-
induced TdP has never been studied.  
 
In women, QTc interval and TdP risk fluctuate throughout the menstrual cycle and during 
pregnancy.25,27 The QTc interval is shorter during the luteal phase than in the follicular 
phase,27 and ibutilide-induced QTc interval response is greatest during menses and 
ovulation.25 There was no relationship between serum estradiol concentrations and QTc 
interval response, but there were significant inverse correlations between serum 
progesterone concentrations and QTc interval25 and between progesterone:estradiol ratio 
and ibutilide-induced QTc interval response, suggesting that progesterone may protect 
against drug-induced QTc lengthening.25 Progesterone is protective effects against QTc 
interval prolongation and arrhythmias associated with the long-QT syndrome.25,28-30 
Progesterone’s structure is androgenic, and progesterone is a testosterone precursor 
during testosterone synthesis in testicular Leydig cells.31 Our data indicates that oral 
progesterone administration attenuates drug-induced QTc interval lengthening in healthy 
premenopausal female volunteers with low endogenous serum estradiol and progesterone 
concentrations.  
 
In view of the above data indicating that older men are at greater risk of drug-induced 
TdP than younger men, that this may be due to declining serum testosterone 
concentrations, and that testosterone exerts protective effects against QTc interval 
lengthening and TdP, we hypothesize that exogenous administration of testosterone 
attenuates drug-induced QTc interval lengthening in older men and reduces the risk of 
TdP. Further, in view of our preliminary data suggesting that progesterone attenuates 
drug-induced QT interval lengthening in premenopausal women and may reduce TdP risk, 
we hypothesize that these findings may extend to older men, and that oral progesterone 
administration attenuates drug-induced QTc interval lengthening in older men.  
 
2.0 
Rationale and Specific Aims 
 
Establishing the influence of exogenous testosterone or progesterone administration as 
preventive methods to reduce the risk of TdP may lead to important advances in 
proarrhythmia risk reduction. Patients at high risk of drug-induced TdP who require 
therapy with a QTc interval-prolonging drug could be pre- or concomitantly treated with 
transdermal testosterone or oral progesterone. Treatment with these exogenous 
hormones could provide additional protection against potentially fatal arrhythmias; this 
hypothesis requires testing in subsequent studies. 
 
Our long-term goal is to determine mechanisms by which drugs cause arrhythmias, to 
identify risk factors for drug-induced arrhythmias, and to determine safe and effective 
methods of prevention and management of drug-induced arrhythmias. The objectives in 
this application are to evaluate and compare the efficacy of novel therapeutic approaches 
to reduce the risk of drug-induced QTc interval prolongation and TdP. Our central 
hypothesis is that acquired QTc interval prolongation and the risk of TdP are attenuated 
by exogenous testosterone or progesterone administration. To test this hypothesis, we 
propose the following specific aims:  
 


6 
 
Specific Aim: Determine the efficacy of exogenous testosterone and 
progesterone administration as preventive methods by which to diminish the 
degree of drug-induced QT interval lengthening in older men. 
Working hypothesis: Transdermal testosterone administration and oral progesterone 
administration are both effective strategies for attenuation of drug-induced QTc interval 
response in older men. To test this hypothesis, transdermal testosterone, oral 
progesterone or placebo will be administered in a three-way crossover study in men ≥ 65 
years of age. QT interval response to ibutilide will be assessed.  
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
     - Men ≥ 65 years of age 
 
Exclusion Criteria: 
- 
Prostate cancer; history of prostate cancer;  
- 
History of breast cancer; benign prostatic hypertrophy;  
- 
Weight < 60 kg 
- 
Weight > 135 kg 
- 
Serum k+ < 3.6 mEq/L;  
- 
Serum mg2+ < 1.8 mg/dL;  
- 
Hemoglobin < 9.0 mg/dL;  
- 
Hematocrit < 26%;  
- 
Hepatic transaminases > 3x upper limit of normal;  
- 
Baseline Bazett’s-corrected QT interval > 450 ms  
- 
Heart failure due to reduced ejection fraction (left ventricular ejection fraction < 
40%) 
- 
Family or personal history of long-QT syndrome, arrhythmias or sudden cardiac 
death;  
- 
Concomitant use of any QT interval-prolonging drug. 
- 
Permanently paced ventricular rhythm  
 
4.0 
Enrollment/Randomization 
 
Subject Recruitment: 
 
Fifteen volunteer subjects 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 
and on the IU Health website asking for volunteers.  Potential subjects will call 
the PI or research coordinator at 317-880-5410 if interested in participating in 
the study.   
 


7 
 
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 baseline visit will be scheduled. 
 
5.0 
Study Procedures 
 
This study will be performed using a crossover design. Each subject will act as his 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 physical 
examination and bloodwork. Using a three-way crossover design (Figure 1), each subject 
will be studied three times, serving as his own control. During each phase, subjects will 
receive a single IV dose of ibutilide 0.003 mg/kg, diluted in normal saline 20 mL and 
infused over 10 minutes.25 Each subject will apply testosterone gel 1% (Androgel®) 100 
mg once daily in the morning applied to the intact skin of the upper shoulders or arms, 
take oral progesterone 400 mg orally once daily, or use dual-matching placebo 
for 7 days. The crossover order will be randomized. 
 
 
This study will be conducted with 4 visits: visit one is a baseline assessment with ECGs; 
visits 2, 3 and 4 includes 7 days of medication self-administration followed by a 10 hour 
ICRC visit. There will be a 4-week washout period between visits 2 and 3 and between 
visits 3 and 4. 
 
Visit 1:  
Subjects will be asked to come to the ICRC at IU Health University Hospital (IUHUH). After 
informed consent is obtained, subjects will undergo a screening history and physical 
examination performed by a physician co-investigator or his designee and blood work will 
be obtained at this time to determine serum potassium, magnesium, creatinine, liver 
enzymes, hemoglobin, hematocrit.  Once laboratory results are obtained and the physical 
Figure 1, Experimental Design 


8 
 
is completed and the subject has met inclusion criteria and has no exclusion criteria, the 
subject will be enrolled in the study.  This process will take approximately 1 hour. 
 
At visit 1, prior to randomization, each subject will undergo 10 hours of continuous ECG 
recordings using 12-lead (Mason-Likar electrode configuration) digital ECG recorders 
(SEER MC 2.0; GE Healthcare, Milwaukee, WI) to calculate QTcI.32 Subjects will perform 
4 postural provocative tests: supine (10 min), unsupported motionless sitting (10 min), 
unsupported motionless standing (15 min) and supine (10 min), to ensure broad heart 
rate ranges.32 Repeated (5x) 10-second 12-lead ECG segments will be extracted from 
recordings obtained during these tests. Also, 10-second 12-lead ECG segments will be 
selected every 30 minutes over 10 hours. QT and RR intervals will be used to determine 
each subject’s QTcI using the parabolic model33 QT = β•RRα as described. The QTF will 
also be calculated and analyzed.34 
  
Immediately following the screening history and physical examination, subjects will be 
randomly assigned to three groups:  
 
Group A: (n= 5 subjects) 
Each subject will apply testosterone gel 1% (Androgel®) 100 mg once daily in the 
morning applied to the intact skin of the upper shoulders or arms and will take a placebo 
capsule once daily in the evening for 7 days. 
Group B: (n= 5 subjects) 
Each subject will take oral progesterone 400 mg orally once daily in the evening and apply 
placebo gel once daily in the morning applied to the intact skin of the upper shoulders or 
arms for 7 days. 
Group C: (n= 5 subjects) 
Each subject will take one placebo capsule once daily in the evening and apply placebo 
gel once daily in the morning applied to the intact skin of the upper shoulders or arms for 
7 days. 
 
Visit 2:  
All subjects will receive a single intravenous (IV) dose of ibutilide 0.003 mg/kg, diluted in 
normal saline 20 mL and infused over 10 minutes. 
 
Continuous ECG recording will be initiated 30 minutes prior to ibutilide and continue for 8 
hours after ibutilide administration. Three 12 lead ECGs one minute apart will be selected 
for QT interval measurement before (time 0) and after ibutilide at: 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 before ibutilide administration, at the end of 
infusion, and 5, 15, 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.25  
 
In addition, blood will be drawn to determine serum progesterone, testosterone, 
magnesium and potassium concentrations at the same time as the time 0 ibutilide 
concentration is drawn.  If the subjects is found to have hypokalemia or hypomagnesia 
as defined in the exclusion criteria, then they will be withdrawn from the study.  
 


9 
 
At the end of this visit, and after at least a 2-week washout period, subjects will take 
another of the study drugs as follows: 
 
Group A: (n= 5 subjects) 
Each subject will take one placebo capsule once daily in the evening and apply placebo 
gel once daily in the morning applied to the intact skin of the upper shoulders or arms   
Group B: (n= 5 subjects) 
Each subject will apply testosterone gel 1% (Androgel®) 100 mg once daily in the 
morning applied to the intact skin of the upper shoulders or arms and will take a placebo 
capsule once daily in the evening for 7 days. 
Group C: (n= 5 subjects) 
Each subject will take oral progesterone 400 mg orally once daily in the evening and apply 
placebo gel once daily in the morning applied to the intact skin of the upper shoulders or 
arms for 7 days. 
 
Visit 3: 
All subjects will receive a single intravenous (IV) dose of ibutilide 0.003 mg/kg, diluted in 
normal saline 20 mL and infused 10 minutes. 
 
Continuous ECG recording will be initiated 30 minutes prior to ibutilide and continue for 8 
hours after ibutilide administration. Three 12 lead ECGs one minute apart will be selected 
for QT interval measurement before (time 0) and after ibutilide at: 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 before ibutilide administration, at the end of 
infusion, and 5, 15, 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.25  
 
In addition, blood will be drawn to determine serum progesterone, testosterone, 
magnesium and potassium concentrations at the same time as the time 0 ibutilide 
concentration is drawn.  If the subjects is found to have hypokalemia or hypomagnesia 
as defined in the exclusion criteria, then they will be withdrawn from the study.  
 
At the end of this visit, and after at least a 2-week washout period, subjects will take 
another of the study drugs as follows: 
 
 
Group A: (n= 5 subjects) 
Each subject will take oral progesterone 400 mg orally once daily in the evening and apply 
placebo gel once daily in the morning applied to the intact skin of the upper shoulders or 
arms for 7 days. 
Group B: (n= 5 subjects) 
Each subject will take one placebo capsule once daily in the evening and apply placebo 
gel once daily in the morning applied to the intact skin of the upper shoulders or arms  for 
7 days. 
Group C: (n= 5 subjects) 


10 
 
Each subject will apply testosterone gel 1% (Androgel®) 100 mg once daily in the 
morning applied to the intact skin of the upper shoulders or arms and will take a placebo 
capsule once daily in the evening for 7 days. 
 
Visit 4: 
 
Continuous ECG recording will be initiated 30 minutes prior to ibutilide and continue for 8 
hours after ibutilide administration. Three 12 lead ECGs one minute apart will be selected 
for QT interval measurement before (time 0) and after ibutilide at: 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 before ibutilide administration, at the end of 
infusion, and 5, 15, 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.25  
 
In addition, blood will be drawn to determine serum progesterone, testosterone, 
magnesium and potassium concentrations at the same time as the time 0 ibutilide 
concentration is drawn.  If the subjects is found to have hypokalemia or hypomagnesia 
as defined in the exclusion criteria, then they will be withdrawn from the study.  
 
 
Following visit 4, subjects’ participation in the study will be complete. 
 
Serum ibutilide concentrations will be performed in the CPAC Laboratory35 and serum 
testosterone and progesterone concentrations will be performed in the IU Health 
Pathology Laboratory as described.36 Peak serum ibutilide concentrations and area under 
the serum ibutilide concentration:time curves from 0-1 hours (AUC0-1) will be compared 
across the groups to assure no differences that could influence QT intervals. QT intervals 
will be measured by a research nurse (Heather Jaynes) with vast training and experience 
in QT interval measurement, and who will be blinded to subjects’ assigned treatment 
groups. AUEC0-1, an index of QTcI exposure, will be calculated using the linear trapezoidal 
rule.  
 
In summary, this study will take a total of 25 days to complete, excluding the washout 
periods.  The total study period will take place over a minimum of 78 days.   Each subject 
will need to complete 4 visits, and take a medication for 6 days prior to the visit.  The first 
visits involves no drug administration, but simply involves a 10 hour stay in the ICRC and 
includes a screening visit, followed by ECGs taken periodically for 10 hours.  Then they 
will begin self-administration of study medications for 7 days. Visit 2 begins on the 7th day 
of medication administration.  During visit 2, the subjects will undergo a 10 hour stay in 
the ICRC. After a minimum of a 28 day washout period, subjects will self-administrator 
study medications for 7 days.  Visit 3 begins on the 7th day of medication 
administration.  During visit 3, the subjects will undergo a 10 hour stay in the ICRC.  After 
minimum of a 28 day washout period, subjects will self-administer study medications for 
7 days.  Visit 4 will begin on the 4th day of medication administration.  During visit 4, 
subjects will undergo a 10 hour stay at the ICRC. 
 
Daily blood draws and ECGs prior to visits 2, 3 and 4 


11 
 
 
Purpose: 
We are trying to learn how long we need to treat patients with progesterone and/or 
testosterone before we see changes in the ECG that would be considered protective 
against developing drug induced Torsades de Pointes.  This will help us determine how 
long patients need to be treated with progesterone and/or testosterone if needs a 
medication that could put them at risk for developing Torsades de Pointes in order to 
reduce that risk. 
 
Study Procedures 
In a subset of people participating in the study (5 subjects total), we are drawing blood 
to test testosterone and progesterone concentrations and taking 3 ECGs one minute 
apart once every morning each day for 7 days prior to visit 2,3 and 4.  These blood 
draws will take 1 teaspoon of blood or 5 milliliters of blood each time.  The first blood 
draw will take place on the day that you are supposed to start taking the study 
medication (progesterone/ testosterone/ placebo) and take place daily until you return 
to the CRC for your scheduled visit.  This means that you will have an additional 6 blood 
draws.  A total of 6 additional teaspoons (30 milliliters) of blood will be taken before 
each visit for a total of 18 additional teaspoons (90milliliters) of blood over the study 
period.   
 
Each visit will take approximately 30 minutes/ day for a total of 3 additional hours prior 
to visit 2, 3, and 4 for a total of 9 additional hours. 
 
Subjects are not required to participate in this part of the study in order to participate in 
the rest of the study as described above and will sign a separate consent if they are willing 
to participate in this portion of the study.   
 
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.37 
Ibutilide prolongs QTc interval dose-dependently, with a rapid onset and return to 
baseline in 2-6 hours .25 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.38,39 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).25 Further, we recently 
completed a study in premenopausal female volunteers during which n=15 subjects 


12 
 
safely received this ibutilide dose, each on two separate occasions.40 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).41 
 
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 for 6 hours following ibutilide administration. 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.  A physician investigator (or his MD designee) will 
be present during ibutilide administration and for 2-3 hours following 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. 
 
Transdermal testosterone at similar (and higher) doses is associated with minimal 
(primarily acne or application site skin reactions) or no adverse effects.42-45 Longer-term 
administration (> 18 months) of testosterone has been associated in some studies with 
adverse CV effects, including an increased risk of all-cause mortality, myocardial infarction, 
and stroke.46 Conversely, however, other studies have found that men with lower serum 
testosterone are at higher risk of metabolic syndrome and other CV risk factors.47-49 A 
recent meta-analysis of randomized controlled trials found no increase in the endpoint of 
CV death, non-fatal myocardial infarction, and stroke associated with testosterone therapy 
compared to placebo.50 The European Medicines Agency’s (EMA) Pharmacovigilance Risk 
Assessment Committee concluded that the benefits of testosterone therapy outweigh the 
risks in appropriate patients.49  
 


13 
 
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 men with no reported adverse effects.51 
 
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. 
 
 
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 David Foster, PharmD, Associate Professor, College of 
Pharmacy, Purdue University and Adjunct Associate Professor, School of Medicine, 
Indiana University. Other members of the DSMB will be one cardiologist faculty member 
of the Krannert Institute of Cardiology, School of Medicine, Indiana University, and one 
faculty member of the Division of Clinical Pharmacology, School of Medicine, Indiana 
University – these individuals will be identified prior to the end of June 2015. 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 every 6 months during the anticipated duration of 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. 


14 
 
 
Data from the study will be monitored continuously throughout the study and will be 
reviewed at each DSMB meeting. 
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>0.45-0.47 seconds; Grade 2, 
QTc >0.47-0.50  seconds and/or increase in QTc ³0.06 seconds above 
baseline; Grade 3, QTc >0.50 seconds; Grade 4, QTc >0.50 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. 
Transdermal testosterone at similar (and higher) doses is associated with minimal or no 
adverse effects.42-45 Oral progesterone 400 mg daily has been administered to men with 
no reported adverse effects.51 While some studies have reported that longer-term 
testosterone administration has been associated adverse CV effects,46 recent studies have 
found that men with lower serum testosterone are at higher risk of metabolic syndrome 
and other CV risks.47-49 A recent meta-analysis of randomized controlled trials found no 
increase in adverse CV endpoints associated with testosterone therapy compared to 
placebo.52 The EMA’s Pharmacovigilance Risk Assessment Committee concluded that the 
benefits of testosterone therapy outweigh risks in appropriate patients.49 Thus, evidence 
suggests that testosterone could be administered safely for long-or short-term reduction 
of risk of drug-associated QTc interval prolongation in high-risk patients that require QTc 
interval-prolonging agents. We propose to administer transdermal testosterone for 7 days; 


15 
 
adverse effects over such a short time frame are uncommon and mild, mainly acne and 
application site reactions.  
 
 
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 
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. The DSMB will meet every 6 months during the anticipated two-
year duration of 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 any 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 
 
Study Endpoints:  Comparison of testosterone, progesterone and placebo phases for: 1) 
Baseline (pre-ibutilide) maximum QTcI & QTF, 2) Ibutilide effect on maximum QTcI & QTF, 
3) Ibutilide effect on maximum % change in QTcI & QTF, and 4) AUEC0-1. Endpoints will 
be correlated with testosterone and progesterone concentrations.  


16 
 
 
Statistical analyses: Will be performed using SPSS 22.0 (SPSS Inc, Chicago, IL). 
Comparisons of primary endpoints in subjects across the three study phases will be 
performed using repeated measures analysis of variance (ANOVA). If statistically 
significant differences are found, post hoc testing will be performed using Tukey’s Honest 
Significant Difference (HSD) test to determine between-group differences. For all 
comparisons, α will be set at 0.05. Correlations between the primary endpoints and serum 
testosterone and progesterone concentrations will be performed using Pearson’s 
correlation coefficient.  
 
Anticipated Outcomes:  
1) Ibutilide-associated maximum QTcI interval and maximum % change in QTcI will be 
significantly smaller during testosterone and progesterone phases compared to placebo  
2) Ibutilide-associated AUEC0-1 will be significantly smaller during testosterone and 
progesterone phases compared to placebo  
3) Maximum change in QTcI interval and AUEC0-1 will be inversely associated with serum 
testosterone and progesterone concentrations 
 
Sample Size Calculation:  In this 3-way crossover study, at a two-sided α level of 0.05 and 
a power of 0.80, a sample size of 15 subjects will be sufficient to detect a difference in 
maximum QTcI of 15 ms, assuming a QTcI interval prolongation of 24±12 ms associated 
with ibutilide in the absence of testosterone or 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.  


17 
 
 
 
 
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. 
 
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. 
 


18 
 
 
 
 
 
 
 
 
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24 
 
 
 
 
 
 
Appendix. Incidence of Ibutilide-Associated Torsades de Pointes in Published Literature 


25 
 
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 
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%) 
 


26 
 
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 
 
 
-- 
 


27 
 
 
 
*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% 
‡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) 
 
 
 
 
 
Tisdale, J 
Clin 
Pharmacol 
2012 
N=15 
Patients with 
AF  
N=6 had 
decreased 
LVEF 
-- 
-- 
-- 
 
 
0/6 
 
 
-- 
 
Tisdale JE et 
al, 
Circulation 
2014 
(abstract) 
N=16, 
randomized 
crossover 
(n=31 doses 
of ibutilide 
0.003 mg/kg) 
Healthy 
premenopausal 
female 
volunteers 
during menses 
phase 
0/31 
 
 
 
 
 
 
 
 
 
Total in all 
studies 
 
 
0/89 
0/252 
1/42 
0/2 
2/40 
20/852 
(2.3%) 
2/152  
(1.3%) 
1/42 
(2.4%) 
10/371 
(2.7%) 
36/1,84
2 
(1.9%)