Clinical trial NCT01970501
Conditions: Current or Recent History of Atrial Fibrillation
Keywords: atrial fibrillation atrial flutter heart failure reduced left ventricle ejection fraction electrical cardioversion GENETIC-AF Medtronic bucindolol pharmacogenetic ARCA Toprol Toprol-XL Metoprolol Metoprolol succinate
Sponsor: ARCA Biopharma, Inc.
Start date: 2014-04-01; Completion date: 2017-12-28
Enrollment: 267 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to compare the effects of bucindolol hydrochloride (bucindolol) to metoprolol succinate (Toprol-XL) on the recurrence of symptomatic atrial fibrillation/atrial flutter in patients with heart failure who have a specific genotype for the beta-1 adrenergic receptor.

Detailed description:
The goal of the GENETIC-AF trial is to demonstrate the superiority of pharmacogenetically targeted bucindolol compared to metoprolol for the prevention of symptomatic atrial fibrillation or atrial flutter in a genotype-defined population with heart failure and/or reduced left ventricular ejection fraction at high risk of atrial fibrillation/atrial flutter recurrence.

Arms: arm 1: bucindolol hydrochloride (bucindolol)

Participants were randomized (1:1) to blinded treatment with bucindolol or metoprolol and titrated weekly to target doses of 50 mg twice daily (BID; \< 75 kg) or 100 mg BID (≥ 75 kg) for bucindolol or 200 mg once daily (QD) for metoprolol. 84% of bucindolol participants attained target dose and 72% of metoprolol participants attained target dose.

The lowest starting dose of bucindolol was 6.25 mg BID with weekly dose titrations to the weight-based target dose or to the maximum tolerated dose. The starting dose assigned was based on the patient's beta-blocker treatment prior to randomization. Capsules for titration were available in the following dosage strengths to be taken twice daily (with or without food): 6.25mg, 12.5mg, 25mg, 50mg, and 100mg. arm 2: metoprolol succinate (Toprol-XL)

Participants were randomized (1:1) to blinded treatment with bucindolol or metoprolol and titrated weekly to target doses of 50 mg twice daily (BID; \< 75 kg) or 100 mg BID (≥ 75 kg) for bucindolol or 200 mg once daily (QD) for metoprolol. 84% of bucindolol participants attained target dose and 72% of metoprolol participants attained target dose.

The lowest starting dose of metoprolol was 25 mg QD with weekly dose titrations to the target dose or to the maximum tolerated dose. The starting dose assigned was based upon the patient's beta-blocker treatment prior to randomization. Capsules for titration were available in the following dosage strengths to be taken twice daily (with or without food): 25mg, 50mg, 100mg, 200mg and/or matching placebo oral capsule to maintain blinded dosing.
Interventions: intervention 1: bucindolol hydrochloride intervention 2: metoprolol succinate intervention 3: Placebo oral capsule
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
ICF_002.pdf: 
[GENETIC-AF ICF v. 3.0 US]                                  
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Informed Consent Cover Page 
 
Study Title: 
GENETIC-AF – A Genotype-Directed Comparative Effectiveness 
Trial of Bucindolol and Toprol-XL for Prevention of 
Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with 
Heart Failure 
Sponsor: 
ARCA biopharma, Inc. 
10170 Church Ranch Way, Suite 100 
Westminster, Colorado 80021 
Phone: 720.940.2100 
Study Drug: 
Bucindolol hydrochloride (bucindolol) 
Comparator:  
Metoprolol succinate (Toprol-XL, metoprolol) 
IND No.: 
118,935 
Indication: 
Atrial Fibrillation 
NCT Number 
01970501 
Date:  
20 April 2022 
 
 
 
 
 
 
 
 


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CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Title of Study: GENETIC-AF – A Genotype-Directed Comparative Effectiveness Trial of 
Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in 
Patients with Heart Failure 
 
Investigator:  [name of site PI, contact information for PI and study team] 
 
WHAT ARE SOME GENERAL THINGS TO KNOW ABOUT RESEARCH STUDIES? 
This form is called an informed consent document or consent form. It contains a full explanation 
about the study in which you are being asked to participate.  Your participation is voluntary.  If 
you agree to participate after reading this document and asking questions about this study, you 
will be asked to sign your approval for consent. This consent form may contain words that you do 
not understand.  Please ask the study doctor or the study staff to explain any words or information 
that you do not clearly understand.   
 
You are being asked to take part in this research study because you have heart failure (HF), which 
is when the pumping power of the heart is weaker than normal.  You are also currently 
experiencing atrial fibrillation (AF), which is an abnormal, rapid heart rhythm, or have 
experienced AF in the last 4 months. 
 
WHO WILL PROVIDE FUNDING? 
ARCA biopharma, Inc. is paying [PI] and the doctor’s research staff to do this study. 
 
WHO WILL BE MY STUDY DOCTOR? 
If you decide to take part in the study, [PI] will be your study doctor. The study doctor may 
contact your regular doctor while you are in the study and afterwards, if needed. 
 
WHY IS THIS STUDY BEING DONE? 
This study is being done to compare the effects of bucindolol hydrochloride (bucindolol) to 
metoprolol succinate (Toprol-XL) on the recurrence of symptomatic AF in people who have HF 
and a specific genotype (called the β1389Arg/Arg AR variant). Your genotype consists of the 
inherited genes you received from your biological parents; differences between people’s genes 
can affect many things, from how they look to how they respond to medication. 
 
Both bucindolol and Toprol-XL belong to the class of drugs called beta blockers. Beta blockers 
reduce heart rate and lower blood pressure by blocking norepinephrine and epinephrine (stress 
hormones) from binding to certain receptors on heart cells known as beta adrenergic receptors.   
 
Bucindolol is an investigational drug, which means it is still being tested in research studies and 
has not been approved by the US FDA. A previous clinical study in HF patients found that 
patients who had the β1389Arg/Arg AR variant and received bucindolol were less likely to 
develop AF compared to patients who received placebo (a sugar pill). This effect was not seen in 
patients who did not have the β1389Arg/Arg AR variant. About 50% of people with HF have the 
β1389Arg/Arg AR gene variant.  
 


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Toprol-XL is approved in the US by the FDA to treat patients with HF and has been shown to 
decrease the rate of death and hospitalization in this patient population. Studies have also shown 
that Toprol-XL decreases the recurrence of AF when given to HF patients who have previously 
experienced AF. In the US, Toprol-XL is often prescribed for this purpose; however, the FDA has 
not approved it for this use.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
This study is being conducted in two phases, Phase 2B and Phase 3.  In Phase 2B, approximately 
200 patients will be enrolled at about 60 institutions in the United States and Canada. Phase 3 will 
begin after review of the Phase 2B data, unless the study is stopped early for any reason. 
Approximately 620 patients will be enrolled in Phase 3 at up to 200 institutions in the United 
States, Canada and other countries around the world. Patients who participate in Phase 2B of the 
study will continue to receive study drug during Phase 3.  
 
Approximately [number] patients will be enrolled at this institution.  
 
HOW LONG WILL I BE IN THIS STUDY? 
Patients will receive study drug for a minimum of 27 weeks and possibly as long as 4 years. All 
patients will continue in the study until the end of Phase 3. It is currently estimated it will take 
approximately 4 years from the time of study initiation to complete the study. 
 
You can choose to stop taking study drug or stop attending study visits at any time without 
penalty or loss of any benefits to which you are entitled. However, if you decide to stop 
participating in any part of the study, we encourage you to talk with your study doctor first.  
 
WHAT IS INVOLVED IN THE STUDY? 
If you agree to be in this study, you will be asked to sign this consent form before any study 
procedures are done. You will visit the study doctor at least 9 times in the first 6 months of the 
study, then once every 3 months until you stop the study.  You may require additional visits to 
manage your study drug dose, or if you experience an illness during the study. The study visits 
are described below: 
 
Screening 
The Screening Visit will take about 1-2 hours. During this visit, tests and procedures will be 
completed to see if you qualify for this research study.  The study staff will review the results of 
these tests and procedures with you.  If you do not qualify, you will be told why. 
 
At this visit the following procedures will be done: 
 
Collection of demographic information including date of birth, gender, ethnicity and race 
 
Collection of medical history (past and present illnesses/diseases, surgeries, smoking 
history and alcohol use) 
 
You will be asked about the medications you have taken and are currently taking 
o Some medications should not be taken with either bucindolol or Toprol-XL and 
some medications are not allowed on the study. You will be asked to discontinue 
these medications to participate in the study. Your study doctor will tell you 
which medications need to be stopped, as well as how and when to stop them. 
 
Records from tests that you have done in the past will be reviewed  
o If the test to measure your left ventricular ejection fraction (LVEF) was not done 
in the last 12 months, you will undergo additional testing to determine your 


[GENETIC-AF ICF v. 3.0 US]                                  
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LVEF. The LVEF is a measurement of the percentage of blood leaving your 
heart each time it contracts and is a general measure of a person’s heart function.  
 
Vital signs (sitting blood pressure, heart rate and respiratory rate), weight and height will 
be collected 
 
An electrocardiogram (ECG), which shows a tracing of the heart’s electrical activity, will 
be done 
 
Approximately 2 teaspoons (9 ml) of blood will be collected for lab safety tests and to 
check for the presence of the β1389Arg/Arg AR variant 
 
If you are female and able to have children, ½ teaspoon (3 ml) of blood will be collected 
to test for pregnancy; you cannot participate in this study if you are pregnant 
 
If you qualify for the study after completing all of the above, you will be scheduled to return to 
the clinic for the Randomization Visit within 28 days. 
 
Medtronic Device Substudy 
You will be asked to participate in a Medtronic Device Substudy to continuously monitor your 
heart rhythm using an implanted device.   
 
If you already have an eligible device, that device can be used for the substudy.  Eligible 
Medtronic devices include pacemakers, implantable cardioverter-defibrillators (ICD), cardiac 
resynchronization therapy (CRT) devices or insertable cardiac monitors (ICM). Only Medtronic 
devices can be used for the substudy.   
 
If you do not already have an eligible Medtronic device, your study doctor may choose to insert 
one as part of your regular medical care, or you can choose to have a Medtronic ICM inserted as 
part of this study after it is confirmed that you qualify for the study. The Medtronic ICM is 
approved by the US FDA for use in patients with AF. Discuss the best option for you with your 
study doctor.  
 
If you do choose to have an ICM inserted for this study, the insertion will occur after 
confirmation that you qualify for the study and up to 7 days after the Randomization Visit. The 
ICM insertion procedure takes between 5-20 minutes depending on the device model and can be 
done under local anesthetic. The doctor will make a small incision, creating a pocket the same 
size and shape of the ICM and place the device just under the skin of your chest to the left of your 
breastbone. 
 
You do not have to agree to participate in the Medtronic Device Substudy to participate in the 
study, but there will be a limited number of patients allowed to enroll without a device during 
Phase 2B of the study.  
 
DNA Bank Substudy 
If you agree, a portion of the blood sample collected at Randomization will be kept for future 
genetic tests; this is called DNA Banking. The DNA Bank may be used in future studies to look 
at genetic markers for AF or HF, and/or to determine if any specific genetic markers may predict 
how patients with AF or HF respond to treatment. The results of these tests will not be available 
to you or your study doctor. Your identity will never be stored with these results; your DNA 
sample will be identified only by a unique identification number, and every effort will be made to 
maintain your confidentiality. The sample may be kept for up to 15 years, but you can choose to 
have the sample destroyed early if you change your mind. You do not have to agree to provide a 
blood sample for the DNA Bank to participate in this study.  


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Randomization 
The Randomization Visit will take about 1 ½ hours and will take place within 28 days of the 
Screening Visit.  
 
At this visit the following procedures will be done: 
 
You will be asked about any changes to your health and medications since your last visit, 
including questions about your HF and AF symptoms 
 
You will be asked about the medications you are taking 
 
A physical exam including your weight and vital signs will be done 
 
You will complete a short questionnaire about your overall health 
 
Approximately 2 teaspoons (9 ml) of blood will be collected to measure heart function 
and to assess two additional genes that may influence the effects of the study drug    
o If you agree, part of this blood sample will be kept in a DNA Bank as described 
above  
 
If you are female and able to have children, a urine pregnancy test will be done; you 
cannot participate in this study if you are pregnant 
 
An ECG will be done 
 
If you are participating in the Medtronic Device Substudy, data will be downloaded from 
your device.   
 
Study Drug Randomization and Dosing 
After all of these procedures are complete and if you continue to qualify for the study, you will be 
randomized to receive either bucindolol or Toprol-XL. Randomized means that the study 
treatment you receive will be assigned by chance, like flipping a coin. Neither you nor your study 
doctor will ever know if you are taking bucindolol or Toprol-XL. However, your study doctor can 
find out what you are receiving in a medical emergency if necessary.  
 
 
Bucindolol will be provided in dosage strengths (amounts) of 6.25, 12.5, 25, 50 and 100 mg. 
Toprol-XL will be provided in dosage strengths of 25, 50, 100 and 200 mg. You will take two 
capsules a day. If you are assigned to bucindolol, both capsules will contain study drug; if 
you are assigned to Toprol-XL, one capsule will contain study drug and one will contain 
placebo (inactive drug). Since you will not know which study drug you have been assigned, it 
is important that you take both capsules every day as instructed by your study doctor. 
 
You will begin on a lower dose of study drug and your dose will be increased slowly over 
several weeks.  
 
At the Randomization Visit you will receive 1-2 cards of study drug.  Each card contains 
enough study drug for one week. You will take one capsule in the morning and one in the 
evening, with or without food. If you miss a dose, you may take it up to 6 hours after 
breakfast or dinner, but do not take two doses at the same time.   
 
Do not remove a capsule from the card until you are ready to take a dose; do not fill pill 
containers with the study drug. It is important that you leave all of the unused capsules in the 
card so your study doctor or nurse can count the number of capsules that you took. 
 
Dose Increases and Decreases 
After the Randomization Visit you will return to the clinic 2 or 3 more times over the next 4 to 5 
weeks to evaluate your response to the study drug and have your study drug dose increased or 
decreased as appropriate. 
 
You will return all study drug cards, including all unused capsules, at these visits and receive 
enough new study drug cards to last until your next visit.  


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 
You may be counseled on dosing instructions if you do not take the study drug as prescribed. 
 
Week 0 Study Visit / Start of Follow-up Period 
The Week 0/Start of Follow-up Visit will take place approximately 3 weeks after randomization.  
This visit can occur as early as 1 week, or as late as 5 weeks, after you begin the study drug, 
depending on your medical condition.  This visit will take approximately 4 hours. 
 
At this visit the following procedures will be done: 
 
You will be asked about any changes to your health and medications since your last visit, 
including questions about your HF and AF symptoms 
 
Vital signs and weight will be collected 
 
An ECG will be done on all patients, regardless of whether you entered the study with a 
regular heart rhythm or AF 
 
If you entered the study with AF and this ECG shows that you now have a 
regular heart rhythm, you will return to the clinic in 24 hours and approximately 
1 teaspoon (6 ml) of blood will be collected to measure how much study drug is 
in your blood. You should not take your study drug on the morning of the blood 
draw; the study doctor or nurse will remind you not to take your study drug dose 
on the morning of the blood draw visit. You will be asked to report the 
approximate times at which you took study drug for the previous 2 days or if you 
have missed any doses during this time period.  
 
If this ECG shows that you have AF, you will undergo a procedure called 
electrical cardioversion (ECV) to restore your heart’s regular rhythm. ECV is a 
standard treatment for AF during which an electric current is used to reset the 
heart's rhythm back to its regular pattern using metal paddles or patches applied 
to the chest. You may need to have the ECV procedure repeated at a later date if 
the first procedure is not successful.  
 
You will return all study drug cards, including all unused capsules, and receive enough 
new study drug cards to last until your next visit. You may be counseled on dosing 
instructions if you do not take the study drug as instructed. 
 
If you have a regular heart rhythm at the end of this visit (with or without having 
undergone ECV) you will be provided with a Transtelephonic Monitoring (TTM) device 
and instructed on its use as described below. 
 
Your heart rhythm will be assessed again on the day after this visit either in the clinic 
with an ECG or at home using the TTM device.  
 
Transtelephonic Monitoring (TTM) 
If you have a regular heart rhythm at the end of the Week 0/Start of Follow-up Visit (with or 
without having undergone ECV), you will be given a TTM device and instructed on its use (if 
you have AF at Week 0 and  the ECV does not result in regular heart rhythm you will not 
participate in TTM monitoring). The TTM device is used to record your heart rhythm and to send 
that information via telephone to the study’s Receiving Center for review by a study Cardiologist 
and entry into the study database.  
 
On the day after the Week 0 visit, you will use the TTM device to collect a single recording of 
your heart rhythm at least 24 hours after your Week 0 ECV, if applicable.   
 
You will use the TTM device to collect TWO recordings of your heart rhythm, at least 10 minutes 
apart at the following time points:  


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 
At 4-week intervals during the 24-week Follow-up Period of the study, beginning at 
Week 2. The TTM recording and transmission schedule is as follows: 
o Week 2, Week 6, Week 10, Week 14, Week 18, Week 22 
 
Any time you experience symptoms of AF or Atrial Flutter; within 2 hours of onset (up to 
Week 24) 
 
To perform a recording you will hold the TTM device (about the size of a deck of cards) against 
your bare chest and press the RECORD button for two seconds until an audible tone is heard, 
then release. Then you will hold as still as possible for approximately 60 seconds. The recording 
is complete when a ‘phone ringing sound’ is heard from the TTM device. You will then wait at 
least 10 minutes, and perform a second recording without deleting the first from the TTM device 
(except on Day 1 where only a single TTM recording is required). When the second recording is 
complete, you will call the Receiving Center using a toll-free contact number to transmit the data. 
The phone technician will ask you some questions about the symptoms you have been 
experiencing, and then will ask you to transmit the TTM data. The technician may not be able to 
tell you about your recordings, but will contact your study doctor if it is suspected that you have 
an abnormal heart rhythm. 
 
24-Week Follow-up Period: Weeks 4, 8, 12, 16, 20 and 24 
During the 24-Week Follow-up Period of the study, you will be asked to return to the clinic every 
4 weeks. These visits will take approximately 1 hour. 
 
At these visits, the following procedures will be done: 
 
You will be asked about any changes to your health and medications since your last visit, 
including questions about your HF and AF symptoms 
 
Vital signs and weight will be collected 
 
You will complete a short questionnaire about your overall health (Weeks 12 and 24 
only) 
 
Blood sample collection: 
 
Approximately 2½ teaspoons (11.5 ml) of blood will be drawn for lab safety tests 
and to measure heart function (Weeks 4, 12 and 24 only) 
 
Before your morning dose of study drug, approximately 1 teaspoon (6 ml) of 
blood will be drawn to measure the amount of study drug in your blood. You will 
be asked to report the approximate times you took your study drug dose for the 
previous 2 days or if you have missed any doses during this time period. The 
study doctor or nurse will remind you not to take your study drug dose prior to 
the visit. (Weeks 4 and 12 only) 
 
If you are participating in the Medtronic Device Substudy, data will be downloaded from 
your device (Weeks 12 and 24 only) 
 
An ECG will be done. 
 
You will return all study drug cards, including all unused capsules, and receive enough 
new study drug cards to last until your next visit. You may be counseled on dosing 
instructions if you do not take the study drug as instructed. 
 
You will return the TTM device, if applicable (Week 24 only) 
 
Treatment Extension Period 
After the Week 24 Visit, you will enter the Treatment Extension Period of the study and return to 
the clinic every 12 weeks. These visits will take approximately 1 hour. You will remain in the 
Treatment Extension Period and continue to receive study drug for up to 4 years. 
 


[GENETIC-AF ICF v. 3.0 US]                                  
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At the Treatment Extension Visits, the following procedures will be done:   
 
You will be asked about any changes to your health and medications since your last visit, 
including questions about your HF and AF symptoms 
 
Vital signs and weight will be collected 
 
Approximately 1 ½ teaspoons (6.5 ml) of blood will be collected for lab safety tests 
 
If you are participating in the Medtronic Device Substudy, data will be downloaded from 
your device  
 
An ECG will be done 
 
You will return all study drug cards, including all unused capsules, and receive enough 
new study drug cards to last until your next visit. You may be counseled on dosing 
instructions if you do not take the study drug as instructed. 
 
You will be asked to contact your study doctor or nurse if you notice any new or 
worsening AF symptoms during the treatment extension period. You may also be asked 
to provide a blood sample to measure your heart function. 
 
End of Study Visit 
When the study ends, you will be asked to return to the clinic for a final study visit that will take 
approximately 1 hour.  
 
At the End of Study Visit, the following procedures will be done: 
 
You will be asked about any changes to your health and medications since your last visit, 
including questions about your HF and AF symptoms 
 
Vital signs and weight will be collected 
 
Approximately 1 ½ teaspoons (6.5 ml) of blood will be collected for lab safety tests 
 
If you are participating in the Medtronic Device Substudy, data will be downloaded from 
your device  
 
An ECG will be done. 
 
You will return all study drug cards, including all unused capsules. 
 
Your study doctor may prescribe a different medication for you.  
 
You will be contacted approximately 3 days after this visit to check on your health status 
and medications 
 
You will be contacted yearly to check on your health status 
 
Early Discontinuation 
If you stop taking the study drug, you will be asked to return to the clinic and complete an End of 
Treatment Visit.  All of the procedures described above for the End of Study Visit will be 
completed. 
 
After you have stopped the study drug, will be asked to remain in the study and complete all of 
the regularly scheduled visits described above.  If you do not wish to continue in the study after 
stopping study drug, you will return to the clinic for an End of Study Visit as described above and 
then will be contacted yearly to check on your health status. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The possible risks and/or discomforts associated with treatments and procedures described in this 
consent form are detailed below.  There may be side effects that are not known at this time.  
 
Bucindolol and Toprol-XL 
Bucindolol is an investigational drug and is not approved by the US FDA for the treatment of HF 
or AF. Toprol-XL is FDA-approved for the treatment of HF but not for AF.  Hospitalization, 


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mortality and other HF outcomes will be monitored carefully by an independent safety board to 
assess potential risk. 
 
Bucindolol and Toprol-XL are both in the beta blocker class of drugs. Beta blockers should not 
be given to patients with pre-existing second or third degree heart block; sick sinus syndrome 
arrhythmias; very slow heart rate (severe bradycardia), unless controlled by a permanent 
pacemaker; or cardiogenic shock or decompensated HF requiring the use of IV inotropic 
medication (medication that changes the strength of heartbeats).   
 
Remember to talk to your doctor before stopping your study drug.  Stopping beta blockers 
quickly can result in worsening angina (chest pain), heart attack or irregular heartbeat.  
 
Toprol-XL may cause some, all, or none of the side effects listed below. 
 
 
tiredness 
 
dizziness 
 
depression 
 
shortness of breath 
 
slow heart rate (bradycardia) 
 
low blood pressure (hypotension) 
 
diarrhea 
 
itchy skin (pruritus) 
 
rash 
 
worsening angina 
 
heart attack (myocardial infarction) 
 
worsening HF 
 
worsening of the heart’s ability to send 
electrical impulses (AV block) 
 
accident and/or injury 
 
Bucindolol may cause some, all, or none of the side effects listed below. 
 
 
fatigue 
 
dizziness 
 
weight gain 
 
diarrhea 
 
joint pain (arthralgia) 
 
high blood sugar (hyperglycemia) 
 
stiff muscles (hypertonia)
 
low blood cells (anemia) 
 
back pain 
 
slow heart rate (bradycardia) 
 
lazy eye (amblyopia) 
 
sinus infection (sinusitis) 
 
high uric acid level in blood 
(hyperuricemia) 
 
Prior to starting bucindolol, patients should not be fluid overloaded (too much fluid in the 
tissues), as this is a symptom of worsening HF. Patients with a history of bronchial asthma or 
related bronchospastic conditions, especially those taking bronchodilators, should not take 
bucindolol. Patients with a history of severe anaphylactic reactions (severe allergic reactions that 
start quickly and may result in death) should not take bucindolol. There is little information about 
the use of bucindolol in patients with moderate to severe hepatic (liver) or severe renal (kidney) 
problems. Therefore, the use of bucindolol in these patients is not recommended.   
 
Cancer History 
In a previous bucindolol HF study, there was a higher number of patients in the bucindolol group 
who had a history of pre-cancerous tumors and/or cancer at the time they were enrolled (prior to 
receiving drug) compared to patients in the placebo group. At the end of the study, there were still 
more bucindolol patients with pre-cancerous tumors and/or cancer than placebo patients. You will 
be asked about your cancer history before you enter this study, and your health will be monitored 
thorough out the study.  If you have a history of cancer that was treated recently or has not been 
treated, you may not be eligible for this study. 
 


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Implanted ICM Device and Device Data Download 
Risks associated with the ICM and implant procedure include swelling, redness or irritation at the 
implant site; infection at the implant site, or movement of the device. 
 
Participating patients will have their device data downloaded periodically during the study. The 
download is painless and is done by placing a small box (about the size of a pager) over the 
device and waiting while the information is transmitted. There is no risk since this procedure only 
transmits data, device settings will not be changed by the transmission process.  
 
Electrical Cardioversion (ECV) 
ECV is a standard treatment for AF to reset the heart's rhythm back to its regular pattern. During 
this procedure, an electric current is directed to the heart using metal paddles or patches applied 
to the chest wall. ECV is a non-invasive therapy which takes a few minutes to complete. You will 
typically receive medication to control pain and cause relaxation. In some cases, the procedure 
may be repeated if the heart rhythm remains abnormal. Risks include slight reddening or irritation 
of the skin where the electrical energy was applied, a reaction to medications given for the 
procedure, worsening of your irregular heartbeat, or in rare cases, a blood clot. 
 
The cardioversion may or may not require the performance of a transesophageal echocardiogram 
(TEE), which involves passing a long, thin, flexible instrument down the throat to briefly look at 
the heart and how it is functioning. Possible risks associated with a TEE include, but are not 
limited to, breathing problems and damage to the esophagus. 
 
Standard ECG 
An electrocardiogram (ECG) shows the electrical tracings of your heart. You will be asked to lie 
down and remain still for a short period. Electrode patches will be attached to your arms, legs and 
chest. The ECG is painless. There is no risk of shock since this procedure only records electrical 
activity and does not send out electricity. Some patients may have itching, bruising, rash, or 
irritation at the spots where the patches were placed. 
 
Transtelephonic Monitoring (TTM) 
The TTM device records your heart rhythm; you will need to hold the device up to your bare 
chest for about 60 seconds. Recording your heart rhythm with the TTM device is painless. There 
is no risk of shock since this procedure only records electrical activity and does not send out 
electricity.  
 
Blood Samples 
Possible side effects from drawing blood include faintness, inflammation of the vein, mild pain, 
bruising, irritation, redness, or bleeding at the site of the puncture. In rare cases, you may get an 
infection.  
 
Genetic Testing 
Genetic testing will be done to test for the β1389Arg/Arg AR variant as well as for two other 
genes that could influence the effects of the study drug. In addition, if you agree to participate in 
the DNA Banking Substudy, a portion of the blood sample drawn at the Randomization Visit will 
be kept and potentially used in future genetic tests. 
 
Since these are genetic tests, there is a potential risk for loss of confidentiality. Every effort will 
be made to protect your confidential information, but this cannot be guaranteed. Information from 
which you may be personally identified will be maintained in a confidential, secure location, 
accessible only by authorized members of the study team, and will not be disclosed to third 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 11 of 17 
 
parties except as described in this consent form, with your permission, or as may be required by 
law.  
In the US, The Genetic Information Nondiscrimination Act (GINA) is a Federal law that will 
protect you in the following ways:  
 
Health insurance companies and group plans may not request genetic information from this 
research;  
 
Health insurance companies and group plans may not use your genetic information when 
making decisions regarding your eligibility or premiums;  
 
Employers with 15 or more employees may not use your genetic information when making a 
decision to hire, promote, or fire you or when setting the terms of your employment.  
 
GINA does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance. GINA also does not protect you against 
discrimination based on an already-diagnosed genetic condition or disease. 
 
Reproductive Risks for Females 
You may not take part in this study if you are female and pregnant, think you are pregnant or 
trying to get pregnant. If you are pregnant, there may be risks to you and the fetus that are not 
known at this time. If you are a woman who is able to get pregnant, pregnancy tests will be done.  
 
If you are sexually active, you must agree to use appropriate contraception for as long as you are 
taking the study drug. Medically acceptable contraceptives include: 
 
Surgical sterilization (such as a tubal ligation or hysterectomy) 
 
Approved hormonal contraceptives (such as birth control pills, patches, implants 
or injections) 
 
Barrier methods (such as a condom or diaphragm) used with a spermicide 
 
Intrauterine device (IUD), or 
 
Exclusive sex partner who has been surgically sterilized or a same sex partner.  
 
Contraceptive measures such as Plan B™, sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. If you become pregnant during this study or if you have 
unprotected sex, you must inform your study doctor immediately. If you become pregnant you 
should stop taking study drug; your study doctor will discuss the risks to you and your fetus. 
 
In addition, there may be uncommon or previously unknown problems that might occur. You 
should report any problems you have to the study team. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may or may not be direct medical benefit to you. The 
information that is learned from this study may benefit other people with the same condition as 
yours and may advance medical understanding of abnormal heart rhythms. You may benefit from 
being evaluated at regular intervals, as required by the study visit schedule. 
 
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY? 
You do not have to participate in this study. You can get treatment or care for your illness even if 
you are not in a research study. Your alternative choices are to continue your current treatment as 
is with no change. Other alternatives may include drug therapy to treat AF, catheter ablation 
procedure, an ablation of the AV node (cluster of cells between the atria and ventricles that slows 
the electrical current as it passes to the ventricles) followed by implantation of a permanent 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 12 of 17 
 
pacemaker, or an open heart operation. Your abnormal heart rhythm may also be treated with a 
pacemaker or other device that can activate when your abnormal heart rhythm occurs. Each of 
these treatments are available outside of the study and each has its own risks and benefits. You 
should think about all of your choices and talk with your doctor about them before you decide if 
you will take part in this study. 
 
WHAT PERSONAL HEALTH INFORMATION ARE YOU ASKING PERMISSION TO 
GET FROM MY MEDICAL RECORD?  
By signing this form, you authorize access to your medical record for study purposes.  
 
What information may be used and given to others? 
The study team will look at your personal and medical information. For example:  
 
Past and present medical records 
 
Research records including phone calls made as part of this research 
 
Records about your study visits 
 
Information gathered for this research about: 
o Physical exams 
o Laboratory, x-ray, and other test results 
o Records about procedures and implantable devices you have or receive 
 
Who may use and give out information about you? 
The study doctor and staff.   
 
Who will get this information? 
The Sponsor of this research, ARCA biopharma, Inc. “Sponsor” means any persons or companies 
that are working for, or with, the Sponsor, or are owned by the Sponsor. 
 
Your information may be given to:  
 
The US Food and Drug Administration (FDA), Department of Health and Human 
Services agencies, Health Canada and other governmental agencies  
 
The Review Board for this institution who reviewed and approved this study  
Why will this information be used and/or given to others? 
 
to do the research 
 
to study the results 
 
to see if the research was done correctly  
 
If the results of this study are made public, information that identifies you will not be used.  
 
If you want to participate in this study, you have to sign this authorization to allow access to your 
medical records. If you choose to not sign it, you are still able to receive medical treatment not 
related to the study. If you do sign it, you can change your mind later by writing a letter that states 
you are taking back your permission. Mail the letter to [Address] or you can send us an email at 
[email address]. Stopping your authorization will prevent sharing of information in the future, 
but will not affect any information that has already been shared.   
 
Research information collected about you might be put in your medical record. It is possible that 
you may not be able to see some of the research study information that has become part of your 
medical record until the entire research study is over. 
 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 13 of 17 
 
The permission you give us to access your medical record will last until the end of the study. You 
will be given a copy of this authorization. 
 
If the results of this study are made public, information that identifies you will not be used.  
 
HOW WILL MY PRIVACY BE PROTECTED? 
We will not use your name or your identity for publication or publicity purposes. Wherever 
possible, study records that identify you will be kept confidential and you will not be identified 
by name, address, telephone number, or any other direct personal identifier in study records 
disclosed outside of [INSTITUTION/HEALTHCARE PROVIDER]. 
 
Your entire medical record will be reviewed by the Sponsor and may be reviewed by the US 
FDA, Health Canada, Health Authorities, Government agencies, or any other applicable agency 
for the purpose of confirming the accuracy of the research data.  
 
A copy of this consent form will go into your medical record. This will allow the doctors caring 
for you to know what study medications or tests you may be receiving as a part of the study and 
know how to take care of you if you have other health problems or needs during the study. 
 
A description of this clinical study will be available on http:www.ClinicalTrials.gov. This website 
will not include information that can identify you. At most, the website will include a summary of 
the results. You can search this website at any time. 
 
WHAT ARE THE COSTS TO ME IF I PARTICIPATE IN THIS STUDY? 
ARCA biopharma, Inc. will provide the study drug free of charge for your use in this study as 
well as pay for any tests and procedures that are required for this study but are not considered to 
be part of your routine medical care or medically indicated for your condition. 
 
(Select the best option regarding device reimbursement for the substudy, based on your site 
contract:) 
Sponsor pay option: 
ARCA biopharma, Inc will also pay for the cost of the ICM, implant procedure and removal 
procedure, for patients participating in the Medtronic Device Substudy.   
 
Insurance pay option: 
For those patients participating in the Medtronic Device Substudy: new ICMs are approved for 
people with AF but are not always considered necessary, so these cost may be denied by your 
insurance provider. If the claim is denied, Medtronic (the device manufacturer) will provide your 
doctor with guidance on how best to file the claim. If the claim is rejected twice, then Medtronic 
has agreed to pay for the ILR. New therapeutic devices (e.g., pacemakers) are considered 
standard of care and will not be reimbursed by Medtronic.  
 
You may wish to contact your insurance representative to discuss costs further before making 
your decision about participating in the study.  
 
You and/or your insurance provider will be responsible for all costs related to your routine 
medical care, which is care you would have received whether or not you were part of this study.  
 
 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 14 of 17 
 
WHAT ABOUT COMPENSATION? 
You will not be paid for participation in this study [OR] You will be reimbursed up to $_____ for 
your expenses related to your participation to cover your parking, gas, and time.  
 
WHAT IF I AM INJURED?  
Immediate necessary medical care is available at [medical center] in the event that you are 
injured as a result of your participation in this research study.  
 
If you are injured as a direct result of any properly performed procedure (carried out according to 
the protocol), the Sponsor will pay for reasonable costs related to your treatment that is not 
covered by your health insurance. Treatment must be authorized by the study doctor except in the 
event of an emergency (in which case the study doctor should be notified as soon as possible). 
Payment for lost wages, disability, discomfort, etc. due to injury is not available. Further 
information regarding medical treatment, reimbursement, or a research related injury can be 
obtained from [insert name here]. By signing this form you do not give up any of your legal 
rights. 
 
If you have questions about this study, or have a research related injury or illness claim, you 
should contact the study doctor at the phone number listed on page 1 of this form. If you have any 
questions regarding your rights as a research patient, you may contact the Ethics 
Committee/Institutional Research Office at: [name and contact information of Ethics 
Committee/Institutional Research Office] 
 
For questions about the study or research-related injury, contact Dr. [ PI] at [phone number here 
with area code] during regular business hours or at [PI’s 24-hour number with area code] after 
hours and on weekends and holidays. 
 
WHAT IF I WANT TO STOP BEFORE MY PART IN THE STUDY IS COMPLETE? 
You can stop taking study medication or withdraw from this study at any time, without penalty. 
The investigators also have the right to stop your participation at any time. This could be because 
you have had an unexpected reaction, or have failed to follow instructions, or because the entire 
study has been stopped. If you withdraw your participation, no new information will be collected 
but we will use data that has already been collected.  
 
If you need to stop study drug for any reason during the study, or if you decide to stop the study, 
you will be asked to complete an End of Treatment/Study Visit as described above. Remember to 
tell your study doctor before you stop the study drug because stopping the drug suddenly may 
harm you. You must return all study drug cards (used and unused) and the TTM device when you 
stop the study. 
 
NEW FINDINGS 
If important new findings come up that might change your decision to be in this study, you will 
be given information about those findings as soon as possible. If you choose to stay in the study, 
you may be asked to sign a new version of the consent form. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have complaints, concerns or 
suggestions about the research, contact Dr. [PI] at [PI’s number with area code] during regular 
business hours and at [PI’s 24-hour number with area code] after hours or on a weekend or 
holiday. 
 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 15 of 17 
 
For questions about your rights as a research participant, contact [the REB name and contact 
number] 
 
 
 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 16 of 17 
 
STATEMENT OF CONSENT  
The purpose of this study, the procedures to be followed and the study’s risks and benefits have 
been explained to me. I have been allowed to ask questions and my questions have been answered 
to my satisfaction. I have been told whom to contact if I have questions, to talk about problems, 
concerns, or suggestions related to the research, or to obtain information or offer input about the 
research. I have read this consent form (or it has been read to me) and I agree to be in this study, 
with the understanding that I may withdraw at any time. I have been told that I will be given a 
copy of this consent form and that a copy of this form will become part of my medical record. 
 
I authorize the use and disclosure of health information from my medical record to the people or 
groups identified in this consent form for the purposes described in this document.  
I have read the information provided above.  I have asked all the questions I have at this time. I 
voluntarily agree to participate in this research study. 
 
OPTIONAL Medtronic Device Substudy: 
I wish to participate in the Medtronic Device Substudy as described in this consent form. 
 
 YES 
 
 NO  
 
OPTIONAL DNA Bank Substudy:  
I wish to participate in the collection of a blood sample for the DNA Bank Substudy. I understand 
that I can change my mind at any time, and that withdrawing this sample will not affect my 
participation in the study. 
   
 YES 
 
 NO 
 
 
 
_____________________________________________________ 
 
__________________ 
Signature of Research Patient 
 
 
Date 
 
_____________________________________________________ 
Printed Name of Research Patient 
 
_____________________________________________________ 
 
__________________ 
Signature of Research Team Member Who Obtained Consent 
 
 
Date 
 
_____________________________________________________ 
Printed Name of Research Team Member Who Obtained Consent 
 
 


[GENETIC-AF ICF v. 3.0 US]                                  
                 Page 17 of 17 
 
This section should only be completed when a patient requests or has a need to prematurely 
and permanently discontinue study participation. 
Premature Discontinuation of Study Participation & Agreed Method of Contact after 
Discontinuation 
Please note agreed method of contact if patient wishes to discontinue study participation.  
To be filled in by the investigator or delegate and signed by the patient: 
Protocol: BUC-CLIN-303 
Patient Initials: ________________ 
 
Site Number: ________________ 
Patient ID: __________________  
 
Date of discontinuation of study drug: ………………………………………………………  
Agreed method of contact: 
 I do not want to continue treatment or attend further follow-up visits. I agree that you 
may continue to contact me and have access to my medical records to assess the status of 
my health.  
 I do not want to continue treatment, study visits or follow up. I withdraw my consent to 
further participation in the study.  
 
____________________________________ 
__________________________ 
Signature of Patient 
Date of Signature 
____________________________________ 
Printed name of Patient (BLOCK CAPITALS) 
 
     ____________________________________ 
__________________________ 
      Signature of witness 
Date of Signature 
 
 
      ____________________________________ 
      Printed name of witness (BLOCK CAPITALS)  
 
 

Prot_000.pdf: 
 
 
IND 118,935 
Page 1 of 98 
CONFIDENTIAL  
 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
GENETIC-AF – A Genotype-Directed Comparative Effectiveness Trial 
of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial 
Fibrillation/Atrial Flutter in Patients with Heart Failure 
Sponsor: 
ARCA biopharma, Inc. 
11080 CirclePoint Road, Suite 140 
Westminster, Colorado 80020 
Phone: 720.940.2100 
Study Drug: 
Bucindolol hydrochloride (bucindolol) 
Comparator:  
Metoprolol succinate (Toprol-XL, metoprolol) 
IND No.: 
118,935 
Indication: 
Atrial Fibrillation 
Protocol ID: 
BUC-CLIN-303 
EudraCT Number 
2016-000302-12 
Protocol Version: 
Version 4.0 
Date:  
29 January 2016 
Ethics Statement: 
The study will be completed according to the ICH guidelines of Good 
Clinical Practice. Compliance with this standard provides public 
assurance that the rights, safety, and well-being of trial patients are 
protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
Proprietary Notice: 
The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in 
whole or in part without the expressed, written consent of ARCA 
biopharma, Inc. 
 
 
 


 
 
ARCA biopharma Inc. 
Bucindolol HCl 
Protocol BUC-CLIN-303 
Version 4.0 
IND 118,935 
Page 2 of 98 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
SYNOPSIS ......................................................................................................................................... 6 
2.0 
BACKGROUND ............................................................................................................................. 14 
2.1 
Atrial Fibrillation in Patients with Heart Failure ..................................................................... 14 
2.1.1 Relationship of AF to Clinical Outcomes .................................................................... 14 
2.1.2 Treatment of Atrial Fibrillation in Heart Failure ......................................................... 15 
2.1.3 -Blocker Therapy for Prevention of Atrial Fibrillation .............................................. 16 
2.2 
Rationale for Pharmacogenetic Targeting of Bucindolol Therapy .......................................... 17 
2.2.1 Genotype-Dependent Effects on Clinical Outcome in HFREF Patients ...................... 17 
2.2.2 Genotype-Dependent Effects on New Onset AF in HFREF Patients .......................... 19 
3.0 
STUDY PLAN ................................................................................................................................. 21 
3.1 
Study Rationale ....................................................................................................................... 21 
3.2 
Study Objectives...................................................................................................................... 22 
3.3 
Study Design ........................................................................................................................... 22 
3.4 
Study Visits ............................................................................................................................. 24 
4.0 
PATIENT POPULATION ............................................................................................................. 25 
4.1 
Number of Patients and Study Centers .................................................................................... 25 
4.2 
Patient Characteristics and Screening Procedures ................................................................... 26 
4.2.1 Inclusion Criteria ......................................................................................................... 26 
4.2.2 Exclusion Criteria ........................................................................................................ 27 
5.0 
STUDY DRUGS AND DEVICES .................................................................................................. 29 
5.1 
Investigational Agent .............................................................................................................. 29 
5.2 
Active Comparator .................................................................................................................. 30 
5.3 
Dose Rationale ........................................................................................................................ 31 
5.4 
Risk/Benefits ........................................................................................................................... 31 
5.5 
Dosage and Administration of Study Drug ............................................................................. 32 
5.6 
Randomization and Blinding ................................................................................................... 34 
5.7 
Description and Handling of Study Drug ................................................................................ 35 
5.7.1 Formulation .................................................................................................................. 35 
5.7.2 Packaging and Labeling ............................................................................................... 35 
5.7.3 Storage and Handling ................................................................................................... 35 
5.8 
Concomitant and Prohibited Medications ............................................................................... 36 
5.9 
Medtronic Devices for AF Burden Substudy .......................................................................... 36 
5.9.1 System Description and Intended Use of Reveal ICM ................................................ 37 
5.9.2 Reveal Insertable Cardiac Monitor .............................................................................. 38 
5.9.3 Medtronic CareLink Programmer ................................................................................ 38 
5.9.4 Reveal Patient Assistant ............................................................................................... 38 
5.9.5 Medtronic CareLink Monitor ....................................................................................... 38 
5.9.6 Medtronic CareLink Network ...................................................................................... 38 
6.0 
STUDY PROCEDURES ................................................................................................................. 39 
6.1 
Timing of Study Procedures .................................................................................................... 39 
6.1.1 Screening and Randomization ..................................................................................... 39 
6.1.1.1 Screening Visit ............................................................................................ 39 
6.1.1.2 Randomization Visit .................................................................................... 40 
6.1.2 Drug Lead-In Period .................................................................................................... 41 
6.1.2.1 Drug Titration Visits .................................................................................... 41 
6.1.3 Start of 24-Week Follow-up Period (Week 0 Visit) .................................................... 41 
6.1.3.1 Patients in Stable SR Who Do Not Require ECV ....................................... 42 


 
 
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Bucindolol HCl 
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Version 4.0 
IND 118,935 
Page 3 of 98 
CONFIDENTIAL 
6.1.3.2 Patients in AF/AFL Who Require ECV ...................................................... 43 
6.1.4 24-week Follow-Up Period .......................................................................................... 44 
6.1.4.1 Clinic Visits during the 24-week Follow-up Period .................................... 45 
6.1.4.2 Telephone Contact during the 24-week Follow-up Period .......................... 45 
6.1.5 Treatment Extension Period and End of Study ............................................................ 46 
6.1.5.1 Treatment Extension Visits.......................................................................... 46 
6.1.5.2 End of Study Visit ....................................................................................... 47 
6.1.6 Premature Discontinuation of Study Drug ................................................................... 47 
6.1.6.1 End of Treatment Visit ................................................................................ 48 
6.1.7 Premature Study Withdrawal ....................................................................................... 49 
6.1.8 Study and Site Discontinuation .................................................................................... 49 
6.2 
Description of Study Procedures ............................................................................................. 50 
6.2.1 Medical History, Diagnostic Test History, and Physical Exam ................................... 50 
6.2.2 Vital Signs, Height and Weight ................................................................................... 50 
6.2.3 Electrical Cardioversion ............................................................................................... 50 
6.2.4 Electrocardiogram ........................................................................................................ 51 
6.2.5 Medtronic Device Procedures ...................................................................................... 52 
6.2.5.1 Implantation of Medtronic Device ............................................................... 52 
6.2.5.2 Programming Requirements ........................................................................ 53 
6.2.5.3 Device Data Interrogations .......................................................................... 54 
6.2.5.4 Device System Modification ....................................................................... 54 
6.2.6 AF Symptoms Questionnaire ....................................................................................... 54 
6.2.7 NYHA Functional Class .............................................................................................. 55 
6.2.8 Clinical Laboratory Tests ............................................................................................. 55 
6.2.9 Required Genetic Analyses (β1389, α2C, CYP2D6) ..................................................... 56 
6.2.10 Optional Genetic Analyses (DNA Bank) ..................................................................... 57 
6.2.11 Population Pharmacokinetic Analysis ......................................................................... 58 
6.2.12 Clinical Events Assessment ......................................................................................... 58 
6.2.13 EQ-5D Questionnaire ................................................................................................... 59 
6.2.14 Concomitant Medications ............................................................................................ 59 
6.2.15 Study Drug Compliance ............................................................................................... 59 
6.3 
Protocol Deviations ................................................................................................................. 59 
7.0 
ASSESSMENTS OF SAFETY ....................................................................................................... 60 
7.1 
Definition of Adverse Events .................................................................................................. 60 
7.2 
Assessment of Adverse Events ................................................................................................ 61 
7.2.1 Assessment of Causality .............................................................................................. 61 
7.2.2 Assessment of Intensity ............................................................................................... 62 
7.3 
Serious Adverse Events ........................................................................................................... 62 
7.3.1 Definition of Serious Adverse Events .......................................................................... 62 
7.3.2 Serious Adverse Event Reporting Requirements ......................................................... 63 
7.3.2.1 Standard Reporting Requirements ............................................................... 63 
7.3.2.2 Expedited Reporting Requirements ............................................................. 64 
7.3.2.3 Post-Study Reporting Requirements ............................................................ 64 
7.4 
Device Related Safety Reporting Requirements ..................................................................... 65 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments .................................. 65 
7.6 
Neoplasms ............................................................................................................................... 65 
7.7 
Overdose .................................................................................................................................. 66 
7.8 
Pregnancy ................................................................................................................................ 67 
7.8.1 Definition of Childbearing Potential and Post-Menopausal ........................................ 67 
8.0 
STATISTICAL CONSIDERATIONS........................................................................................... 68 
8.1 
Definitions of Analysis Populations and Endpoint Follow-up Periods ................................... 68 


 
 
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Bucindolol HCl 
Protocol BUC-CLIN-303 
Version 4.0 
IND 118,935 
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CONFIDENTIAL 
8.2 
Study Population Analyses ...................................................................................................... 69 
8.3 
Primary Endpoint .................................................................................................................... 70 
8.4 
Secondary Endpoints ............................................................................................................... 72 
8.5 
Tertiary Endpoints ................................................................................................................... 73 
8.6 
Safety Endpoints...................................................................................................................... 74 
8.7 
Optional Substudies ................................................................................................................. 75 
8.8 
Power and Sample Size ........................................................................................................... 76 
8.9 
Interim Analyses...................................................................................................................... 77 
8.10 Significance ............................................................................................................................. 77 
8.11 Deviation Reporting ................................................................................................................ 77 
9.0 
RESPONSIBILITIES ..................................................................................................................... 78 
9.1 
Trial Conduct ........................................................................................................................... 78 
9.1.1 Ethical Considerations ................................................................................................. 78 
9.1.2 Conflict of Interest Policy ............................................................................................ 78 
9.1.3 Quality Control and Quality Assurance ....................................................................... 78 
9.1.4 Steering Committee ..................................................................................................... 79 
9.1.5 Data and Safety Monitoring Board .............................................................................. 79 
9.1.6 Clinical Events Committee .......................................................................................... 80 
9.1.7 Clinical Research Organization ................................................................................... 80 
9.2 
Investigator Responsibilities ................................................................................................... 81 
9.2.1 Good Clinical Practice ................................................................................................. 81 
9.2.2 Institutional Review Board/Independent Ethics Committee Approval ........................ 82 
9.2.3 Informed Consent......................................................................................................... 82 
9.2.4 Confidentiality ............................................................................................................. 82 
9.2.5 Study Files and Retention of Records .......................................................................... 83 
9.2.6 Case Report Forms ....................................................................................................... 84 
9.2.7 Drug Accountability ..................................................................................................... 84 
9.2.8 Inspections ................................................................................................................... 84 
9.2.9 Protocol Compliance .................................................................................................... 85 
9.3 
Sponsor Responsibilities ......................................................................................................... 85 
9.3.1 Protocol Modifications ................................................................................................. 85 
9.3.2 Clinical Study Reports ................................................................................................. 85 
9.4 
Joint Investigator/Sponsor Responsibilities ............................................................................ 85 
9.4.1 Access to Information for Monitoring ......................................................................... 85 
9.4.2 Access to Information for Auditing or Inspections ...................................................... 86 
9.4.3 Study Discontinuation .................................................................................................. 86 
9.5 
Publication Committee ............................................................................................................ 86 
9.5.1 Data Analysis and Release of Results .......................................................................... 86 
9.5.2 Review Process ............................................................................................................ 86 
9.5.3 Authorship: Primary Outcome Paper ........................................................................... 87 
9.5.4 Authorship: Other Study Papers, Abstracts and Presentations .................................... 87 
10.0 REFERENCES ................................................................................................................................ 88 
11.0 APPENDICES ................................................................................................................................. 91 
 
 
 


 
 
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Version 4.0 
IND 118,935 
Page 5 of 98 
CONFIDENTIAL 
TABLE OF FIGURES 
Figure 1: 
New Onset AF in the BEST Trial for β1389 Subgroups ................................... 21 
Figure 2: 
GENETIC-AF Study Visit Schedule ................................................................ 25 
Figure 3: 
Components of the Medtronic Reveal ICM System ......................................... 37 
 
LIST OF TABLES 
Table 1: 
New Onset AF in BEST and Relationship to Annualized Clinical Outcomes .. 15 
Table 2: 
Meta-analysis of New Onset AF from β-blocker Heart Failure Trials.............. 16 
Table 3: 
Major Clinical Endpoints in the BEST trial by Genotype Subgroup ................ 18 
Table 4: 
New Onset AF in the BEST DNA Substudy by β1389 Arg/Gly Genotype ...... 20 
Table 5: 
Study Drug Titration Schedule.......................................................................... 33 
Table 6: 
System Component Information ....................................................................... 37 
Table 7: 
ICM Device Programming Requirements ......................................................... 53 
Table 8: 
Programming Parameters for Medtronic IPG, ICD or CRT devices ................ 54 
Table 9: 
New York Heart Association Functional Class................................................. 55 
Table 10: 
Power for Primary Endpoint: 620 Patients and Alpha = 0.01 ........................... 76 
Table 11: 
Power for Primary Endpoint: 620 Patients and Alpha = 0.05 ........................... 77 
 
 
 


 
 
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Bucindolol HCl 
Protocol BUC-CLIN-303 
Version 4.0 
IND 118,935 
Page 6 of 98 
CONFIDENTIAL 
1.0 SYNOPSIS 
Name of Sponsor/Company 
ARCA biopharma, Inc. 
Name of Test Product 
bucindolol 
Name of Active Ingredient 
bucindolol hydrochloride 
IND / Protocol Number 
118,935 / BUC-CLIN-303 
Phase / Indication 
Phase 2B-3 / Atrial Fibrillation 
Version / Date 
Version 4.0 / 29 January 2016 
Study Title: GENETIC-AF: A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and 
Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure. 
Study Rationale:  Most anti-arrhythmic agents currently approved for the treatment of atrial fibrillation 
(AF) and atrial flutter (AFL) are either contraindicated or have label warnings for use in heart failure (HF) 
patients due to an increased risk of mortality in this patient population. 
Bucindolol hydrochloride (bucindolol) is a nonselective β-adrenergic receptor (AR) blocking agent with 
mild vasodilator properties, which was previously studied in the BEST Phase 3 HF trial.  In a large 
pharmacogenomic substudy of the BEST trial, two unique pharmacologic properties of bucindolol, 
sympatholysis and inverse agonism, were shown to interact with AR polymorphisms in such a way that 
targeting specific genotypes of these variants could improve therapeutic index.  Specifically, patients with 
the β1389Arg/Arg AR variant had more efficacious treatment responses to bucindolol, as assessed by HF 
clinical outcomes and the reduction of new onset AF, compared to patients with the β1389Gly 
polymorphism (i.e., Gly carriers). 
Metoprolol succinate (Toprol-XL, henceforth referred to as metoprolol) is a β1-AR selective β-blocker 
indicated for the treatment of stable, symptomatic (NYHA Class II or III) HF of ischemic or non-ischemic 
origin.  Metoprolol has demonstrated mild efficacy for the prevention of new onset AF in a HF patient 
population and is often used off-label in this setting (Class IIa indication with a "C" level of evidence for 
AF prevention per ACC/AHA/ESC Joint Guidelines).  In a previous study, metoprolol decreased the 
incidence of AF recurrence, compared to placebo, in patients with persistent AF who had recently 
undergone electrical cardioversion (ECV) to sinus rhythm (SR).  In contrast to bucindolol, metoprolol 
does not appear to confer added clinical benefits in HF with reduced left ventricle ejection fraction 
(HFREF) patients that possess the β1389Arg/Arg AR variant.  In addition, limited data from the MERIT-
HF DNA substudy did not indicate any evidence of a β1389 Arg/Gly polymorphism differential effect for 
preventing AF. 
The goal of the GENETIC-AF trial is to demonstrate the superiority of pharmacogenetically targeted 
bucindolol compared to metoprolol for the prevention of symptomatic AF/AFL in a genotype-defined 
β1389Arg/Arg HFREF population at high risk of AF/AFL recurrence.  The trial utilizes an interim 
analysis/adaptive design element that will examine preliminary data from the initial Phase 2B population.  
If the independent Data and Safety Monitoring Board (DSMB) determines that the preliminary Phase 2B 
data are consistent with pre-trial assumptions (i.e., absence of futility, event rate), the trial will proceed to 
Phase 3.  
Objectives:  The primary objective of this study is to compare the effects of bucindolol and metoprolol on 
the recurrence of symptomatic AF/AFL in patients with HFREF who have a β1389 arginine homozygous 
(β1389Arg/Arg) genotype. 
The secondary objectives of this study are to compare the effects of bucindolol and metoprolol on clinical 
outcomes and other electrocardiographic parameters, and to assess the effects on rate control in patients 
who have developed recurrent AF/AFL. The safety and tolerability of bucindolol and metoprolol will also 
be evaluated. 


 
 
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Study Design:  GENETIC-AF is a double-blind, two-arm, genotype-directed, active-controlled, adaptive-
designed, superiority study that compares the effects of bucindolol and metoprolol on the time to first 
event of symptomatic AF/AFL in HFREF patients in SR who are at high risk of AF/AFL recurrence.  
Two patient populations at high risk of AF/AFL recurrence will be included in this study: 1) patients with 
symptomatic paroxysmal or persistent AF who are indicated for ECV to attain SR, and; 2) patients in SR 
who have experienced a recent episode (i.e., ≤ 180 days) of paroxysmal or persistent AF who are 
indicated for ECV to attain SR if AF/AFL recurs.  Patients must have HF, a left ventricle ejection fraction 
(LVEF) < 0.50 in the past 12 months, and no contraindication for -blocker therapy.  -blocker therapy is 
permitted at screening but is not required to be eligible for the study.  Patients must be receiving optimal 
anticoagulation therapy for stroke prevention prior to randomization.  Patients will be genotyped for 
1389 AR at screening and those who are 1389Arg/Arg (50% of patients) will be randomized to study 
drug. 
A subset of patients participating in the trial will have their cardiac rhythm continuously monitored to 
assess AF burden (AFB).  AFB monitoring will be done via the Medtronic Reveal insertable cardiac 
monitor (ICM) or a Medtronic pacemaker (IPG), implantable cardioverter-defibrillator (ICD), or cardiac 
resynchronization therapy (CRT) device with a minimum of an atrial and a ventricular lead.  Patients 
participating in the optional AFB substudy must either have a pre-existing Medtronic device that can 
measure AFB, or agree to have one inserted as clinically indicated.  Patients who agree to have a 
Medtronic device inserted may do so at the Randomization Visit or at any time prior to the start of the 24-
week Follow-up Period.    
Eligible patients will be randomized (1:1) to blinded treatment with bucindolol or metoprolol (i.e., study 
drug) and up-titrated weekly to target doses of 50 mg BID (< 75 kg) or 100 mg BID (≥ 75 kg) for 
bucindolol or 200 mg QD for metoprolol.  Randomization will be centralized and stratified by: 1) HF 
etiology (ischemic vs. non-ischemic); 2) LVEF (< 0.35 vs. ≥ 0.35); 3) type of Medtronic device (Reveal 
vs. Non-Reveal vs. No Device), and; 4) rhythm status at randomization (SR vs. AF/AFL).  
Patients in AF at randomization who do not spontaneously convert to stable SR and are in AF/AFL after 
3 weeks of treatment with study drug will undergo ECV to establish stable SR. Patients in SR at 
randomization who are in AF/AFL after 3 weeks of study drug treatment will also undergo ECV to 
establish stable SR. Patients in SR at randomization who are in stable SR after 3 weeks (± 3 days) of study 
drug treatment will start the 24-week Follow-up Period at the Week 0 Visit.   
ECV may be performed as early as 1 week after randomization if all of the following conditions are met: 
1) the patient is receiving the target dose of study drug; 2) the patient is receiving guideline indicated oral 
anticoagulation therapy for stroke prevention, and; 3) a delay of ECV could be detrimental to patient 
outcome.  The first ECV attempt may also be performed as late as 8 weeks after randomization if, in the 
opinion of the Investigator, additional time is needed to attain target doses of study drug or to achieve 
appropriate anticoagulation status prior to ECV.  
The primary endpoint, i.e., time to first event of symptomatic AF/AFL or all-cause mortality (ACM), will 
be assessed during the 24-week Follow-up Period after establishment of stable SR on study drug. For 
patients requiring ECV, establishment of stable SR will be confirmed by electrocardiogram (ECG) at least 
1 hour post-ECV.  Patients who do not demonstrate stable SR following ECV will undergo a subsequent 
ECV to establish a baseline SR unless, in the opinion of the Investigator, it would not be the best course 
of treatment for the patient. The 24-week Follow-up Period will begin on the day of: 1) the ECG that 
establishes stable SR; 2) the last ECV attempt for patients who fail to convert to stable SR, or; 3) the 
Week 0 Visit for patients in AF/AFL who do not undergo ECV for any reason. 
During the 24-week Follow-up Period, heart rhythm will be assessed by 12-lead ECG at scheduled clinic 
visits. At the time of each ECG assessment, patients will be queried for symptoms potentially related to 
AF/AFL. Scheduled telephone contacts will occur at Week 6, Week 10, Week 14, Week 18 and Week 22.  
Patients will be also be instructed to contact the site immediately if they experience new or worsening 


 
 
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symptoms.  Patients will be queried for symptoms potentially related to AF/AFL during the scheduled and 
patient-initiated telephone contacts.  If the Investigator suspects that a new AF/AFL event has occurred 
between scheduled clinic visits (i.e., a change in rhythm from SR to AF/AFL), the patient will be 
instructed to return to the clinic within 3 business days for further assessments. Patients experiencing 
recurrence of AF/AFL will be encouraged to remain on blinded study drug and may undergo subsequent 
ECV procedures or medical interventions as clinically indicated.   
After the Week 24 Visit, patients will enter the Treatment Extension Period and continue to receive 
blinded study drug.  Phase 3 follow-up will continue until a total of at least 330 primary endpoint events 
have been observed.  After this event, all patients will complete the 24-week Follow-up Period or return to 
the clinic for an end of study visit if already in the Treatment Extension Period.  At the end of the study, 
patients will discontinue study drug and should transition to commercially-available β-blocker therapy per 
Investigator discretion.  Investigators and patients will not be informed of the blinded study drug 
assignment at the time of study completion. 
Number of Patients:  Approximately 250 patients will be randomized in Phase 2B and an additional 370 
patients will be randomized in Phase 3 (i.e., a total of 620 patients). The 1389Arg/Arg genotype is 
expected in approximately 50% of screened patients; therefore, a 65% screen-fail rate is assumed for the 
study (15% for general criteria and a 50% screen-fail rate due to genotype). 
The DSMB will examine preliminary data from the initial Phase 2B population to assess the presence or 
absence of futility for proceeding to Phase 3, as well as consistency with other pre-trial assumptions 
including event rate.  If the DSMB determines there is absence of futility, acceptable safety, and pre-trial 
assumptions regarding event rate and other factors are correct, the trial will proceed to Phase 3. 
A second interim analysis will be conducted by the DSMB during Phase 3 to assess the absence of futility 
and whether an expansion of the total sample size is warranted. The DSMB may also make suggestions to 
the Steering Committee for adjustment in sample size based on other factors (e.g., event rate, 
discontinuation rate, etc.) or other modifications to the protocol that would improve trial conduct.  
Number of Study Centers:  Approximately 150 centers will be included in this study.  Enrollment is 
competitive with a maximum of 62 randomized patients per center permitted in the overall study (10% of 
total enrollment). 
Treatment Duration:  Patients will be eligible to receive study drug for a minimum of 27 weeks and will 
continue to receive study drug until at least 330 primary endpoint events have been observed (currently 
estimated to require approximately 6 years from the time of first patient randomization). 
Inclusion Criteria: 
Patients must meet all of the following inclusion criteria to be eligible for randomization in this study. 
1. Age ≥ 18 years and ≤ 85 years at the Screening Visit. 
2. Weight ≥ 40 kg at the Randomization Visit. 
3. Possess the β1389Arg/Arg genotype. 
4. History of heart failure with reduced left ventricle ejection fraction (HFREF). 
a. LVEF < 0.50 assessed at any time during the previous 12 months of the Screening Visit.  
5. At least one symptomatic paroxysmal or persistent AF episode ≤ 180 days of the Screening Visit.  
a. Qualifying AF episode may be documented by ECG, Holter, TTM, or implanted device. AF 
documented by implanted device must be a single episode ≥ 60 minutes in duration. Atrial flutter 
is not considered a qualifying AF episode.   
b. Must have experienced AF symptoms ≤ 180 days of the Screening Visit, but these symptoms may 


 
 
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overlap with HF symptoms, i.e. may be “arrhythmic” (e.g. palpitations, dizziness) or “heart 
failure” (e.g. breathlessness, fatigability) in nature.  
6. Clinically appropriate for ECV if AF/AFL is present at the Week 0 Visit, including: 
a. Patients with AF/AFL at randomization determined by the Investigator to require ECV. 
b. Patients in SR at randomization determined by the Investigator to require ECV if AF/AFL recurs.  
7. Receiving guideline indicated oral anticoagulation therapy at the Randomization Visit, which is 
considered optimal for stroke prevention in the opinion of the Investigator. 
8. Systolic blood pressure > 90 mmHg and < 150 mmHg at the Randomization Visit. 
9. Female of childbearing potential must have a negative serum pregnancy test at the Screening Visit 
and a negative urine pregnancy test at the Randomization Visit.   
a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered  
to be of childbearing potential. 
10. Female of childbearing potential must agree to use a highly effective contraception for the duration  
of the trial and for at least 30 days following the last dose of study drug.   
a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered 
to be of childbearing potential. 
11. Must agree not to participate in a clinical study involving another investigational drug or device 
throughout the duration of this study. 
12. Must be competent to understand the information given in the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) approved informed consent form (ICF). Must sign the ICF prior 
to the initiation of any study procedure and not withdraw consent prior to the Randomization Visit. 
Exclusion Criteria: 
Patients who meet any of the following exclusion criteria are not eligible for randomization in this study. 
1. NYHA Class IV symptoms at the Randomization Visit. 
2. Significant fluid overload at the Randomization Visit, in the opinion of the Investigator.   
Evidence of significant fluid overload may include: 
a. Mean jugular venous pressure above the clavicle at 90°. 
b. Liver congestion. 
c. Moist pulmonary rales post-cough. 
d. Peripheral edema beyond 1+ pedal not explained by local factors. 
3. Permanent AF at the Screening Visit. 
a. Permanent AF is defined as an ongoing AF event 1 year or longer in duration in which  
there is no intervening evidence of SR. 
4. More than two ECV procedures within 6 months of the Randomization Visit or if the most recent 
ECV within 6 months of the Randomization Visit failed to produce SR. 
5. Use of any of the following < 7 days of the Randomization Visit: 
a. Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, propafenone, sotalol, 
non-dihydropyridine calcium channel blockers, daily NSAIDS (e.g., ibuprofen, celecoxib), 
thiazolidinediones, or frequent use of short acting nitroglycerin (e.g., > 6 sublingual tablets/week). 
b. Note: Amiodarone and dofetilide can be restarted after the start of follow-up if the patient 
experiences an AF/AFL event or after failure to convert to SR following ECV (see Section 5.8). 
6. The presence of a left ventricular assist device (LVAD) or a condition that is likely to require LVAD 
placement within 6 months of the Randomization Visit. 
7. History of a successful atrioventricular node ablation. 
8. History of an AF ablation or AFL ablation within 30 days of the Randomization Visit. 
9. History of untreated second degree Mobitz II or third degree heart block. 
10. History of untreated symptomatic bradycardia or if symptomatic bradycardia is likely on full dose  
of study drug in the opinion of the Investigator.  
11. Heart rate < 60 beats per minute at the Randomization Visit for patients who were not receiving 
β-blocker therapy during the screening period. 


 
 
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12. Heart rate > 180 beats per minute at the Randomization Visit. 
13. Contraindication or previous history of intolerance to β-blocker therapy (e.g., untreated valvular 
disease) or Toprol-XL (e.g., inability to tolerate at least 25 mg QD). 
14. Myocardial infarction, unstable angina, acute coronary syndrome, cardiac surgery (including PTCA or 
stent placement), or evidence of new ischemic changes as assessed by ECG ≤ 90 days of the 
Randomization Visit.  
15. Moderate to severe asthma or other obstructive lung disease requiring chronic use (> 2 days/week)  
of an inhaled β2-selective adrenergic agonist < 7 days of the Randomization Visit. 
16. History of pulmonary hypertension, defined as a systolic pulmonary arterial pressure ≥ 70 mmHg at 
rest as assessed by echocardiography or right heart catheterization.  
17. Known reversible causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, 
acute pericarditis, or hypoxemia. 
18. Evidence of an appropriate firing of an ICD device for ventricular tachycardia (VT) or ventricular 
fibrillation (VF) ≤ 90 days of the Randomization Visit.  
a. Exception: does not include anti-tachycardia pacing.  
19. Untreated thyroid disease, in the opinion of the Investigator, at the Randomization Visit. 
20. Serum potassium < 3.5 mmol/L at the Screening Visit.   
a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results 
must be corrected prior to randomization as documented by either the central or local lab. 
21. Renal failure requiring dialysis, serum creatinine > 2.5 mg/dL, or an estimated creatinine clearance 
< 30 mL/min (Cockcroft-Gault) at the Screening Visit.  
a. Lab values will be assessed by the central lab at the Screening Visit and any exclusionary results 
must be corrected prior to randomization as documented by either the central or local lab. 
22. Significant intrinsic liver disease or a total bilirubin > 2.5 mg/dL at the Screening Visit.  
a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results 
must be corrected prior to randomization as documented by either the central or local lab.  
23. Use of strong inhibitors of cytochrome P450 2D6 (e.g., fluoxetine, paroxetine, propafenone, 
quinidine, or ritonavir) < 7 days prior to the Randomization Visit for patients who were  
not receiving β-blocker therapy during the screening period. 
24. Participation in a clinical study or treatment with an investigational drug or device within 30 days  
of the Screening Visit (or 5 half-lives of the investigational agent, whichever is longer). 
25. Comorbid condition or illness which, in the opinion of the Investigator, may limit life expectancy  
to less than 1 year. 
26. Serious or active medical or psychiatric condition which, in the opinion of the Investigator,  
may interfere with treatment, assessment, or compliance with the protocol. 
27. Treatment for a malignancy ≤ 2 years prior to screening, the presence of a treated malignancy that has 
evidence of disease progression, or the presence of a malignancy that is expected to require radiation 
therapy, chemotherapy, hormonal treatment, or surgical intervention during the study. 
a. Exceptions for localized, resectable skin carcinomas and in situ carcinoma of the cervix. 
28. History of alcohol, drug, or chemical abuse that, in the opinion of the Investigator, could impair or 
limit the patient’s full participation in the study. 
 
 


 
 
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Randomized Treatment: 
Previous Commercial -blocker Dose1 
Randomized  
-blocker Dose 
Metoprolol 
XL/CR 
(mg QD) 
Metoprolol 
IR 
(mg BID) 
Carvedilol  
CR 
(mg QD) 
Carvedilol 
IR 
(mg BID) 
Bisoprolol 
 
(mg QD) 
Nebivolol 
 
(mg QD) 
Metoprolol 
XL 
(mg QD) 
Bucindolol 
 
(mg BID) 
> 
≤ 
> 
≤ 
> 
≤ 
> 
≤ 
> 
≤ 
> 
≤ 
= 
= 
- 
50 
- 
25 
- 
20 
 
6.25 
- 
2.5 
- 
1.25 
25 
6.25 
50 
100 
25 
50 
20 
40 
6.25 
12.5 
2.5 
5 
1.25 
2.5 
50 
12.5 
100 
200 
50 
100 
40 
80 
12.5 
25 
5 
10 
2.5 
5 
100 
25 
2003 
- 
1003 
- 
803 
- 
253 
- 
103 
- 
5 
103 
200 
50 
- 
- 
- 
- 
 
 
- 
- 
 
 
- 
- 
200 
1002 
 
Transition to Starting Dose of Study Drug  
Up-titration  
1Transition from β-blockers other than those above requires approval from the Sponsor or its designee prior to randomization. 
2Patients who weigh < 75 kg at randomization will receive a maximum bucindolol dose of 50 mg BID. 
3Patients receiving commercial β-blocker doses higher than those currently approved will require pre-approval from the 
Sponsor or its designee prior to randomization.  
 
Patients who are not receiving -blocker therapy at randomization will initiate treatment with either 
6.25 mg twice daily (BID) bucindolol or 25 mg once daily (QD) metoprolol and will be up-titrated in 
a blinded manner to the target doses. 
 
Patients receiving β-blocker therapy at baseline will discontinue this treatment at the time of 
randomization, initiate blinded β-blocker therapy as described below, and will be up-titrated in a 
blinded manner to the target doses. 
 
Study drug should be up-titrated to the target dose for all patients unless clinically contraindicated. 
Target doses for study drug are: 1) 200 mg QD metoprolol; 2) 50 mg BID bucindolol for patients who 
weigh < 75 kg, and; 3) 100 mg BID bucindolol for patients who weigh ≥ 75 kg.  
 
Investigators should make every reasonable attempt to up-titrate study drug on a weekly schedule, but 
can delay up-titration if required clinically (i.e., up-titration at a two week interval).  Up-titration 
intervals shorter than one week are not permitted without prior approval from the Sponsor or its 
designee. 
 
Study drug may continue to be up-titrated to target -blocker doses after ECV and/or the start of the 
24-week Follow-up Period. 
 
Study drug dose may be reduced at any time in the event of documented intolerance. 
 
At the end of the study, patients will discontinue study drug and should transition to commercially-
available β-blocker therapy per Investigator discretion.  Transition to commercial -blocker therapy is 
recommended to occur in a similar manner as described for initiation of blinded -blocker therapy. 
Visit Schedule: 
 
There is a maximum of 8 weeks between the Screening Visit and the Randomization Visit. 
 
Unscheduled visits are allowed during titration to achieve maximum tolerated dose of study drug or 
anytime during the study to assess heart rhythm, associated symptoms or adverse events. 
 
If needed, the first ECV should be performed 3 weeks after randomization, but it may be performed as 
early as 1 week or as late as 8 weeks after randomization, if clinically required (Section 6.1.3).  
 
During the 24-week Follow-up Period, patients will return to the clinic at scheduled intervals for 
routine assessments of safety and efficacy. In addition, telephone contacts will be required at Week 6, 


 
 
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Week 10, Week 14, Week 18, and Week 22 to administer the AF Symptom Questionnaire (AFSQ) 
and determine if the patient has experienced any new or worsening symptoms that could potentially 
be related to AF/AFL. 
 
During the Treatment Extension Period, patients will return to the clinic every 12 weeks for routine 
assessments of efficacy and safety. 
 
Phase 3 follow-up will continue until a total of at least 330 primary endpoint events have been 
observed.  After this event, all patients will complete the 24-week Follow-up Period or return to the 
clinic for an end of study visit if already in the Treatment Extension Period. 
 
 
 
Note: ECV should be performed 3 weeks after randomization, but may be performed as early as 1 week or as late as 8 weeks 
after randomization, if clinically required. Week 0 for patients in SR at randomization is 3 weeks (± 3 days) unless ECV is 
required (see Section 6.1.3). Patients who agree to have a Medtronic device inserted may do so at the Randomization Visit or at 
any time prior to the start of the 24-week Follow-up Period. S = Screening Visit; R = Randomization Visit; W = week; ECV = 
electrical cardioversion; 1EP = primary endpoint; EOS = end of study. Solid line = clinic visit, dashed line = telephone contact. 
Primary Efficacy Endpoint: 
 
Time to first event of symptomatic AF/AFL or ACM during the 24-week Follow-up Period after 
establishment of stable SR on study drug. 
 Stable SR on study drug is defined as any of the following: 
 SR confirmed ≥ 1 hour after ECV. 
 SR confirmed ≥ 1 hour after spontaneous conversion from AF/AFL. 
 SR confirmed ≥ 1 hour at the Week 0 Visit for patients randomized in SR.  
 An AF/AFL event is defined as AF or AFL observed on two consecutive measures  
separated by at least 10 minutes as assessed by ECG. 
 A symptomatic AF/AFL event is defined as an AF/AFL event that is associated with a clinically 
relevant change in patient-reported symptoms, as determined by the Clinical Events Committee 
(CEC) examination of blinded data. 
Secondary Efficacy Endpoints: 
 
Time to first event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during the 24-week 
Follow-up Period. 
 
Proportion of patients with VT, VF, or symptomatic supraventricular tachycardia (SVT) during the 
24-week Follow-up Period. 
 Includes VF and symptomatic SVT events of any duration, VT events of ≥ 15 seconds, and VT 
events that result in appropriate firing of an ICD. 
 
Total number of hospitalization days per patient (all-cause) during the Total Study Period. 


 
 
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 
Time to first event of AF/AFL (i.e., symptomatic or asymptomatic), HF hospitalization (as assessed 
by the Investigator), or ACM during the Total Study Period. 
 
Proportion of patients with adequate ventricular rate control in the setting of AF/AFL. 
 Defined by (a) a ventricular response rate (VRR) between 40 and 80 beats per minute at rest on 
the last tracing demonstrating AF/AFL during the 24-week Follow-up Period and (b) the absence 
of symptoms associated with bradycardia. 
Safety Endpoints: 
 
Incidence of ACM during the Total Study Period. 
 
Incidence of ACM, cardiovascular-related hospitalization (as assessed by the Investigator), or 
withdrawal of study drug due to an adverse event (AE) during the Drug Titration Period. 
 
Incidence of heart block during the Total Study Period.  
 Defined as third degree heart block, second degree heart block requiring pacemaker 
implantation, or symptomatic second degree heart block as determined by the CEC. 
 
Incidence and severity of treatment-emergent AEs/SAEs over time during the Total Study Period. 
 
Incidence of neoplasm-related AEs/SAEs during the Total Study Period. 
 
Change from baseline in clinical laboratory tests over time during the Total Study Period. 
 
Change from baseline in vital signs and weight over time during the Total Study Period. 
 
Change from baseline in quantitative ECG parameters (i.e., QTc, QRS, PR and HR). 
 
Proportion of patients attaining target study drug dose during the Drug Titration Period.  
Optional Substudies: 
 
DNA Bank for patients who agree to participate in the substudy. 
 
AFB for patients who agree to participate in the AFB substudy. 
 AFB is defined as the amount of time per day that a patient is in AF/AFL,  
as measured by a Medtronic implanted device. 
 VRR during periods of AF/AFL, as collected by implanted Medtronic devices,  
will also be evaluated. 
 
 
 


 
 
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2.0 BACKGROUND 
2.1 
Atrial Fibrillation in Patients with Heart Failure 
Atrial fibrillation (AF) is increasing in incidence in the U.S. to epidemic proportions.1,2  Currently 2.7 to 
3.2 million people in the U.S. have AF, with 40,000-50,000 new cases per year.2  AF and chronic heart 
failure (CHF) are the two cardiovascular (CV) diseases/disease syndromes that are exhibiting a steady 
increase in prevalence.3  This is not coincidental, as both AF and CHF are related to dysfunction and 
remodeling of the myocardium, and as such share many pathophysiologic features including chamber 
dilatation, increased interstitial fibrosis and cardiac myocyte apoptosis.4-6  Unfortunately, most anti-
arrhythmic agents with AF indications are either contraindicated or have significant label warnings for 
use in HF patients due to an increased risk of mortality.  Considering these safety concerns, as well as the 
negative clinical consequences of AF in heart failure (HF) patients described below, there is a clear unmet 
medical need for a drug that is effective in preventing AF in HF patients with reduced left ventricle 
ejection fraction (HFREF). 
2.1.1 Relationship of AF to Clinical Outcomes 
AF is an important CV endpoint and it has an even greater impact in patients with HFREF.  A major 
important clinical consequence of AF in HFREF is an increase in the risk of embolic events including 
stroke,3 and for this reason alone it is preferable for a HF patient to be in sinus rhythm (SR).  In patients 
with established HF it is clear that new onset AF, including new AF events after conversion of persistent 
AF to SR, is associated with increased mortality and worsening HF risks.  Framingham data indicate there 
is an interrelationship between the development of AF and CHF, with each condition developing as HF 
progresses and often (i.e., 21% of the time) both presenting contemporaneously.6  In the Framingham 
study, when AF developed after CHF there was a 1.6-fold (95% CI: 1.2, 2.1) increase in mortality after 
adjusting for potential modifiers, and when CHF developed after AF the hazard ratio was 2.7 (95% CI: 
1.9, 3.7).6 
Even more impressive are recently published data from the Women's Health Study, which were based on 
1011 AF cases developed over a 15.4 year span.7  In this study, new onset AF was associated with a 2.1-
fold (95% CI: 1.6, 2.8) increase in all-cause mortality (ACM) and a 4.2-fold (95% CI: 2.7, 6.5) increase in 
CV mortality (CVM).  Moreover, in women with new onset AF the risk of developing HF increased by 
14.7-fold (95% CI: 11.2, 19.2).7  New onset AF also worsens the prognosis8-10 in patients with established 
HFREF, a finding that was clearly observed in the BEST trial as well (Table 1). 


 
 
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Table 1: 
New Onset AF in BEST and Relationship to Annualized Clinical Outcomes 
Group 
Mean f/u 
days 
ACM 
event rate 
CV 
event rate 
CVH 
days/pt 
HFH 
days/pt 
ACH 
days/pt 
No new onset AF, (n = 2202) 
722 
15.1% 
12.8% 
6.9 ± 0.5 
6.2 ± 0.5 
10.4 ± 0.6 
New onset AF, (n = 190)¶ 
794‡ 
32.1% 
28.4% 
13.3 ± 2.1 
11.4 ± 2.0 
17.2 ± 2.1 
Fold increase 
[p-value§] 
– 
2.13 
[< 0.0001] 
2.22 
[< 0.0001] 
1.93 
[< 0.0001] 
1.84 
[< 0.0001] 
1.65 
[< 0.0001] 
Hosp. pre AF event, (n = 
190) 
381 
– 
– 
4.4 ± 0.7 
3.5 ± 0.6 
6.1 ± 0.8 
Hosp. during/post AF event 
413 
– 
– 
13.8 ± 2.0 
11.9 ± 1.9 
19.0 ± 2.1 
Fold increase 
[p-value†] 
– 
– 
– 
3.14 
[< 0.0001] 
3.40 
[< 0.0001] 
3.11 
[< 0.0001] 
AF as determined by AE and ECG assessments.  Data are presented as annualized event rates.  ACM = All-cause mortality; 
CV = cardiovascular mortality; HFH=total # days hospitalized for HF (Investigator/CRF determined); CVH = total # days 
hospitalized for cardiovascular causes (adjudicated by committee); ACH = total # days hospitalized for all causes.  § log rank 
statistic for ACM and CV, Wilcoxon Rank sum Test for HFH, CVH and ACH; † Wilcoxon Signed-Ranks test; ‡mortality 
endpoint length of follow-up = 413 days; ¶ for ACM and CV, follow-up calculated from the date of new onset AF. 
2.1.2 Treatment of Atrial Fibrillation in Heart Failure 
Unfortunately, most anti-arrhythmic agents approved for the treatment of AF and atrial flutter (AFL) are 
either contraindicated or have label warnings for use in HF patients due to an increased risk of mortality 
in this patient population.  Dronedarone (Multaq, potassium channel blocker), dofetilide (Tykosyn, 
potassium channel blocker), propafenone (Rythmol, sodium channel blocker), flecainide (Tambocor, 
sodium channel blocker) and sotalol (Betapace AF, multi-channel blocker with -blocking activity) are 
FDA-approved for prevention of recurrent AF, but dronedarone is contraindicated in HF, and 
propafenone, flecainide, and sotalol have warnings in their labels.  Although dofetilide is effective in 
treating and preventing AF in patients with HFREF, it is pro-arrhythmic and treatment must be initiated in 
the hospital in order to monitor rhythm and QTc.  Amiodarone is widely used off-label for AF prevention 
and may be the outpatient drug of choice in patients with HFREF,5 but this multichannel anti-arrhythmic 
is also pro-arrhythmic and is associated with a multitude of serious adverse effects that require careful 
surveillance.  Considering these safety concerns, there is a clear unmet medical need for a drug that is 
effective in preventing AF, which does not have unfavorable effects on the natural history of HF. 
-blockers, which are currently indicated for the treatment of HF, have demonstrated mild efficacy for the 
prevention of new onset AF (Table 2) and are often used off-label in this setting (Class IIa indication with 
a "C" level of evidence for AF prevention per ACC/AHA/ESC Joint Guidelines).  Therefore, -blockers 
may be a more appropriate treatment for the prevention of AF in a setting of HFREF, particularly if a -
blocker could be developed with greater efficacy than those currently being used off-label. 


 
 
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Table 2: 
Meta-analysis of New Onset AF from β-blocker Heart Failure Trials 
Data Source 
Patients in SR  
at baseline (N) 
Patients with new onset AF during trial 
Placebo 
N (%) 
-blockers 
N (%) 
Relative Risk 
(95% CI) 
CIBIS I (bisoprolol) 
556 
13 (4.7) 
9 (3.2) 
0.68 (0.29, 1.57) 
MERIT HF (metoprolol) 
3,358 
54 (3.2) 
33 (2.0) 
0.61 (0.39, 0.94) 
BEST (bucindolol) 
2,405 
111 (9.3) 
78 (6.5) 
0.69 (0.52, 0.92) 
COPERNICUS (carvedilol) 
2,289 
22 (1.9) 
12 (1.0) 
0.53 (0.26, 1.07) 
Waagstein (metoprolol) 
165 
8 (10.1) 
1 (1.2) 
0.11 (0.01, 0.89) 
SENIORS (nebivolol) 
1,390 
74 (10.8) 
78 (11.0) 
1.02 (0.75, 1.37) 
CAPRICORN (carvedilol) 
1,789 
31 (3.5) 
16 (1.8) 
0.51 (0.28, 0.93) 
Total 
11,951 
313 (5.3) 
227 (3.8) 
0.73 (0.61, 0.86) 
Adapted from Nasr et al11 
2.1.3 -Blocker Therapy for Prevention of Atrial Fibrillation 
In the meta-analysis summarized in Table 2,11 the annualized event rate for new onset AF was 5.3% for 
placebo and 3.8% for active β-blocker treatment.  This low order event rate would dictate a very large 
sample size (i.e., > 4,000 patients) if new onset AF in HFREF patients were the primary endpoint in a 
clinical trial.  However, there is a patient population in which the onset of AF is much higher in frequency 
– patients with persistent AF who have recently undergone electrical cardioversion (ECV) to SR. 
In this setting, approximately 50% of patients will experience a recurrence of AF within 6 months of ECV 
to SR, even with the use of Class I and Class III anti-arrhythmic drugs.12  In study populations that 
included both HFREF and non-HF/left ventricle (LV) dysfunction patients, β-blockers have demonstrated 
a reduction in risk (effect size) for the recurrence of AF on the order of 30%,13,14 which is similar to the 
effects observed in major β-blocker HF trials for new onset AF (Table 2). 
In a recent study, patients with symptomatic persistent AF were treated with metoprolol (n = 83) or 
placebo (n = 85) and underwent ECV to SR approximately one week after treatment initiation.12  At the 
end of the 6 month follow-up period, the incidence of AF recurrence was significantly lower (p < 0.01) in 
the metoprolol group (52%) compared to the placebo group (74%), with significant differences observed 
between the groups as early as one week post-ECV (p < 0.05). 
Earlier studies in similar patient populations (i.e., persistent AF recently converted to SR) have shown 
similar event rates for the recurrence of AF following ECV.  For example, Katritsis et al compared the 
effects of carvedilol (n = 43) and bisoprolol (n = 47) in patients with persistent AF recently converted to 
SR and observed AF recurrence rates of 32% and 46%, respectively.13  Similarly, Plewan et al compared 
the effects of sotalol (n=64) and bisoprolol (n=64) in patients with persistent AF recently converted to SR 
and observed AF recurrence rates of 41% and 42%, respectively.14  In both of these studies, nearly all AF 


 
 
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events occurred during the first 6 months post-ECV.  Importantly, it should be noted that all of these 
studies examined mixed populations that included both HFREF and non-HF/LV dysfunction patients.  A 
significantly greater event rate would be expected for a pure HFREF population with persistent 
symptomatic AF converted to SR since HF progression and AF are related.5  In contrast to the low order 
event rates observed for new onset AF, the event rates expected for recurrent symptomatic AF would 
allow for adequately-powered and well-controlled comparative studies to be conducted in a reasonable 
timeframe. 
These data also indicate that metoprolol, and potentially other drugs in the -blocker class, have favorable 
effects on the prevention of AF recurrence in patients with persistent symptomatic AF who have recently 
undergone ECV to SR.  As -blockers are also indicated in HF populations to improve survival and other 
outcome measures, it stands to reason that this class of drugs may be a more appropriate treatment for AF 
in the setting of HFREF than the currently approved anti-arrhythmic drugs.  However, as seen in the 
placebo-controlled metoprolol trial, more than half of the patient population still reverted to AF from SR 
within 6 months of ECV, so clearly there is still a significant unmet medical need for the treatment of AF 
in HFREF patients. 
2.2 
Rationale for Pharmacogenetic Targeting of Bucindolol Therapy 
Bucindolol hydrochloride (bucindolol) is a nonselective β-adrenergic receptor (AR) blocking agent with 
mild vasodilator properties, which was previously studied in the Beta Blocker Evaluation of Survival 
Trial (BEST).15  Bucindolol has two unique anti-adrenergic properties not possessed by other -blockers 
currently approved for the treatment of HF: 1) it is moderately sympatholytic, i.e., it lowers adrenergic 
drive to a level that can be easily detected on measurements of central or systemic venous norepinephrine 
levels,15,23 and, 2) through “inverse agonism” promotes inactivation of active-state human myocardial β1-
ARs in a genotype specific manner.16  As described below, these properties were shown to interact with 
AR polymorphisms in such a way that targeting specific genotypes of these variants could improve 
therapeutic index.  Thus, bucindolol is likely to be most effective in β1389 arginine homozygous 
(1389Arg/Arg, also known as ADRB1 Arg389Arg) HF patients, which comprise approximately 50% of 
the general United States (US) population.17 
2.2.1 Genotype-Dependent Effects on Clinical Outcome in HFREF Patients  
Recent data indicate that human β1-ARs are genetically and functionally quite heterogeneous, comprised 
of a population of high efficiency signal transduction/high cardiomyopathic potential receptors and 
another population with lower functional activity and low cardiomyopathic potential.16,18-20  These two 
genetic variants of the β1-AR (which have very different functional properties) are the result of a single 
nucleotide (nt) polymorphism at nt position 1165, resulting in an arginine (Arg, higher function) or a 


 
 
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glycine (Gly, lower function) at amino acid 389.19  Specifically, the β1389Arg/Arg variant has increased 
affinity for norepinephrine21 and increased coupling to Gs resulting in greater downstream stimulation of 
adenylyl cyclase.16,19  The β1389Arg/Arg variant also has a greater constitutive activity in the absence of 
catecholamine agonist.16,20  Considering this functional heterogeneity, the therapeutic challenge for -
blocker therapy is to down-modulate adrenergic signaling towards normal without eliminating adrenergic 
support completely, as there is evidence that excessively lowering adrenergic drive may compromise the 
benefits of β-blockade or may even be harmful in CHF.21,22  In particular, because of its increased 
potential to mediate adverse biologic signaling,22 the 389 Arg version of the 1-AR needs specific 
therapeutic intervention, by a treatment that lowers constitutive activity16 as well as addresses its high 
affinity for norepinephrine.21 
Optimal modulation of adrenergic signaling can be accomplished with bucindolol through 
pharmacogenetic targeting.  This hypothesis was demonstrated in the prospectively designed analysis that 
was conducted on a large pharmacogenomic substudy of the BEST trial, which evaluated the effects of 
bucindolol vs. placebo in an advanced HFREF population.21  In this analysis, two unique pharmacologic 
properties of bucindolol, sympatholysis and inverse agonism, were shown to interact with AR 
polymorphisms in such a way that targeting specific genotypes of these variants could improve 
therapeutic index.  Specifically, the β1389Arg/Arg higher functioning variant was associated with more 
efficacious HF endpoint treatment responses to bucindolol than the lower functioning Gly polymorphism 
(Table 3).16,21 
Table 3: 
Major Clinical Endpoints in the BEST trial by Genotype Subgroup 
Endpoint 
β1389 Arg/Arg (n = 493) 
β1389 Gly carrier (n = 547) 
ACM, TTE 
0.62 (0.39, 0.99) 
p = 0.042 
0.92 (0.63, 1.35) 
p = 0.661 
CV, TTE 
0.52 (0.31, 0.88) 
p = 0.014 
0.78 (0.51, 1.18) 
p = 0.233 
HF progression, TTE 
0.66 (0.49, 0.88) 
p = 0.005 
0.85 (0.66, 1.11) 
p = 0.233 
HF Hosp days/pt§ 
48% reduction 
p = 0.008 
7% reduction 
p = 0.232 
CV Hosp, TTE 
0.64 (0.48, 0.86) 
p = 0.002 
0.93 (0.72, 1.21) 
p = 0.588 
Notes: ACM = all-cause mortality; CV = cardiovascular mortality; HF progression = time to sudden death, death from pump 
failure, HF hospitalization or ER visit for HF w/o a hospital admission; TTE = time to event.  For all endpoints except HF 
Hosp days/pt, a hazard ratio and 95% confidence interval from a COX model are presented, along with a p-value generated 
using the logrank statistic.  For HF days/pt, the p-value is generated using the Wilcoxon Rank Sum statistic. 
Based on data from BEST and from molecular pharmacology studies, the basis for this enhanced effect of 
bucindolol in patients with the β1389Arg/Arg variant is not a disproportionally higher event rate in the 
Arg/Arg placebo-treated subgroup that is then abrogated by bucindolol, but rather a greater therapeutic 
effect of bucindolol on the Arg/Arg vs. Gly receptor.  This effect is likely mediated by inactivation of 
active state Arg/Arg receptors plus greater absolute inhibition of signal transduction due in part to 
norepinephrine lowering.  The enhanced clinical responses in patients with the β1389Arg/Arg genotype is 


 
 
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the cornerstone for a genetically based treatment algorithm where approximately 50% of the general US 
population have this genotype, and would be expected to have therapeutic effects that are better than for 
non-genetically targeted β-blocker therapy. 
2.2.2 Genotype-Dependent Effects on New Onset AF in HFREF Patients 
AF was not an efficacy endpoint in the BEST trial, but it was captured via adverse events (AEs) and 
limited electrocardiogram (ECG) assessments (i.e., baseline, 3 months, and 12 months).23  As shown in 
Table 4, the vast majority of AF events were symptomatic and associated with one or more AEs (n = 
161); whereas relatively few AF events were captured on routine ECGs that were not also reported as an 
AE (n = 29). 
Most of the 2708 BEST trial patients were not in AF at baseline (88.8%, 2176 in SR and 216 other 
rhythms), with similar incidence in the two treatment groups (Table 4).  During the trial, 7.4% of these 
patients developed new onset AF, with a greater incidence observed in the placebo group (9.7%) 
compared to the bucindolol group (6.2%).  This corresponded to a 36.1% reduction in the incidence of 
new onset AF (i.e., crude effect size) for patients receiving bucindolol (p = 0.002).  Similar results were 
observed when the analysis excluded AF events captured on routine ECGs that were not reported as an 
AE (39.3% reduction, p = 0.0012).  In a time to event analysis, the risk of new onset AF was reduced by 
41% (p = 0.0004) with bucindolol treatment, and by 45% (p = 0.0002) when excluding AF events that 
were captured by routine ECGs only. 
Genotype analyses from the 1040 patient DNA substudy demonstrate that the drug-related reduction in 
new onset AF was driven almost exclusively by the response of the 1389 Arg/Arg subgroups (Table 4).23  
For example, there was a 65.9% reduction in new onset AF in the 1389 Arg/Arg subgroup (p = 0.001) 
compared to no reduction (0.0%) in the 1389 Gly carrier subgroup (p = 0.98).  Importantly, a test for 
interaction between genotypes and treatment groups was significant for total new onset AF (p = 0.016).  
A similar genotype-dependent reduction in new onset AF was observed when excluding AF events that 
were captured by routine ECGs only (70.9% and 10.8%, respectively) and a significant interaction by 
treatment and genotype was also observed (p = 0.024). 
In a time to event analysis, the risk of new onset AF was reduced by 74% (p = 0.0003) with bucindolol 
treatment in the 1389Arg/Arg subgroup, and by 78% (p = 0.0002) when excluding AF events that were 
captured by routine ECGs only (Table 4 and Figure 1).  In contrast, no reduction was observed for the 
1389Gly carrier subgroup.  A test for interaction between genotypes and treatment groups was also 
significant for the time to event analysis of new onset AF (p = 0.008).  A significant interaction by 
treatment and genotype was also observed when excluding AF events that were captured by routine ECGs 
only (p = 0.013). 


 
 
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Table 4: 
New Onset AF in the BEST DNA Substudy by β1389 Arg/Gly Genotype 
Treatment Group 
Patients not in AF 
at baseline 
assessed by ECG 
Patients with 
new onset AF reported 
as AE during trial 
Total patients  
with new onset AF 
during trial# 
Entire study cohort 
All, n (%) 
2392 (88.8%) 
161 (6.7%) 
190 (7.4%) 
Placebo, n (%) 
1190 (88.3%) 
100 (8.4%) 
115 (9.7%) 
Bucindolol, n (%) 
1202 (89.2%) 
61 (5.1%) 
75 (6.2%) 
Reduction of new onset AF in bucindolol group (%)* 
39.3 
p = 0.0012 
36.1 
p = 0.002 
Time to first event of new onset AF, 
hazard ratio (95% CI)† 
0.55 (0.44, 0.76) 
p = 0.0002 
0.59 (0.44, 0.79) 
p = 0.0004 
1389 Arg/Arg subgroup 
Placebo, n (%) 
206 (87.3%) 
24 (11.7%) 
26 (12.6%) 
Bucindolol, n (%) 
235 (91.4%) 
8 (3.4%) 
10 (4.3%) 
Reduction of new onset AF in bucindolol group (%)* 
70.9 
p = 0.001 
65.9 
p = 0.001 
Time to first event of new onset AF, 
hazard ratio (95% CI)† 
0.22 (0.09, 0.52) 
p = 0.0002 
0.26 (0.12, 0.57) 
p = 0.0003 
1389 Gly carrier subgroup 
Placebo, n (%) 
254 (88.5%) 
21 (8.3%) 
23 (9.1%) 
Bucindolol, n (%) 
230 (89.8%) 
17 (7.4%) 
21 (9.1%) 
Reduction of new onset AF in bucindolol group (%)* 
10.8 
p = 0.72 
0.0 
p = 0.98 
Time to first event of new onset AF, 
hazard ratio (95% CI)† 
0.91 (0.47, 1.74) 
p = 0.77 
1.01 (0.56, 1.84) 
p = 0.97 
Interaction by genotype and treatment group  
Reduction of new onset AF 
p = 0.024 
p = 0.016 
Time to first event of new onset AF 
p = 0.013 
p = 0.008 
# Total patients include AF as reported by AEs plus AF as assessed via ECG only; *based on crude effect size; p-value is 
Chi-square statistic for bucindolol vs. placebo; † Cox proportional hazards regression model.  Data are based on the 
bucindolol NDA safety database, which features a customized version of COSTART resulting in minor changes in the AF 
events but no change in the bucindolol treatment effect. 
Finally, the genotype-dependent reduction in AF event rate is consistent with the 1389 Arg/Gly 
polymorphism-dependent effects of bucindolol on major HF clinical endpoints (Table 3).  These data 
suggest that new onset AF has the same pharmacogenetic patterns of 1389Arg/Gly differentiation of 
treatment effects as do major HF endpoints, which most likely is due to a common pathophysiological 
mechanism.23 
 


 
 
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Figure 1: 
New Onset AF in the BEST Trial for β1389 Subgroups 
 
Note: The p-value for the interaction test is based on a Cox proportional hazards logistic regression model with terms for 
genotype, treatment, treatment x genotype and the four strata (CAD, RACE, SEX, Baseline LVEF). 
3.0 STUDY PLAN 
3.1 
 Study Rationale 
Most anti-arrhythmic agents currently approved for the treatment of AF and AFL are either 
contraindicated or have label warnings for use in HF patients due to an increased risk of mortality in this 
patient population. 
Bucindolol hydrochloride (bucindolol) is a nonselective β-AR blocking agent with mild vasodilator 
properties, which was previously studied in the BEST Phase 3 HF trial.  In a large pharmacogenomic 
substudy of the BEST trial, two unique pharmacologic properties of bucindolol, sympatholysis21,24 and 
inverse agonism,16 were shown to interact with AR polymorphisms in such a way that targeting specific 
genotypes of these variants could improve therapeutic index.  Specifically, patients with the 
β1389Arg/Arg AR variant had more efficacious treatment responses to bucindolol, as assessed by HF 
clinical outcomes and the reduction of new onset AF, compared to patients with the β1389Gly 
polymorphism (i.e., Gly carriers).16,21 
Metoprolol succinate (Toprol-XL, henceforth referred to as metoprolol) is a β1-AR selective β-blocker 
indicated for the treatment of stable, symptomatic (NYHA Class II or III) HF of ischemic or non-ischemic 
origin.  Metoprolol has demonstrated mild efficacy for the prevention of new onset AF in a HF patient 
population11,25 (Table 2) and is often used off-label in this setting (Class IIa indication with a "C" level of 
evidence for AF prevention per ACC/AHA/ESC Joint Guidelines).  In a previous study, metoprolol 
1389 Arg/Arg (n =  441; 36 events)
Hazard Ratio = 0.26 (0.12 – 0.57)
P-value = 0.0003
Risk reduction 74%
0.70
0.75
0.80
0.85
0.90
0.95
1.00
0
6
12
18
24
30
36
42
48
Probability of Event-Free Survival
Months After Randomization
Placebo
Bucindolol
Hazard Ratio = 1.01 (0.56 – 1.84)
P-value = 0.969
1389 Gly carriers (n = 484; 44 events)
No risk reduction 
Interaction p = 0.008
0.70
0.75
0.80
0.85
0.90
0.95
1.00
0
6
12
18
24
30
36
42
48
Probability of Event-Free Survival
Months After Randomization
Placebo
Bucindolol


 
 
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decreased the incidence of AF recurrence, compared to placebo, in patients with persistent AF who had 
recently undergone ECV to SR.12  In contrast to bucindolol, metoprolol does not appear to confer added 
clinical benefits in HFREF patients that possess the β1389Arg/Arg AR variant.26,27  In addition, limited 
data from the MERIT-HF DNA substudy27 do not indicate any evidence of a β1389Arg/Gly 
polymorphism differential effect for preventing AF (van Velduisen DJ, personal communication). 
The goal of the GENETIC-AF trial is to demonstrate the superiority of pharmacogenetically targeted 
bucindolol compared to metoprolol for the prevention of symptomatic AF/AFL in a genotype-defined 
β1389Arg/Arg HFREF population at high risk of AF/AFL recurrence.  The trial utilizes an interim 
analysis/adaptive design element that will examine preliminary data from the initial Phase 2B population. 
If the independent Data and Safety Monitoring Board (DSMB) determines that the preliminary Phase 2B 
data are consistent with pre-trial assumptions (i.e., absence of futility, event rate), the trial will proceed to 
Phase 3.  
3.2 
Study Objectives 
The primary objective of this study is to compare the effects of bucindolol and metoprolol on the 
recurrence of symptomatic AF/AFL in patients with HFREF who have a β1389 arginine homozygous 
(1389Arg/Arg) genotype.  
The secondary objectives of this study are to compare the effects of bucindolol and metoprolol on clinical 
outcomes and other electrocardiographic parameters, and to assess the effects on rate control in patients 
who have developed recurrent AF/AFL. The safety and tolerability of bucindolol and metoprolol will also 
be evaluated. 
The study endpoints are described in Section 8.0. 
3.3 
Study Design 
GENETIC-AF is a double-blind, two-arm, genotype-directed, active-controlled, adaptive-designed, 
superiority study that compares the effects of bucindolol and metoprolol on the time to first event of 
symptomatic AF/AFL in HFREF patients in SR who are at high risk of AF/AFL recurrence.  
Two patient populations at high risk of AF/AFL recurrence will be included in this study: 1) patients with 
symptomatic paroxysmal or persistent AF who are indicated for ECV to attain SR, and; 2) patients in SR 
who have experienced a recent episode (i.e., ≤ 180 days) of paroxysmal or persistent AF who are 
indicated for ECV to attain SR if AF/AFL recurs.  Patients must have HF, a left ventricle ejection fraction 
(LVEF) < 0.50 in the past 12 months, and no contraindication for -blocker therapy.  -blocker therapy is 
permitted at screening but is not required to be eligible for the study.  Patients must be receiving optimal 
anticoagulation therapy for stroke prevention prior to randomization.  Patients will be genotyped for 


 
 
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1389 AR at screening and those who are 1389Arg/Arg (50% of patients) will be randomized to study 
drug. 
A subset of patients participating in the trial will have their cardiac rhythm continuously monitored to 
assess AF burden (AFB).  AFB monitoring will be done via the Medtronic Reveal insertable cardiac 
monitor (ICM) or a Medtronic pacemaker (IPG), implantable cardioverter-defibrillator (ICD), or cardiac 
resynchronization therapy (CRT) device with a minimum of an atrial and a ventricular lead.  Patients 
participating in the optional AFB substudy must either have a pre-existing Medtronic device that can 
measure AFB, or agree to have one inserted as clinically indicated.  Patients who agree to have a 
Medtronic device inserted may do so at the Randomization Visit or at any time prior to the start of the 24-
week Follow-up Period.   
Eligible patients will be randomized (1:1) to blinded treatment with bucindolol or metoprolol (i.e., study 
drug) and up-titrated weekly to target doses of 50 mg BID (< 75 kg) or 100 mg BID (≥ 75 kg) for 
bucindolol or 200 mg QD for metoprolol.  Randomization will be centralized and stratified by: 1) HF 
etiology (ischemic vs. non-ischemic); 2) LVEF (< 0.35 vs. ≥ 0.35); 3) type of Medtronic device (Reveal 
vs. Non-Reveal vs. No Device), and; 4) rhythm status at randomization (SR vs. AF/AFL).  
Patients in AF at randomization who do not spontaneously convert to stable SR and are in AF/AFL after 
3 weeks of treatment with study drug will undergo ECV to establish stable SR. Patients in SR at 
randomization who are in AF/AFL after 3 weeks of study drug treatment will also undergo ECV to 
establish stable SR. Patients in SR at randomization who are in stable SR after 3 weeks (± 3 days) of 
study drug treatment will start the 24-week Follow-up Period at the Week 0 Visit.   
ECV may be performed as early as 1 week after randomization if all of the following conditions are met: 
1) the patient is receiving the target dose of study drug; 2) the patient is receiving guideline indicated oral 
anticoagulation therapy for stroke prevention, and; 3) a delay of ECV could be detrimental to patient 
outcome.  The first ECV attempt may also be performed as late as 8 weeks after randomization if, in the 
opinion of the Investigator, additional time is needed to attain target doses of study drug or to achieve 
appropriate anticoagulation status prior to ECV.  
The primary endpoint, i.e., time to first event of symptomatic AF/AFL or ACM, will be assessed during 
the 24-week Follow-up Period after establishment of stable SR on study drug. For patients requiring 
ECV, establishment of stable SR will be confirmed by ECG at least 1 hour post-ECV.  Patients who do 
not demonstrate stable SR following ECV will undergo a subsequent ECV to establish a baseline SR 
unless, in the opinion of the Investigator, it would not be the best course of treatment for the patient.  The 
24-week Follow-up Period will begin on the day of: 1) the ECG that establishes stable SR; 2) the last 


 
 
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ECV attempt for patients who fail to convert to stable SR, or; 3) the Week 0 Visit for patients in AF/AFL 
who do not undergo ECV for any reason. 
During the 24-week Follow-up Period, heart rhythm will be assessed by 12-lead ECG at scheduled clinic 
visits.  At the time of each ECG assessment, patients will be queried for symptoms potentially related to 
AF/AFL.  Scheduled telephone contacts will occur at Week 6, Week 10, Week 14, Week 18 and 
Week 22.  Patients will be also be instructed to contact the site immediately if they experience new or 
worsening symptoms.  Patients will be queried for symptoms potentially related to AF/AFL during the 
scheduled and patient-initiated telephone contacts (Section 6.2.6).  If the Investigator suspects that a new 
AF/AFL event has occurred between scheduled clinic visits (i.e., a change in rhythm from SR to 
AF/AFL), the patient will be instructed to return to the clinic within 3 business days for further 
assessments (Section 6.1.4.2). Patients experiencing recurrence of AF/AFL will be encouraged to remain 
on blinded study drug and may undergo subsequent ECV procedures or medical interventions as clinically 
indicated.   
After the Week 24 Visit, patients will enter the Treatment Extension Period and continue to receive 
blinded study drug.  Phase 3 follow-up will continue until a total of at least 330 primary endpoint events 
have been observed.  After this event, all patients will complete the 24-week Follow-up Period or return 
to the clinic for an end of study visit if already in the Treatment Extension Period.  At the end of the 
study, patients will discontinue study drug and should transition to commercially-available β-blocker 
therapy per Investigator discretion.  Investigators and patients will not be informed of the blinded study 
drug assignment at the time of study completion. 
3.4 
Study Visits 
 
There is a maximum of 8 weeks between the Screening Visit and the Randomization Visit. 
 
Unscheduled visits are allowed during titration to achieve maximum tolerated dose of study drug 
or anytime during the study to assess heart rhythm, associated symptoms or adverse events. 
 
If needed, the first ECV should be performed 3 weeks after randomization, but it may be 
performed as early as 1 week or as late as 8 weeks after randomization, if clinically required 
(Section 6.1.3). 
 
During the 24-week Follow-up Period, patients will return to the clinic at scheduled intervals for 
routine assessments of safety and efficacy. In addition, telephone contacts will be required at 
Week 6, Week 10, Week 14, Week 18, and Week 22 to administer the AF Symptom 
Questionnaire (AFSQ) and determine if the patient has experienced any new or worsening 
symptoms that could potentially be related to AF/AFL.  


 
 
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 
During the Treatment Extension Period, patients will return to the clinic every 12 weeks for 
routine assessments of efficacy and safety. 
 
Phase 3 follow-up will continue until a total of at least 330 primary endpoint events have been 
observed.  After this event, all patients will complete the 24-week Follow-up Period or return to 
the clinic for an end of study visit if already in the Treatment Extension Period. 
Figure 2: 
GENETIC-AF Study Visit Schedule 
 
Note: ECV should be performed 3 weeks after randomization, but may be performed as early as 1 week or as late as 8 weeks 
after randomization, if clinically required. Week 0 for patients in SR at randomization is 3 weeks (± 3 days) unless ECV is 
required (see Section 6.1.3). Patients who agree to have a Medtronic device inserted may do so at the Randomization Visit or at 
any time prior to the start of the 24-week Follow-up Period.  S = Screening Visit; R = Randomization Visit; W = week; ECV = 
electrical cardioversion; 1EP = primary endpoint; EOS = end of study. Solid line = clinic visit, dashed line = telephone contact.  
4.0 PATIENT POPULATION 
4.1 
Number of Patients and Study Centers 
Approximately 250 patients will be randomized in Phase 2B and an additional 370 patients will be 
randomized in Phase 3 (i.e., a total of 620 patients). The β1389Arg/Arg genotype is expected in 
approximately 50% of screened patients; therefore, a 65% screen-fail rate is assumed for the study (15% 
for general criteria and a 50% screen-fail rate due to genotype). 
The DSMB will examine preliminary data from the initial Phase 2B population to assess the presence or 
absence of futility for proceeding to Phase 3, as well as consistency with other pre-trial assumptions 
including event rate.  If the DSMB determines there is absence of futility, acceptable safety, and pre-trial 
assumptions regarding event rate and other factors are correct, the trial will proceed to Phase 3. 
A second interim analysis will be conducted by the DSMB during Phase 3 to assess the absence of futility 
and whether an expansion of the total sample size is warranted. The DSMB may also make suggestions to 


 
 
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the Steering Committee for adjustment in sample size based on other factors (e.g., event rate, 
discontinuation rate, etc.) or other modifications to the protocol that would improve trial conduct.    
Approximately 150 centers will be included in this study.  Enrollment is competitive with a maximum of 
62 randomized patients per center permitted in the overall study (10% of total enrollment). 
4.2 
Patient Characteristics and Screening Procedures 
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be eligible 
for randomization in this study.  Any patient who fails screening for any reason (other than genotype) 
may be re-screened two additional times.  Patients who are re-screened will be assigned a new screening 
number and will sign a new informed consent form (ICF).  Each screening must be adequately 
documented in the source documents.  Previous screening tests that still meet the study entry criteria do 
not need to be repeated for patients who are being re-screened. 
4.2.1 Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for randomization in this study. 
1. Age ≥ 18 years and ≤ 85 years at the Screening Visit. 
2. Weight ≥ 40 kg at the Randomization Visit. 
3. Possess the β1389Arg/Arg genotype. 
4. History of heart failure with reduced left ventricle ejection fraction (HFREF). 
a.  LVEF < 0.50 assessed at any time during the previous 12 months of the Screening Visit. 
5. At least one symptomatic paroxysmal or persistent AF episode ≤ 180 days of the Screening Visit.  
a. Qualifying AF episode may be documented by ECG, Holter, TTM, or implanted device. AF 
documented by implanted device must be a single episode ≥ 60 minutes in duration. Atrial flutter 
is not considered a qualifying AF episode.   
b. Must have experienced AF symptoms ≤ 180 days of the Screening Visit, but these symptoms may 
overlap with HF symptoms, i.e. may be “arrhythmic” (e.g. palpitations, dizziness) or “heart 
failure” (e.g. breathlessness, fatigability) in nature.  
6. Clinically appropriate for ECV if AF/AFL is present at the Week 0 Visit, including: 
a. Patients with AF/AFL at randomization determined by the Investigator to require ECV. 
b. Patients in SR at randomization determined by the Investigator to require ECV if AF/AFL recurs.  
7. Receiving guideline indicated oral anticoagulation therapy at the Randomization Visit, which is 
considered optimal for stroke prevention in the opinion of the Investigator. 
8. Systolic blood pressure > 90 mmHg and < 150 mmHg at the Randomization Visit. 


 
 
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9. Female of childbearing potential must have a negative serum pregnancy test at the Screening Visit 
and a negative urine pregnancy test at the Randomization Visit.   
a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered to be 
of childbearing potential. 
10. Female of childbearing potential must agree to use a highly effective contraception for the duration of 
the trial and for at least 30 days following the last dose of study drug.   
a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered to be 
of childbearing potential. 
11. Must agree not to participate in a clinical study involving another investigational drug or device 
throughout the duration of this study. 
12. Must be competent to understand the information given in the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) approved ICF. Must sign the ICF prior to the initiation of any 
study procedure and not withdraw consent prior to the Randomization Visit. 
4.2.2 Exclusion Criteria 
Patients who meet any of the following exclusion criteria are not eligible for randomization in this study. 
1. NYHA Class IV symptoms at the Randomization Visit. 
2. Significant fluid overload at the Randomization Visit, in the opinion of the Investigator. 
Evidence of significant fluid overload may include: 
a. Mean jugular venous pressure above the clavicle at 90°. 
b. Liver congestion. 
c. Moist pulmonary rales post-cough. 
d. Peripheral edema beyond 1+ pedal not explained by local factors. 
3. Permanent AF at the Screening Visit.   
a. Permanent AF is defined as an ongoing AF event 1 year or longer in duration in which there is no 
intervening evidence of SR.   
4. More than two ECV procedures within 6 months of the Randomization Visit or if the most recent 
ECV within 6 months of the Randomization Visit failed to produce SR. 
5. Use of any of the following < 7 days of the Randomization Visit: 
a. Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, propafenone, sotalol, non-
dihydropyridine calcium channel blockers, daily NSAIDS (e.g., ibuprofen, celecoxib), 
thiazolidinediones, or frequent use of short acting nitroglycerin (e.g., > 6 sublingual tablets/week). 


 
 
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b. Note: Amiodarone and dofetilide can be restarted after the start of follow-up if the patient 
experiences an AF/AFL event or after failure to convert to SR following ECV (see Section 5.8).  
6. The presence of a left ventricular assist device (LVAD) or a condition that is likely to require LVAD 
placement within 6 months of the Randomization Visit. 
7. History of a successful atrioventricular node ablation. 
8. History of an AF ablation or AFL ablation within 30 days of the Randomization Visit. 
9. History of untreated second degree Mobitz II or third degree heart block. 
10. History of untreated symptomatic bradycardia or if symptomatic bradycardia is likely on full dose  
of study drug in the opinion of the Investigator. 
11. Heart rate < 60 beats per minute at the Randomization Visit for patients who were not receiving 
β-blocker therapy during the screening period. 
12. Heart rate > 180 beats per minute at the Randomization Visit. 
13. Contraindication or previous history of intolerance to β-blocker therapy (e.g., untreated valvular 
disease) or Toprol-XL (e.g., inability to tolerate at least 25mg QD). 
14. Myocardial infarction, unstable angina, acute coronary syndrome, cardiac surgery (including PTCA 
or stent placement), or evidence of new ischemic changes as assessed by ECG ≤ 90 days of the 
Randomization Visit. 
15. Moderate to severe asthma or other obstructive lung disease requiring chronic use (> 2 days/week)  
of an inhaled β2-selective adrenergic agonist < 7 days of the Randomization Visit. 
16. History of pulmonary hypertension, defined as a systolic pulmonary arterial pressure ≥ 70 mmHg at 
rest as assessed by echocardiography or right heart catheterization.   
17. Known reversible causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, 
acute pericarditis, or hypoxemia. 
18. Evidence of an appropriate firing of an ICD device for ventricular tachycardia (VT) or ventricular 
fibrillation (VF) ≤ 90 days of the Randomization Visit.  
a. Exception: does not include anti-tachycardia pacing.  
19. Untreated thyroid disease, in the opinion of the Investigator, at the Randomization Visit. 
20. Serum potassium < 3.5 mmol/L at the Screening Visit. 
a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results 
must be corrected prior to randomization as documented by either the central or local lab.   


 
 
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21. Renal failure requiring dialysis, serum creatinine > 2.5 mg/dL or an estimated creatinine clearance 
< 30 mL/min (Cockcroft-Gault) at the Screening Visit. 
a. Lab values will be assessed by the central lab at the Screening Visit and any exclusionary results 
must be corrected prior to randomization as documented by either the central or local lab. 
22. Significant intrinsic liver disease or a total bilirubin > 2.5 mg/dL at the Screening Visit. 
a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results 
must be corrected prior to randomization as documented by either the central or local lab. 
23. Use of strong inhibitors of cytochrome P450 2D6 (e.g., fluoxetine, paroxetine, propafenone, 
quinidine, or ritonavir) < 7 days prior to the Randomization Visit for patients who are not receiving 
β-blocker therapy at screening. 
24. Participation in a clinical study or treatment with an investigational drug or device within 30 days of 
the Screening Visit (or 5 half-lives of the investigational agent, whichever is longer). 
25. Comorbid condition or illness which, in the opinion of the Investigator, may limit life expectancy to 
less than 1 year. 
26. Serious or active medical or psychiatric condition which, in the opinion of the Investigator, may 
interfere with treatment, assessment, or compliance with the protocol. 
27. Treatment for a malignancy ≤ 2 years prior to randomization, the presence of a treated malignancy 
that has evidence of disease progression, or the presence of a malignancy that is expected to require 
radiation therapy, chemotherapy, hormonal treatment, or surgical intervention during the study. 
a. Exceptions for localized, resectable skin carcinomas and in situ carcinoma of the cervix. 
28. History of alcohol, drug, or chemical abuse that, in the opinion of the Investigator, could impair or 
limit the patient’s full participation in the study. 
5.0 STUDY DRUGS AND DEVICES 
5.1 
Investigational Agent 
Bucindolol hydrochloride (bucindolol) is a nonselective β-AR blocking agent with mild vasodilator 
properties, which was previously studied in the BEST trial.15  Bucindolol has two unique anti-adrenergic 
properties not possessed by other -blockers currently approved for the treatment of HF: 1) it is 
moderately sympatholytic, i.e., it lowers adrenergic drive to a level that can be easily detected on 
measurements of central or systemic venous norepinephrine levels,24,28 and, 2) through “inverse agonism” 
promotes inactivation of active-state human myocardial β1-ARs in a genotype specific manner.16  As 


 
 
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described in Section 2.2, these properties were shown to interact with AR polymorphisms in such a way 
that targeting specific genotypes of these variants could improve therapeutic index.  Thus, bucindolol is 
most effective in β1389Arg/Arg homozygous HF patients, which comprise approximately 50% of the 
general US population. 
Unlike metoprolol (i.e., active comparator; Section 5.2), bucindolol induces a mild degree of vasodilation, 
through slight α1 AR blockade29 and nitric oxide generation.30  In contrast to metoprolol and carvedilol, 
the only two currently FDA-approved HF β-blockers, bucindolol also possesses β3 agonist activity which 
promotes the release of nitric oxide.30  The hemodynamic benefit of vasodilation is a slight reduction in 
both pulmonary capillary wedge pressure and systemic vascular resistance, which results in a slight 
increase in cardiac index.  The favorable effect on hemodynamic parameters creates an optimal 
pharmacologic profile for use in patients with HF.  The vasodilation confers an “unloading effect” which 
helps support the failing heart as it adjusts to the initial negative chronotropic and inotropic effects of -
blockade. 
Consistent with this mechanism, the BEST trial showed that 75% of patients were able to reach the target 
dose of bucindolol.15  This is in contrast to a lower percentage of HF patients that achieved the target dose 
in COPERNICUS31 (66%) with carvedilol, or in MERIT-HF32 (64%) with metoprolol.  This is 
particularly impressive when considering that patients in BEST were more hemodynamically 
compromised than patients in either COPERNICUS or MERIT-HF, based on the sensitive indicator of 
average systolic blood pressure at entry.  Importantly, this high target dose attainment was achieved 
without causing symptoms typically associated with excess vasodilation such as dizziness, orthostatic 
hypotension, and syncope. 
5.2 
Active Comparator 
Metoprolol succinate (metoprolol; Brand name: Toprol-XL), the active comparator, is a β1-selective -
blocker indicated for the prevention of mortality plus hospitalization in patients with NYHA Class II or 
III HF of ischemic, hypertensive or cardiomyopathic origin, and showed a 34% reduction in mortality in 
its pivotal trial, MERIT-HF.32,33 
Metoprolol has demonstrated mild efficacy for the prevention of new onset AF in a HF patient population 
(Table 2) and is often used off-label in this setting (Class IIa indication with a "C" level of evidence for 
AF prevention per ACC/AHA/ESC Joint Guidelines).  In a recent study, metoprolol decreased the 
incidence of AF recurrence compared to placebo in patients with persistent AF who had recently 
undergone ECV to SR (Section 2.1.3).12 
Importantly, metoprolol does not appear to confer added clinical benefits in patients that possess the 
β1389Arg/Arg ARs.26,27  The molecular basis for this may be that, unlike bucindolol, metoprolol does not 


 
 
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possess inverse agonist activity for the β1389Arg/Arg ARs.34  Metoprolol was therefore the most logical 
choice as a comparator β-blocker in this study, as it is critical that the selected comparator have no 
pharmacogenetic treatment effect. 
The other possible comparator is carvedilol.22  Neither carvedilol nor metoprolol have been shown to 
possess differential treatment effects on clinical endpoints by genotype;26 however, the negative clinical 
evidence against modulation of effectiveness by β1389Arg/Gly polymorphisms is less robust for 
carvedilol.  In addition, compared to metoprolol,25 the efficacy of carvedilol is not established in HFREF, 
and in patients with permanent AF who are β1389Arg homozygotes carvedilol does not provide rate 
control.35  In the Treatment Extension Period of the protocol, the majority of patients in the study will 
likely be in permanent AF, and rate control may be important in HFREF-AF patients.36  Thus, in order to 
select a comparator that has unequivocal evidence of no differential effect on the β1389Arg/Gly 
polymorphisms, as well as to provide the most effective active control for the study population, 
metoprolol is the appropriate choice. 
5.3 
Dose Rationale 
The starting dose of bucindolol will be 6.25 mg BID with weekly dose titrations as tolerated until the 
target dose, or the maximum tolerated dose, is achieved.  This is similar to the dosing protocol employed 
in the BEST trial, where on average patients had clinical HF that was more advanced (NYHA Class III or 
IV) than is anticipated to be the case for the current protocol (i.e., NYHA Class II-III).15  The bucindolol 
target dose varies based on the patient’s weight on the day of randomization: patients < 75 kg receiving a 
target dose of 50 mg BID (100 mg daily) and patients > 75 kg receiving a target dose of 100 mg BID (200 
mg daily). 
The dosing of metoprolol is consistent with the prescribing information for HFREF, which is based on the 
methods used in the MERIT-HF trial.32  Specifically, the starting dose is 25 mg daily with dose titrations 
until 200 mg once daily or the maximum tolerated dose is achieved. 
Blinding of study drug will be achieved by over-encapsulation of bucindolol and metoprolol tablets using 
the same capsule size and color.  See Section 5.7.1 for more details. 
5.4 
Risk/Benefits 
In patients with established HF it is clear that new onset AF, including new AF events after conversion of 
persistent AF to SR, is associated with increased mortality and worsening HF risks (Section 2.1.1).  
However, all anti-arrhythmic agents currently approved for the treatment of AF are either contraindicated 
or have label warnings for use in HF patients due to an increased pro-arrhythmia or worsening HF risk in 
this patient population (Section 2.1.2). 


 
 
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-blocker therapy is considered a standard of care in patients with HF.22  -blocker therapy has also 
demonstrated mild efficacy for the prevention of new onset AF in a HF patient population11,25 (Table 2) 
and is often used off-label in this setting (Class IIa indication with a "C" level of evidence for AF 
prevention per ACC/AHA/ESC Joint Guidelines).  In a recent study, metoprolol (the active comparator in 
this trial) decreased the incidence of AF recurrence, compared to placebo, in patients with persistent AF 
who had recently undergone ECV to SR (Section 2.1.3). 
In a large pharmacogenomic substudy of the BEST HF trial, patients with the β1389Arg/Arg AR variant 
had a greater treatment responses to bucindolol, as assessed by HF clinical outcomes (Table 3) and the 
reduction of new onset AF (Table 4) compared to patients with the Gly polymorphism (i.e., Gly carriers).  
Metoprolol does not appear to confer added clinical benefits in HFREF patients that possess the 
β1389Arg/Arg AR variant.26,27  In addition, limited data from the MERIT-HF DNA substudy27 do not 
indicate any evidence of a β1389Arg/Gly polymorphism differential effect for preventing AF (DJ van 
Velduisen, personal communication). 
Considering the lack of available treatment for AF in the setting of HF, as well as the established use of 
-blocker therapy for the treatment of both HF and AF, this active-controlled, comparative -blocker 
study provides sufficient potential for benefit and an acceptable potential for risk for the planned study 
population. 
5.5 
Dosage and Administration of Study Drug 
Patients who are not receiving β-blocker therapy at randomization will initiate treatment with either 6.25 
mg BID bucindolol or 25 mg QD metoprolol and will be up-titrated in a blinded manner to the target 
doses (Table 5). Patients receiving β-blocker therapy at baseline will discontinue this treatment at the time 
of randomization, initiate blinded β-blocker therapy as described in Table 5, and will be up-titrated in a 
blinded manner to the target doses. 
One capsule of study drug (i.e., bucindolol or metoprolol) should be taken twice daily (BID), in the 
morning and then approximately 12 hours later in the evening, unless instructed otherwise.  Study drug 
can be taken with or without food.  
The first dose of study drug should be administered in the clinic on the day of randomization after all 
protocol-specified assessments are completed. Therefore, patients receiving commercial β-blocker 
therapy during the screening period should be instructed to withhold this medication on the day of the 
Randomization Visit.  Patients who do not qualify for randomization may immediately reinitiate their 
commercial β-blocker therapy per the Investigator’s discretion.    
For all randomized patients, the first evening dose of study drug should be taken approximately 12 hours 
after the first dose, but no earlier than 6 hours after the first dose of study drug.  If this is not possible, 


 
 
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then the patient should skip the Day 1 evening dose and take the first Day 2 dose the following morning. 
Similarly, if a patient does not withhold their morning dose of commercial β-blocker therapy on the day 
of the Randomization Visit, they should be instructed to skip the first morning dose and take the first 
evening dose approximately 12 hours, but no earlier than 6 hours, after their last dose of commercial 
β-blocker therapy. 
Table 5: 
Study Drug Titration Schedule 
Previous Commercial -blocker Dose1 
Randomized  
-blocker Dose 
Metoprolol 
XL/CR 
(mg QD) 
Metoprolol 
IR 
(mg BID) 
Carvedilol  
CR 
(mg QD) 
Carvedilol 
IR 
(mg BID) 
Bisoprolol 
 
(mg QD) 
Nebivolol 
 
(mg QD) 
Metoprolol 
XL 
(mg QD) 
Bucindolol 
 
(mg BID) 
> 
≤ 
> 
≤ 
> 
≤ 
> 
≤ 
> 
≤ 
> 
≤ 
= 
= 
- 
50 
- 
25 
- 
20 
 
6.25 
- 
2.5 
- 
1.25 
25  
6.25 
50 
100 
25 
50 
20 
40 
6.25 
12.5 
2.5 
5 
1.25 
2.5 
50 
12.5 
100 
200 
50 
100 
40 
80 
12.5 
25 
5 
10 
2.5 
5 
100  
25 
2003 
- 
1003 
- 
803 
- 
253 
- 
103 
- 
5 
103 
200 
50 
- 
- 
- 
- 
 
 
- 
- 
 
 
- 
- 
200 
1002 
Transition to Starting Dose of Study Drug  
Up-titration  
1Transition from β-blockers other than those above requires approval from the Sponsor or its designee prior to randomization. 
2Patients who weigh < 75 kg at randomization will receive a maximum bucindolol dose of 50 mg BID. 
3Patients receiving commercial β-blocker doses higher than those currently approved will require pre-approval from the 
Sponsor or its designee prior to randomization.  
Study drug should be up-titrated to the target dose for all patients unless clinically contraindicated. Target 
doses for study drug are: 1) 200 mg QD metoprolol; 2) 50 mg BID bucindolol for patients who weigh 
< 75 kg, and; 3) 100 mg BID bucindolol for patients who weigh ≥ 75 kg.  Investigators should make 
every reasonable attempt to up-titrate study drug on a weekly schedule, but can delay up-titration if 
required clinically (i.e., up-titration at a two week interval).  Up-titration intervals shorter than one week 
are not permitted without prior approval from the Sponsor or its designee. Study drug dose may be 
reduced at any time in the event of documented intolerance.  The goal of up-titration should be to reach 
the target dose of study drug within 3 weeks of randomization.  For patients who are in AF/AFL requiring 
ECV, the pre-ECV Drug Lead-in Period may be prolonged if they have not attained target dose within 
3 weeks of randomization (see Section 6.1.3). In the event that ECV cannot be delayed and/or a patient 
cannot tolerate the target dose, it is recommended to reach at least study drug level M100/B25 (Table 5) 
prior to ECV. Patients who cannot reach target dose by the time of ECV should have up-titration 
continued to target levels after SR is achieved, as achievement of SR may improve study drug tolerability.   
Patients who forget to take a dose of study drug by more than 6 hours should be instructed to skip that 
dose and take the subsequent dose of study drug at the next designated interval.  Patients who experience 


 
 
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dose interruptions of more than 2 days (i.e., 4 doses) should contact the site to determine if dose 
adjustment is necessary prior to re-initiation of study drug.   
At the end of the study, patients will discontinue study drug and should transition to commercially-
available β-blocker therapy per Investigator discretion. Transition to commercial β-blocker therapy is 
recommended to occur in a similar manner as the dosing algorithm described for initiation of blinded 
β-blocker therapy. If commercial β-blocker therapy is not being considered at the end of the study, then 
transition off study drug will require down-titration over several weeks. This will be accomplished via 
unscheduled visits prior to the end of study (EOS) Visit. 
5.6 
Randomization and Blinding 
The Sponsor or a specified designee will prepare the randomization code.  Only persons not involved in 
the day-to-day conduct of the study will know the randomization code before unblinding.  The 
randomization will be performed with the use of an Interactive Voice/Web Response System 
(IVRS/IWRS) via the telephone or internet.  Randomization will be centralized and stratified by: 1) HF 
etiology (ischemic/non-ischemic); 2) LVEF (< 0.35/ ≥ 0.35); 3) type of Medtronic device (Reveal/Non-
Reveal/No Device) and; 4) rhythm status at randomization (SR vs. AF/AFL).  The ‘Non-Reveal’ stratum 
will include patients with a Medtronic pacemaker (IPG), ICD, or CRT devices with a minimum of an 
atrial and a ventricular lead.  The ‘No Device’ stratum will include: a) patients who have a Medtronic 
device that cannot assess AFB; b) patients who have a Medtronic device who do not consent to participate 
in the AFB substudy; c) patients who have a device from any other manufacturer, and; d) patients who 
have no device.  
Blinding will be accomplished by providing study drug (i.e., bucindolol or metoprolol tablets) in capsules 
that are visually indistinguishable and provided in numbered kits.  Only the numbers of the kits to be 
administered to a given patient, and not the identity of the study drug, will be provided to sites.  
Investigators, site personnel, and patients will not be informed of the blinded study drug assignment at the 
time of study completion. 
In the case of a medical emergency, the Investigator may request unblinding of the study drug assignment 
for a patient via IVRS/IWRS.  Unblinding should only be done if diagnosis or treatment of the medical 
emergency is dependent on knowledge of study drug received.  The Sponsor or its designee must be 
contacted immediately and informed of any unblinding events.  Once unblinded, the patient may be 
required to discontinue from study drug but he/she should continue to participate in all other study-related 
activities including assessments of efficacy.  The Sponsor or its designee will document any patient who 
is unblinded, including the rationale for and date of unblinding. 


 
 
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5.7 
Description and Handling of Study Drug 
5.7.1 Formulation 
Clinical supplies of study drug, which include the investigational medicinal product (bucindolol 
hydrochloride) and the active comparator (metoprolol succinate), are supplied by the Sponsor.  The 
metoprolol succinate used in this study is Toprol-XL (AstraZeneca).  Blinding is achieved by over-
encapsulation of bucindolol and metoprolol tablets using the same capsule size and color.  Since 
bucindolol is administered twice daily, and metoprolol is given once per day, a placebo capsule has been 
manufactured for the active comparator arm. 
Over-encapsulated bucindolol is provided in the following dosage strengths: 6.25, 12.5, 25, 50 and 100 
mg.  Over-encapsulated metoprolol is provided in the following dosage strengths: 25, 50, 100, and 200 
mg. 
Small quantities of microcrystalline cellulose have been added to the study drug capsules as part of the 
over-encapsulation process to backfill the remaining void space.  Placebo capsules for the metoprolol arm 
of the study have been prepared by filling the over-capsules with microcrystalline cellulose. 
5.7.2 Packaging and Labeling 
Over-encapsulated bucindolol and metoprolol tablets have identical packaging for blinding purposes.  
Capsules are packaged in a PVC/aluminum blister card format in a 2 x 9 format.  This provides enough 
study drug for a 7 day (weekly) dosing regimen, plus two extra days.  In the case of bucindolol, both 
capsules for a daily treatment contain active drug product.  In the case of metoprolol, one of the capsules 
for a daily treatment is active, and one is placebo.  Blister strips are coded with a unique batch number 
assigned to each dose strength.  The batch number on each blister strip is obscured within the sealed 
portion of the study drug kit, and is not visible to patients or Investigators.  Study drug kits are child 
resistant to meet FDA and other regulatory agency requirements and are pre-printed as approved by the 
Sponsor.  The study drug kits contain a clinical trial label containing a unique kit number, as well as 
pertinent dosing and storage information.   
Study drug kits are packaged and supplied to clinical pharmacies either as individual weekly titration 
cards, or in cartons of four cards, which are adequate for four weeks of dosing.  Cartons are labeled with a 
single panel clinical trial label similar to the individual cards. 
5.7.3 Storage and Handling 
The study drug must be kept in a secure cabinet or room with access restricted to only necessary study 
personnel.  Temperature must be maintained at controlled room temperature, 15°C to 30°C (59°F to 
86°F).  Excursions outside of this range must be reported to the Sponsor or designee. 


 
 
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5.8 
Concomitant and Prohibited Medications 
Previous β-blocker therapy must be discontinued at the time of randomization to study drug and 
concomitant use is not permitted at any time during the study. 
Usage of the following anti-arrhythmic medications is prohibited < 7 days prior to randomization and at 
any time during the study, unless otherwise stated.  Concomitant usage of these anti-arrhythmic 
medications is allowed after the start of follow-up if the patient experiences an AF/AFL event or after 
failure to convert to SR following ECV.  Similarly, non-investigational procedures to treat arrhythmia 
(e.g., ablation, ECV) are also allowed after the start of follow-up if the patient experiences an AF/AFL 
event or after failure to convert to SR following ECV.  If this occurs, the patient should remain in the 
study and complete all follow-up visits and assessments. 
 
Amiodarone (e.g., Pacerone®, Nexterone®, Cordarone®) 
 
Dofetilide (e.g., Tikosyn®) 
Usage of any of the following medications is prohibited < 7 days prior to randomization and at any time 
during the study while receiving study drug. 
 
Disopyramide (e.g., Norpace®, Norpace CR®, Rythmodan®, Rythmodan-LA®) 
 
Dronedarone (e.g., Multaq®) 
 
Flecainide (e.g. Tambocor®) 
 
Propafanone (e.g. Rythmol®, Rythmol SR®, Rytmonorm®)  
 
Non-dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem)  
 
Sotalol (e.g., Betapace®, Betapace AF®, Sotalex®, Sotacor®) 
 
Daily NSAIDs (e.g., ibuprofen, celecoxib, diclofenac) 
 
Thiazolidinediones (e.g., rosiglitazone, pioglitazone, troglitazone) 
 
Frequent use of short acting nitroglycerin (e.g., > 6 sublingual tablets/week) 
5.9 
Medtronic Devices for AF Burden Substudy 
Patients who choose to participate in the optional AFB substudy will have their cardiac rhythm monitored 
continuously via a Medtronic implanted device.  Eligible Medtronic devices must be able to measure 
AFB, which include the Medtronic Reveal ICM (Section 5.9.2), and Medtronic pacemaker (IPG), ICD, or 
CRT devices with a minimum of an atrial and a ventricular lead.  Eligible devices can be previously 
placed or de novo inserted as clinically indicated.  Patients who agree to have a Medtronic device inserted 
may do so at the Randomization Visit or at any time prior to the start of the 24-week Follow-up Period.    


 
 
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5.9.1 System Description and Intended Use of Reveal ICM 
Depicted in Figure 3 and outlined in Table 6 are the components for the Reveal insertable cardiac monitor 
(ICM).  The Medtronic Reveal ICM system is being used within the study in accordance with the FDA-
approved indications for the device. 
The Reveal ICM is indicated for: 
 
Individuals with clinical syndromes or situations at increased risk of cardiac arrhythmias. 
 
Individuals who experience transient symptoms such as dizziness, palpitation, syncope, and chest 
pain that may suggest a cardiac arrhythmia. 
Figure 3: 
Components of the Medtronic Reveal ICM System 
Reveal XT 
Reveal LINQ 
 
 
Instructions for use of the devices are provided in their respective manuals.  Study system components are 
being used without modification. 
Table 6: 
System Component Information 
Model Number 
Component 
Market-released 
Model 9529 with FullViewTM Software 
(or later Medtronic releases) 
Reveal Insertable Cardiac Monitor 
Yes 
Model 2090 with FullViewTM Software 
(or later Medtronic releases) 
Medtronic CareLink Programmer 
Yes 
9538/9539 (or later Medtronic releases) 
Reveal Patient Assistant 
Yes 
2490G (or later Medtronic releases) 
Medtronic CareLink Monitor 
Yes 
Note:  The labels for the Reveal ICM components are available in English and where available in the local language. 
 


 
 
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5.9.2 Reveal Insertable Cardiac Monitor 
The Reveal ICM (model 9529 with FullViewTM software Model SW007 or later Medtronic releases) is a 
leadless device that is typically implanted under the skin in the region of the thorax.  Two electrodes on 
the body of the device continuously monitor the patient’s subcutaneous ECG.  The device can store up to 
22.5 minutes of ECG recordings from the patient-activated episodes and up to 27 minutes of ECG 
recordings from automatically detected arrhythmias.  When the ECG storage log within the monitor is 
full, the ECG record from the most recent episode will overwrite the ECG data from the oldest stored 
episode for that same arrhythmia category.  Documentation of episode occurrence will be retained.   
5.9.3 Medtronic CareLink Programmer 
The Medtronic CareLink Programmer (Model 2090 with FullViewTM software Model SW007 or later 
Medtronic releases) is used to program the Reveal ICM to detect arrhythmias with various pre-specified 
characteristics.  In addition, the programmer allows the physician to view, save, and print the ECG 
records currently held within the Reveal ICM. 
5.9.4 Reveal Patient Assistant 
The Reveal Patient Assistant (Model 9538 or later Medtronic releases) is a battery-operated, hand-held 
telemetry device that enables the patient, on experiencing symptoms potentially indicative of a cardiac 
event, to manually trigger the Reveal ICM to collect and store an ECG record.  When the recording is 
manually triggered in this way (i.e., the Symptoms button is pressed), the Patient Assistant device also 
shows the patient whether it successfully received the telemetry transfer from the Reveal ICM, as well as 
whether the battery of the Patient Assistant device is low. 
The patient can also use a query button on certain models of the Patient Assistant device for direct 
feedback about whether the Reveal has registered an arrhythmia and/or whether criteria have been met for 
the patient to take action to contact the physician or clinic.  The notification criteria are selected and pre-
programmed by the care provider. 
5.9.5 Medtronic CareLink Monitor 
The CareLink Monitor (Model 2490G or later Medtronic releases) is a device that enables the device 
diagnostic data (which includes ECG data) to be transmitted directly from the Reveal ICM to the 
Medtronic CareLink Network for review by the physician. 
5.9.6 Medtronic CareLink Network 
The Medtronic CareLink Network is an internet-based remote service for monitoring patients with 
implanted Medtronic cardiac devices.  The physician can access the CareLink Network, a secured 


 
 
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network with restricted access, to review the device data that has been uploaded from the implanted 
Reveal monitor. 
6.0 STUDY PROCEDURES 
6.1 
Timing of Study Procedures 
6.1.1 Screening and Randomization 
Written informed consent for participation in the study must be obtained before performing any study-
specific screening tests or evaluations.  Informed Consent Forms for all screened patients, including 
patients who are not subsequently randomized (i.e. screen failures), will be maintained at the study site.  
Screening tests and evaluations will be performed within 8 weeks prior to the Randomization Visit, unless 
otherwise specified.  The Investigator will maintain a screening log to record details of all patients 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Any patient who fails screening for any reason (other than genotype) may be re-screened two additional 
times.  Patients who are re-screened will be assigned a new screening number and will sign a new ICF.  
Each screening must be adequately documented in the source documents.  Previous screening tests that 
still meet the study entry criteria do not need to be repeated for patients who are being re-screened. 
During screening, potential patients must be assessed to ensure that they meet inclusion/exclusion criteria 
prior to collection of samples for central laboratory tests and β1AR genotyping.  At the Randomization 
Visit, potential patients must meet all inclusion/exclusion criteria prior to collection of samples for 
additional required genotyping, optional DNA banking, norepinephrine, and N-terminal pro B-type 
natriuretic peptide (NT-proBNP).  All screening evaluations must be completed and reviewed to confirm 
that patients meet all eligibility criteria before randomization.  There is a maximum of 8 weeks between 
the Screening Visit and the Randomization Visit. 
Patients who agree to have a Medtronic device inserted may do so at the Randomization Visit or at any 
time prior to the start of the 24-week Follow-up Period.   
6.1.1.1 Screening Visit  
At the Screening Visit, the following procedures will be done as per Appendix 4: 
 
Obtain written informed consent. 
 
Procedures to be performed prior to collection of laboratory samples: 
o Review inclusion/exclusion criteria (Section 4.2). 
o Assess medical history including arrhythmia, cardiovascular and neoplasm history (Section 
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o Review historical diagnostic tests including ECGs and echocardiograms (Section 6.2.1). 
o Collect vital signs, including height and weight (Section 6.2.2). 
o Record concomitant medications including all medications taken within 4 weeks of the 
Screening Visit (Sections 5.8 and 6.2.14). 
 
Collect laboratory samples for B1389 AR genotype (Section 6.2.9). 
 
Collect laboratory samples for chemistry and hematology, as well as serum pregnancy if 
applicable (Section 6.2.8). 
 
Complete the Screening Module in IVRS/IWRS. 
 
Complete applicable electronic case report forms (eCRFs). 
A 12-lead ECG is not required at the Screening Visit; however, if one is collected during this visit the 
results should be entered into the Screening ECG eCRF (Section 6.2.4). 
Patients who meet all entry criteria will return to the clinic within 8 weeks of screening for the 
Randomization Visit. 
6.1.1.2 Randomization Visit  
At the Randomization Visit the following procedures will be done as per Appendix 4: 
 
Procedures to be performed prior to collection of laboratory samples: 
o Review inclusion/exclusion criteria (Section 4.2). 
o Assess vital signs and weight (Section 6.2.2). 
o Perform physical exam (Section 6.2.1). 
o Assess NYHA class (Section 6.2.7). 
o Administer EQ-5D questionnaire (Section 6.2.13). 
o Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
o Perform 12-lead ECG (Section 6.2.4). 
o Assess for clinical events (Section 6.2.12). 
o Record all reported AEs (Section 7.0). 
o Record all concomitant medications (Sections 5.8 and 6.2.14). 
 
Collect central laboratory samples for NT-proBNP and plasma norepinephrine (Section 6.2.8). 
 
Collect central laboratory samples for 2c AR and CYP2D6 genotype (Section 6.2.8). 
 
Collect central laboratory samples for DNA Bank, if patient has consented (Section 6.2.10). 
 
Perform urine pregnancy test, if applicable (Section 6.2.8). 
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 
 
Complete Randomization Worksheet: 


 
 
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o If patient meets all entry criteria, access IVRS/IWRS to randomize and receive initial study 
drug assignment.  
o Dispense study drug and administer the first dose to the patient (Section 5.5).   
o If patient fails to meet all entry criteria, access IVRS/IWRS to register screen failure. 
 
Complete applicable eCRFs and update Master Drug Log and Patient Drug Accountability Log. 
 
Schedule the Week 0 Visit and ECV if applicable. 
Patients participating in the optional AFB substudy who require implant of a Medtronic REVEAL device 
may do so at the Randomization Visit or at any time prior to the start of the 24-week Follow-up Period 
(Section 6.2.5). 
6.1.2 Drug Lead-In Period  
During the Drug Lead-in Period (i.e., after randomization at the Randomization Visit and prior to the start 
of the 24-week Follow-up Period at the Week 0 Visit), patients will have their study drug dose up-titrated.  
Investigators should make every reasonable attempt to up-titrate study drug on a weekly schedule, but can 
delay up-titration if required clinically (i.e., up-titration at a two week interval).   
As starting doses and titration schedules will vary for individual patients, the up-titration of study drug 
will be managed via unscheduled visits during the Drug Lead-in Period to provide flexibility for optimal 
patient management.  After the Week 0 Visit, Investigators may continue to up-titrate study drug via 
scheduled and unscheduled clinic visits to achieve maximum tolerated dose of study drug. 
6.1.2.1 Drug Titration Visits 
During any unscheduled visit for drug titration, the following procedures will be performed: 
 
Collect used/unused drug dispensed at prior visit and assess accountability. 
 
Access IVRS/IWRS Unscheduled Visit Module to obtain next study drug assignment. 
 
Complete Master Drug Log, Patient Accountability Drug Log, and eCRF Drug Log. 
No additional assessments are required at these titration visits; however, if any procedures and/or safety 
evaluations are performed, they will be entered on an unscheduled visit eCRF. 
6.1.3 Start of 24-Week Follow-up Period (Week 0 Visit) 
The primary endpoint and multiple secondary and tertiary endpoints will be assessed from the start of the 
24-week Follow-up Period (i.e., Week 0 Visit) and all subsequent study visits will be relative to this time 
point (Appendix 4).  The 24-week Follow-up Period will begin on the day of: 1) the ECG that establishes 
stable SR; 2) the last ECV attempt for patients who fail to convert to stable SR, or; 3) the Week 0 Visit, 
for patients in AF/AFL who do not undergo ECV for any reason.   


 
 
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If a patient is in AF/AFL after 3 weeks of study drug treatment, they will undergo ECV to establish stable 
SR (Section 6.1.3.2).  ECV may also be performed as early as 1 week after randomization if all of the 
following conditions are met: 1) the patient is receiving the target dose of study drug; 2) the patient is 
receiving guideline indicated oral anticoagulation therapy for stroke prevention and; 3) a delay of ECV 
could be detrimental to patient outcome.  The first ECV attempt may also be performed as late as 8 weeks 
after randomization if, in the opinion of the Investigator, additional time is needed to attain target doses of 
study drug or to achieve appropriate anticoagulation status prior to ECV.  Conversion to stable SR will be 
confirmed at least 1 hour after ECV by ECG.  Patients who do not establish stable SR post-ECV will 
undergo a second ECV procedure to establish stable SR unless, in the opinion of the Investigator, it would 
not be the best course of treatment for the patient.  No more than two ECV attempts are permitted per 
protocol prior to the start of the 24-week Follow-up Period.  If a patient does not establish stable SR after 
the second ECV attempt, the patient is considered an ‘ECV failure’ and will enter the 24-week Follow-up 
Period. 
If a patient who was in AF/AFL at randomization undergoes spontaneous conversion to stable SR prior to 
the protocol-specified ECV procedure, then all procedures and assessments required for the Week 0 Visit 
(except ECV) must be performed at that time (Section 6.1.3.1). 
If a patient who was in SR at randomization is in AF/AFL following 3 weeks (± 3 days) of study drug 
treatment, then the patient will undergo ECV to establish stable SR on study drug (Section 6.1.3.2). For 
patients in SR at randomization, it is recommended that ECV be scheduled at the time of study drug 
initiation to allow the patient to undergo ECV 3 weeks (± 3 days) after randomization (without 
reschedule) if they have reverted from SR to AF/AFL.    
If a patient who was in SR at randomization is in stable SR following 3 weeks (± 3 days) of study drug 
treatment, then all procedures and assessments required for the Week 0 Visit (except ECV) must be 
performed at that time (Section 6.1.3.1).   
6.1.3.1 Patients in Stable SR Who Do Not Require ECV 
Unless noted otherwise, all of the following procedures will be performed as per the Week 0 Visit in 
Appendix 4 for: 1) patients in AF/AFL at randomization who spontaneously (medically) convert to stable 
SR prior to ECV, and; 2) patients in SR at randomization who are in stable SR after 3 weeks (± 3 days) of 
study drug treatment. 
 
Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
 
Perform a 12-lead ECG to determine rhythm (Section 6.2.4). 
 
Do NOT perform the ECV procedure (patient is in SR).  
 
Perform a 12-lead ECG at least 1 hour after the first ECG to confirm rhythm (Section 6.2.4). 


 
 
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 
Assess vital signs and weight (Section 6.2.2). 
 
Assess for clinical events (Section 6.2.12).  
 
Record all reported AEs (Section 7.0). 
 
Record concomitant medications, including all changes and additions (Sections 5.8 and 6.2.14). 
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 
 
Collect used/unused drug dispensed at prior visit and assess accountability (Section 6.2.15). 
 
Access IVRS/IWRS to register the Week 0 Visit (i.e., start of follow-up, use the date of the first 
ECG) and obtain next study drug assignment, if needed.  
 
Update Master Drug Log and Patient Drug Accountability Log. 
 
Enter data from this visit into the eCRF as the Week 0 Visit. 
 
Schedule the Week 2 Visit. 
 
For patients who spontaneously convert from AF to SR prior to ECV.   
o Instruct the patient to return to the clinic within 48 hours of spontaneous conversion to SR to 
obtain a trough blood sample for Population PK analysis.  On the day of this visit, the patient 
should be instructed to withhold their morning dose of study drug. After the sample has been 
obtained the patient should be administered the next dose of study drug (Section 6.2.11). 
6.1.3.2 Patients in AF/AFL Who Require ECV  
Unless noted otherwise, all of the following procedures will be performed as per the Week 0 Visit in 
Appendix 4 for: 1) patients in AF/AFL at randomization who do not spontaneously convert to SR and 
require ECV to establish stable SR, and; 2) patients in SR at randomization who are in AF/AFL after 3 
weeks (± 3 days) of study drug treatment and require ECV to establish stable SR. 
 
Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
 
Perform a 12-lead ECG to determine rhythm (Section 6.2.4). 
 
Assess vital signs and weight (Section 6.2.2). 
 
Assess for clinical events (Section 6.2.12). 
 
Record all reported AEs (Section 7.0). 
 
Record concomitant medications, including all changes and additions (Sections 5.8 and 6.2.14). 
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 
 
Collect used/unused drug dispensed at prior visit and assess accountability (Section 6.2.15). 
 
Perform the ECV procedure per standard of care (Section 6.2.3).  
 
Perform a 12-lead ECG at least 1 hour after ECV to confirm rhythm (Section 6.2.4). 
o If the patient is in SR at least 1 hour after ECV: 
 Schedule a time to call the patient the following day to collect the AFSQ. 


 
 
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 Access IVRS/IWRS to register the Week 0 Visit (i.e., start of follow-up)  
and obtain next study drug assignment, if needed.  
 Update Master Drug Log and Patient Drug Accountability Log. 
 Schedule the Week 2 Visit. 
 The next day, contact the patient and administer the AFSQ (Section 6.2.6).  
 Enter data from this visit into the eCRF as the Week 0 Visit. 
o If the patient is in AF/AFL following ECV and an additional ECV attempt is clinically 
appropriate and permitted per protocol: 
 If needed, access IVRS/IWRS Unscheduled Visit Module to obtain next study drug 
assignment. 
 Update Master Drug Log and Patient Drug Accountability Log. 
 Enter all data from this visit into the eCRF as an Unscheduled Visit.  
 Schedule the next ECV procedure, which should be performed within 2 weeks of the 
initial ECV attempt. Note: only two ECV attempts are permitted per protocol prior to 
the start of follow-up.   
o If the patient is in AF/AFL following ECV and an additional ECV attempt is NOT 
clinically appropriate or permitted per protocol (i.e., ECV failure): 
 Access IVRS/IWRS to register the Week 0 Visit (i.e., start of follow-up) and obtain 
next study drug assignment, if needed.  
 Update Master Drug Log and Patient Drug Accountability Log. 
 Enter data from this visit into the eCRF as the Week 0 Visit. 
 Schedule the Week 2 Visit.  
6.1.4 24-week Follow-Up Period  
During the 24-week Follow-up Period, patients will return to the clinic at scheduled intervals for routine 
assessments of safety and efficacy.  During these visits, heart rhythm will be assessed by 12-lead ECG 
and the patient will be queried for symptoms potentially related to AF/AFL. Scheduled telephone contacts 
will occur at Week 6, Week 10, Week 14, Week 18 and Week 22.  Patients will be also be instructed to 
contact the site immediately if they experience new or worsening symptoms.  Patients will be queried for 
symptoms potentially related to AF/AFL during the scheduled and patient-initiated telephone contacts 
(Section 6.2.6).  If the Investigator suspects that a new AF/AFL event has occurred between scheduled 
clinic visits (i.e., a change in rhythm from SR to AF/AFL), the patient will be instructed to return to the 
clinic within 3 business days for further assessments (Section 6.1.4.2). 
  


 
 
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6.1.4.1  Clinic Visits during the 24-week Follow-up Period  
The following procedures will be performed at all clinic visits, unless otherwise noted, as per Appendix 4: 
 
Assess vital signs and weight (Section 6.2.2). 
 
Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
 
Perform 12-lead ECG (Section 6.2.4). 
 
Week 12 and Week 24 only: Perform Medtronic device interrogation if patient is participating in 
AFB substudy (Section 6.2.5.3). 
 
Week 12 and Week 24 only: Assess NYHA class (Section 6.2.7). 
 
Assess for clinical events (Section 6.2.12). 
 
Week 12 and Week 24 only: Administer EQ-5D questionnaire (Section 6.2.13). 
 
Week 4, Week 12, and Week 24 only: Collect central laboratory samples for chemistry, 
hematology, NT-proBNP and plasma norepinephrine (Section 6.2.8). 
 
Week 4 and Week 12 only: Collect central laboratory samples for Population PK analysis (Section 
6.2.11).  Patients must be reminded via a documented telephone contact 24 - 72 hours in advance 
of these visits to withhold their morning dose of study drug until a pre-dose (trough) sample for 
Population PK analysis has been collected at the clinic.   
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 
 
Record all reported AEs (Section 7.0). 
 
Record concomitant medications, including all changes and additions (Sections 5.8 and 6.2.14). 
 
Not required at Week 2: Collect used/unused drug dispensed at prior visit and assess 
accountability (Section 6.2.15). 
 
Not required at Week 2: Access IVRS/IWRS to register visit and obtain next study drug 
assignment. 
 
Weeks 4, 8, 12, 16, and 20: Schedule the next telephone contact (Section 6.1.4.2). 
 
Schedule the next Clinic Visit (i.e., Week 4, Week 8, etc.). 
 
Complete applicable eCRFs and update Master Drug Log and Patient Drug Accountability Log. 
6.1.4.2 Telephone Contact during the 24-week Follow-up Period  
Scheduled telephone contacts will occur at Week 6, Week 10, Week 14, Week 18 and Week 22. Patients 
will be also be instructed to contact the site immediately if they experience new or worsening symptoms. 
Patients will be queried for symptoms potentially related to AF/AFL during the scheduled and patient-
initiated telephone contacts. Telephone contacts will continue through the 24-week Follow-up Period 
regardless of heart rhythm status, (i.e., even if the patient has subsequently reverted to AF/AFL). No 
telephone contact is required for patients who did not established stable SR at the start of follow-up (i.e., 


 
 
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ECV failures) and no telephone contact is required for any patients during the Treatment Extension 
Period.   
The following procedures will be performed at telephone contacts required during the 24-week Follow-up 
Period. 
 
Contact the patient and administer the AFSQ (Section 6.2.6).  
 
If the Investigator suspects that a new AF/AFL event has occurred between scheduled clinic visits 
(i.e., a change in rhythm from SR to AF/AFL), the patient will be instructed to return to the clinic 
within 3 business days for an unscheduled visit to administer the AFSQ and perform a 12-lead 
ECG. Additional assessments performed during this visit should also be documented in the eCRF. 
6.1.5 Treatment Extension Period and End of Study 
After the Week 24 Visit, patients will enter the Treatment Extension Period and continue to receive 
blinded study drug.  During the Treatment Extension Period, patients will return to the clinic every 
12 weeks for routine assessments of efficacy and safety (Appendix 4).   
Phase 3 follow-up, which is inclusive of patients enrolled during Phase 2B, will continue until a total of at 
least 330 primary endpoint events have been observed.  After this event, all patients will complete the 
24-week Follow-up Period or return to the clinic for an EOS Visit if already in the Treatment Extension 
Period.  At the EOS Visit, patients will return all remaining study drug and should transition to 
commercially-available β-blocker therapy per Investigator discretion.  Transition to commercial -blocker 
therapy is recommended to occur in a similar manner as described for initiation of blinded -blocker 
therapy.  If commercial β-blocker therapy is not being considered at the end of the study, then transition 
off study drug will require down-titration over several weeks.  This will be accomplished via unscheduled 
visits prior to the EOS Visit. 
Investigators and patients will not be informed of the blinded study drug assignment at the time of study 
completion.  
6.1.5.1 Treatment Extension Visits 
At the Treatment Extension Visits, the following procedures will be performed as per Appendix 4: 
 
Assess vital signs and weight (Section 6.2.2). 
 
Assess NYHA class (Section 6.2.7). 
 
Assess for clinical events (Section 6.2.12). 
 
Record all reported AEs (Section 7.0). 
 
Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
 
Perform 12-lead ECG (Section 6.2.4).  


 
 
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 
Perform Medtronic device interrogation if patient is participating in the AFB substudy (Section 
6.2.5.3). 
 
Collect central laboratory samples for chemistry and hematology (Section 6.2.8). 
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 
 
Record concomitant medications, including all changes and additions (Sections 5.8 and 6.2.14). 
 
Collect used/unused drug dispensed at prior visit and assess accountability (Section 6.2.15). 
 
Access IVRS/IWRS to register visit and obtain next study drug assignment.  
 
Complete applicable eCRFs and update Master Drug Log and Patient Drug Accountability Log. 
 
Schedule the next clinic visit. 
6.1.5.2 End of Study Visit 
At the EOS Visit, the following procedures will be performed as per Appendix 4: 
 
Assess vital signs and weight (Section 6.2.2). 
 
Assess NYHA class (Section 6.2.7). 
 
Assess for clinical events (Section 6.2.12). 
 
Record all reported AEs (Section 7.0). 
 
Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
 
Perform 12-lead ECG (Section 6.2.4). 
 
Perform Medtronic device interrogation if patient is participating in the AFB substudy (Section 
6.2.5.3). 
 
Collect central laboratory samples for chemistry and hematology (Section 6.2.8). 
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 
 
Record concomitant medications, including all changes and additions (Sections 5.8 and 6.2.14). 
 
Collect used/unused drug dispensed at prior visit and assess accountability (Section 6.2.15). 
 
Prescribe commercial -blocker therapy as clinically indicated. 
 
Access IVRS/IWRS to register End of Study. 
 
Contact patient by telephone 72 hours (± 24 hours) following study discontinuation to check 
health status, record AEs and concomitant medications. 
 
Complete applicable eCRFs and update Master Drug Log and Patient Drug Accountability Log. 
6.1.6 Premature Discontinuation of Study Drug 
The Investigator has the right to discontinue a patient from study drug at any time.  In addition, patients 
have the right to voluntarily discontinue study drug at any time for any reason.  Reasons for 
discontinuation of study drug may include, but are not limited to, the following: 


 
 
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 
Patient withdrawal of consent at any time. 
 
Any medical condition that the Investigator or Sponsor determines may jeopardize the patient’s 
safety if he or she continues in the study. 
 
Investigator or Sponsor determines it is in the best interest of the patient. 
 
Patient noncompliance, such as missing scheduled visits, non-adherence with concomitant 
medications, etc. 
 
Discontinuation of the study at the request of the Sponsor, a regulatory agency, or an IRB/IEC. 
 
Lost to follow-up. 
If possible, the patient should return to the clinic for an end of treatment (EOT) Visit prior to 
discontinuation of study drug and complete all assessments (Appendix 4).  After study drug is 
discontinued, the patient should remain in the study whenever possible and complete all study visits 
according to the planned schedule of assessments (except for patients who have withdrawn consent).  The 
primary reason for premature discontinuation of study drug should be documented on the appropriate 
eCRF.  
If a patient chooses to discontinue study drug and withdraw from the study, then the patient should return 
to the clinic for an EOS Visit (Section 6.1.5.2). 
Patients who prematurely discontinue study drug will not be replaced. 
6.1.6.1 End of Treatment Visit  
At the EOT Visit, the following procedures will be performed as per Appendix 4: 
 
Assess vital signs and weight (Section 6.2.2). 
 
Assess NYHA class (Section 6.2.7). 
 
Assess for clinical events (Section 6.2.12). 
 
Record all reported AEs (Section 7.0). 
 
Administer the AFSQ prior to determination of the patient’s current rhythm (Section 6.2.6). 
 
Perform 12-lead ECG (Section 6.2.4). 
 
Perform Medtronic device interrogation if patient is participating in the AFB substudy (Section 
6.2.5.3). 
 
Collect central laboratory samples for chemistry and hematology (Section 6.2.8). 
 
If possible, a trough blood sample for Population PK analysis (Section 6.2.11) should also be 
obtained prior to discontinuation of study drug for any patient who experiences a SAE leading to 
permanent discontinuation of study drug.   
 
Record coagulation status if patient is receiving warfarin (Section 6.2.8). 


 
 
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 
Record concomitant medications, including all changes and additions (Sections 5.8 and 6.2.14). 
 
Collect used/unused drug dispensed at prior visit and assess accountability (Section 6.2.15). 
 
Initiate commercial -blocker therapy as clinically indicated. 
 
Access IVRS/IWRS to register End of Treatment. 
 
Contract patient by telephone 72 hours (± 24 hours) following study discontinuation to check 
health status, record AEs and concomitant medications. 
 
Complete applicable eCRFs and update Master Drug Log and Patient Drug Accountability Log. 
6.1.7 Premature Study Withdrawal 
All patients have the right to withdraw from study participation without prejudice at any time during the 
study.  If a patient terminates participation in the study, the Investigator should make a reasonable effort 
to determine the cause for study withdrawal.  If, for whatever reason, a patient withdraws from the study 
or the study is terminated while the patient is receiving study drug, an EOS Visit should be performed 
(Section 6.1.5.2). 
Patients who withdraw from the study must be contacted by telephone 72 hours (± 24 hours) following 
study drug discontinuation to check on their health status, and this telephone contact must be documented 
in the eCRFs.  If the patient has experienced any AEs or changes to medications, all pertinent information 
must be collected and recorded on the appropriate eCRF(s). 
Patients who withdraw from the study will be asked to sign a separate consent form to allow telephone 
contacts by the site for the periodic assessment of vital status. 
Patients who prematurely withdraw from study participation will not be replaced. 
6.1.8 Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the study may 
include, but are not limited to, the following: 
 
The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
patients. 
 
Patient enrollment is unsatisfactory. 
 
Data recording is inaccurate or incomplete. 
The Sponsor will notify the Investigator if the study is placed on hold, or if the Sponsor decides to 
discontinue the study or development program. 
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site may include, but are 
not limited to, the following: 


 
 
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 
Excessively slow recruitment. 
 
Poor protocol adherence. 
 
Inaccurate or incomplete data recording. 
 
Non-compliance with the International Conference on Harmonisation (ICH) guideline for Good 
Clinical Practice. 
6.2 
Description of Study Procedures 
6.2.1 Medical History, Diagnostic Test History, and Physical Exam 
All ongoing conditions and relevant/significant medical history from the past five years (including all 
major hospitalizations and surgeries) will be recorded.  Any neoplastic conditions, irrespective of the time 
of diagnosis, should be noted.  Symptoms related to AF, HF, and/or the underlying etiology of either 
condition should be listed on the arrhythmia and heart failure history form. 
Historical diagnostic tests, such as ECGs and echocardiograms, will be reviewed to ensure that all of the 
inclusion and none of the exclusion criteria are met.  The historical determination of LVEF for study 
inclusion can be based on echocardiogram, cardiac catheterization, radionuclide, angiography, or MRI 
studies and must have been performed within 12 months prior to the Screening Visit.  If the historical 
determination of LVEF has not been assessed within 12 months of screening, it can be re-assessed during 
the Screening Period per standard of care.   
A physical exam of the major body systems will be conducted at the Randomization Visit.  Patient vital 
signs and weight will also be assessed during the physical exam. 
6.2.2 Vital Signs, Height and Weight 
Vital signs (including sitting blood pressure, heart rate, and respiratory rate) and weight will be collected 
throughout the study.  Height will be collected once at the Screening Visit. One measurement of blood 
pressure and heart rate after the patient has been sitting quietly for at least 5 minutes should be taken.  
This same procedure should be followed throughout the study. 
Vital Signs must be assessed prior to, or at least one hour after, a blood draw.  All measures of blood 
pressure will be performed using standard sphygmomanometry.  If possible, the same 
sphygmomanometer and arm should be used. 
6.2.3 Electrical Cardioversion 
Patients in AF/AFL at randomization who are in AF/AFL after 3 weeks of treatment with study drug will 
undergo direct current ECV to establish stable SR per standard of care according to standard clinical 
practice.4  Cardioversion via ICD or a comparable implanted device cannot substitute for direct current 


 
 
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ECV.  Patients in SR at randomization who are in AF/AFL after 3 weeks of study drug treatment will also 
undergo ECV to establish stable SR. Patients in AF/AFL at randomization who spontaneously convert to 
stable SR and patients in SR at randomization who are in SR after 3 weeks (± 3 days) of study drug 
treatment will not undergo ECV (Section 6.1.3.1).  
ECV may be performed as early as 1 week after randomization if all of the following conditions are met: 
1) the patient is receiving the target dose of study drug; 2) the patient is receiving guideline indicated oral 
anticoagulation therapy for stroke prevention, and; 3) a delay of ECV could be detrimental to patient 
outcome.  The first ECV attempt may also be performed as late as 8 weeks after randomization if, in the 
opinion of the Investigator, additional time is needed to attain target doses of study drug or to achieve 
appropriate anticoagulation status prior to ECV. 
A 12-lead ECG will be performed prior to ECV and at least 1 hour post-ECV to determine if SR has been 
achieved.  If the Investigator assessment of the post-ECV ECG indicates that the patient has achieved SR, 
the patient will complete the Week 0 Visit and will be contacted the following day to be assessed for 
potential AF/AFL symptoms via the AFSQ (Section 6.2.6).  
Patients who do not demonstrate SR at the post-ECV time point will undergo a subsequent ECV to 
establish a baseline SR unless, in the opinion of the Investigator, it would not be the best course of 
treatment for the patient.  Secondary ECV procedures should be performed within 2 weeks of the initial 
ECV attempt.  Patients who fail to convert to SR following a second ECV attempt will be considered 
ECV failures and will be included in the endpoint calculation as experiencing the event on Day 1 of 
follow-up (Section 8.3). 
Patients who revert to AF/AFL after the start the 24-week Follow-up Period may undergo additional ECV 
procedures or medical interventions as clinically indicated; however, the schedule for the 24-week 
Follow-up Period will not be restarted. 
6.2.4 Electrocardiogram 
At clinic visits, patients will be queried prior to ECG assessment to determine if they have experienced 
any symptoms since their last clinic visit that could potentially be related to AF/AFL (Section 6.2.6). 
AF will be assessed at scheduled clinic visits via a 12-lead ECG (Appendix 4).  To minimize variability, 
it is important that patients be in a resting position for several minutes prior to ECG evaluation.  Body 
position should be consistently maintained for each ECG evaluation to prevent changes in heart rate.  
ECGs should be performed prior to meals and any scheduled vital sign measurements or blood draws.  


 
 
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ECGs will be labeled with the following: patient number, patient initials, protocol number, and date 
recorded. In addition, the Investigator is required to sign and date the ECG after they have reviewed and 
assessed the data. 
During the follow-up period, if a 12-lead ECG indicates a change in rhythm from SR to AF/AFL, the 
patient should remain in the resting position and a second rhythm assessment must be collected at least 
10 minutes after the initial read.  If AF/AFL is confirmed with the second read, this will be considered an 
AF/AFL event.  
A 12-lead ECG is not required at the Screening Visit; however, if one is collected during this visit the 
results should be entered into the Screening ECG eCRF. Two ECGs are required at the Week 0 Visit. For 
patients in SR who do not require ECV, these two ECGs must be performed at least 1 hour apart to 
establish stable SR and the start of the 24-week Follow-up Period. For patients in AF/AFL who require 
ECV, one ECG will be performed before ECV and one ECG will be performed at least 1 hour after ECV 
to establish stable SR and the start of the 24-week Follow-up Period.  
In addition to all scheduled ECGs, if the Investigator becomes aware of any non-protocol specified ECGs 
or other rhythm assessments that indicate a change in rhythm during the 24-week Follow-up Period, these 
must also be documented in the eCRF and may be requested for potential adjudication by the CEC. 
Any clinically relevant findings, as assessed by the Investigator, will be captured in the eCRFs. Potential 
AF/AFL events will be adjudicated by a blinded Clinical Events Committee (CEC) until the primary 
endpoint has been met. 
Patients experiencing recurrence of AF/AFL will be encouraged to remain on blinded study drug and 
continue their participation in the study.  These patients may undergo subsequent ECV procedures or 
other medical interventions, as clinically indicated.  If this occurs, the patient should still complete all 
remaining assessments as described in Appendix 4. 
6.2.5 Medtronic Device Procedures 
6.2.5.1 Implantation of Medtronic Device 
Patients who agree to have a Medtronic device inserted may do so at the Randomization Visit or at any 
time prior to the start of the 24-week Follow-up Period. Implantation of the Medtronic ICM must be 
performed in accordance with the hospital’s standard implant practice and in accordance with the 
Medtronic Reveal ICM implant instructions.  After the Reveal ICM device is implanted, the surgical team 
should perform diagnostic testing specific to R-wave sensing to ensure that the Reveal ICM device is 
accurately identifying R-waves and calculating heart rate from R-R intervals per standard implant 
recommendations.  The programmer ECG trace with marker annotations is used to evaluate R-wave 


 
 
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sensing and adjust gain as necessary to prevent under- or over-sensing.  Ideally, this should be done at the 
time of implantation, and then repeated post-operatively prior to discharge from the hospital. 
The following information will be collected at the time of implant: 
 
Reveal ICM device serial number. 
 
Device interrogation and data transfer (e.g. save-to-disk, USB data transfer). 
6.2.5.2 Programming Requirements 
The Reveal ICM device is to be programmed according to Table 7.  Reprogramming of the parameters 
that are “OFF” may be done only if needed for clinical reasons.  However, they should be reprogrammed 
again back to the initial settings as soon as clinically feasible and a protocol deviation should be reported.   
Table 7: 
ICM Device Programming Requirements 
Parameter 
Required Setting 
  
REVEAL-XT 
REVEAL-LINQ 
Type of AT/AF detection 
AF only 
AF only 
AF Detection 
Balanced sensitivity 
Balanced sensitivity 
AT/AF Record ECG of/Recording Threshold 
≥ 60 minutes 
≥ 60 minutes 
Ectopy Rejection 
ON 
Nominal 
FVT Detection 
OFF 
Tachy Detection OFF 
FVT ECG recording 
OFF 
VT Detection 
OFF 
VT ECG recording 
OFF 
Brady Detection 
OFF 
Brady Detection OFF 
Brady ECG recording 
OFF 
Asystole Detection 
OFF 
Pause Detection OFF 
Asystole ECG recording 
OFF 
AT/AF Detection 
AF Only 
AF Only 
For patients who have a pre-existing or newly implanted Medtronic pacemaker (IPG), ICD, or CRT 
device, Table 8 outlines the recommended programming for these devices.  The other parameters for 
these devices are to be programmed based on the Investigator’s opinion. 


 
 
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Table 8: 
Programming Parameters for Medtronic IPG, ICD or CRT devices 
 Parameter 
 Recommended Setting 
 Atrial preference pacing (APP) 
 OFF 
 Atrial rate stabilization (ARS) 
 OFF 
 Post-mode switch overdrive pacing (PMOP) 
 OFF 
 Atrial Anti-tachycardia pacing (ATP) 
 OFF 
 AT/AF detection and EGM collection  
 Nominal 
6.2.5.3 Device Data Interrogations 
Some Medtronic devices can be interrogated by the patient and uploaded directly to the CareLink 
Network.  However, to ensure consistent data collection, all patients participating in the AF burden 
substudy will have their devices interrogated at specific clinic visits (Appendix 4) via the Medtronic 
Carelink Programmer and the data will be electronically sent to Medtronic.   
AFB data cannot substitute for ECG assessments required to define an AF/AFL event; however, these 
data may be considered by the CEC as supplemental information to adjudicate individual events. 
6.2.5.4 Device System Modification 
A system modification will be reported in the event that the Reveal ICM device requires invasive 
modification, i.e., the implanted monitor is repositioned, replaced or explanted.  If the Reveal ICM is 
explanted and a Medtronic pacemaker (IPG), ICD, or CRT device is implanted the patient can continue 
participation in this study.  For a system modification the following activities are required: 
 
Pre-modification: device interrogation with download. 
 
Post-modification: device interrogation with download (if the modification involved only 
repositioning or explant with replacement). 
6.2.6 AF Symptoms Questionnaire 
The AFSQ is attached as Appendix 6 and will be administered by the site to the patient prior to each ECG 
assessment (Appendix 4).  At the time of ECV (if needed), the AFSQ will be administered prior to the 
pre-ECV ECG assessment and a second AFSQ will be administered the following day for those patients 
achieving stable SR post-ECV. For patients in SR who do not require ECV at this visit, the AFSQ 
collected prior to the Week 0 ECG must be recorded but a second AFSQ the following day is not 
required.    
Scheduled telephone contacts will occur at Week 6, Week 10, Week 14, Week 18 and Week 22. Patients 
will be also be instructed to contact the site immediately if they experience new or worsening symptoms. 


 
 
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Patients will be queried via the AFSQ for symptoms potentially related to AF/AFL during the scheduled 
and patient-initiated telephone contacts (Section 6.1.4.2). If the Investigator suspects that a new AF/AFL 
event has occurred between scheduled clinic visits (i.e., a change in rhythm from SR to AF/AFL), the 
patient will be instructed to return to the clinic within 3 business days for further assessments (Section 
6.1.4.2).  
6.2.7 NYHA Functional Class 
The Investigator or designee will complete the NYHA functional class assessment at specific clinic visits 
(Appendix 4).  Every effort should be made to have the same Investigator assess the patient at each study 
visit. 
Table 9: 
New York Heart Association Functional Class  
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. no shortness 
of breath when walking, climbing stairs etc. 
II 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. 
walking short distances (20–100 m). Comfortable only at rest. 
III 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary 
activity. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
6.2.8 Clinical Laboratory Tests 
A central laboratory will analyze the following protocol-specified laboratory tests collected at specific 
clinic visits (Appendix 4); collection, processing, labeling, and shipping of the samples will be completed 
following central laboratory guidelines.  
Chemistry: The following chemistry tests are required: alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total bilirubin, creatinine, blood 
urea nitrogen, bicarbonate, calcium, chloride, magnesium, sodium, phosphorous, potassium, total 
cholesterol, uric acid, glucose, total protein, and albumin. 
Hematology: The following hematology tests are required: hemoglobin, hematocrit, complete blood 
count, red cell count, red cell indices, white blood cell count (total and differential) and platelet count. 
Pregnancy: A serum pregnancy test will be required at the Screening Visit for all female patients of child-
bearing potential.  Bulk urine pregnancy tests will be included within the central laboratory supplies and 
will be performed at the site for all female patients of child-bearing potential at the Randomization Visit. 
Biomarkers: The following biomarker tests are required: NT-proBNP, norepinephrine.  Results of 
individual patient data for the NT-proBNP and norepinephrine will not be provided to sites to protect the 
treatment blind.   


 
 
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For patients receiving warfarin, coagulation status (i.e., INR) will be monitored per standard of care via 
local laboratories to ensure optimal anticoagulation therapy for stroke prevention (e.g., INR 2-3).  
Laboratory values and normal ranges from local laboratories will not be collected.  However, coagulation 
status will be recorded categorically via INR ranges (e.g., < 1, ≥ 1 and < 2, ≥ 2 and < 3, ≥ 3 and < 4, ≥ 4) 
at specific clinic visits (Appendix 4).  
6.2.9 Required Genetic Analyses (β1389, α2C, CYP2D6) 
A blood sample to assess 1389 AR genotype will be collected at the Screening Visit for all patients after 
written consent has been obtained.  A central reference laboratory will analyze DNA from the 1389 AR 
samples.  Collection, processing, labeling, and shipping of the samples will be completed following 
central laboratory guidelines.  1389 AR genotype results are expected 5-10 business days from the time 
of collection, and review of 1389 AR genotype results is required prior to randomization.  Only patients 
who have the 1389Arg/Arg genotype will be eligible to be randomized and receive study drug. 
A blood sample to assess other bucindolol-related genes will be collected at the Randomization Visit for 
all randomized patients.  A central reference laboratory will analyze DNA from this sample for the 
following genes: α2C AR and CYP2D6.  Collection, processing, labeling, and shipping of the samples will 
be completed following central laboratory guidelines.  Genotyping for α2C AR and CYP2D6 is required 
for all randomized patients to explore the potential for polymorphisms in these genes to alter the 
effectiveness of bucindolol.  However, as these data are not required to confirm study eligibility or patient 
management, they will not be provided to the Investigator. 
Patients must consent to the required genetic analyses to participate in the trial.  A duplicate sample may 
need to be collected at a later time if the original sample cannot be analyzed.  Samples for the required 
genetic analyses will be coded in a manner which allows them to be matched to a study site and/or a 
patient number, but will not carry personal identifiers which could be traced to a specific individual.  If 
DNA is extracted from the sample, the DNA may be subjected to sample quality control analysis.  This 
analysis may involve the genotyping of several genetic markers to confirm the integrity of individual 
samples.  If inconsistencies are identified in the analysis, those samples may be destroyed. 
Samples for the required genetic analyses may be kept by the Sponsor for up to 15 years after the last 
patient has completed study participation.  However, if it is determined that a sample is not needed, the 
samples may be destroyed earlier.     
If a patient withdraws from the study for any reason other than “lost to follow-up”, the patient will be 
given the following options regarding the required genetic analyses samples, if the sample has already 
been collected: 


 
 
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 
The sample will be maintained per the patient’s original consent. 
 
The patient’s consent will be withdrawn and any remaining sample will be destroyed. 
If a patient withdraws consent and requests sample destruction, the Investigator must complete the 
appropriate documentation to request sample destruction within the timeframe specified by the Sponsor or 
its designee, and maintain documentation in the site study records.  The Sponsor will only keep data that 
are collected or generated up to the point at which consent to use the sample is withdrawn by the patient. 
6.2.10 Optional Genetic Analyses (DNA Bank) 
Blood samples for future genetic analyses will be collected on a subset of patients who choose to 
participate in an optional DNA bank substudy.  Patients may consent to participate in the clinical study 
and still decline participation in the optional DNA bank substudy.  Patients will be asked to accept or 
decline participation in the DNA bank substudy at the time the ICF is reviewed and signed.  Consent for 
participation in the DNA bank substudy must be obtained in addition to the patient’s consent to 
participate in the clinical study and the patient may still withdraw consent for participation in the DNA 
bank substudy at any time without withdrawing consent for participation in the clinical study. 
For patients who agree to participate in the DNA bank substudy, a sample for potential genetic analyses 
will be collected at the Randomization Visit for all randomized patients.  Complete instructions regarding 
the processing, packaging, and shipping of samples will be provided in separate laboratory guidelines.  A 
duplicate sample may need to be collected at a later time if the original sample cannot be analyzed.  
Samples for the DNA bank substudy will be coded in a manner which allows them to be matched to a 
study site and/or a patient number, but will not carry personal identifiers which could be traced to a 
specific individual.  If DNA is extracted from the sample, the DNA may be subjected to sample quality 
control analysis.  This analysis may involve the genotyping of several genetic markers to confirm the 
integrity of individual samples.  If inconsistencies are identified in the analysis, those samples may be 
destroyed. 
Samples for the DNA bank substudy may be kept by the Sponsor for up to 15 years after the last patient 
has completed study participation.  However, if it is determined that a sample is not needed, the samples 
may be destroyed earlier. In some cases, the samples may never be utilized, for example, if there are not 
an adequate number of samples to perform the analysis.   
If a patient who has consented to participate in the genetic analysis withdraws from the study for any 
reason other than “lost to follow-up”, the patient will be given the following options regarding the DNA 
bank substudy sample, if the sample has already been collected: 
 
The sample will be maintained per the patient’s original consent. 
 
The patient’s consent will be withdrawn and any remaining sample will be destroyed. 


 
 
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If a patient withdraws consent from the DNA bank substudy and/or requests sample destruction, the 
Investigator must complete the appropriate documentation to request sample destruction within the 
timeframe specified by the Sponsor or its designee, and maintain documentation in the site study records.  
The Sponsor will only keep data that are collected or generated up to the point at which consent to use the 
sample is withdrawn by the patient.  Withdrawal of consent from the DNA bank substudy does not affect 
consent to participate in the clinical study. 
6.2.11 Population Pharmacokinetic Analysis 
Pharmacokinetic (PK) samples will be collected at specific clinic visits to determine plasma 
concentrations of bucindolol hydrochloride and metoprolol succinate (Appendix 4).  For patients who 
spontaneously convert to stable SR, an additional trough blood sample will be collected within 48 hours 
of spontaneous conversion to SR.  If possible, a trough blood sample should also be obtained prior to 
discontinuation of study drug for any patient who experiences a SAE leading to permanent 
discontinuation of study drug.   
Patients will be reminded via a documented telephone contact 24 - 72 hours in advance of these visits to 
withhold their morning dose of study drug until a pre-dose (trough) sample for Population PK analysis 
has been collected at the clinic.  Patients will be queried to determine the approximate times of study drug 
dosing for the previous two doses and to determine if the patient missed any study drug doses during the 
previous two days.  The trough blood sample will be collected and the time will be recorded.  The patients 
will then receive the morning dose of study drug and will continue with the remainder of their clinical 
assessments. 
A designated reference laboratory will analyze all PK samples.  Collection, processing, labeling, and 
shipping of the samples will be completed following central laboratory guidelines. 
6.2.12 Clinical Events Assessment 
Patients will be queried at specific clinic visits (Appendix 4) to determine if any significant clinical events 
have occurred since their last clinic visit and these events will be recorded in the eCRF.  Details of the 
event(s) will be recorded, including any AE/SAE that led to the event(s) and Investigator assessment of 
cause (e.g., CV/other, HF/ischemia/arrhythmia/stroke/other CV).  Clinical events include cardiovascular 
events (e.g. CAD intervention, stroke, TIA, etc.) and intervention for rhythm events (e.g. catheter 
ablation, initiation of anti-arrhythmic therapy, implantation of a therapeutic device, etc.). 
Vital status will also be determined at regular intervals (e.g., annually) for all patients, including those 
who have withdrawn from the study and have consented to routine telephone contact.  


 
 
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6.2.13 EQ-5D Questionnaire 
The EQ-5D Questionnaire is provided in Appendix 5.  A paper copy of the questionnaire will be 
completed by the patient at specific clinic visits (Appendix 4) and the responses will be recorded in the 
eCRF. 
6.2.14 Concomitant Medications 
At the Screening Visit, review all medications currently ongoing or that have been administered within 4 
weeks of the Screening Visit.  If a patient is receiving any prohibited concomitant medications (Section 
5.8), determine if the patient can discontinue treatment prior to randomization to maintain study 
eligibility. 
At each study visit, all medications will be reviewed and any changes will be documented in the source 
documents and captured on the appropriate eCRF.  Document any changes in concomitant medication via 
a telephone call 72 hours following discontinuation of study and any changes in concomitant medication 
associated with SAEs identified within 30 days of last study drug dose or within 30 days of last study 
evaluation, whichever is longer. 
6.2.15 Study Drug Compliance 
Patients should be instructed to bring their used and unused study drug containers with them to every visit 
to assess compliance and drug accountability.  At each clinic visit the patient will be reminded of the 
importance of taking the study medication exactly as prescribed.  The study drug will be supplied in 
packaging containing adequate study medication to last until the next clinic visit.  Capsule counts will be 
made, with or without the patient's knowledge (at discretion of study personnel), as a means of assessing 
patient compliance.  Site staff should calculate and review compliance, and counsel the patient if 
compliance issues are observed. 
6.3 
Protocol Deviations 
This study will be conducted as described in this protocol except for emergency situations in which the 
protection, safety, and well-being of the patient requires immediate intervention based upon the judgment 
of the Investigator (or a responsible, appropriately trained and credentialed professional(s) designated by 
the Investigator).  In the event of any deviation from the protocol, the Investigator or a specified designee 
must notify the Sponsor and/or specified designee.  This will allow an early joint decision to be made as 
to whether or not the patient should continue in the study.  Both the Investigator and Sponsor or specified 
designee will document this decision. 


 
 
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7.0 ASSESSMENTS OF SAFETY 
7.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product (or medical device), and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not considered 
related to the medicinal (investigational) product.  Any pre-existing condition that increases in severity, or 
changes in nature during or as a consequence of the study drug phase of a human clinical trial, will also 
be considered an AE.  All AEs will be recorded after the patient signs informed consent and throughout 
the study, regardless of study drug administration. 
AEs may also include, but are not limited to, the following: 
 
Pre- or post-treatment complications that occur as a result of a protocol-associated procedure 
(e.g., invasive procedures such as venipuncture or biopsy) during or after screening (before the 
administration of study drug). 
 
Sequelae of overdose or drug abuse/misuse. 
 
Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of the study drug phase of this clinical study. 
An AE does not include the following: 
 
Arrhythmia and heart failure diagnoses, events, and interventions with an onset date before 
screening; these should be documented on the Arrhythmia and Heart Failure History eCRF.  
 
AF/AFL events (other than those resulting in death), as these are being assessed as study 
endpoints. This includes symptoms related to AF/AFL events, which will be collected via the 
AFSQ for the primary endpoint. 
 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
screening that is not related to arrhythmia or heart failure; it is considered to be pre-existing and 
should be documented on the Medical History eCRF.   
 
Any medical condition or clinically significant laboratory abnormality present or detected before 
screening that does not worsen.  
 
Anticipated day-to-day fluctuations of pre-existing conditions that do not represent a clinically 
significant exacerbation or worsening.   


 
 
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 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions). 
 
Overdose without clinical sequelae (Section 7.7). 
7.2 
Assessment of Adverse Events 
All AEs will be assessed by the Investigator and recorded on the AE eCRF.  For each patient, the safety 
reporting period begins immediately following the signing of informed consent and continues until the 
end of study participation, regardless of study drug administration.  See Section 7.3.2.3 for additional 
post-study reporting requirements. 
An AE entry should indicate whether or not the AE was serious, the start date (AE onset), the stop date 
(date of AE resolution), whether or not the AE was related to study drug, or to a study procedure, the 
action taken with study drug due to the AE, the severity of the AE, and the outcome of the AE. 
AEs already documented in the eCRF (i.e., at a previous assessment) and designated as “ongoing” should 
be reviewed at subsequent visits as necessary.  Upon resolution, the date and time (if applicable) of 
resolution should be recorded in the eCRF.  If an AE increases in frequency or severity during a study 
period, a new record of the event should be started. 
AEs should be documented in terms of a medical diagnosis.  When this is not possible, the AE should be 
documented in terms of signs and/or symptoms observed by the Investigator or reported by the patient at 
each study visit. 
For AEs associated with laboratory abnormalities, the AE should be graded on the basis of the clinical 
severity in the context of the underlying conditions.  Collection of changes in laboratory values as AEs 
should be restricted to those considered clinically significant by the Investigator that result in a change, 
interruption, or discontinuation of study drug; that are considered a SAE; or that require medical 
intervention or treatment.  Laboratory values associated with clinical signs and symptoms should be 
reported as an AE based on the clinical signs and symptoms, not as the laboratory value. 
7.2.1 Assessment of Causality 
Every effort should be made by the Investigator to explain each AE and assess its relationship, if any, to 
study drug treatment.  Causality should be assessed using the following categories: 
 
Unrelated:  Evidence exists that the AE has an etiology other than the study drug (e.g., 
pre-existing condition, underlying disease, intercurrent illness, or concomitant medication). 


 
 
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 
Possibly Related:  A direct cause and effect relationship between the study drug and adverse 
experience has not been demonstrated, but there is a reasonable possibility that the experience 
was caused by the study drug. 
 
Probably Related:  A temporal relationship exists between the event onset and the administration 
of the study drug, and appears with some degree of certainty to be related based on the known 
therapeutic and pharmacological actions of the study drug.  It cannot be readily explained by the 
patient’s clinical state or concomitant therapies.  In the case of cessation or reduction of the dose, 
the event abates or resolves. 
The degree of certainty with which an AE is attributed to study drug treatment (or alternative causes, e.g., 
natural history of the underlying disease, concomitant therapy, etc.) will be determined by how well the 
experience can be understood in terms of one or more of the following: 
 
Temporal relationship of event onset to the initiation of study drug. 
 
Course of the event, considering especially the effects of dose reduction, discontinuation of study 
drug, or reintroduction of study drug (where applicable). 
 
Known association of the event with the study drug or with similar treatments. 
 
Known association of the event with the disease under study. 
 
Presence of risk factors in the patient or use of concomitant medications known to increase the 
occurrence of the event. 
 
Presence of non-treatment-related factors that are known to be associated with the occurrence of 
the event. 
7.2.2 Assessment of Intensity 
Adverse events will be graded and reported as indicated on the eCRF.  Maximum intensity should be 
assigned to one of the following categories: 
 
Mild: Discomfort noticed, but no disruption of normal daily activity. 
 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
 
Severe: Incapacitating with inability to work or to perform normal daily activity. 
7.3 
Serious Adverse Events 
7.3.1 Definition of Serious Adverse Events 
A serious adverse event (SAE) is any AE that meets any of the following criteria: 
 
Fatal (i.e., the AE actually causes or leads to death). 


 
 
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 
Life-threatening (i.e., the AE, in the view of the Investigator, places the patient at immediate risk 
of death).  This does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization. 
 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions). 
 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug. 
 
Significant medical event in the Investigator's judgment (e.g., may jeopardize the patient or may 
require medical/surgical intervention to prevent one of the outcomes listed above). 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an AE, rated as 
mild, moderate, or severe (Section 7.2.2); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 
SAEs are required to be reported by the Investigator to the Sponsor immediately (i.e., no more than 24 
hours after learning of the event). 
7.3.2 Serious Adverse Event Reporting Requirements 
7.3.2.1 Standard Reporting Requirements 
The Sponsor, or the Contract Research Organization (CRO) on the behalf of the Sponsor, must be notified 
immediately regarding the occurrence of any SAE that occurs after the patient signs informed consent and 
throughout the study, regardless of study drug administration, including SAEs resulting from protocol-
associated procedures, as defined in relevant legislation.  The procedures for reporting all SAEs, 
regardless of causal relationship, are as follows: 
 
Record the SAE on the AE eCRF and complete the “Serious Adverse Event Report” form within 
the electronic database. 
 
In the event the electronic database is not functional, a paper SAE form will be available for the 
reporting of SAEs. 
The Sponsor may request additional information from the Investigator to ensure the timely completion of 
accurate safety reports. 
The Investigator must take all therapeutic measures necessary for resolution of the SAE.  Any 
medications and/or procedures or interventions necessary for treatment of the SAE must be recorded in 


 
 
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the event description section of the online SAE event form as well as in the CONMED section of the 
patient’s eCRF. 
Follow-up of AEs/SAEs will continue through the last day on study and/or until the Investigator and/or 
the Sponsor determine that the patient’s condition is stable.  The Sponsor may request that certain 
AEs/SAEs be followed until resolution. 
7.3.2.2 Expedited Reporting Requirements 
The Sponsor will promptly evaluate all SAEs against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to Investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the expectedness of 
these events using the following reference documents: 
 
Bucindolol Investigator’s Brochure 
 
Toprol-XL US Package Insert 
The Sponsor will compare the severity of each event and the cumulative event frequency reported for the 
study with the severity and frequency reported in the applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality and seriousness, 
with allowance for upgrading by the Sponsor as needed. 
Certain events are anticipated to occur in the study population at some frequency independent of study 
drug exposure and will be excluded from expedited reporting.  These anticipated events include, but are 
not limited to, the following: 
 
Recurrence of AF/AFL (symptomatic or asymptomatic), hospitalizations or procedures related to 
AF/AFL recurrence, or subsequent AEs/SAEs related to AF/AFL recurrence. 
 
Worsening HF, hospitalizations or procedures related to worsening HF, or subsequent AEs/SAEs 
related to worsening HF. 
The DSMB will monitor these anticipated events at regular intervals during the study.  An aggregate 
report of any clinically relevant imbalances that do not favor the test product will be submitted to health 
authorities. 
7.3.2.3 Post-Study Reporting Requirements 
Any SAEs, regardless of cause or relationship, occurring within 30 days of last study drug dose or within 
30 days of last study evaluation, whichever is longer, must also be reported. 


 
 
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Investigators are not obligated to actively seek out SAEs beyond the follow-up period for patients.  
However, if the Investigator learns of an SAE occurring after the completion/termination visit he/she 
should promptly report the event to the Sponsor. 
7.4 
Device Related Safety Reporting Requirements 
All Medtronic devices used in this study are market released.  It is the responsibility of the Investigator to 
report all product complaints and malfunctions immediately via the regular channels for market approved 
products.  Per FDA regulations, Device User Facilities are required to report Medical Device Reports 
(MDR) on market approved products (21 CFR 803, subpart C).  A Device User Facility is defined as a 
hospital, an ambulatory surgical facility, a nursing home, an outpatient treatment facility, or an outpatient 
diagnostic facility which is not a physician’s office. 
The reporting of product complaints and malfunctions for market released devices is not part of the 
clinical study and should be done independent of any AE reporting requirements.  However, any 
untoward medical occurrence (i.e., AEs) associated with a device-related procedure (e.g., hematoma 
following device insertion) should be reported as an AE for this study as described in Section 7.2. 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities are usually not recorded as AEs or SAEs.  However, laboratory abnormalities 
(e.g., clinical chemistry, hematology) independent of the underlying medical condition that require 
medical or surgical intervention or lead to study drug interruption or discontinuation must be entered as 
an AE, as well as an SAE, if applicable. 
In addition, laboratory or other abnormal assessments (e.g., ECG, X-rays, vital signs) that are associated 
with signs and/or symptoms must be entered as an AE or SAE if they meet the definition of an AE or 
SAE.  If the laboratory abnormality is part of a syndrome, the syndrome or diagnosis should be recorded. 
If the changes are mild and in the opinion of the Investigator not clinically significant, the Investigator 
should continue to carefully monitor the values.  Local laboratory tests may be repeated, as clinically 
indicated, without prior approval by the Sponsor or specified designee. 
7.6 
Neoplasms 
In the BEST study, a numerical imbalance in the incidence of neoplasms was observed at baseline in 
patients randomized to bucindolol compared to placebo.  This imbalance was maintained during the trial 
with the addition of new treatment-emergent neoplasms.  Although there is no known class effect or 
mechanism of action associated with this observation, the Sponsor will collect a detailed history of all 
historical and treatment-emergent neoplastic events as AEs of special interest. 
The following events will be considered AEs of special interest for this study: 


 
 
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 
Development of treatment-emergent neoplastic conditions. 
 
Progression or worsening of pre-study neoplastic conditions. 
 
Progression or worsening of treatment-emergent neoplastic conditions. 
During the Screening Period, all pre-existing neoplastic conditions should be recorded as part of the 
medical history assessment.  After randomization, record any changes in historical neoplastic conditions 
and describe any new neoplastic events that have occurred during the study as AEs.  Neoplasm AEs of 
special interest should be entered into the AE eCRF within 7 days of identification.  Supplemental 
information will also be recorded on a neoplasm specific eCRF for all neoplasm AEs.  The eCRF will 
include, but is not limited to: 
 
History of pre-study neoplastic conditions (e.g., description, type, severity date of onset). 
 
Description of treatment-emergent neoplastic condition suitable for MedDRA coding. 
 
Type of treatment-emergent neoplastic condition (e.g., benign, pre-cancerous, malignant). 
 
Severity of treatment-emergent neoplastic condition (e.g., early [Stage 1 or 2], locally-advanced 
[Stage 3], metastatic [Stage 4]). 
 
Estimated date of onset of neoplastic condition and details of the diagnosis. 
 
Current status of disease (e.g., resolved, in remission, active/ongoing). 
The DSMB will closely monitor neoplasm AEs during the study and an aggregate report of any clinically 
relevant imbalances that do not favor the test product will be submitted to health authorities. 
7.7 
Overdose 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study drug is not an AE unless it results in 
untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on the eCRF.  All AEs 
associated with an overdose or incorrect administration of study drug should be recorded on the AE 
eCRF. 
An overdose will be considered a SAE only if any of the seriousness criteria are met.  If the associated 
AE fulfills serious criteria, the event should be entered into the online database immediately (i.e., no more 
than 24 hours after learning of the event). 
Any clinical sequelae in association with the overdose should be reported as an AE or SAE along with the 
overdose.  Details of signs or symptoms, clinical management and outcome should be reported, if 
available. 


 
 
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7.8 
Pregnancy 
Bucindolol is considered a Pregnancy Category C investigational drug.  Bucindolol has not been shown to 
be teratogenic, but other adverse effects (i.e., developmental delays) have been shown in rats when given 
at doses as low as 15 mg/kg/day, which is approximately 7 times the human dose. 
Pregnancy information for bucindolol is based upon animal studies.  Bucindolol hydrochloride did not 
affect reproduction or fertility in the rat or rabbit; when administered to rabbits during organogenesis it 
did not affect fetal viability or produce malformations.  For more details see the Bucindolol Investigator’s 
Brochure.  There are no adequate and well-controlled studies in pregnant women.  No pregnancies have 
been reported in any clinical study conducted with bucindolol. 
Similarly, metoprolol tartrate (a drug similar to metoprolol succinate) has been shown to increase post-
implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the 
daily dose of 200 mg in a 60-kg patient.  Distribution studies in mice confirm exposure to the fetus when 
metoprolol tartrate is administered to pregnant animals.  These studies have revealed no evidence of 
impaired fertility or teratogenicity.  There are no adequate and well-controlled studies of metoprolol 
tartrate or metoprolol succinate in pregnant women. 
Therefore, females of childbearing potential must have a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at the Randomization Visit to be eligible for the study.  Females 
of childbearing potential must also agree to use a highly effective contraception for the duration of the 
trial and for at least 30 days following the last dose of study drug. 
All women of childbearing potential should be instructed to notify the Investigator if they become 
pregnant at any time during the study, or if they become pregnant within 30 days of last study evaluation.  
While pregnancy in and of itself is not considered to be an SAE, all pregnancies must be reported on the 
paper Pregnancy Report Form to the CRO Safety Department within 24 hours of the Investigator’s 
knowledge of the pregnancy. Any SAE associated with the pregnancy that occurs to the 
mother/fetus/child will be recorded on the SAE eCRF within 24 hours of becoming aware of the event 
(Section 7.3.1).  Study drug must be discontinued immediately unless the pregnancy is terminated.  Any 
premature terminations of pregnancy must be reported. 
Whenever possible, a pregnancy should be followed by the study site to term, and the status of the mother 
and child should be reported to the CRO Safety Department after delivery. 
7.8.1 Definition of Childbearing Potential and Post-Menopausal 
All female patients are considered to be of childbearing potential unless they meet one of the following 
criteria: 


 
 
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 
The patient has been postmenopausal for 12 or more months. 
 
The patient had a surgical bilateral oophorectomy (with or without hysterectomy) more than 6 
weeks prior to randomization. 
 
The patient had a hysterectomy. 
Female patients of reproductive or childbearing potential who are not willing to use a highly effective 
method of contraception for the duration of the study and for 30 days after the last dose of study drug will 
be excluded from study participation. 
Examples of highly effective contraception include the following: 
 
Contraceptive pill or transdermal patch 
 
Single barrier plus spermicide 
 
Intrauterine device 
 
Implants for contraception 
 
Injections for contraception (with prolonged release) 
 
Hormonal vaginal device 
 
Sterilization, surgical tubal ligation 
 
Sole sexual partner consisting of surgically sterilized male partner with appropriate post-surgical 
documentation of the absence of spermatozoa in the ejaculate 
 
Same sex partner 
8.0 STATISTICAL CONSIDERATIONS 
A formal statistical analysis plan (SAP) for the combined Phase 2B/Phase 3 study will be finalized prior 
to the end of patient follow-up and unblinding of randomized treatment assignments. 
8.1 
Definitions of Analysis Populations and Endpoint Follow-up Periods 
The efficacy analysis will follow the intent-to-treat (ITT) principle and all patients randomized to study 
treatment will be included regardless of the success of the titration process.  As an additional sensitivity 
analysis, the efficacy endpoint testing will be performed on a protocol-compliant subpopulation.  The 
safety analyses will include those patients which actually received at least one dose of blinded study 
treatment.  The screened population includes any patient who signs informed consent for the study.  The 
screen failure population is a subpopulation of the screened population who are not randomized to study 
drug for any reason. 
Four follow-up periods will be defined for inclusion of each patient’s results in endpoint calculations: 


 
 
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 
Drug Titration Period: Starts on the day of randomized treatment initiation and extends for 6 
weeks after randomization. 
 
24-week Follow-up Period: Starts on the day of: 1) the ECG that establishes stable SR; 2) the last 
ECV attempt for patients who fail to convert to stable SR, or; 3) the Week 0 Visit, for patients in 
AF/AFL who do not undergo ECV for any reason.  Follow-up will be censored at Week 24 for 
the primary endpoint and all other 24-week endpoints for patients who have not experienced an 
event by this visit. 
 
Total Follow-up Period: Starts on the same day as the 24-week Follow-up Period initiation and 
extends until the EOS Visit.  
 
Total Study Period: Starts on the day of randomized treatment initiation and extends until the 
EOS Visit. 
8.2 
Study Population Analyses 
Screen failure reasons will be tabulated, ordered by frequency. 
The distributions of the following characteristics will be contrasted between the randomized treatment 
groups with descriptive statistics (e.g., mean, standard error, standard deviation, median, minimum, 
maximum and patient count for continuous variables, and counts with percentages for categorical 
variables): 
 
Demographics 
 
Cardiovascular disease history and AF risk factors 
 
Physical exam abnormalities 
 
Baseline results for CHADS2 score, NYHA functional class, vital signs, ECG and laboratory 
parameters 
 
Other bucindolol-related genes (i.e., CYP2D6 and α2C) 
 
Final study disposition categories (completed, discontinued due to a non-fatal AE, etc.) 
 
Treatment exposure, by 
o Patients attaining target dose 
o Length and outcome of titration period 
o Days of double blind treatment by dose and overall 
o Compliance 
 
Concomitant medication usage at baseline and throughout study 
 
Protocol deviations 
 


 
 
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Metrics for several key study procedures will be presented with descriptive statistics by randomized 
treatment group: 
 
Type of Medtronic device 
 
Elapsed days on treatment prior to de novo insertion of Medtronic Reveal ICM 
 
Elapsed days on treatment prior to ECV 
 
Outcome of ECV 
 
Compliance with procedures for upload of Medtronic device results 
8.3 
Primary Endpoint 
The primary endpoint is elapsed time to first event of symptomatic AF/AFL or ACM during the 24-week 
Follow-up Period.  This is a time to event endpoint censored at 24 weeks of follow-up after establishment 
of stable SR on study drug.  The treatment group results will be compared with a log rank statistic for p-
value generation and the Cox proportional hazards model will be used for calculation of an estimated 
hazard ratio and 95% confidence interval.  Both calculations will be stratified by the pre-specified 
randomization strata: HF etiology (ischemic/non-ischemic); LVEF (< 0.35 / ≥ 0.35); type of Medtronic 
device (Reveal/Non-Reveal/No Device), and; rhythm status at randomization (SR vs. AF/AFL).  The 
analysis methodology will also be applied separately to each component of this compound endpoint (i.e., 
time to first event of symptomatic AF/AFL and time to ACM). 
The following definitions apply to this endpoint: 
 
Stable SR on study drug is defined as any of the following:  
o SR confirmed ≥ 1 hour after ECV. 
o SR confirmed ≥ 1 hour after spontaneous conversion from AF/AFL. 
o SR confirmed ≥ 1 hour at the Week 0 Visit for patients randomized in SR.  
 
An AF/AFL event is defined as AF or AFL observed on two consecutive measures separated by 
at least 10 minutes as assessed by ECG. 
 
A symptomatic AF/AFL event is defined as an AF/AFL event that is associated with a clinically 
relevant change in patient-reported symptoms, as determined by the CEC examination of blinded 
data. 
The CEC charter will describe their approach for identifying an AF/AFL event as symptomatic and their 
approach for identifying the onset date and time of the event. 
AF/AFL will be assessed at scheduled clinic visits via 12-lead ECG and via unscheduled ECG whenever 
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queried at the time of each ECG assessment to determine if they have experienced any change in 
symptoms that could be potentially related to AF/AFL. 
The following scenarios are possible for a small subgroup of patients: 
1. Spontaneous conversion to stable SR during titration prior to the planned cardioversion.  For 
these patients, the day of the first ECG assessment that meets the definition of stable SR, as 
defined above, will be designated as Day 1 of the 24-week Follow-up Period. 
2. Failure to attain stable SR because the ECV procedure was not performed due to drop out or any 
other reason other than those described below.  These patients will be included in the analysis as 
censored on Day 1 of follow-up. 
3. Failure to attain stable SR following ECV.  These patients will be included in the endpoint 
calculation as experiencing the event on Day 1 of follow-up. 
4. Deaths occurring after randomization and prior to conversion to stable SR will be counted as 
events on Day 1. 
5. A life-threatening AF/AFL event may lead to emergent cardioversion or medical intervention 
based on a single rhythm assessment. In these cases, the requirement for a second confirmatory 
rhythm assessment at least 10 minutes after the initial rhythm assessment may not be necessary.  
Inclusion of these events for the primary endpoint will be determined in a blinded manner by the 
CEC.   
In exploratory analyses, the following covariates as well as the stratification variables and study phase 
will be included as potentially relevant explanatory variables in the Cox regression models: 
1. Baseline NYHA Class 
2. CHADS2 Score 
3. Gender 
4. Race 
5. Age 
6. Baseline norepinephrine level 
7. Baseline heart rate 
8. Baseline systolic blood pressure 
9. Previous amiodarone use  
10. Ablation procedure prior to study 
11. For the subset of patients in AF/AFL at randomization, type of rhythm abnormality (paroxysmal 
AF, persistent AF). 
12. For the subset of patients in SR at randomization: the time since last attaining SR, the type of 
previous rhythm abnormality, and the intervention that ended the previous AF episode. 


 
 
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13. 2C AR polymorphisms (i.e., Del carriers vs. 2C wild type homozygotes). 
14. Other clinically significant AF risk factors. 
8.4 
Secondary Endpoints 
The following endpoints will be tested for superiority of bucindolol benefit relative to metoprolol by fixed 
sequence provided that bucindolol meets the superiority criteria on the primary endpoint.  The time to 
first event endpoints will be analyzed with the same methodology as the primary endpoint with the 
exception of non-AF rhythm endpoints (e.g., VT/VF, SVT, etc.).  For these endpoints, the patients who 
failed to convert to stable SR will have follow-up results and will therefore not be censored on Day 1 
since these events may still be observed.  The following statistical analysis methodologies for the study 
will be described in further detail in the Statistical Analysis Plan. 
 
Time to first event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during the 24-week 
Follow-up Period.  A supportive analysis will involve the same analysis methodology applied to 
each component (i.e., AF, AFL and ACM). Supportive analysis will also be conducted to 
examine this endpoint and its components for the Total Follow-up Period.   
 
Proportion of patients with VT, VF, or symptomatic supraventricular tachycardia (SVT) during 
the 24-week Follow-up Period. Includes VF and symptomatic SVT events of any duration, VT 
events of ≥ 15 seconds, and VT events that result in appropriate firing of an ICD.  This endpoint 
will be tested with a Cochran-Mantel-Haenszel statistic to control for the four stratification 
variables. The components will also be examined individually with the same methodology.  A 
supportive analysis will also be conducted to examine this endpoint and its components for the 
Total Follow-up Period.   
 
Total number of hospitalization days per patient (all-cause) during the Total Study Period.  This 
count will be normalized for the total number of days of follow-up prior to testing with the 
Wilcoxon Rank Sum statistic.  A supportive analysis for this endpoint will also be conducted that 
compares patients who are in AF at the EOS Visit and have VRR control to patients who are in 
AF at the EOS Visit without VRR control. A supportive analysis for this endpoint will also be 
conducted for the subset of heart-failure related hospitalization days per patient during the Total 
Study Period. 
 
Time to first event of AF/AFL (i.e., symptomatic or asymptomatic), HF hospitalization (as 
assessed by the Investigator), or ACM during the Total Study Period.  Supportive analyses will 
also be performed for the 24-week Follow-up Period only, for each endpoint component, and for 
each endpoint combination (i.e., AF/AFL+ACM, AF/AFL+HFH, HFH+ACM). 


 
 
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 
Proportion of patients with adequate ventricular rate control in the setting of AF/AFL.  These 
patients will be identified by the CEC and the condition will be defined by (a) a ventricular 
response rate (VRR) between 40 and 80 beats per minute at rest on the last tracing demonstrating 
AF/AFL during the 24-week Follow-up Period and (b) the absence of symptoms associated with 
bradycardia. This endpoint will be tested with a Cochran-Mantel-Haenszel statistic to control for 
the four stratification variables.  A supportive analysis will also be performed to evaluate this 
endpoint at the time of study drug discontinuation.   
8.5 
Tertiary Endpoints 
 
Time to first event of VT/VF or ACM during the Total Follow-up Period.  Includes VF events of 
any duration, VT events of ≥ 15 seconds, and VT events that result in appropriate firing of an 
ICD. 
 
Time to first event of AF/AFL (i.e., symptomatic or asymptomatic), CV-related hospitalization 
(as assessed by the Investigator), or ACM during the Total Study Period. Supportive analyses will 
also be performed for the 24-week Follow-up Period only, for each endpoint component, and for 
each endpoint combination (i.e., AF/AFL+ACM, AF/AFL+CVH, CVH+ACM). Proportion of 
patients with stroke or systemic embolism during the Total Follow-up Period.  This endpoint will 
be tested with a Cochran-Mantel-Haenszel statistic to control for the four stratification variables.  
The components will also be examined individually with the same methodology.  Stroke is 
defined as a focal neurologic deficit from a non-traumatic ischemic, hemorrhagic, or uncertain 
cause lasting at least 24 hours (as assessed by the Investigator). 
 
Total number of new or worsening symptoms reported on the AFSQ during the 24-week Follow-
up Period. Supportive analyses will also be conducted to examine symptoms reported prior to 
recurrence of AF/AFL and symptoms reported in periods of SR during the 24-week Follow-up 
Period. 
 
Proportion of patients who convert from AF/AFL to stable SR (i.e., spontaneously or post-ECV) 
and enter the 24-week Follow-up Period.  This endpoint will be tested with a Cochran-Mantel-
Haenszel statistic to control for the four stratification variables.  Supportive analyses will also be 
conducted to individually examine spontaneous conversion to stable SR that leads to avoidance of 
protocol-scheduled ECV and the establishment of stable SR at the time of the initial protocol-
scheduled ECV procedure.  A supportive analysis will also be conducted to examine this endpoint 
for the Total Follow-up Period.  


 
 
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 
Total number of ECV procedures per patient during the Total Study Period.  This count will be 
normalized for the total number of days of follow-up prior to testing with the Wilcoxon Rank 
Sum statistic. 
 
Total number of persistent AF/AFL episodes per patient during the 24-week Follow-up Period.  
Persistent AF/AFL is defined as AF/AFL observed on two consecutive ECG assessments 
separated by > 7 days.  This count will be normalized for the total number of days of follow-up 
prior to testing with the Wilcoxon Rank Sum Statistic. Supportive analyses will also examine the 
time to first event of persistent AF/AFL and the proportion of patients at the end of follow-up 
who are in a state of persistent AF/AFL. This endpoint and both supportive analyses will also be 
evaluated for the Total Follow-up Period.  
 
Proportion of patients at Week 24 who are receiving study drug and have not had an AF/AFL 
event.  This endpoint will be tested with a Cochran-Mantel-Haenszel statistic to control for the 
four stratification variables. 
 
Change in NT-proBNP, assessed relative to baseline.  Change from baseline will be tested for 
greater reduction in the bucindolol treatment group with the Wilcoxon Rank Sum test because of 
the historically high lack of normality of this measure. 
 
Change in norepinephrine, assessed relative to baseline. 
 
The EQ-5D questionnaire has 5 dimensions (mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression) and each is self-rated by the patient as no problems, some problems, or 
severe problems. The bucindolol treatment group will be tested for superior response using a 
Cochran-Mantel-Haenszel statistic to control for the four stratification variables. 
 
Population PK analysis. Details of this analysis will be prespecified in a separate analysis plan. 
 
Pharmacoeconomic modeling of healthcare utilization.  Details of this analysis will be 
prespecified in a separate analysis plan. 
8.6 
Safety Endpoints 
The results for the following safety endpoints will be compared with descriptive statistics between the 
treatment groups for all patients receiving study treatment.  All results collected from first dose of study 
drug to within 14 days of the last dose for each patient will be included in the assessments of safety unless 
otherwise stated.  Exploratory analyses will also examine polymorphisms in other bucindolol-related 
genes (i.e., α2C AR and CYP2D6) and their relationship to the safety endpoints. 
 
Incidence of ACM during the Total Study Period.  This will also be tabulated for the Total 
Follow-up Period.  A supportive analysis for this endpoint will also be conducted to examine the 


 
 
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association of VRR control with mortality using the final heart rate measurement available for 
each patient (comparisons will be within the treatment groups).  
 
Incidence of ACM, CV-related hospitalization (as assessed by the Investigator), or withdrawal of 
study drug due to an AE during the Drug Titration Period.  The components will also be 
examined individually. 
 
Incidence of heart block during the Total Study Period. Defined as third degree heart block, 
second degree heart block requiring pacemaker implantation, or symptomatic second degree heart 
block as determined by the CEC. 
 
Incidence and severity of treatment-emergent AEs/SAEs over time during the Total Study Period. 
 
Incidence of neoplasm-related AEs during the Total Study Period.  The AEs of special interest 
will be tabulated according to the following characteristics: 
o Development of treatment-emergent neoplastic conditions. 
o Progression or worsening of pre-study neoplastic conditions. 
o Progression or worsening of treatment-emergent neoplastic conditions. 
 
Change from baseline in clinical laboratory tests over time during the Total Study Period.  Also 
for clinical laboratory tests, the numbers and percentages of patients with values exceeding the 
bounds of normal ranges. 
 
Change from baseline in vital signs and weight over time during the Total Study Period. 
 
Change from baseline in quantitative ECG parameters (i.e., QTc, QRS, PR and HR). 
 
Proportion of patients attaining target study drug dose during the Drug Titration Period. 
Supportive analyses will also be performed for the subpopulations receiving and not receiving 
previous -blocker therapy at randomization. 
8.7 
Optional Substudies 
 
DNA Bank, with collection at time of screening for patients who agree to participate in the 
substudy. 
 
AFB for patients who agree to participate in the substudy. 
o AFB is defined as the amount of time per day that a patient is in AF/AFL, as measured by a 
Medtronic implanted device.   
o The primary AFB endpoint will be measured through the Week 24 Visit.  It will be a time to 
first event analysis, with an AF/AFL event defined as at least 6 hours of AFB in a single 
day.  It will be analyzed with the same methodology as the primary endpoint.  


 
 
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o AFB will also be presented as hours/day with descriptive statistics and graphical displays. 
o Additional analyses will examine all available AFB data, including VRR during periods of 
AF/AFL as collected by implanted Medtronic devices. 
8.8 
Power and Sample Size 
In a previous study involving post-ECV follow-up, the AF event rate in successfully converted patients 
who were subsequently treated for approximately 6 months with metoprolol was 52%.  This study 
included both HF and non-HF/LV dysfunction patients and the average LVEF was 49%.  In a second 
study with a similar design and patient population (i.e., post-ECV follow-up of HF and non-HF/LV 
dysfunction patients), the 6 month event rate was 46% in the group of patients treated with bisoprolol.  In 
the EURIDIS and ADONIS studies, which primarily enrolled non-HF/LV dysfunction patients in SR who 
had experienced at least one episode of AF in the preceding 3 months, the 6 month event rate was 
approximately 54% in patients who received dronedarone, compared to 65% for patients receiving 
placebo.37  Because enrollment in the current study is limited to a HFREF population, it can be assumed 
that the AF event rate will be higher than these previously published studies.  This study also considers 
failure to achieve normal SR post-ECV (expected to be 5-10%) and ACM (expected to be 1-2%) as 
events for the primary endpoint. 
Power level estimates for the primary endpoint given a variety of metoprolol event rate and treatment 
benefit assumptions appear below.  In particular, assuming an event rate of 60% at 6 months in the 
metoprolol group and a bucindolol effect size of 25%, a 620-patient study (310 patients in each group) 
with at least 330 accrued endpoint events would have 98% power to achieve a p-value  0.050 and a 90% 
power to achieve a p-value  0.01.  Therefore, the study design should be sufficient to test the hypothesis 
that bucindolol is superior to metoprolol for the prevention of symptomatic AF/AFL in HFREF patients 
with the 1389Arg/Arg genotype. Further evaluation of sample size will be performed via an interim 
analysis conducted by the DSMB during Phase 3 (Section 8.9).  
Table 10: 
Power for Primary Endpoint: 620 Patients and Alpha = 0.01 
Metoprolol Group 
Event Rate 
Treatment Benefit of Bucindolol 
15% 
20% 
25% 
30% 
35% 
40% 
50% 
26% 
49% 
74% 
91% 
98% 
99% 
52.5% 
29% 
54% 
79% 
93% 
99% 
99% 
55% 
32% 
59% 
83% 
96% 
99% 
99% 
57.5% 
36% 
65% 
87% 
97% 
99% 
99% 
60% 
40% 
70% 
90% 
98% 
99% 
99% 
 


 
 
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Table 11: 
Power for Primary Endpoint: 620 Patients and Alpha = 0.05 
Metoprolol Group 
Event Rate 
Treatment Benefit of Bucindolol 
15% 
20% 
25% 
30% 
35% 
40% 
50% 
48% 
73% 
90% 
98% 
99% 
99% 
52.5% 
52% 
77% 
92% 
99% 
99% 
99% 
55% 
56% 
80% 
94% 
99% 
99% 
99% 
57.5% 
60% 
84% 
96% 
99% 
99% 
99% 
60% 
65% 
87% 
98% 
99% 
99% 
99% 
8.9 
Interim Analyses 
Blinded safety data (e.g., group A and group B) will be summarized for inspection by the DSMB and will 
be reviewed at regular intervals.  The DSMB Chair will also monitor a subset of safety data at periodic 
intervals during the study (e.g., monthly).  If a clinically significant imbalance in the groups is observed at 
any time, the DSMB Chair may request an unblinded analysis. 
In addition to these routine safety reviews, an interim analysis of unblinded data will be conducted by the 
DSMB for the purpose of ruling out futility for meeting the Phase 3 primary endpoint.  The DSMB will 
determine the timing of the interim analysis based on pre-specified thresholds for patient enrollment. If 
the DSMB determines there is absence of futility, acceptable safety, and pre-trial assumptions regarding 
the endpoint event rate and other factors are correct, the trial will proceed to Phase 3.   
A second interim analysis will be conducted by the DSMB during Phase 3 to assess the absence of futility 
and whether an expansion of the total sample size is warranted. The DSMB may also make suggestions to 
the Steering Committee for adjustment in sample size based on other factors (e.g., event rate, 
discontinuation rate, etc.) or other modifications to the protocol that would improve trial conduct.  Further 
details of the Phase 2B and Phase 3 interim analyses are available in the DSMB charter. 
8.10 Significance 
At the end of Phase 3, the alpha level for the primary endpoint will be reduced to 0.04989 to adjust for the 
Phase 2B ( = 0.00001) and Phase 3 ( = 0.0001) interim analyses. 
8.11 Deviation Reporting 
All patients with protocol deviations will be included in the ITT analyses; a limited per-protocol analysis 
will be performed separately.  During study initiation, sites will receive instructions on the reporting of 
protocol deviations or violations.  In addition, sites will be responsible for reporting such occurrences to 
their respective IRB/IEC as required.  If protocol deviations and/or violations during monitoring visits are 
observed, education of the offending sites will occur and repeat offenders may be suspended from 


 
 
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enrolling additional patients.  Differences in protocol deviations/violations between treatment groups will 
be analyzed. 
9.0 RESPONSIBILITIES 
9.1 
Trial Conduct 
9.1.1 Ethical Considerations 
This study will be conducted according to US (FDA regulations 21CFR312 for IND studies) and 
international standards (ICH E6) Good Clinical Practices.  Applicable local government regulations will 
also be followed. 
This protocol and any amendments will be submitted to the IRB/IEC for formal approval to conduct the 
study.  The decision of the IRB/IEC concerning the conduct of the study will be made in writing to the 
Investigator. 
All patients for this study will be provided a consent form describing this study and providing sufficient 
information for patients to make an informed decision about their participation in the study.  The consent 
form will be submitted with the protocol for review and approval by the IRB/IEC.  The formal consent of 
a patient, using the IRB/IEC-approved consent form, will be obtained before that patient is submitted to 
any study procedure.  The patient or a legally acceptable surrogate must sign the consent form, and the 
Investigator-designated research professional obtaining the consent. 
9.1.2 Conflict of Interest Policy 
Investigators and participants in this study should have no significant conflict of interest with respect to 
financial holdings in companies that may benefit from the results of this study.  Full disclosure of all ties 
to pharmaceutical and device manufacturers will be required as stipulated by FDA regulations and ICH 
guidelines.  The Executive Committee (Section 9.1.4) will determine if a significant conflict of interest 
exists and will make recommendations about courses of action. 
9.1.3 Quality Control and Quality Assurance 
The clinical performance of the study will be monitored according to ICH Good Clinical Practice (GCP) 
guidelines by means of on-site visits, remote monitoring, telephone calls and regular inspection of the 
case report forms with sufficient frequency to assess the following: patient enrollment; compliance with 
the protocol procedures; the completeness and exactness of data entered in the eCRFs; verification against 
original source documents; and occurrence of AEs.  Monitoring visits are to be conducted by appropriate 
staff as designated by the Sponsor (e.g., the CRO).  Data verification will be accomplished by comparing 
eCRFs to the source documents (e.g., medical files, laboratory printouts, etc.). 


 
 
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9.1.4 Steering Committee 
The Steering Committee oversees all aspects of the study and during the trial will remain blinded to 
treatment group results.  The Steering Committee has the authority to propose protocol amendments to 
the Sponsor based on its monitoring of the progress of the trial, including reports or recommendations 
received from the DSMB. 
The Steering Committee will be responsible for the design of the final protocol and any substudies, as 
well as the publication of trial results.  The Steering Committee will meet regularly to monitor the 
progress of the study using blinded tabulations based on all patients (i.e., the Steering Committee will not 
receive the blinded ‘Group A’ and ‘Group B’ reports provided to the DSMB).  Based on recommendation 
from the DSMB, the Steering Committee has the authority to stop the trial for unexpected safety reasons. 
The Steering Committee will establish committees to develop procedures and report their 
recommendations to the full Steering Committee for approval.  An Executive Committee, a subset of the 
Steering Committee that includes the Steering Committee Chair, will develop the meeting agendas and 
make recommendations for consideration by the Steering Committee.  The Executive Committee will 
provide study direction between meetings of the Steering Committee.  A Publication Committee 
appointed by the Steering Committee will review all publications following the guidelines (Section 9.5) 
and report its recommendations to the Steering Committee.  Additional Committees may be added by the 
Steering Committee during the course of the trial. 
Chairpersons of the committees will be appointed by the Steering Committee.  For voting, each Steering 
Committee member shall have a single vote, and no clinical investigation site shall have more than one 
vote. 
9.1.5 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be established with a charter and standard operating 
procedures designed to follow FDA Guidance on the Establishment and Operation of Clinical Trial Data 
Monitoring.  The DSMB will be comprised of experts in relevant biomedical fields such as 
electrophysiology, cardiology and biostatistics.  The members will have no direct relationship to the 
study, or to the Sponsor.  The DSMB Chair and committee members will be selected by the Sponsor and 
the Steering Committee; either can nominate DSMB members with approval by the other.  Once 
established, the DSMB will operate independently of the Steering Committee and the Sponsor. 
The DSMB will review the protocols of the main study and substudies during the planning phase.  
Thereafter it will periodically monitor the progress, data, outcomes, toxicity, safety and other confidential 
data.  The DSMB Chair will also monitor a subset of safety data at periodic intervals during the study 
(e.g., monthly).  For these monitoring activities, the DSMB will be provided with tabulations by blinded 


 
 
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group (e.g., Group A versus Group B).  The DSMB may choose to examine specific unblinded data if 
they identify a significant imbalance of clinical concern in the blinded group analysis.  Based on these 
monitoring activities, the DSMB is empowered to recommend to the Steering Committee any change in 
the design of the study required to ensure the safety of the enrolled patients and the scientific integrity of 
the trial. 
In addition to these routine safety reviews, a Phase 2B interim analysis of unblinded data will be 
conducted by the DSMB primarily for the purpose of ruling out futility for meeting the Phase 3 primary 
endpoint.  If the trial proceeds to Phase 3, a second interim analysis will be conducted by the DSMB to 
determine the absence of futility and to assess whether an expansion of the Phase 3 sample size is 
warranted. The DSMB will determine the timing of these interim analyses based on pre-specified 
thresholds for patient enrollment and will ensure that the endpoint event count is consistent with protocol 
assumptions.  Further details of the Phase 2B and Phase 3 interim analyses are available in the DSMB 
charter. 
9.1.6 Clinical Events Committee 
A Clinical Events Committee (CEC) will be established with a charter and standard operating procedures.  
The CEC is an independently appointed panel of experts in relevant biomedical fields such as 
electrophysiology and cardiology, who are not participating in this trial and will not be affiliated with the 
Sponsor.  The CEC members, who are selected by the CRO and approved by the Sponsor and Steering 
Committee, will be convened to review the study specific endpoints and is charged with the development 
of specific criteria used for the adjudication of clinical events. 
At the onset of the trial, the CEC will establish rules outlining the minimum amount of data required and 
the algorithms to be followed in order to classify a clinical event.  The rules will be documented in the 
CEC charter.  All members of the CEC will be blinded to the patient treatment assignment. 
The CRO will compile all clinical event packets when the necessary data is available from the trial sites 
and provide to the CEC.  The CEC will meet based on event accrual rate to review and adjudicate all 
clinical events for which the required minimum data is available, including evaluation of all pertinent 
ECG data. 
Criteria for adjudication, procedures, data flow, and the meeting schedule are described in a separate CEC 
charter maintained by the Sponsor and the CEC. 
9.1.7 Clinical Research Organization 
A Clinical Research Organization (CRO) will be utilized to manage database creation and maintenance, 
and generation of blinded data analyses for trial monitoring.  Unless stated elsewhere, all CRO study 


 
 
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personnel will remain blinded to treatment assignment until the final patient visit has been completed, all 
outstanding data queries are resolved and the database is considered locked. 
An unblinded statistician at the CRO will have access to the randomization schedule and will only 
provide that schedule to a limited number of entities involved in study drug packaging and distribution, as 
well as those required for safety reporting.  The CRO or its designee will generate all unblinded interim 
analyses pre-specified in the protocol.  The CRO will also provide blinded pooled data to the Steering 
Committee for the evaluation of event rate and other study design considerations.  Final study analyses 
will be conducted by the CRO and/or the Sponsor after the database has been locked and the study has 
been unblinded. 
9.2 
Investigator Responsibilities 
9.2.1 Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with the principles of the ICH 
guidelines, or with the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the study patient. 
The Sponsor and Investigators will follow requirements as set forth in the U.S. Code of Federal 
Regulations (CFR), 21CFR Parts 50, 54, 56, and 312 and the ICH E6 GCP Consolidated Guidance.  
Investigator responsibilities are set out in Section 4 of the E6 Guideline.  Sponsor responsibilities are set 
out in Section 5 of the E6 ICH Guideline. 
Since this is a “covered” clinical trial, the Investigator will ensure that 21CFR Part 54, 1998, is adhered 
to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a marketing 
application or reclassification petition subject to this part that the applicant or FDA relies on to establish 
that the product is effective (including studies that show equivalence to an effective product) or that make 
a significant contribution to the demonstration of safety.”  This requires that Investigators and all sub-
Investigators must provide documentation of their financial interest or arrangements with the Sponsor, or 
proprietary interests in the drug being studied.  This documentation must be provided before participation 
of the Investigator and any sub-Investigator.  The Investigator and Sub-Investigator agree to notify the 
Sponsor of any change in reportable interests during the study and for one year following completion of 
the study.  Study completion is defined as the date that the last patient has completed the protocol-defined 
activities. 
This study is also subject to and will be conducted in accordance with 21CFR Part 320 “Retention of 
Bioavailability and Bioequivalence Testing Samples.” 


 
 
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9.2.2 Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as advertisements, 
patient information sheets, or descriptions of the study used to obtain informed consent) will be submitted 
by the Investigator to an IRB/IEC.  Approval from the IRB/IEC must be obtained before starting the 
study and should be documented in a letter to the Investigator specifying the protocol number, protocol 
version, protocol date, documents reviewed, and date on which the committee met and granted the 
approval. 
All documents subject to review during the study, including, but not limited to, any modifications made to 
the protocol after receipt of IRB/IEC approval and SAE safety reports must also be submitted to the 
committee for review and/or approval prior to implementation (if applicable). 
If requested as part of the written application to the IRB/IEC, the Investigator should provide the 
committee with a current copy of the Investigator’s Brochure.  If the Investigator’s Brochure is updated 
during the study, the Investigator should supply an updated copy to the committee. 
9.2.3 Informed Consent 
The Investigator is responsible for obtaining written informed consent from each individual participating 
in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the 
study and before undertaking any study-related procedures.  The Investigator must utilize an IRB/IEC-
approved consent form for documenting written informed consent.  Each informed consent will be 
appropriately signed and dated by the patient or the patient’s legally authorized representative and the 
person obtaining consent. 
9.2.4 Confidentiality 
The Investigator must assure that patients’ anonymity will be strictly maintained and that their identities 
are protected from unauthorized parties.  Only an identification code (i.e., not names) should be recorded 
on any form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory.  The Investigator 
must keep a patient identification log showing codes, names, and addresses for all patients screened and 
for all patients participating in the trial. 
The Investigator agrees that all information received from the Sponsor, including but not limited to the 
Investigator Brochure, this protocol, eCRFs, the study drug, and any other study information, remain the 
sole and exclusive property of the Sponsor during the conduct of the study and thereafter.  This 
information is not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from the Sponsor.  The 


 
 
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Investigator further agrees to take all reasonable precautions to prevent the disclosure by any employee or 
agent of the study site to any third party or otherwise into the public domain. 
9.2.5 Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified.  These documents should be classified 
into at least the following two categories: 1) Investigator’s study file, and 2) patient clinical source 
documents. 
The Investigator’s study file will contain the protocol/amendments, eCRF and query forms, IRB/IEC and 
governmental approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key efficacy/safety 
parameters independent of the eCRFs) would include (although not be limited to) the following: patient 
hospital/clinic records, physician’s and nurse’s notes, appointment book, original laboratory reports, 
ECG, X-ray, pathology and special assessment reports, consultant letters, etc. 
All clinical study documents must be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) and until there 
are no pending or contemplated marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is discontinued and 
regulatory authorities have been notified.  Investigators may be required to retain documents longer if 
required by applicable regulatory requirements or an agreement with the Sponsor.  The Investigator must 
notify the Sponsor before destroying any clinical study records. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the Investigator and the Sponsor to store these in 
sealed containers outside of the site so that they can be returned sealed to the Investigator in case of a 
regulatory audit.  When source documents are required for the continued care of the patient, appropriate 
copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for a period 
up to 15 years for purposes of this study. 


 
 
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9.2.6 Case Report Forms 
For each patient, an eCRF must be completed and signed by the Principal Investigator within a reasonable 
time period after data collection.  This also applies to records for those patients who fail to complete the 
study (even during a pre-randomization Screening Period if an eCRF was initiated).  If a patient 
withdraws from the study, the reason must be noted on the eCRF.  If a patient is withdrawn from the 
study because of a treatment-limiting AE, thorough efforts should be made to clearly document the 
outcome. 
All protocol required data will be collected in a case report form or via electronic means.  A list of 
systems used to create, modify, maintain, archive, retrieve, or transmit data will be maintained by the 
Sponsor or their designee. 
9.2.7 Drug Accountability 
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability of all 
used and unused study drug.  This includes acknowledgment of receipt of each shipment of study product 
(quantity and condition) and patient dispensing records and returned or destroyed study product.  
Dispensing records will document quantities received from the Sponsor or its representative and 
quantities dispensed to patients, including lot number, date dispensed, patient identifier number, patient 
initials, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study drug 
disposal/destruction in order to ensure that it complies with Sponsor requirements.  Drug may be returned 
or destroyed on an ongoing basis during the study, if appropriate, as directed by the site’s monitor.  
During or at the end of the study (as appropriate by site), following acceptable final drug inventory 
reconciliation by the monitor, the study site will dispose of and/or destroy all unused study drug supplies, 
including empty containers, according to these procedures.  If the site cannot meet the Sponsor’s 
requirements for disposal, arrangements will be made between the site and the Sponsor or its 
representative for destruction or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the study 
monitor over the course of the study. 
9.2.8 Inspections 
The Investigator should understand that source documents for this trial should be made available to 
appropriately qualified personnel from the Sponsor or its representatives, to the IRB/IEC, or to regulatory 
authority or health authority inspectors. 


 
 
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9.2.9 Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the procedures and 
evaluations described in this protocol. All deviations from the protocol must be noted by the Investigator 
and may result in retraining of study personnel and/or discontinuation of site participation.  All patients 
who miss a scheduled visit must be contacted via phone to confirm continued participation in the study.  
9.3 
Sponsor Responsibilities 
9.3.1 Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be made 
only by the Sponsor.  All protocol modifications must be submitted to the IRB/IEC in accordance with 
local requirements.  Approval must be obtained before changes can be implemented. 
A protocol change intended to eliminate an apparent immediate hazard to patients may be implemented 
immediately, provided the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the Investigator must await approval before 
implementing the changes.  The Sponsor will submit protocol amendments to the appropriate regulatory 
authorities for approval. 
If, in the judgment of the IRB/IEC, the Investigator, and/or the Sponsor, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the patient and/or has an 
impact on the patient's involvement as a study participant, the currently approved written ICF will require 
similar modification.  In such cases, informed consent will be renewed for patients randomized in the 
study before implementing protocol changes. 
9.3.2 Clinical Study Reports 
A clinical study report will be prepared and provided to regulatory agencies.  The Sponsor will ensure that 
the report meets the standards set out in the ICH Guideline for Structure and Content of Clinical Study 
Reports (ICH E3).  Note that an abbreviated report may be prepared in certain cases. 
9.4 
Joint Investigator/Sponsor Responsibilities 
9.4.1 Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the Investigator’s 
source documentation in order to verify the data recorded in the eCRFs for consistency. 


 
 
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The monitor is responsible for routine review of the eCRFs at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them.  The monitor should have access to any patient records needed to verify the entries on 
the eCRFs.  The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
9.4.2 Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the Sponsor may conduct inspections or audits of the 
clinical study.  If the Investigator is notified of an inspection by a regulatory authority, the Investigator 
agrees to notify the designated Sponsor representative immediately.  The Investigator agrees to provide to 
representatives of a regulatory agency or the Sponsor access to records, facilities, and personnel for the 
effective conduct of any inspection or audit. 
9.4.3 Study Discontinuation 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time.  Should this be 
necessary, both parties will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies), IRBs, and IECs.  In terminating the study, the Sponsor and the Investigator will assure that 
adequate consideration is given to the protection of the patients’ interests. 
9.5 
Publication Committee 
A Publication Committee will review all publications following the guidelines given below and report its 
recommendations to the Steering Committee.  The Publications Committee will be comprised of the 
Principal Investigator, the Chair and the Co-Chair of the Steering Committee, and a Sponsor 
representative.  The Publication Committee Chair will be selected by the Steering Committee. 
9.5.1 Data Analysis and Release of Results 
The scientific integrity of the study requires that the data from all clinical sites be analyzed and reported 
study-wide.  Thus, an individual center or group of centers may not independently report data.  All 
presentations and publications must protect the integrity of the major objectives of the study; data that 
would release endpoint results will not be presented prior to the release of the main study results.  The 
timing of presentation of any data and the venue in which the data are presented will be subject to the 
review and approval of the Steering Committee. 
9.5.2 Review Process 
Each paper, abstract, or presentation of previously unreported data from the trial must be submitted to the 
Publication Committee for review of scientific merit and appropriateness for submission or presentation.  


 
 
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Slides or posters containing data from the trial should be submitted to the Publications Committee before 
their initial presentation.  All submissions should be made at least two weeks before the presentation or 
the abstract deadline.  The committee may recommend changes to the authors and will submit its 
recommendations to the Steering Committee for approval.  The final determination about whether or not a 
particular analysis represents a primary outcome will be made by the Steering Committee. 
9.5.3 Authorship: Primary Outcome Paper 
Authorship on primary outcome manuscripts will be "The Trial Investigators".  For such manuscripts, 
there will be an appendix containing the names of the various organizational units and their Principal 
Investigators and Coordinators.  Members of the DSMB and contributing Sponsor personnel will also be 
included in these manuscripts. 
9.5.4 Authorship: Other Study Papers, Abstracts and Presentations 
All studies other than those designated “primary outcome” fall into this category.  Papers or abstracts 
resulting from these studies will have named authorship of individuals involved, ending with the phrase 
"and the Trial Investigators".  Suitability of authorship will be subject to approval by the Publications 
Committee.  Papers will either have an appendix with the names of the organizational units and their 
Principal and Co-Investigators, or a reference to a methods or primary outcome paper with such a list.  
The Publications Committee must review all papers and abstracts prior to being submitted for publication. 
 
 


 
 
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10.0 
REFERENCES  
1. 
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national 
implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors 
in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-5. 
2. 
Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter 
in the United States. Am J Cardiol 2009;104:1534-9. 
3. 
Savelieva I, John Camm A. Atrial fibrillation and heart failure: natural history and pharmacological 
treatment. Europace 2004;5 Suppl 1:S5-19. 
4. 
Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into 
the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report 
of the American College of Cardiology Foundation/American Heart Association Task Force on 
practice guidelines. Circulation 2011;123:e269-367. 
5. 
Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 
2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the 
American College of Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines Developed in Collaboration With the International Society for Heart and Lung 
Transplantation. J Am Coll Cardiol 2009;53:e1-e90. 
6. 
Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart 
failure and their joint influence on mortality: the Framingham Heart Study. Circulation 
2003;107:2920-5. 
7. 
Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy 
women with new-onset atrial fibrillation. JAMA 2011;305:2080-7. 
8. 
Corell P, Gustafsson F, Schou M, Markenvard J, Nielsen T, Hildebrandt P. Prevalence and 
prognostic significance of atrial fibrillation in outpatients with heart failure due to left ventricular 
systolic dysfunction. Eur J Heart Fail 2007;9:258-65. 
9. 
Rivero-Ayerza M, Scholte Op Reimer W, Lenzen M, et al. New-onset atrial fibrillation is an 
independent predictor of in-hospital mortality in hospitalized heart failure patients: results of the 
EuroHeart Failure Survey. Eur Heart J 2008;29:1618-24. 
10. Swedberg K, Olsson LG, Charlesworth A, et al. Prognostic relevance of atrial fibrillation in patients 
with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Eur 
Heart J 2005;26:1303-8. 
11. Nasr IA, Bouzamondo A, Hulot JS, Dubourg O, Le Heuzey JY, Lechat P. Prevention of atrial 
fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis. Eur Heart J 
2007;28:457-62. 
12. Nergardh AK, Rosenqvist M, Nordlander R, Frick M. Maintenance of sinus rhythm with metoprolol 
CR initiated before cardioversion and repeated cardioversion of atrial fibrillation: a randomized 
double-blind placebo-controlled study. Eur Heart J 2007;28:1351-7. 
13. Katritsis DG, Panagiotakos DB, Karvouni E, et al. Comparison of effectiveness of carvedilol versus 
bisoprolol for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. Am J 
Cardiol 2003;92:1116-9. 
14. Plewan A, Lehmann G, Ndrepepa G, et al. Maintenance of sinus rhythm after electrical 
cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol. Eur Heart J 2001;22:1504-10. 
15. Beta-Blocker Evaluation of Survival Trial I. A trial of the beta-blocker bucindolol in patients with 
advanced chronic heart failure. N Engl J Med 2001;344:1659-67. 


 
 
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16. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et al. A polymorphism within a conserved beta(1)-
adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. 
Proc Natl Acad Sci U S A 2006;103:11288-93. 
17. Taylor MR, Sun AY, Davis G, Fiuzat M, Liggett SB, Bristow MR. Race, common genetic variation, 
and therapeutic response disparities in heart failure. JACC Heart failure 2014;2:561-72. 
18. Dockstader K, Nunley K, Karimpour-Fard A, et al. Temporal analysis of mRNA and miRNA 
expression in transgenic mice overexpressing Arg- and Gly389 polymorphic variants of the beta1-
adrenergic receptor. Physiol Genomics 2011;43:1294-306. 
19. Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein 
coupling domain of the human beta1-adrenergic receptor. J Biol Chem 1999;274:12670-4. 
20. Mialet Perez J, Rathz DA, Petrashevskaya NN, et al. Beta 1-adrenergic receptor polymorphisms 
confer differential function and predisposition to heart failure. Nat Med 2003;9:1300-5. 
21. O'Connor CM, Fiuzat M, Carson PE, et al. Combinatorial pharmacogenetic interactions of 
bucindolol and beta1, alpha2C adrenergic receptor polymorphisms. PLoS One 2012;7:e44324. 
22. Bristow MR. Treatment of chronic heart failure with beta-adrenergic receptor antagonists: a 
convergence of receptor pharmacology and clinical cardiology. Circ Res 2011;109:1176-94. 
23. Aleong RG SW, Davis G, Murphy GA, Port JD, Anand IS, Fiuzat M, O'Connor CM, Abraham WT, 
Liggett SB, Bristow MR. Prevention of Atrial Fibrillation by Bucindolol Is Dependent on the 
Beta1389 Arg/Gly Adrenergic Receptor Polymorphism. JACC: Heart Failure 2013;In Press. 
24. Bristow MR, Murphy GA, Krause-Steinrauf H, et al. An alpha2C-adrenergic receptor polymorphism 
alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in 
chronic heart failure. Circ Heart Fail 2010;3:21-8. 
25. van Veldhuisen DJ, Aass H, El Allaf D, et al. Presence and development of atrial fibrillation in 
chronic heart failure. Experiences from the MERIT-HF Study. Eur J Heart Fail 2006;8:539-46. 
26. Sehnert AJ, Daniels SE, Elashoff M, et al. Lack of association between adrenergic receptor 
genotypes and survival in heart failure patients treated with carvedilol or metoprolol. J Am Coll 
Cardiol 2008;52:644-51. 
27. White HL, de Boer RA, Maqbool A, et al. An evaluation of the beta-1 adrenergic receptor 
Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail 
2003;5:463-8. 
28. Bristow MR, Krause-Steinrauf H, Nuzzo R, et al. Effect of baseline or changes in adrenergic activity 
on clinical outcomes in the beta-blocker evaluation of survival trial. Circulation 2004;110:1437-42. 
29. Bristow MR. beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558-
69. 
30. Mason R, Kubant, R, Jacob, RF, Jacoby AM, Port JD, Bristow MR, and Malinski T. Effect of the 
3-receptor antagonist SR59230A on bucindolol-induced release of nitric oxide and peroxynitrite 
from human endothelium. J Cardiac Fail 2008;Supplement  
31. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with 
severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival 
(COPERNICUS) study. Circulation 2002;106:2194-9. 
32. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention 
Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7. 
33. Toprol XL US Package Insert. Astra Zeneca. 2013, at http://www1.astrazeneca-us.com/pi/toprol-
xl.pdf.) 


 
 
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34. ARCA. Study Report HBM007 (on file). 
35. Rau T, Dungen HD, Edelmann F, et al. Impact of the beta1-adrenoceptor Arg389Gly polymorphism 
on heart-rate responses to bisoprolol and carvedilol in heart-failure patients. Clin Pharmacol Ther 
2012;92:21-8. 
36. Kao DP, Davis G, Aleong R, et al. Effect of bucindolol on heart failure outcomes and heart rate 
response in patients with reduced ejection fraction heart failure and atrial fibrillation. Eur J Heart 
Fail 2013;15:324-33. 
37. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial 
fibrillation or flutter. N Engl J Med 2007;357:987-99. 
 
 
 


 
 
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11.0 
APPENDICES 
Appendix 1   Study Personnel Information 
Appendix 2   Investigator Signature Page 
Appendix 3   Abbreviations and Definition of Terms 
Appendix 4   Schedule of Assessments 
Appendix 5   EQ-5D Questionnaire 
Appendix 6   AF Symptoms Questionnaire 
 
Appendix 1  Study Personnel Information 
 
 
 
Sponsor: 
ARCA biopharma, Inc. 
11080 CirclePoint Road, Suite 140 
Westminster, CO 80020 
Phone: 720-940-2100 
Data Coordinating Center: 
Duke Clinical Research Institute 
2400 Pratt Street, Durham, NC 27705 
Principal Investigator: Jonathan Piccini, MD 
Phone: 919-668-8700 
SAE/Safety Monitor: 
Duke Clinical Research Institute 
2400 Pratt Street, Durham, NC 27705 
Medical Monitor: Karen Alexander, MD 
Phone: 919-668-8624 or 866-668-7799 (toll free) 
Email: dcrisafetysurveillance@dm.duke.edu 
Central Laboratory 
LabCorp Clinical Trials 
4307 Emperor Blvd. Suite 200 
Durham, NC 27703 




 
 
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Appendix 3 Abbreviations and Definition of Terms 
Abbreviation 
Definition 
ACM 
all-cause mortality 
AE 
adverse event 
AF 
atrial fibrillation 
AFB 
atrial fibrillation burden 
AFL 
atrial flutter 
AFSQ 
AF symptoms questionnaire 
AR 
adrenergic receptor 
BEST 
Beta Blocker Evaluation of Survival Trial 
BID 
twice daily 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations  
CHF 
chronic heart failure 
CONMED 
concomitant medication 
CRO 
contract research organization 
CRT  
cardiac resynchronization therapy 
CV 
cardiovascular 
CVH 
cardiovascular hospitalization 
CVM 
cardiovascular mortality 
DNA 
deoxyribonucleic acid 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECV 
electrical cardioversion 
EOS 
end of study 
EOT 
end of treatment 
EP 
electrophysiology 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HF 
heart failure 
HFREF 
heart failure with reduced left ventricle ejection fraction 
ICD 
implantable cardioverter-defibrillator  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
ICM 
insertable cardiac monitor  


 
 
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IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPG 
implantable pulse generator 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System  
LV 
left ventricle 
LVEF 
left ventricle ejection fraction 
MDR 
Medical Device Reports 
NSAID 
nonsteroidal anti-inflammatory drug 
NT-proBNP 
n-terminal pro B-type natriuretic peptide 
NYHA 
New York Heart Association 
PK 
pharmacokinetic 
PTCA  
percutaneous transluminal coronary angioplasty 
PVC 
polyvinylchloride 
QD 
once daily 
SAE 
serious adverse event 
SR 
sinus rhythm 
SVT 
supraventricular tachycardia 
TTM 
transtelephonic monitor 
VF 
ventricular flutter 
VRR 
ventricular response rate 
VT 
ventricular tachycardia 
 


 
 
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Appendix 4  Schedule of Assessments 
 
Screen Period 
24-week Follow-Up Period (Week) 
Treatment Extension 
Period 
  
Screen 
Visit 
Rand 
Visit 
01 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
EXT 
Visit2 
EOT 
Visit3 
EOS 
Visit4  
Visit window  
- 
- 
- 
2d 
2d 
2d 
2d 
2d 
2d 
2d 
2d 
2d 
2d 
2d 
2d 
4d 
- 
- 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device implant5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device interrogation6 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
NYHA class assessment 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Electrical cardioversion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG7 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Telephone contact8 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
AF symptoms questionnaire9 
 
X 
X10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D questionnaire 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Clinical events assessment 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Β1389 AR genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2c AR/CYP2D6 genotype11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional DNA bank11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry/hematology 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
NT-proBNP12 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Plasma norepinephrine 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Population PK13 
 
 
X14 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test15 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation status16 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
AE collection 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Study drug collect/dispense 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 


 
 
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1Up-titration of study drug during the Drug Lead-in Period (i.e., after randomization and prior to the Week 0 Visit) will be managed via unscheduled Drug 
Titration Visits to provide flexibility for optimal patient management (Section 6.1.2.1). Study drug collections/dispensation is the only required procedure for 
these visits; however, if any unscheduled procedures and/or safety evaluations are performed, they must be entered into the eCRFs. 
2Extension Visit: Clinic visits will be every 12 weeks after the Week 24 Visit.    
3End of Treatment Visit: Only required for patients who prematurely discontinue study drug who will continue to participate in the study.  These patients 
should complete the EOT Visit prior to discontinuation of study drug (if possible) and then remain in the study and complete all remaining visits.  Patients 
who wish to discontinue study drug and study participation should complete all assessments described for the EOS Visit. 
4End of Study Visit: Phase 3 follow-up will continue until a total of at least 330 primary endpoint events have been observed.  After this event, all patients will 
complete the 24-week Follow-up Period or return to the clinic for an EOS Visit if already in the Treatment Extension Period. 
5Patients who agree to have a Medtronic device inserted may do so at the Randomization Visit or at any time prior to the start of the 24-week Follow-up Period.   
6Devices interrogated via the Medtronic Carelink Programmer and uploaded to the Medtronic Clinical Transfer Site. 
7A 12-lead ECG is not required at the Screening Visit; however, if one if collected during this visit the results should be entered into the Screening ECG eCRF.  
Two 12-lead ECGs are required at the Week 0 Visit.  
8Schedule telephone contacts to administer the AFSQ and determine if the patient has experienced any new or worsening symptoms that could potentially be 
related to AF/AFL (Section 6.1.4.2).  If the Investigator suspects that a new AF/AFL event has occurred between scheduled clinic visits (i.e., a change in 
rhythm from SR to AF/AFL), the patient will be instructed to return to the clinic within 3 business days for further assessments (Section 6.1.4.2).  
9AFSQ must be collected prior to ECG at clinic visits (Section 6.2.6). 
10At the Week 0 Visit the AFSQ will be collected prior to the ECV procedure and a second AFSQ will be administered the following day for those patients 
achieving stable SR post-ECV. The second AFSQ assessment can be performed via telephone, if necessary. For patients in SR who do not require ECV at this 
visit, the AFSQ will be collected prior to the first ECG assessment only. 
11Samples should be collected prior to first dose of study drug for randomized patients only. 
12Whenever possible, NT-proBNP should also be collected at the time of an AF/AFL event. 
13Study drug must be withheld on the morning of these visits until the Population PK sample is collected. If possible, a trough blood sample should also be 
obtained prior to discontinuation of study drug for any patient who experiences a SAE leading to permanent discontinuation of study drug. 
14Population PK sample at Week 0 is only required for patient who spontaneously converts from AF/AFL to SR prior to the protocol-specified ECV procedure.  
15Women of childbearing potential only. Serum pregnancy test at Screening Visit and urine pregnancy test at the Randomization Visit (Section 6.2.8). 
16Local labs used to monitor coagulation status per standard of care. Local lab results will not be collected but coagulation status relative to normal limits will 
be collected via eCRFs. 
 
 
 
 


 
 
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Appendix 5  EQ-5D Questionnaire 
A. 
Administrative Information 
1. Date of questionnaire completion ________________ 
B. 
EQ-5D 
1. Mobility: 
 
   I have no problems in walking about. 
   I have some problems in walking about. 
   I am confined to bed. 
 
2. Self-care: 
 
   I have no problems with self-care. 
   I have some problems washing or dressing myself. 
   I am unable to wash or dress myself. 
 
3. Usual Activities (e.g. work, study, housework, family or leisure activities): 
 
   I have no problems with performing my usual activities. 
   I have some problems with performing my usual activities. 
   I am unable to perform my usual activities. 
 
4. Pain/discomfort: 
 
   I have no pain or discomfort. 
   I have moderate pain or discomfort. 
   I have extreme pain or discomfort. 
 
5. Anxiety/depression:  
   I am not anxious or depressed. 
   I am moderately anxious or depressed. 
   I am extremely anxious or depressed. 
 
 
 


 
 
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Appendix 6  AF Symptoms Questionnaire 
1. Since your last clinic visit, have you experienced any of the following: 
a) Heart palpitations (pounding, racing or irregular heart beat)? [Yes/No] 
b) Shortness of breath?  [Yes/No] 
c) Chest pain or pressure?  [Yes/No] 
d) Fatigue or tiredness?  [Yes/No] 
e) Weakness or problems exercising?  [Yes/No] 
f) Lightheadedness, dizziness or fainting?  [Yes/No] 
g) Confusion/trouble concentrating?  [Yes/No] 
h) Sweating unrelated to physical activity?  [Yes/No] 
i) Weight gain greater than 2 pounds?  [Yes/No] 
j) Swelling of both legs and/or feet?  [Yes/No] 
 
2. Which symptom do you consider the predominant or worst symptom?   
[choose only one from above, or ‘NA’ if no symptom experienced] 
 
3. For questions 1a-j, if “yes” collect the following: 
a) How frequently have you experienced this symptom?  [rarely, sometimes, often, always] 
b) How would you rate the intensity/discomfort of this symptom?  [mild, moderate, severe] 
c) When did you first experience this symptom during this reporting period?  [MM/DD/YYYY] 
d) When did you last experience this symptom during this reporting period?  [MM/DD/YYYY] 
 

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CONFIDENTIAL 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Study Title: 
GENETIC-AF – A Genotype-Directed Comparative Effectiveness 
Trial of Bucindolol and Toprol-XL for Prevention of 
Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with 
Heart Failure 
Sponsor: 
ARCA biopharma, Inc. 
11080 CirclePoint Road, Suite 140 
Westminster, Colorado 80020 
Phone: 720.940.2100 
Study Drug: 
Bucindolol hydrochloride (bucindolol) 
Comparator:  
Metoprolol succinate (Toprol-XL, metoprolol) 
IND No.: 
118,935 
Indication: 
Atrial Fibrillation 
Protocol ID: 
BUC-CLIN-303 
Date:  
15 March 2017 
 
 
Note: The interim analysis methodology is not included in this plan.  That methodology can 
be found in the DSMB Charter and DSMB Statistical Analysis Plan documents. 
 
 
 


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TABLE OF CONTENTS 
 
1 
DEFINITIONS OF ANALYSIS POPULATIONS AND ENDPOINT FOLLOW-UP 
PERIODS ........................................................................................................................... 3 
2 
PATIENT CHARACTERISTICS ..................................................................................... 4 
2.1 
Screen Failure ............................................................................................................. 4 
2.2 
Randomization ........................................................................................................... 4 
2.3 
Baseline Characteristics ............................................................................................. 4 
2.4 
Treatment Exposure and Compliance ........................................................................ 4 
2.5 
Concomitant Medications .......................................................................................... 5 
2.6 
Metrics for Key Study Procedures ............................................................................. 5 
2.7 
Final Study Disposition .............................................................................................. 6 
2.8 
Protocol Deviations .................................................................................................... 6 
3 
EFFICACY ANALYSIS ................................................................................................... 6 
3.1 
General Methodology ................................................................................................. 6 
3.1.1 
Time-to-Event Analysis Methodology ............................................................... 6 
3.1.2 
Components of Combined Endpoints ................................................................. 7 
3.1.3 
Adjudication ........................................................................................................ 7 
3.1.4 
Core Lab and Transtelephonic Monitoring ......................................................... 8 
3.1.5 
Hospitalization .................................................................................................... 8 
3.1.6 
Data Collection Cut-off at End of Study............................................................. 8 
3.1.7 
Missing Data Due to Withdrawal or Loss to Follow-up ..................................... 9 
3.1.8 
P-value Adjustment for Interim Analysis ........................................................... 9 
3.2 
Efficacy Endpoints ..................................................................................................... 9 
3.2.1 
Primary Efficacy Endpoint ................................................................................. 9 
3.2.2 
Secondary Efficacy Endpoints .......................................................................... 13 
3.2.3 
Tertiary Efficacy Endpoints .............................................................................. 15 
4 
SAFETY ANALYSIS ..................................................................................................... 18 
5 
MEASUREMENTS OF INTEREST AND SUBSTUDIES ............................................ 22 
 
 
 


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1 DEFINITIONS OF ANALYSIS POPULATIONS AND ENDPOINT 
FOLLOW-UP PERIODS 
The efficacy analysis will follow the intent-to-treat (ITT) principle and all patients 
randomized to study treatment will be included regardless of (1) the success of the treatment 
titration process and (2) result of electrical cardioversion (ECV) aimed at converting atrial 
fibrillation (AF) to sinus rhythm (SR).  As an additional sensitivity analysis, testing of the 
primary and secondary endpoints will be repeated on a protocol-compliant subpopulation.  
Further sensitivity analyses specific to endpoints are described below.  The safety analyses 
will include all patients that received at least one dose of blinded study treatment.  The 
screened population includes any patient who signs informed consent for the study.  The 
screen failure population is a subpopulation of the screened population who are not 
randomized to study drug for any reason. 
Four follow-up periods will be defined for inclusion of each patient’s results in endpoint 
calculations: 
 Drug Titration Period: starts on the day of randomized treatment initiation and 
extends for six weeks after randomization. 
 24-Week Follow-up Period:  starts on the day of 1) the first ECG that establishes 
stable SR (defined in Section 3.2.1), or; 2) the last ECV attempt for patients who fail 
to convert to stable SR, or; 3) the Week 0 Visit, for patients in AF who do not 
undergo ECV for any reason.  Ends on the day of the Week 24 Visit or the End of 
Study (EOS) Visit, if patient discontinues prior to Week 24 Visit. 
 Total Follow-up Period:  starts on the same day as the 24-Week Follow-up Period and 
extends until the EOS Visit. 
 Total Study Period:  starts on the day of the Randomization Visit and extends until 
the EOS Visit. 


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2 PATIENT CHARACTERISTICS 
2.1 
Screen Failure 
Screen failure reasons will be tabulated in order of frequency.  These reasons are collected on 
the eCRF DEMOG form. 
2.2 
Randomization 
Randomized treatment assignment is centralized and in versions 1 and 2 of the protocol was 
stratified by: 1) HF etiology (ischemic/non-ischemic); 2) LVEF (< 0.35/ ≥ 0.35) and; 3) type 
of Medtronic device (Reveal/Non-Reveal/No Device).  In protocol version 3 a fourth strata 
was added: rhythm status at randomization: (SR vs AF).  The count of patients randomized 
by strata within each treatment group will be tabulated by site and overall.  The 
randomization process will be described in full detail. 
2.3 
Baseline Characteristics 
The treatment groups will be examined for comparability with respect to demographics, 
cardiovascular history, AF risk factors, current disease state, HF and AF therapies, physical 
exam abnormalities, CYP2D6 and α2C genotyping, vital signs, ECG and laboratory 
parameters using descriptive statistics.  Continuous variables will be analyzed with a mean, 
standard error, standard deviation, median, minimum, maximum and n=count of results 
available.  Categorical variables will be described with n=count of results available and 
percentage of study population, with a clear explanation of the denominators provided in 
footnotes when necessary. 
2.4 
Treatment Exposure and Compliance 
The treatment groups will be examined for comparability with respect to the outcome of the 
titration period (broken down by pre-study beta blocker usage), the attainment of target dose 
and the days of double blind treatment by dose level and overall.  Elapsed days and days of 
treatment exposure during the four follow-up periods will also be described by treatment 
group. 
Compliance since the previous visit is reported by the sites on the VISREC eCRF form.  
Overall compliance rates for the 24-Week Follow-up Period and the Total Study Period will 
be calculated for each patient and compared between the two treatment groups with 


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descriptive statistics.  Note that if a patient discontinues study treatment, compliance is 
calculated through the date of discontinuation. 
2.5 
Concomitant Medications 
Patients must be receiving optimal anticoagulation therapy for stroke prevention.  A tabulation 
of anticoagulant drug usage by treatment group will be generated.  For warfarin users, INR is 
collected on the LAB eCRF as the following ranges: < 1, ≥ 1 and < 2, ≥ 2 and < 3, ≥ 3 and < 
4, ≥ 4.  A tabulation of these reported ranges by treatment group will be generated for each of 
the study visits in which reporting is required. 
Reported usage of all concomitant medications during the study will be standardized with 
preferred name and Anatomical Therapeutic Classification (ATC) using the WHODrug 
dictionary for tabulation by treatment group. 
2.6 
Metrics for Key Study Procedures 
Metrics for the following study procedures and medical interventions will be presented with 
descriptive statistics by randomized treatment group: 
 The cardiac rhythm status of every patient at both the Randomization Visit and at the 
start of the 24-Week Follow-up Period will be tabulated as follows. 
– Patients in Stable SR at Week 0 who did not require ECV 
 Pts in SR at Randomization 
 Pts in AF at Randomization 
–  Patients in Stable SR at Week 0 who did require ECV 
 Pts in SR at Randomization 
 Pts in AF at Randomization 
–  Patients in AF/AFL at Week 0 
 Pts in SR at Randomization 
 Pts in AF at Randomization 
–  Death/Loss to Follow-up (LTF) prior to Week 0 
 Pts in SR at Randomization 
 Pts in AF at Randomization 
 Elapsed days on treatment prior to ECV. 
 Outcome of ECV. 


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 Compliance with procedures for collection of transtelephonic monitoring (TTM) 
results, and 
 Compliance with procedures for collection of Medtronic device results. 
2.7 
Final Study Disposition 
The disposition of patients screened and randomized into the study will be tabulated by 
treatment group and displayed with a flow diagram.  This will include the counts of screens, 
screen failures, re-screens, randomizations, completion of the Week 24 Visit, reasons for 
permanent discontinuation of study treatment and reasons for discontinuation of study 
follow-up (broken down by pre/post Week 24 Visit).  Note that all patients classified as 
completing the Week 24 Visit will have all components of the primary and secondary 
endpoints ascertained through the entire 24-Week Follow-up Period. 
2.8 
Protocol Deviations 
ARCA Clinical Operations maintains an Excel spreadsheet of protocol deviations reported 
during the study.  Each protocol deviation is classified as being Major or Minor, based on its 
potential impact on clinical results per ARCA SOP CLIN-005.  Tabulations and listings of 
the reported protocol deviations will be provided for both treatment groups. 
3 EFFICACY ANALYSIS 
3.1 
General Methodology 
3.1.1 Time-to-Event Analysis Methodology 
Time-to-event is calculated as the date of the event minus the date of initiation of efficacy 
follow-up, with 1 added in order to include both the start date and end date of the interval. 
For all endpoints, follow-up will be censored when a patient receives a cardiac transplant, is 
declared to be permanently lost to follow-up or withdraws consent.  The follow-up periods 
and specific censoring rules are identified in the endpoint descriptions. 
These analyses will be a two-tailed comparison of bucindolol and metoprolol, using the log 
rank statistic with the exact variance calculation stratified by the randomized treatment 
assignment strata: 1) HF etiology (ischemic/non-ischemic); 2) LVEF (< 0.35/ ≥ 0.35); 3) type 
of Medtronic device (Reveal/Non-Reveal/No Device); and 4) rhythm status at randomization: 


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(SR vs AF).  Note that patients enrolled under versions 1 and 2 of the protocol were not 
stratified by rhythm status however their rhythm status is known due to inclusion criteria (all 
were in AF).  The calculations will be performed with the SAS® LIFETEST procedure, with 
the stratification variables specified in the STRATA statement and the TEST statement used 
to specify the treatment group comparator and any covariates being examined.  Cox’s 
proportional hazards model will be used to calculate estimated hazard ratios and 95% 
confidence intervals.  The calculations will be performed with the SAS PHREG procedure, 
with the stratification variables specified in the STRATA statement and the treatment group 
comparator and any covariates being examined specified in the MODEL statement.  For the 
primary endpoint, the appropriateness of assuming proportional hazards will be explored by 
the graphing of log (-log(survival function)) over follow-up for each treatment group. 
Where appropriate, Kaplan-Meier survival curves for bucindolol versus metoprolol will be 
generated to provide a graphical comparison of the two treatment groups. 
Follow-up for the time-to-event endpoints will generally end either at the Week 24 Visit or 
the EOS Visit for the Total Follow-up Period or Total Study Period endpoints.  If the Week 
24 Visit falls later than day 180, follow-up will be censored on day 180. 
3.1.2 Components of Combined Endpoints 
This report will contain many endpoints that involve the time to the first occurrence of 
multiple events, such as AF/AFL onset, mortality or hospitalization.  For these endpoints, the 
count of first events provided by each component will be tabulated.  In addition, each 
component of the combined endpoints will be analyzed separately with a time-to-first-event 
analysis following the same methodologies used for the combined statistic. 
3.1.3 Adjudication 
A Clinical Events Classification (CEC) group will adjudicate the primary endpoint, first 
symptomatic AF/AFL event or death during the 24-Week Follow-up Period.  As part of the 
adjudication process for the primary endpoint, the CEC will also evaluate the secondary 
endpoint of first AF/AFL event (i.e., symptomatic or asymptomatic).  Specifically, the ECGs 
for the first report of AF/AFL will be reviewed and adjudicated for the presence of AF/AFL 
regardless of the symptom status.  If the first protocol-defined AF/AFL event is not 


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considered a symptomatic AF/AFL event, the triggering process will continue for that patient 
until the first symptomatic AF/AFL event is identified for the primary endpoint.  The CEC 
over-read of ECG tracings will be used in the calculation of other pertinent study endpoints 
(such as non-symptomatic AF/AFL within the 24-Week Follow-up Period).  More details can 
be found in the CEC Charter. 
3.1.4 Core Lab and Transtelephonic Monitoring 
In the original study protocol, an Electrophysiology Core Lab (Agility Centralized Research 
Services) provided a centralized ECG interpretation of the individual ECGs performed at the 
clinic site and the transtelephonic monitors (TTM) worn by the patients, both during the 24-
Week Follow-up Period.  In version 4 of the protocol, the collection of these two sources of 
data was discontinued.  The CEC adjudication process was not in production mode at that 
time point, so it was decided the CEC would perform their own interpretation (over-reads) of 
the site ECG tracings and not use any of the Core Lab interpretations.  Further, the CEC 
adjudication would make use of available TTM data. 
3.1.5 Hospitalization 
Many of the efficacy endpoints involve hospitalization.  Only non-voluntary, overnight 
hospital admissions will be included in these endpoints; emergency room visits will not be 
included.  Patients in this study will often have scheduled hospital admissions for treatment 
of their AF and/or HF.  Examples include ablation procedures, Tikosyn induction, 
placement/replacement of implanted devices, and IV drug treatment.  These will not be 
included in the endpoints.  The eCRF specifically collects the investigator’s assessment of 
hospitalization causation, which includes assessments of non-CV, CV and HF 
hospitalizations.  In addition to the investigator assessment of causation, the data will be 
reviewed by the Sponsor via a blinded listing review prior to database lock to confirm which 
hospitalizations are considered voluntary, overnight admissions. 
3.1.6 Data Collection Cut-off at End of Study 
The protocol states the study will end with approximately 620 randomized patients and 
accrual of at least 330 primary endpoint events, presuming the sample size and target event 
counts are not altered due to the Phase 3 interim analysis (see DSMB Charter).  At this point, 
any patients still participating in the 24-Week Follow-up Period will remain on blinded study 


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treatment until they complete the Week 24 Visit.  Those patients in the Extension Period will 
be called in for an EOS Visit. 
3.1.7 Missing Data Due to Withdrawal or Loss to Follow-up 
The rate of withdrawal or loss to follow-up prior to the Week 24 Visit is expected to be low.  
If a withdrawal or loss to follow-up occurs prior to the Week 24 Visit, all time-to-event 
endpoints will be censored as of the last completed visit.  Note that patients that withdraw 
from the study will be requested to consent to have their vital status checked via phone calls.  
If deaths are detected by this procedure the date of death will be incorporated into the 
efficacy and safety datasets and analyses. 
3.1.8 P-value Adjustment for Interim Analysis 
The goals and operational details for the interim efficacy analysis and ongoing safety 
monitoring can be found in the DSMB Charter and the DSMB SAP. 
At the end of Phase 3, the alpha level for the primary endpoint will be reduced to 0.04989 to 
adjust for the Phase 2B (α = 0.00001) and Phase 3 (α = 0.0001) interim analyses. 
3.2 
Efficacy Endpoints 
3.2.1 Primary Efficacy Endpoint 
The primary endpoint is elapsed time-to-first-event of symptomatic AF/AFL or all-cause 
mortality (ACM) during the 24-Week Follow-up Period.  This is a time-to-event endpoint 
censored at the end of the 24-Week Follow-up Period.  The identification of first event of 
symptomatic AF/AFL or death is provided by the CEC.  The CEC does not distinguish 
between the presence of AF or AFL so a component analysis will not be possible. 
The following definitions apply to this endpoint: 
 Stable SR on study drug is defined as any of the following: 
– SR confirmed ≥ 1 hour after ECV. 
– SR confirmed ≥ 1 hour after spontaneous conversion from AF/AFL. 
– SR confirmed ≥ 1 hour at the Week 0 Visit for patients randomized in SR. 
 An AF/AFL event is defined as AF or AFL observed on two consecutive measures 
separated by at least 10 minutes as assessed by ECG/TTM. 


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 A symptomatic AF/AFL event is defined as an AF/AFL event that is associated with 
a clinically relevant change in patient-reported symptoms, as determined by the CEC 
examination of blinded data. 
The CEC charter and associated documents describe the “triggers” that are established to 
identify events for their consideration and the data sources to be used in their adjudication 
proceedings.  The charter also describes their approach for identifying an AF event as 
symptomatic and for identifying the onset date and time of the event since that is needed for 
this time-to-event endpoint.  Note that version 3 of the protocol involved a comprehensive 
change to the symptoms collected, with 6 of the original 8 symptoms having their 
descriptions modified and 2 new symptoms being added.  Also the symptom characteristics 
were clarified with addition of a ‘frequency’ field to the collection form.  All of these 
changes were made to give the CEC more specific information to support their identifying 
symptoms that were new or worsened in association with AF onset.  Since these changes 
were implemented after only 12 patients were randomized (2% of the planned 620) and the 
identification of overall symptom onset/worsening is an adjudicated decision, no 
modification of analysis methodology is planned. 
AF/AFL will be assessed at scheduled and unscheduled clinic visits via 12-lead ECG.  
Patients will be queried at the time of each ECG assessment to determine if they have 
experienced any change in symptoms that could be potentially related to AF. 
The vast majority of patients will either be in SR or successfully convert from AF to SR after 
one or two ECV procedures around three weeks after they begin randomized treatment.  
However, there are several scenarios that depart from this norm and the methodology for 
establishing the start of efficacy follow-up and censoring for the primary endpoint is 
described below: 
1. Spontaneous conversion to stable SR prior to the planned cardioversion.  For these 
patients, the day of the first ECG assessment that meets the definition of stable SR, as 
defined above, will be designated as Day 1 of the 24-Week Follow-up Period. 
2. Failure to attain stable SR because the ECV procedure was not performed due to drop 
out or any reason other than those described below.  These patients will be included 
in the analysis as censored on Day 1 of the 24-Week Follow-up Period. 


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3. Failure to attain stable SR, either spontaneously or following ECV.  These patients 
will be included in the endpoint calculation as experiencing the event on Day 1 of the 
24-Week Follow-up Period. 
4. Deaths occurring after randomization and prior to conversion to stable SR will be 
counted as events on Day 1 of the 24-Week Follow-up Period. 
5. Patients with AF/AFL stopped at the Week 0 Visit by any means other than ECV will 
be censored on Day 1 of the 24-Week Follow-up Period.  An example is the 
performance of AV nodal ablation at the Week 0 Visit.  
The primary endpoint analysis will also be performed within the following prospectively 
identified subgroups based on pathophysiological or clinical importance: 
1) Started the 24-Week Follow-up Period in SR vs AF 
2) LVEF strata at randomization:  ≤0.35 vs. >35 
3) Gender 
4) Ischemic etiology vs. nonischemic 
5) Age above/below median 
6) Duration of AF diagnosis above and below median. 
7) Baseline norepinephrine above and below median 
8) Baseline NT-proBNP 
9) 2C AR polymorphisms (i.e., Del carriers vs. 2C wild type homozygotes). 
In exploratory analyses, the following covariates will be included as potentially relevant 
explanatory variables in the Cox regression models: 
1. Initial study treatment dose level.  
2. Baseline NYHA Class. 
3. Gender. 
4. Race. 
5. Age. 
6. Baseline serum creatinine. 
7. Baseline norepinephrine level. 
8. Baseline heart rate. 


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9. Baseline systolic blood pressure. 
10. History of diabetes. 
11. Duration of AF diagnosis. 
12. Previous amiodarone use (both historical and stopped just prior to randomization). 
13. Ablation procedure prior to study. 
14.  Therapeutic device type: CRT, ICD, single ventricular lead pacemaker. 
15. For the subset of patients in AF at baseline, type of rhythm abnormality: (paroxysmal 
AF or persistent AF). 
16. For the subset of patients in SR at baseline: the time since last attaining SR, the type 
of previous rhythm abnormality, and the intervention that ended the previous AF 
episode. 
17. Elapsed days of treatment from randomization date to start of the 24-Week Follow-up 
Period. 
18. CYP2D6 metabolizer status. 
19. 2C AR polymorphisms (i.e., Del carriers vs. 2C wild type homozygotes). 
20. Country in which clinic site is located. 
21. Other clinically significant AF risk factors. 
Additional exploratory analyses will include the following: 
 A qualitative analysis of the symptoms associated with the primary endpoint events.  
The symptoms will be classified as arrhythmia-related (palpitations or 
lightheadedness/dizziness) HF-related (fatigue or tiredness, weakness or problems 
exercise, weight gain or swelling of both legs and/or feet), or both. 
 For patients with primary endpoint events of symptomatic AF/AFL, how many had 
prior events of asymptomatic AF/AF that progressed into symptomatic. 
The following sensitivity analyses will be performed: 
 A subpopulation analysis including only those patients beginning the 24-Week 
Follow-up Period in SR. 
 In the per-protocol analysis, endpoint events and deaths that occur more than 30 days 
after permanent discontinuation of study treatment are omitted. 


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 All Week 24 Visits included (ie - no exclusion of events observed at Week 24 Visits 
after day 180). 
 Patients that have not previously reverted to AF/AFL that withdraw or are lost to 
follow-up prior to the Week 24 Visit, will be assigned an AF/AFL event at the first 
missed clinic visit or scheduled TTM. 
 Patients that withdraw or are lost to follow-up prior to the Week 24 Visit are omitted 
from the analysis. 
3.2.2 Secondary Efficacy Endpoints 
The following endpoints will be tested for superiority of bucindolol benefit relative to 
metoprolol by fixed sequence provided that bucindolol is found to be significantly superior in 
the primary endpoint.  The time-to-event endpoint methodology described in Sections 3.1.1 
and 3.2.1 for events involving AF/AFL recurrence will be used unless otherwise noted: 
 Time-to-first-event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during 
the 24-Week Follow-up Period. 
Supportive Analyses: 
– Events accrued during the Total Follow-up Period. 
– For patients with events based on symptomatic AFL, the rate of patients 
subsequently progressing to AF.  Also for these patients, the elapsed time 
from symptomatic AFL to AF. 
Data Source: 
– ECG (over-read by CEC for first 24 weeks) 
– TTM (first 24 weeks only) 
 Proportion of patients with VT, VF, or symptomatic supraventricular tachycardia 
(SVT) during the 24-Week Follow-up Period. Includes VF and symptomatic SVT 
events of any duration, VT events ≥ 15 seconds, and VT events that result in 
appropriate firing of an ICD.  It will be tested with a Cochran-Mantel-Haenszel 
statistic to control for the four stratification variables. 


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Supportive Analyses: 
– Events accrued during the Total Follow-up Period. 
Data Source: 
– The CVEVENT eCRF form is the source of all components of these 
compound endpoints. 
 Total all-cause hospitalization days per patient during the Total Study Period.  The 
count of hospitalization days will be normalized for the total number of days of 
follow-up prior to testing with the Wilcoxon Rank Sum statistic. 
Supportive Analyses: 
– Number of heart failure hospitalization days per patient. 
– All-cause hospitalization days through first recurrence of AF/AFL versus days 
after recurrence, normalized for days of follow-up within each period.  The 
comparison will take place within treatment group and across treatment. 
– All-cause hospitalization days for patients with ventricular rate control (VRR) 
control compared to those without VRR control.  The comparison will take 
place within treatment group and across treatment. 
Data Source: 
– The HOSP eCRF form provides the number of hospitalization days and the 
reason for hospitalization. 
– The ECG and AE eCRF will be used to identify the patients in AF with VRR 
control at the end of the study. 
 Time-to-first-event of AF/AFL (i.e., symptomatic or asymptomatic), HF 
hospitalization (as assessed by the Investigator), or ACM during the Total Follow-up 
Period.  As in the primary endpoint, any incidence of ACM prior to start of the 24-
Week Follow-up Period will be analyzed as an event on Day 1.  Hospitalization prior 
to Week 0 are not included, but those are included in the safety analyses. 
Supportive Analyses: 


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– Events accrued during the 24-Week Follow-up Period. 
– Combinations of each component ((i.e., AF/AFL+ACM, AF/AFL+HFH, 
HFH+ACM). 
Data Source: 
– ECG (over-read by CEC for first 24 weeks), HOSP and DEATH eCRF forms. 
– TTM (first 24 weeks only). 
 Proportion of patients with adequate ventricular rate control (VRR) in the setting of 
AF/AFL.  Adequate VRR in setting of AF/AFL is defined as follows: 1) the presence 
of AF or AFL; 2) a VRR between 40 and 80 beats per minute (bpm) at rest; and 3) the 
absence of symptoms associated with bradycardia.  Thus this is a subset analysis only 
involving patients with AF/AFL recurrence.  The endpoint is evaluated for the last 
tracing demonstrating AF/AFL during the 24-Week Follow-up Period prior to 
intervention (eg: ablation, ECV, initiation of anti-arrhythmic drugs).  Will be tested 
with a Cochran-Mantel-Haenszel statistic to control for the four stratification 
variables. 
Supportive Analyses: 
– Evaluated for the last tracing demonstrating AF/AFL when the patient is still 
on study treatment during the 24-Week Follow-up Period. 
Data Source: 
– ECG and AE eCRF form (for symptomatic bradycardia). 
3.2.3 Tertiary Efficacy Endpoints 
The following endpoints will be tested for superiority of bucindolol benefit relative to 
metoprolol. The time-to-event endpoint methodology described in Sections 3.1.1 and 3.2.1 
for events involving AF/AFL recurrence will be used unless otherwise noted: 
 Time-to-first-event of VT/VF or ACM during the Total Follow-up Period.  Includes 
VF events of any duration, VT events of ≥ 15 seconds, and VT events that result in 
appropriate firing of an ICD. 


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Supportive Analyses:  
– Events accrued during the 24-Week Follow-up Period. 
Data Source: 
– CVEVENT and DEATH eCRF forms. 
 Time-to-first-event of AF/AFL (i.e., symptomatic or asymptomatic), CV-related 
hospitalization (as assessed by the Investigator), or ACM during the Total Study 
Follow-up Period. 
Supportive Analyses: 
– Events accrued during the 24-Week Follow-up Period. 
– Combinations of each component (i.e., AF/AFL+ACM, AF/AFL+CVH, 
CVH+ACM). 
Data Source: 
– ECG (over-read by CEC during the 24-Week Follow-up Period), HOSP and 
DEATH eCRF forms. 
– TTM (24-Week Follow-up Period). 
 Proportion of patients with stroke or systemic embolism during the Total Follow-up 
Period.  Stroke is defined as a focal neurologic deficit from a non-traumatic ischemic, 
hemorrhagic, or uncertain cause lasting at least 24 hours (as assessed by the 
Investigator).  Tested with a Cochran-Mantel-Haenszel statistic to control for the four 
stratification variables. 
Data Source: 
– CVEVENT eCRF form. 
 Proportion of patients randomized with AF/AFL who convert to stable SR 
(spontaneous or post-ECV) and enter the 24-Week Follow-up Period.  Tested with a 
Cochran-Mantel-Haenszel statistic to control for the four stratification variables. 
Supportive Analyses: 


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– Subset of patients with spontaneous conversion. 
Data Source: 
– FUSTART eCRF form. 
 Total number of ECV procedures per patient during the Total Study Period.  This 
count will be normalized for the total number of days of follow-up prior to testing 
with the Wilcoxon Rank Sum statistic. 
Data Source: 
– ECV eCRF form. 
 Proportion of patients at Week 24 Visit who are receiving study drug and have not 
had an AF/AFL event.  Tested with a Cochran-Mantel-Haenszel statistic to control 
for the four stratification variables. 
Data Source: 
– ECG (over-read by CEC), DRUGLOG and EOT eCRF forms. 
– TTM (24-Week Follow-up Period). 
 Change in NT-proBNP, assessed relative to baseline (Randomization Visit).  Change 
from baseline will be tested for greater reduction in the bucindolol treatment group 
with the Wilcoxon Rank Sum test because of the expected lack of normality of this 
measure. 
Data source: 
– LabCorp vendor dataset. 
 Change in norepinephrine, assessed relative to baseline (Randomization Visit).  
Change from baseline will be tested for greater reduction in the bucindolol treatment 
group with the Wilcoxon Rank Sum test because of the expected lack of normality of 
this measure. 
Data source:  
– LabCorp vendor dataset. 


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 The EQ-5D questionnaire has 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression) and each is self-rated by the patient as no 
problems, some problems, or severe problems.  The results for each dimension will be 
analyzed individually at both time points.  The change from randomization to each 
visit will be categorized as improved or no change/worsened and the proportions of 
these categories in both treatment groups will be tabulated with a 2 by 2 table.  The 
bucindolol treatment group will be tested for superior response using a Cochran-
Mantel-Haenszel statistic to control for the four stratification variables. 
Data source: 
– EQ-5D eCRF form. 
 Pharmacoeconomic modeling of healthcare utilization.  Details of this analysis will be 
prespecified in a separate analysis plan. 
4 SAFETY ANALYSIS 
The following four periods are established for analysis of safety endpoints: 
 24-Week On-Drug Period:  starts at day of randomization and extends to latest visit 
attended through Week 24 Visit.  For patients that discontinue treatment early, data 
collected through 30 days after the final dose of study treatment are included. 
 24-Week On-Study Period:  starts at day of randomization and extends to latest visit 
attended through Week 24 Visit.  For patients that discontinue the study prior to 
Week 24, data collected through 30 days after the final study visit are included.  
Study treatment status is not considered for data inclusion. 
 Total Study On-Drug Period:  starts at day of randomization and extends through 30 
days after the final dose of study treatment. 
 Total Study On-Study Period:  starts at day of randomization and extends through 30 
days after final clinic visit attended.  Study treatment status is not considered for data 
inclusion. 
Analysis of SAEs will be performed for all four timeframes.  For the other safety endpoints, 
the 24-Week On-Study and Total Study On-Study Periods will be used.  If treatment group 


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imbalances are observed for an endpoint, it will be further analyzed with the other data 
inclusion timeframes. 
The results for the following safety endpoints will be compared with descriptive statistics 
between the treatment groups for all patients receiving study treatment.  Results collected 
from first dose of study drug to 30 days after the last dose for each patient will be included in 
the assessments of safety.  Results specific to scheduled visits will be included in the by-visit 
analyses if they were collected within a ± 7-day window for the prescribed visit study day. 
 Incidence of ACM during the Total Study Period. 
Supportive Analyses: 
– The association of VRR control with mortality will be examined using the 
final heart rate measurement available for each patient (comparisons will be 
within the treatment groups). 
Data Source: 
– DEATH eCRF form. 
 Incidence of ACM, CV-related hospitalization (as assessed by the Investigator), or 
withdrawal of study drug due to an AE during the Drug Titration Period. 
Data source: 
– DEATH, HOSP, EOS and AE eCRF forms. 
 Incidence of symptomatic heart block during the Total Study Period.  Symptomatic 
Heart Block is defined as the first of any of the following:  1) 3rd degree heart block 
(complete heart block); 2) any 2nd degree heart block with the presence of symptoms 
attributable to, and temporally correlated with the occurrence of heart block which 
include any of the following: Near-fainting or fainting (syncope) / Dizziness; 
Weakness or Fatigue; Shortness of breath; Chest pain; or 3) 2nd or 3rd degree heart 
block requiring implantation of a permanent pacemaker (with or without 
defibrillator). 
Data source: 
– CVEVENT and AE eCRF forms. 


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 Overall incidence and severity of treatment-emergent AEs/SAEs over time during the 
Total Study Period.  Also events associated with device implantation.  The events will 
have standardized MedDRA preferred terms and System Organ Classes assigned to 
them for tabulation. 
Supportive analyses: 
– Incidence of AEs leading to reduction, interruption or permanent 
discontinuation of study treatment. 
– Incidence of AEs associated with device implantation. 
– Incidence of AEs by CYP2D6 metabolizer status. 
– Incidence of AEs by α2C AR polymorphisms. 
Data source: 
– AE eCRF form. 
 Incidence of neoplasm-related AEs during the Total Study Period.  The AEs of 
special interest will be tabulated according to the following characteristics. 
– Development of treatment-emergent neoplastic conditions. 
– Progression or worsening of pre-study neoplastic conditions. 
– Progression or worsening of treatment-emergent neoplastic conditions. 
Data source:  
– AE, NEOPLHX and NEOPLAS eCRF forms. 
 Clinical Chemistry and Hematology.  
– Visit collection: screen, start of follow-up Week 0 (protocol versions 1 and 2), 
Week 4 (protocol versions 3 and 4), Week 12 (protocol versions 3 and 4), 
Week 24, every 24 weeks during extension, end of treatment and end of study.  
Screen results will serve as the pre-treatment baseline. 
– Change from baseline to each planned study visit of collection will be 
calculated and analyzed with descriptive statistics. 


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– The numbers and percentages of patients with values exceeding the bounds of 
normal ranges will be tabulated for scheduled visits. 
– The numbers and percentages of patients with values exceeding the panic 
bounds each visit. 
Data source: 
– LabCorp vendor-supplied dataset. 
 ECG quantitative parameters. 
– Measured at every visit.  Randomization Visit measurement prior to first dose 
will serve as the baseline.  Will be analyzed at Week 0, 4, 12 and 24 visits as 
well as end of treatment and end of study. 
– Change from baseline to each analysis visit will be calculated and analyzed 
with descriptive statistics. 
– The numbers and percentages of patients with QTc increase from baseline 
exceeding 60 ms at any time point during the study. 
Data source:  
– 
ECG eCRF form. 
 Vital signs and weight (data source: VITALS eCRF form). 
– Measured at every in-clinic visit.  Randomization Visit measurement prior to 
first dose will serve as the baseline.  Will be analyzed at Week 0, 4, 12 and 24 
visits as well as end of treatment and end of study. 
– Change from baseline to each analysis visit will be calculated and analyzed 
with descriptive statistics. 
Data source: 
– VITALS eCRF form. 
 Proportion of patients attaining target study drug dose during the Drug Titration 
Period.  Will be calculated for all patients, those receiving -blocker therapy prior to 
randomization and those not previously receiving -blocker therapy. 


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Data Sources: 
– VISREC and DRUGLOG eCRF forms. 
 
5 MEASUREMENTS OF INTEREST AND SUBSTUDIES 
 AF Burden (AFB) Substudy. 
In this optional substudy, AFB, defined as the amount of time per day that a patient is 
in AF/AFL, is measured by implanted Medtronic devices, including cardiac monitors, 
pacemakers, cardioverter-defibrillators, and cardiac resynchronization therapy.  These 
devices also measure VRR during periods of AF.  Approximately 50% of the study 
participants are expected to participate in the AFB substudy. 
The distribution of device types will be presented by treatment group, by patient 
baseline characteristics, by disease severity, by treatment exposure prior to device 
implantation and elapsed days to start of the 24-Week Follow-up Period.  AFB will 
be presented as hours/day in graphical displays for each patient with the dates of 
randomization and initial ECV and other interventions annotated. 
The treatment efficacy endpoint will be the time to first device-detected event or 
ACM, with an event defined as at least 6 hours of AFB in a single day.  This endpoint 
will be analyzed through the Week 24 Visit with the same methodology used for the 
study primary endpoint. Patients with no AFB data available after the start of the 24-
Week Follow-up Period will be excluded.  Patients with an implanted therapeutic 
device that produces paced rhythm which confounds the measurement of AFB will 
also be excluded. 
Supportive Analyses: 
– Time to device detected AF/AFL event during the Total Follow-up Period. 
– The proportion of patients with VRR on the last day demonstrating AF/AFL 
during the 24-Week Follow-up Period.  Will be tested using a Cochran-
Mantel-Haenszel statistic to control for the four stratification variables. 
– The percent of follow-up days in AFB, calculated as the number of days with 
AFB of at least six hours divided by the total number of days in the 24-Week 


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Follow-up Period.  Statistical testing will be performed with the Wilcoxon 
Rank Sum Statistic.  A sensitivity analysis will be performed on the subset of 
patients beginning the 24-Week Follow-up Period in SR. 
Data Sources: 
– Medtronic vendor-supplied dataset. 
 DNA Bank, with collection at time of screening, for patients who agree to participate 
in the substudy.  No analysis of these data have been pre-planned. 
 Sparse sampling of bucindolol hydrochloride plasma concentrations for population 
pharmacokinetic analysis.  The analysis plan for the substudy will be prepared 
separately prior to unblinding.