Clinical trial NCT05004077
Conditions: Atrial Fibrillation
Sponsor: Kevin W Hatton, MD, PhD
Start date: 2021-11-02; Completion date: 2022-10-10
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a single-center, prospective, randomized, open-label trial of subjects who develop atrial fibrillation after non-emergent cardiac surgery at the University of Kentucky Chandler Medical Center (UKCMC). Patients will be randomized to receive either a conventional amiodarone dosing regimen (CDR) or a repeated amiodarone bolus dosing regimen (RBDR).

Detailed description:
This study will screen and consent approximately 150 patients undergoing non-emergent cardiac surgery. Approximately 60 of these patients are likely to develop stable postoperative atrial fibrillation (POAF) in the postoperative period. Amiodarone is commonly given as an initial intravenous (IV) bolus (150 mg IV) followed by a combined IV and oral load to a total dose of 8 gm. Because of amiodarone's beta-blocker activity, the IV bolus in patients with POAF is associated with a reduced heart rate that may lead to restoration of NSR. For this reason, some clinicians will provide up to 5 additional IV amiodarone boluses during the drug's loading period to treat RVR.

Arms: arm 1: Initial amiodarone bolus of 150 mg IV over 10 minutes then a 24-hour amiodarone loading infusion (1 mg/min for 6 hours followed by 0.5 mg/min for 18 hours), followed by enteral (400 mg amiodarone oral or per tube three times daily or 2 times daily if the patient has gastrointestinal intolerance when taking the drug three times daily) or intravenous amiodarone (0.5 mg/min continuous infusion) to complete an 8-gm total amiodarone load. Maintenance amiodarone (200 mg amiodarone oral or per tube once daily) at discretion of attending physician. arm 2: Initial amiodarone bolus of 150 mg IV over 10 minutes, then 1.0 mg/min IV amiodarone infusion for 6 hours, then a 0.5 mg/min IV amiodarone infusion for 18 hours, followed by enteral (400 mg amiodarone oral or per tube three times daily or 2 times daily if the patient has gastrointestinal intolerance when taking the drug three times daily) or intravenous amiodarone (0.5 mg/min continuous infusion) to complete an 8-gm total amiodarone load. In addition, patients in the RBDR will receive an additional 150 mg IV amiodarone bolus whenever the patient develops tachycardia (Heart Rate (HR) = 110 beats per minute) lasting more than 10 minutes. This bolus may be repeated up to a total of 5 times (6 total boluses) over the first 24 hours. Maintenance amiodarone (200 mg amiodarone oral or per tube once daily) at discretion of attending physician.
Interventions: intervention 1: AMIODARONE
Intervention descriptions: intervention 1: Assess the effectiveness of different dosing strategies of amiodarone.

Protocol documents:
Prot_002.pdf: 
 
 
1 
 
 
Document Coversheet 
 
 Study Title: Repeated Amiodarone Dosing In Cardiac surgicaL Procedures 
Institution/Site:  
University of Kentucky 
Document (Approval/Update) Date: 
24 OCT 2022 
NCT Number: 
NCT05004077 
IRB Number 
67919 
Coversheet created: 
10/25/2023 
 
 
 


 
 
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COMPARING THE EFFECTIVENESS OF TWO DIFFERENT AMIODARONE DOSING 
STRATEGIES TO TREAT STABLE ATRIAL FIBRILLATION AFTER NON-EMERGENT 
CARDIAC SURGERY  
 
Primary Investigator: 
• Kevin W. Hatton, MD, PhD 
 
Co-Investigators: 
• Michael Sekela, MD 
 
Research Coordinators: 
• Amy Banfield 
• Meredith McBrayer 
 


 
 
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TABLE OF CONTENTS 
1. 
Background .............................................................................................................................. 7 
2. 
Study Hypothesis ..................................................................................................................... 8 
3. 
Objectives ................................................................................................................................ 8 
3.1 
Primary Objective ............................................................................................................ 8 
3.2 
Secondary Objectives ....................................................................................................... 8 
3.3 
Exploratory Objectives ..................................................................................................... 9 
4. 
Study Design.......................................................................................................................... 10 
5. 
Study Population.................................................................................................................... 10 
5.1 
Inclusion criteria ............................................................................................................. 10 
5.2 
Exclusion criteria............................................................................................................ 11 
6. 
Subject Recruitment Methods and Privacy ........................................................................... 11 
7. 
Advertising ............................................................................................................................ 13 
8. 
Informed Consent Process ..................................................................................................... 13 
9. 
Research Procedures .............................................................................................................. 14 
9.1 
Conventional Dosing Regimen (CDR) .......................................................................... 15 
9.2 
Repeated Bolus Dosing Regimen (RBDR) .................................................................... 16 
9.3 
Informed Consent ........................................................................................................... 16 
9.4 
Enrollment ...................................................................................................................... 16 
9.5 
Randomization ............................................................................................................... 17 


 
 
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9.6 
Assignment of Subject Identification Number ............................................................... 17 
10. 
Data Collection .................................................................................................................. 17 
10.1 Preoperative data ............................................................................................................ 17 
10.2 Intraoperative data .......................................................................................................... 18 
10.3 Postoperative data .......................................................................................................... 18 
11. 
Statistical Analysis Plan ..................................................................................................... 20 
11.1 Baseline and demographic data ...................................................................................... 21 
11.2 Primary Objective .......................................................................................................... 21 
11.3 Secondary Objectives ..................................................................................................... 22 
11.4 Exploratory Objectives ................................................................................................... 24 
12. 
Resources ........................................................................................................................... 25 
13. 
Potential risks ..................................................................................................................... 26 
14. 
Safety precautions .............................................................................................................. 26 
14.1 Risks from Breach of Confidentiality ............................................................................ 26 
15. 
Benefit versus Risk ............................................................................................................ 26 
16. 
Available Alternative Treatment........................................................................................ 27 
17. 
Research Materials, Records, and Privacy ......................................................................... 27 
18. 
Confidentiality ................................................................................................................... 27 
19. 
Payment.............................................................................................................................. 27 


 
 
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20. 
Costs to Subjects ................................................................................................................ 28 
21. 
Data and Safety Monitoring ............................................................................................... 28 
22. 
Subject Complaints ............................................................................................................ 29 
23. 
Research Involving Non-English-Speaking Subjects or Subjects from a Foreign Culture 29 
24. 
HIV/AIDS Research .......................................................................................................... 29 
25. 
Appendices ......................................................................................................................... 29 
  
 
 


 
 
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ABBREVIATIONS 
 
AE 
Adverse event 
AF 
Atrial fibrillation 
BPM 
Beats per minute 
CABG 
Coronary artery bypass graft 
CDR 
Conventional dosing regimen 
HR 
Heart rate 
HIPAA 
Health insurance portability and accountability act 
ICF 
Informed consent form 
ICU 
Intensive care unit 
IRB 
Institutional review board 
IV 
Intravenous 
LAR 
Legally-authorized representative 
NSR 
Normal sinus rhythm 
ORI 
Office of research integrity 
PI 
Principal Investigator 
RBDR 
Repeated bolus dosing regimen 
RVR 
Rapid ventricular response 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SID 
Subject identification number 
UBACC 
University of San Diego Brief Assessment of Capacity to Consent 
UKCMC 
University of Kentucky Chandler Medical Center 
 
 


 
 
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1. BACKGROUND  
Atrial fibrillation (AF) is a common complication following cardiac surgery, occurring in 
approximately 33% of all patients after cardiac surgery.  AF can sometimes cause a rapid 
ventricular rate (RVR), defined as a HR greater than 110 beats per minute (BPM).  AF is 
typically characterized as either stable (systolic blood pressure (SBP) ≥ 90 mmHg) or unstable 
(SBP <90 mmHg).  Patients with unstable AF with or without RVR may require immediate 
electrical cardioversion to restore normal sinus rhythm (NSR) and an appropriate blood pressure; 
whereas, patients with stable AF frequently undergo medical therapy to either treat RVR or to 
restore NSR.  
 
Amiodarone is a class III antiarrhythmic with beta-blocker activity that also blocks myocardial 
potassium, sodium and calcium channels.  In stable AF, amiodarone is frequently given to 
control the HR and restore NSR after cardiac surgery.  In this setting, amiodarone is commonly 
given as an initial intravenous (IV) bolus (150 mg IV) followed by a combined IV and oral load 
to a total dose of 8 gm.  Because of amiodarone’s beta-blocker activity, the IV bolus is 
associated with a reduced HR and may lead to restoration of NSR on its own.  For this reason, 
some clinicians will provide up to 5 additional IV amiodarone boluses during the drug’s loading 
period to treat RVR.  Other clinicians will not specifically treat RVR in stable AF and will 
continue with the routine amiodarone IV and oral load.  At this time, both dosing regimens are 
routinely used for patients after cardiac surgery, the decision to use one over the other is made 
based on clinician preference.  It is not known whether the repeated amiodarone dosing regimen 
is better than the conventional amiodarone dosing regimen with regard to successful conversion 
to NSR or the time to conversion to NSR in patients with stable AF. 


 
 
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2. STUDY HYPOTHESIS 
We hypothesize that, compared to a conventional dosing regimen (CDR), a repeated bolus 
dosing regimen (RBDR) of amiodarone will result in an increased percentage of patients who 
convert to normal sinus rhythm within 24 hours of initial AF. 
 
3. OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to compare, in patients who develop stable AF after non-
emergent cardiac surgery, the percentage of patients who have converted to NSR at 24-hours 
after receiving a repeated amiodarone bolus and loading dose regimen to the percentage of 
patients who have converted to NSR after a conventional amiodarone IV loading dose regimen. 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• Compare the total time, in minutes, during the first 24 hours that the patient achieves 
target HR (HR < 110 bpm) between patients who receive a repeated amiodarone bolus 
dosing regimen and those who receive a conventional amiodarone bolus dosing regimen. 
• Compare the time to achieve target HR (HR < 110 bpm) between patients who receive a 
repeated amiodarone bolus dosing regimen and those who receive a conventional 
amiodarone bolus dosing regimen. 


 
 
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• Compare the time to achieve NSR between patients who receive a repeated amiodarone 
bolus dosing regimen and those who receive a conventional amiodarone bolus dosing 
regimen. 
• Compare the percentage of patients who achieve NSR by ICU discharge and hospital 
discharge between patients who receive a repeated amiodarone bolus dosing regimen and 
those who receive a conventional amiodarone bolus dosing regimen. 
• Compare the percentage of patients who have recurrent AF before ICU discharge and 
before hospital discharge between who patients who receive a repeated amiodarone bolus 
dosing regimen and those who receive a conventional amiodarone bolus dosing regimen. 
• Compare the incidence and severity of hypotension between patients who receive a 
repeated amiodarone bolus dosing regimen and those who receive a conventional 
amiodarone bolus dosing regimen. 
• Compare the incidence and severity of conduction abnormalities between patients who 
receive a repeated amiodarone bolus dosing regimen and in those who receive a 
conventional amiodarone bolus dosing regimen. 
• Compare the incidence and severity of amiodarone-related pulmonary fibrosis between 
patients who receive a repeated amiodarone bolus dosing regimen and those who receive 
a conventional amiodarone bolus dosing regimen. 
 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are: 


 
 
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• Evaluate preoperative, intraoperative and postoperative factors that affect the efficacy of 
the amiodarone dosing strategy in achieving NSR at 24 hours, ICU discharge and hospital 
discharge. 
• Evaluate preoperative, intraoperative and postoperative factors that affects the safety 
profile of the repeated amiodarone bolus dosing regimen. 
 
4. STUDY DESIGN  
This study is a single-center, prospective, randomized, open-label trial of subjects who develop 
AF after non-emergent cardiac surgery at the University of Kentucky Chandler Medical Center 
(UKCMC).  Patients will be randomized to receive either a conventional amiodarone dosing 
regimen (CDR) or to a repeated amiodarone bolus dosing regimen (RBDR).   
 
5. STUDY POPULATION 
This study will include 150 patients undergoing non-emergent cardiac surgery.  We anticipate 
approximately 60 of these patients will develop stable AF in the postoperative period.  Patients 
will be ≥ 18 years of age.  The proposed dates of enrollment will be July 1, 2021 through June 
30, 2023 or until full recruitment has been completed, whichever comes first. 
 
5.1 
Inclusion criteria 
To be enrolled in this study, the subject must meet all of the following criteria: 
• Subject must be ≥ 18 years old 
• Subject must be willing to give written informed consent 


 
 
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• Subject must undergo non-emergent cardiac surgery, including coronary artery bypass 
grafting (CABG), non-infectious valve repair or replacement, atrial or septal defect 
repair, thoracic aortic replacement surgery or any combination of these procedures 
 
5.2 
Exclusion criteria 
The subject will be excluded from the study if any of the following criteria are met: 
• Documented allergy to amiodarone or iodine 
• History of atrial fibrillation or other heart conduction system abnormality 
• History of cardiac maze, pulmonary vein isolation, or other procedure affecting the 
conduction system 
• Scheduled cardiac maze, pulmonary vein isolation, or other procedure affecting the 
conduction system 
• Low cardiac index or cardiogenic shock requiring pharmacologic or mechanical support 
• History of pre-existing respiratory system disease requiring oxygen therapy prior to 
admission 
• History of cirrhosis or other chronic liver disease 
• Pregnancy or breastfeeding mothers 
• Prisoners  
 
6. SUBJECT RECRUITMENT METHODS AND PRIVACY 
Subjects will be screened and recruited in one of three ways. 
 


 
 
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First, potential subjects will be primarily screened in the Anesthesiology Preoperative Clinic and 
recruited by the PI or a member of the IRB-approved research team.  These subjects will be 
consented for this study by the PI or a member of the IRB-approved research team during a 
scheduled clinic visit.  The screening process will utilize ordinary standard of care procedures 
(e.g., medical evaluation, physical examination and diagnostic testing at the discretion of the 
attending cardiovascular surgeon and/or perioperative anesthesia team).  Prior medical records 
documenting these evaluations, examinations and testing may be used as source documents for 
the baseline visit.   
 
Second, because some patients may be hospitalized prior to their operation and will not present 
to the Anesthesiology Preoperative Clinic prior to their operation, hospitalized patients scheduled 
for surgery will be screened and consented using the above process prior to their operation.   
 
Third, because some outpatients will not present to the Anesthesiology Preoperative Clinic and 
some inpatients will not be screened and consented prior to their operation, for a variety of 
reasons.  These patients will be screened in the early postoperative period, after admission to the 
ICU.  These patients will be recruited by the PI or a member of the IRB-approved research team.  
The screening process will utilize ordinary standard of care procedures (e.g., medical evaluation, 
physical examination and diagnostic testing at the discretion of the attending cardiovascular 
surgeon and/or perioperative anesthesia team).  Prior medical records documenting these 
evaluations, examinations and testing may be used as source documents for the baseline visit.  
 


 
 
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Regardless of recruitment pathway, during the screening and recruitment process, the PI or 
another member of the research team will verify that the eligibility criteria have been met.  
Preoperative outpatients who meet the inclusion and exclusion criteria will be approached for 
informed consent.  Inpatient preoperative and all postoperative patients who meet the inclusion 
and exclusion criteria will be further assessed for the continuous infusion of sedating agents.  For 
these patients, the legally-authorized representative (LAR) will be approached for informed 
consent.  For postoperative patients who meet the inclusion and exclusion criteria and are not 
receiving a continuous infusion of sedating agents, the University of San Diego Brief 
Assessment of Capacity to Consent (UBACC) test will be performed.  For patients with a 
UBACC score of <18, the LAR will be approached for informed consent.  For patients with a 
UBACC score of ≥ 18, informed consent will be discussed with the patient.   Written informed 
consent and a Health Insurance Portability and Accountability Act (HIPAA) authorization must 
be obtained prior to performance of any protocol-specific procedures. 
 
7. ADVERTISING 
None. 
 
8. INFORMED CONSENT PROCESS 
A full consent discussion will be held with the patient or legally-authorized representative LAR 
at which time the study protocol, procedures, risks/benefits, alternatives, and the voluntary nature 
of the research will be explained by the study staff.  There will be an opportunity for the patient 
or LAR to ask questions and for private consideration/discussion with family, if needed.  If the 
patient or LAR wishes to be involved in the protocol, study procedures will begin after the 


 
 
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patient’s or LAR’s signature is obtained on the informed consent and HIPAA documents. If the 
patient would like to take time outside the clinic visit to decide about enrollment, the patient may 
return the signed consent to their next visit, including preoperatively on the day of surgery.  For 
patients who have LAR consent and are no longer on continuous infusions of sedation and who 
regain consciousness and their UBACC score improves to ≥ 18, the patient themselves will be 
re-consented using the process and procedures previously described.  No study procedures will 
begin until after the signed copy of the informed consent and HIPAA documents are obtained. A 
note in the patient file will be written explaining how the patient meets study criteria, the process 
of informed consent and the nature of the discussion, and who participated in the consent 
process.  This note will be generated by the PI or another member of the study team. 
 
9. RESEARCH PROCEDURES 
All enrolled patients will receive the standard of care perioperative institutional protocol for their 
cardiac surgical procedure.  The preoperative and intraoperative management will be performed 
at the discretion of the cardiovascular surgery team, the anesthesia team, and other healthcare 
teams.  The postoperative management will be performed at the discretion of the cardiovascular 
surgery team and the consultant anesthesiology critical care team according to standard 
management protocols. 
 
As part of standard postoperative management, all patients will undergo continuous 
electrocardiographic (ECG) monitoring in the postoperative period.  If new AF is identified 
within the first 72 hours after they are admitted to ICU following their surgical procedure, the 
patient will be assessed for hemodynamic stability.  If the patient is unstable (SBP <90 mmHg) 


 
 
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or requires a significant increase in vasopressor infusion (an increase of more than 1.5x in 
baseline infusion rate) to maintain SBP>90 mmHg, the standard of care patient management will 
be provided and the patient will not be randomized to either study group.  If the patient is stable 
(SBP>90 mmHg and requires less than 1.5x more vasopressor infusion to maintain SBP>90 
mmHg), the patient will be given up to 15 mg IV metoprolol, in divided doses, and monitored for 
20 minutes for conversion to NSR.  If stable AF persists, the patient will be randomized 
according to the plan described below to either the conventional amiodarone dosing regimen 
(CDR) or to the repeated amiodarone bolus dosing regimen (RBDR).   
 
Patients in both groups will receive an amiodarone bolus of 150 mg IV over 10 minutes then a 
24-hour amiodarone loading infusion (1 mg/min for 6 hours followed by 0.5 mg/min for 18 
hours).  After these infusions have been completed, patients in both groups will receive 
additional enteral (400 mg amiodarone oral or per tube three times daily or 2 times daily if the 
patient has gastrointestinal intolerance when taking the drug three times daily) or intravenous 
amiodarone (0.5 mg/min continuous infusion) to complete an 8-gm total amiodarone load.  After 
the amiodarone load is completed, patients in both groups will receive maintenance amiodarone 
(200 mg amiodarone oral or per tube once daily).  Further management of amiodarone dosing 
will be at the discretion of the attending cardiac surgeon, critical care medicine specialist or 
cardiologist.  Other medications will be at the discretion of the attending cardiac surgeon, critical 
care medicine specialist or cardiologist.  Patients will be monitored continuously throughout the 
24-hour amiodarone IV load time period according to standard protocol.  
     
9.1 
Conventional Dosing Regimen (CDR) 


 
 
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Patients randomized to the CDR group will receive the previously-described amiodarone bolus 
followed by a 1.0 mg/min IV amiodarone infusion for 6 hours and then a 0.5 mg/min IV 
amiodarone infusion for 18 hours.   
 
9.2 
Repeated Bolus Dosing Regimen (RBDR) 
Patients randomized to the RBDR group will receive the previously-described amiodarone bolus 
followed by a 1.0 mg/min IV amiodarone infusion for 6 hours and then a 0.5 mg/min IV 
amiodarone infusion for 18 hours.  In addition, patients in the RBDR will receive an additional 
150 mg IV amiodarone bolus whenever the patient develops tachycardia (Heart Rate (HR) ≥ 110 
beats per minute) lasting more than 10 minutes.  This bolus may be repeated up to a total of 5 
times (6 total boluses) over the first 24 hours.   
 
9.3 
Informed Consent 
The PI or another study team member will explain the study to the subject, answer all of the 
subject’s questions, and obtain written informed consent before the collection of any study data 
or performance of any study-related procedures.  
 
The subject must be willing and able to sign and date the informed consent form (ICF) prior to 
the collection of any study-related data. The original, signed informed consent will be retained 
with the subjects’ records and a copy provided to the subject. 
 
9.4 
Enrollment  


 
 
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All subjects who sign the ICF will be considered eligible for this study.  Subjects who are 
eligible and meet all the inclusion criteria and do not meet any of the exclusion criteria will be 
considered enrolled in the study.  Enrolled patients who have persistent, stable AF will be 
randomized and treated according to the research procedures described above.   
 
9.5 
Randomization 
All enrolled patients who develop persistent, stable AF will be randomized using a simple 
randomization scheme.     
 
9.6 
Assignment of Subject Identification Number  
All enrolled subjects will be assigned a three-digit subject identification number in sequential 
order, starting with 001. 
 
10. DATA COLLECTION  
Preoperative, intraoperative, and postoperative data will be recorded and entered in the 
appropriate data collection sheets for all randomized patients.  Study data will not be collected on 
non-enrolled patients or enrolled patients who are not randomized.  Data will include, but is not 
limited to, previously-obtained preoperative, intraoperative, and postoperative data, concomitant 
procedures, procedure related complications and adverse events. All study data will be 
maintained on a REDCap database and will only be accessed for study purposes. A list of the 
data to be collected is provided below:  
 
10.1 Preoperative data  


 
 
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• Demographics (sex, age, height, weight, and body mass index) 
• Preoperative use of beta-blocker therapy 
• Preoperative left ventricular ejection fraction 
• Preoperative tobacco use (smoking) 
• Preoperative alcohol use 
• Preoperative benzodiazepine use 
 
10.2 Intraoperative data  
• Surgical procedure(s) performed 
• Date/time of OR entry 
• Date/time of anesthesia induction 
• Date/time of surgery start 
• Date/time of cardiopulmonary bypass start 
• Date/time of aortic cross-clamp 
• Date/time of aortic cross-clamp removal 
• Date/time of cardiopulmonary bypass end 
• Estimated blood loss 
• IV fluid administered 
• Blood transfused 
 
10.3 Postoperative data 
• Date/time of ICU admission 
• Date/time of extubation 


 
 
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• Date/time of ICU discharge 
• Date/time of hospital discharge 
• Vasopressor (norepinephrine, vasopressin) use at ICU admission 
• Inotrope (dopamine, epinephrine, milrinone, dobutamine) use at ICU admission 
• Pacemaker use at ICU admission 
• Date/time of first AF 
• Presence of rapid ventricular response with first AF 
• Heart rate at time of AF diagnosis 
• Heart rate at initiation of study group treatment (initial amiodarone bolus) 
• Hourly heart rate for 24 hours, beginning at start of study group treatment 
• Date/time of study randomization 
• Date/time of first study drug administration 
• Total number of amiodarone boluses administered 
• Restoration of normal sinus rhythm by ICU discharge 
• Restoration of normal sinus rhythm by hospital discharge 
• Date/time of normal sinus rhythm 
• Total number of stable AF episodes (excluding initial episode) prior to ICU discharge 
• Total number of stable AF episodes (excluding initial episode) prior to hospital discharge 
• Presence of hypotension (SBP < 90 mmHg or increase in vasopressor infusion by 1.5x to 
achieve SBP > 90 mmHg) after amiodarone therapy during amiodarone IV load period 
• Severity of hypotension after amiodarone therapy during amiodarone IV load period 
o Mild: No intervention needed 
o Moderate: Hypotension resolved after fluid bolus 


 
 
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o Severe: Hypotension requiring vasopressor or inotropic therapy 
o Very Severe: Hypotension requiring multiple vasopressor or inotropic therapies 
• Presence of bradycardia (HR <60 beats per minute) after amiodarone therapy during 
amiodarone IV load period 
• Presence of conduction abnormality during amiodarone IV load period 
• Severity of conduction abnormality during amiodarone IV load period  
o Mild: No intervention  
o Moderate: Temporary pacemaker required for ≤ 12 hrs 
o Severe: Temporary pacemaker required for 12-48 hrs 
o Very Severe: Temporary pacemaker required for ≥ 48 hrs or permanent 
pacemaker required 
• Presence of pulmonary fibrosis related to amiodarone therapy 
• Severity of pulmonary fibrosis related to amiodarone therapy 
o Mild: No intervention needed 
o Moderate: Discharged on oxygen at night only 
o Severe: Discharged on continuous oxygen 
o Very Severe: Discharged on mechanical ventilation or patient death due to 
pulmonary fibrosis 
 
 
11. STATISTICAL ANALYSIS PLAN 
Because the effect size of the RBDR regimen is unknown, a sample size calculation was not 
completed.  After all research procedures have been completed for 60 subjects (30 subjects in 


 
 
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each treatment group) that have been randomized, the primary outcome analysis will be 
performed as described below.  If there is a clinically-significant and a statistically-significant 
finding in the primary outcome analysis, defined as a p-value <0.05, the study will be closed and 
all statistical analyses described below will be completed.  If there is a clinically-significant but 
not statistically significant finding in the primary outcome analysis, defined as a p-value between 
0.05 and 0.10, the study will be extended to randomize another 20 subjects.  Following the 
recruitment of these additional 20 subjects, the study will be closed and all statistical analyses 
described below will be completed.  If there is neither a clinically-significant or statisticially-
significant finding in the primary outcome analysis, defined as a p-value > 0.10, the study will be 
closed and all statistical analyses described below will be completed.   
 
11.1 Baseline and demographic data 
To describe baseline and demographic data, preoperative, intraoperative and postoperative data 
will be summarized and compared between patients randomized to the CDR and RBDR groups.  
Binomial and categorical data will be described as number (N) and percentage.  Continuous data 
will be analyzed for normality.  Data will be tested for normality using the Shapiro-Wilk test.  
Normal data will be described by the mean and standard deviation; whereas, non-normal data 
will be described by the median and interquartile range.  Nominal data will be compared with the 
Fischer’s Exact test or the Chi-Square test, as appropriate.  Normal continuous data will be 
compared with the 2-tailed, student t-test.  Non-normal continuous data will be compared with 
the Mann-Whitney U test.  All results with p<0.05 will be considered significant. 
 
11.2 Primary Objective 


 
 
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To assess the primary objective, the number and percentage of patients in each group who have 
converted to NSR after 24 hours will be calculated.  The number of patients who convert to NSR 
in each group will be compared with either the Fischer’s Exact test or the Chi-Square test, as 
appropriate. 
 
11.3 Secondary Objectives    
To assess the secondary objectives, the following statistical analysis plan will be used: 
• To compare the total time, in minutes, during the first 24 hours that the patient achieves 
target HR (HR < 110) between groups, first, the time that each patient has the target HR 
will be calculated.  The total time at target HR will be calculated as the number of hourly 
HR measures ≤ 100 x 60 minutes.  This calculated time data for each group will be will 
be analyzed for normality.  Normal data will be described by the mean and standard 
deviation; whereas, non-normal data will be described by the median and interquartile 
range.  If one group is normal and one group is non-normal, both groups will be reported 
as non-normal data.  The total time at target HR between groups will then compared with 
either the 2-tailed, independent samples student t-test (normal data) or with the Mann-
Whitney U test (non-normal data). 
 
• To compare the time to achieve target HR (HR ≤ 110 bpm) between patients in each 
group, the time to achieve target HR will be calculated for each patient.  This time will be 
calculated as the total time, in minutes, between the start of the initial amiodarone bolus 
and the first recorded HR ≤ 110 bpm.  The time to achieve NSR data will be analyzed for 
normality.  Normal data will be described by the mean and standard deviation, whereas 


 
 
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non-normal data will be described by the median and interquartile range.  If one group is 
normal and one group is non-normal, both groups will be reported as non-normal data.  
The time to achieve NSR will then compared with either the 2-tailed, independent 
samples student t-test (normal data) or with the Mann-Whitney U test (non-normal data). 
 
• To compare the time to achieve NSR between patients in each group, the time to achieve 
NSR will be calculated for each patient.  For patients who do not convert to NSR by the 
time they are discharged from the hospital, the date/time that they achieve NSR will be 
the date/time of hospital discharge. The time to achieve NSR data will be analyzed for 
normality.  Normal data will be described by the mean and standard deviation, whereas 
non-normal data will be described by the median and interquartile range.  If one group is 
normal and one group is non-normal, both groups will be reported as non-normal data.  
The time to achieve NSR will then compared with either the 2-tailed, independent 
samples student t-test (normal data) or with the Mann-Whitney U test (non-normal data). 
 
• To compare the percentage of patients who achieve NSR by ICU discharge and hospital 
discharge, the number of patients in each group who have converted to NSR at each time 
point will be calculated and reported as number and percentage.  The number who have 
achieved NSR will be compared with the Fischer’s Exact test or the Chi-Square test, as 
appropriate. 
 
• To compare the percentage of patients who have recurrent AF before ICU discharge and 
hospital discharge, the number of AF episodes after the initial AF episode will be counted 


 
 
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for each patient in each group prior to ICU discharge and prior to hospital discharge.  The 
mean (normal data) or median (non-normal data) number of additional AF episodes will 
be compared between the groups using the 2-tailed, independent samples student t-test 
(normal data) or with the Mann-Whitney U test (non-normal data). 
 
• To compare the incidence and severity of hypotension, the number of patients who 
develop hypotension will first be calculated and reported as number and percentage.  The 
number of patients with hypotension will be compared with the Fischer’s Exact test or the 
Chi-Square test, as appropriate .  The number of patients who develop mild, moderate, 
severe or very severe hypotension will then be calculated and reported as number and 
percentage.  The number of patients with each severity class will then be compared 
between groups using Somers’ D test for ordinal data. 
 
• To compare the incidence and severity of conduction abnormalities, the number of 
patients who develop bradycardia will first be calculated and reported as number and 
percentage.  The number of patients with bradycardia will be compared with the Fischer’s 
Exact test or the Chi-Square test, as appropriate.  The number of patients who develop 
mild, moderate, severe or very severe conduction abnormalities will then be calculated 
and reported as number and percentage.  The number of patients with each severity class 
will then be compared between groups using Somers’ D test for ordinal data. 
 
11.4 Exploratory Objectives 


 
 
25 
 
• To evaluate preoperative, intraoperative and postoperative factors that affect the efficacy 
of the amiodarone dosing strategy in achieving NSR at 24 hours, ICU discharge and 
hospital discharge, multiple variable logistic regression modeling will be constructed 
using any significant variable discovered in the bivariate analysis.  
• Evaluate preoperative, intraoperative and postoperative factors that affects the safety 
profile of the repeated amiodarone bolus dosing regimen, multiple variable logistic 
regression modeling will be constructed using any significant variable discovered in the 
bivariate analysis. 
 
12. RESOURCES 
All usual care for a post-operative surgical patient will be provided to enrolled patients by 
hospital staff.  Emergency medical equipment, medications, and supplies will be at the 
physician’s disposal should the patient have an acute, unexpected reaction to study drugs.  The 
anesthesiology critical care team will be responsible for ordering study-related drugs, according 
to standard of care protocols, and for responding to unexpected reactions to study drugs.  
Evaluations, examinations, and tests will be ordered by the cardiovascular surgery, 
anesthesiology critical care medicine or other consultants according to standard of care 
protocols.  Research staff of the Anesthesiology Research Program will be responsible for 
randomizing enrolled patients, communicating group assignment to the anesthesiology critical 
care medicine team, monitoring study-related complications and adverse events, and collecting 
study-related data.   
 


 
 
26 
 
13. POTENTIAL RISKS 
Because this study compares 2 amiodarone dosing strategies already used in the proposed study 
population, there are no specific study-related risks of amiodarone administration.  Regardless of 
whether they are enrolled in this study, patients with persistent, postoperative stable AF will 
receive amiodarone IV bolus and infusion, unless they have a contraindication to its uses.  These 
patients may receive either the CDR or the RBDR, based entirely on clinician preference.  In this 
study, we are comparing the efficacy and safety of the currently used dosing regimens.   
 
The primary risk of this study is, therefore, only a risk of breach of confidentiality. 
 
14. SAFETY PRECAUTIONS 
14.1 Risks from Breach of Confidentiality 
All enrolled patients will be given a 3-digit study identification number (SID) at the time of 
study enrollment.  All patient data will be identified only with the SID and will be maintained 
only on the REDCap online database.  All informed consent records will be scanned in the 
Department of Anesthesiology, stored on the REDCap online database, and then immediately 
destroyed in the Department of Anesthesiology in a paper shredder. 
 
15. BENEFIT VERSUS RISK 
Patients enrolled in this study may receive a direct benefit from their enrollment or 
randomization to either group.  The risk in this study will be the same across both groups. 
 


 
 
27 
 
16. AVAILABLE ALTERNATIVE TREATMENT 
For patients that do not consent to enrollment in this study, they will receive current standard of 
care treatment for stable, postoperative AF, as determined by the cardiovascular surgery and/or 
anesthesiology critical care medicine teams. 
 
17. RESEARCH MATERIALS, RECORDS, AND PRIVACY 
The research team maintains the right to keep, preserve, use and dispose of the findings from this 
study. Research records from this study will be maintained in a confidential manner; subjects’ 
names will not be associated with any study procedures or published results. All data will be 
used for the purpose of research. All data will be retained for six years after study closure.  
Electronic records will be deleted at the specified times according to UK policy A13-050. 
 
18. CONFIDENTIALITY 
All electronic data containing identifiers will be stored on the secure REDCap database. Only 
designated study personnel will have access to data files. Investigational records for this study 
will be maintained in a confidential manner; subjects’ names will not be associated with any 
published results nor used for any purpose.  All data will be used for the purpose of research. All 
data will be retained for six years after study closure. 
 
19. PAYMENT 
No financial compensation will be provided to subjects. 
 


 
 
28 
 
20. COSTS TO SUBJECTS 
The patient, the patient’s insurance company, Medicare, or Medicaid will be responsible for the 
costs of all care and treatment that they receive during this study, including the cost of the study 
drug.  Because both amiodarone dosing regimens are currently used, the cost of the study drug 
and other costs are considered medically reasonable and necessary and will be part of the care 
the patient would receive if they did not take part in this study. 
 
21. DATA AND SAFETY MONITORING 
Each subject will be monitored for adverse events (AE) and serious adverse events (SAE) by the 
PI and/or a member of the research team.  Because hypotension and conduction system 
abnormalities are expected, reversible and treatable complications of amiodarone, they will be 
monitored but will only be considered AE if they reach “severe” criteria and will only be 
considered as SAE if they reach “very severe” criteria.  Other known complications of 
amiodarone therapy will be reported as AE or SAE, as appropriate.  All AE and SAE will be 
reported to the IRB per IRB guidelines. 
 
The PI and co-investigators will review the AE and SAE reports after the first 10 patients have 
completed the research protocol to evaluate patient safety.  If, after the first 10 patient have been 
evaluated, there were no AE or SAE reported, the PI and clinical co-investigators will continue 
to review the AE/SAE reports after every additional 20 patients have completed the protocol.  If, 
during these periodic reviews, there are reported AE or SAE, the PI and clinical co-investigators 
will consider whether to continue patient enrollment and study procedures based on an 
assessment of benefit versus risk.  The PI will have the responsibility, in consultation with the 


 
 
29 
 
clinical co-investigators, to decide whether to continue the study at each 20-patient interim safety 
analysis.  The PI will inform the IRB if study procedures will be terminated. 
 
22. SUBJECT COMPLAINTS 
If patients have complaints in relationship to their participation in this research study, they may 
contact the staff in the University of Kentucky (UK) Office of Research Integrity (ORI) between 
the business hours of 8am and 5pm EST, Monday-Friday at 859-257-9428 or toll free at 1-866-
400-9428. 
 
23. RESEARCH INVOLVING NON-ENGLISH-SPEAKING SUBJECTS OR SUBJECTS 
FROM A FOREIGN CULTURE 
Not Applicable. 
 
24. HIV/AIDS RESEARCH 
Not Applicable. 
 
25. APPENDICES 
None.  

SAP_003.pdf: 
 
 
 
Document Coversheet 
 
 Study Title: Repeated Amiodarone Dosing In Cardiac surgicaL Procedures 
Institution/Site:  
University of Kentucky 
Document (Approval/Update) Date: 
24 OCT 2022 
NCT Number: 
NCT05004077 
IRB Number 
67919 
Coversheet created: 
10/25/2023 
 
 
 


1. STATISTICAL ANALYSIS PLAN 
Because the effect size of the RBDR (Repeated Bolus Dosing Regimen) regimen is unknown, a 
sample size calculation was not completed.  After all research procedures have been completed 
for 60 subjects (30 subjects in each treatment group) that have been randomized, the primary 
outcome analysis will be performed as described below.  If there is a clinically-significant and a 
statistically-significant finding in the primary outcome analysis, defined as a p-value <0.05, the 
study will be closed and all statistical analyses described below will be completed.  If there is a 
clinically-significant but not statistically significant finding in the primary outcome analysis, 
defined as a p-value between 0.05 and 0.10, the study will be extended to randomize another 20 
subjects.  Following the recruitment of these additional 20 subjects, the study will be closed and 
all statistical analyses described below will be completed.  If there is neither a clinically-
significant or statisticially-significant finding in the primary outcome analysis, defined as a p-
value > 0.10, the study will be closed and all statistical analyses described below will be 
completed.   
 
1.1 
Baseline and demographic data 
To describe baseline and demographic data, preoperative, intraoperative and postoperative data 
will be summarized and compared between patients randomized to the CDR (Conventional 
Dosing Regimen) and RBDR groups.  Binomial and categorical data will be described as number 
(N) and percentage.  Continuous data will be analyzed for normality.  Data will be tested for 
normality using the Shapiro-Wilk test.  Normal data will be described by the mean and standard 
deviation; whereas, non-normal data will be described by the median and interquartile range.  
Nominal data will be compared with the Fischer’s Exact test or the Chi-Square test, as 


appropriate.  Normal continuous data will be compared with the 2-tailed, student t-test.  Non-
normal continuous data will be compared with the Mann-Whitney U test.  All results with 
p<0.05 will be considered significant. 
 
1.2 
Primary Objective 
To assess the primary objective, the number and percentage of patients in each group who have 
converted to NSR after 24 hours will be calculated.  The number of patients who convert to NSR 
in each group will be compared with either the Fischer’s Exact test or the Chi-Square test, as 
appropriate. 
 
1.3 
Secondary Objectives    
To assess the secondary objectives, the following statistical analysis plan will be used: 
• To compare the total time, in minutes, during the first 24 hours that the patient achieves 
target HR (HR < 110) between groups, first, the time that each patient has the target HR 
will be calculated.  The total time at target HR will be calculated as the number of hourly 
HR measures ≤ 100 x 60 minutes.  This calculated time data for each group will be will 
be analyzed for normality.  Normal data will be described by the mean and standard 
deviation; whereas, non-normal data will be described by the median and interquartile 
range.  If one group is normal and one group is non-normal, both groups will be reported 
as non-normal data.  The total time at target HR between groups will then compared with 
either the 2-tailed, independent samples student t-test (normal data) or with the Mann-
Whitney U test (non-normal data). 
 


• To compare the time to achieve target HR (HR ≤ 110 bpm) between patients in each 
group, the time to achieve target HR will be calculated for each patient.  This time will be 
calculated as the total time, in minutes, between the start of the initial amiodarone bolus 
and the first recorded HR ≤ 110 bpm.  The time to achieve NSR data will be analyzed for 
normality.  Normal data will be described by the mean and standard deviation, whereas 
non-normal data will be described by the median and interquartile range.  If one group is 
normal and one group is non-normal, both groups will be reported as non-normal data.  
The time to achieve NSR will then compared with either the 2-tailed, independent 
samples student t-test (normal data) or with the Mann-Whitney U test (non-normal data). 
 
• To compare the time to achieve NSR between patients in each group, the time to achieve 
NSR will be calculated for each patient.  For patients who do not convert to NSR by the 
time they are discharged from the hospital, the date/time that they achieve NSR will be 
the date/time of hospital discharge. The time to achieve NSR data will be analyzed for 
normality.  Normal data will be described by the mean and standard deviation, whereas 
non-normal data will be described by the median and interquartile range.  If one group is 
normal and one group is non-normal, both groups will be reported as non-normal data.  
The time to achieve NSR will then compared with either the 2-tailed, independent 
samples student t-test (normal data) or with the Mann-Whitney U test (non-normal data). 
 
• To compare the percentage of patients who achieve NSR by ICU discharge and hospital 
discharge, the number of patients in each group who have converted to NSR at each time 
point will be calculated and reported as number and percentage.  The number who have 


achieved NSR will be compared with the Fischer’s Exact test or the Chi-Square test, as 
appropriate. 
 
• To compare the percentage of patients who have recurrent AF before ICU discharge and 
hospital discharge, the number of AF episodes after the initial AF episode will be counted 
for each patient in each group prior to ICU discharge and prior to hospital discharge.  The 
mean (normal data) or median (non-normal data) number of additional AF episodes will 
be compared between the groups using the 2-tailed, independent samples student t-test 
(normal data) or with the Mann-Whitney U test (non-normal data). 
 
• To compare the incidence and severity of hypotension, the number of patients who 
develop hypotension will first be calculated and reported as number and percentage.  The 
number of patients with hypotension will be compared with the Fischer’s Exact test or the 
Chi-Square test, as appropriate .  The number of patients who develop mild, moderate, 
severe or very severe hypotension will then be calculated and reported as number and 
percentage.  The number of patients with each severity class will then be compared 
between groups using Somers’ D test for ordinal data. 
 
• To compare the incidence and severity of conduction abnormalities, the number of 
patients who develop bradycardia will first be calculated and reported as number and 
percentage.  The number of patients with bradycardia will be compared with the Fischer’s 
Exact test or the Chi-Square test, as appropriate.  The number of patients who develop 
mild, moderate, severe or very severe conduction abnormalities will then be calculated 


and reported as number and percentage.  The number of patients with each severity class 
will then be compared between groups using Somers’ D test for ordinal data. 
 
1.4 
Exploratory Objectives 
• To evaluate preoperative, intraoperative and postoperative factors that affect the efficacy 
of the amiodarone dosing strategy in achieving NSR at 24 hours, ICU discharge and 
hospital discharge, multiple variable logistic regression modeling will be constructed 
using any significant variable discovered in the bivariate analysis.  
• Evaluate preoperative, intraoperative and postoperative factors that affects the safety 
profile of the repeated amiodarone bolus dosing regimen, multiple variable logistic 
regression modeling will be constructed using any significant variable discovered in the 
bivariate analysis.