Clinical trial NCT03168529
Conditions: Heart Failure
Keywords: Acute Heart Failure Observation Ivabradine
Sponsor: Phillip Levy
Start date: 2018-07-01; Completion date: 2021-12-31
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Ivabradine (IVA) has been shown to decrease the risk of hospitalizations for worsening Heart Failure and was associated with a trend towards improved mortality in the SHIFT1 trial. SHIFT1 excluded patients within 4 weeks of hospital discharge, so the efficacy and safety of IVA in this setting is less clear.

In today's health care environment more and more patients that present to the Emergency Department (ED) for mild Acute Heart Failure (AHF) are being placed into observation unit and subsequently discharged, or discharged outright from the ED. This is not only a growing segment of patients, but also represents an important window of opportunity to intervene with a potentially effective therapy.

Moreover, at this point in a patient's experience (being discharged after getting treated for exacerbation of Heart Failure), it's not clear that beta blockers (BB) should yet be increased/started due to the recent state of exacerbation.

Standard treatment of worsened heart failure presenting to the ED or urgent care includes diuretics (e. g. furosemide) and vasodilators (e.g. ACE-I, ARB, Hydralazine/Isosorbide or ARNi), but according to usual standard of care, titration of beta blockade is often reserved for outpatient follow up after a period of demonstrated stability (in the ambulatory setting).

This is in contradistinction to hospitalized patients, where patients have been observed by the treating team for days, presumably show stability and improvement, and starting low dose BB at the time of hospital discharge has been shown to be safe. As such these ED/Observation discharge patients are often not optimal candidates for intensification of BB at the time of release, and could be considered to be at maximally tolerated BB dose (for at least for 2-4 weeks). This may represent a vulnerable period for these patients; its unknown in the setting of Observation discharge but evidence from hospitalized patients indicates that the highest daily risk of rehospitalization is in the days just after discharge. IVA may be effective post observation unit management (where lower risk Heart Failure (HF) patients are typically placed), to reduce heart rate (without decreasing contractility, such as a BB would) to help reduce the risk of hospitalization or emergency care, but safety and efficacy (in terms of heart rate lowering) in this setting has not been previously explored.

Additionally, the SHIFT1 trial lacked African Americans and this unique patient population has not been previously studied with IVA. The investigating sites serve a predominantly African American patient population. Therefore the proposed study represents an important opportunity to gather data on IVA effect in this understudied group of patients.

Detailed description:
Subjects will be enrolled at the time of discharge from the observation unit (visit 1), all baseline procedures will be performed at this time, these would include blood draw for biomarker assessments, vitals, physical examination, and IP dispensation. At the baseline visit, the study team will schedule a follow-up appointment post Day 28 +/- 2 (Visit 3) with the subject's primary care physician(PCP)/cardiologist, if the subject does not have their own PCP/cardiologist the study team will schedule and facilitate this appointment with the Gateway Clinic. A list of current medications and doses will be provided. At Day 14 +/-1 (visit 2) the subject will return for a follow up visit for IP accountability and titration (if needed), BB uptitration (if needed), replacement of the HR monitor (Zio patch), assessment of any adverse events, ECG, vital signs, and will undergo a physical examination. At Day 28 +/-2 (visit 3), the patient will return for study exit procedures, which include blood draw for biomarker assessments, vitals, physical examination, assessment of adverse events (if any), and IP return.

As with any clinical trial, no un-blinding will occur unless there is a concern for patient safety, as this could affect the integrity of data. The study team will provide the patient and patient's PCP/cardiologist a clinical summary, inclusive of ECGs. On-going management for the patient's condition will be at the discretion of their PCP/cardiologist and will not be influenced directly by participation in this study.

At Randomization the initial Ivabradine dose will be 5 mg BID. At Day 14 follow up, medication adjustments will be made (if needed). At Day 28 follow up, IP will be permanently stopped.

At the last visit, the study team will contact the patient's primary care physician and/or the cardiologist to notify that the patient has completed the study and is off study drug and it is now the PCP/cardiologist's discretion to prescribe open label ivabradine (Corlanor) to the patient or not, as clinically indicated. If the patient's primary care physician and/or cardiologist prescribes open label ivabradine (Corlanor) after the completion of the study, the patient or patient's insurance will be responsible for payment as this would then be part of routine clinical care.

The Zio patch will be placed at discharge from the observation unit. At the 14-day follow-up the original Zio patch will be collected and a second one will be placed. At the 28-day follow-up the second Zio patch will be collected

Based on the SHIFT1 study, the mean heart rate reduction with IVA is 8 bpm with a standard deviation of 13 bpm. A sample size of 57 in each group will have 90% power to detect a difference in means of 8.0 assuming that the common standard deviation is 13.0 using a two group t-test with a 0.05 two-sided significance level. To account for a projected dropout rate of 15%, 66 subjects will be enrolled in each group (132 total for the study over a 2-year period). Furthermore, the investigators expect that the enrollment centers will recruit a cohort that is 75% self-identified African Americans. This number (n=99) will provide 80% power to detect the same effect size when analyzed in African Americans only.

For the safety endpoint (unplanned presentation for medical care), assuming an event rate of 25% at 1 month (estimated based on local hospital readmission rates), the sample size will provide 80% power to detect a doubling of the relative risk. If the Control group event rate is higher there will be greater power; for example, with an event rate of 35% we would have 98% power for risk ratio of 2.0 and 83% power for risk ratio of 1.75.

Arms: arm 1: All subjects will complete the same number of follow-ups, dose titrations (if necessary) and study procedures however, subjects in this arm will be receiving active drug for study duration. arm 2: All subjects will complete the same number of follow-ups, dose titrations (if necessary) and study procedures however, subjects in this arm will be receiving placebo for study duration.
Interventions: intervention 1: Ivabradine intervention 2: Placebo
Intervention descriptions: intervention 1: At discharge from the observation unit, subjects will receive a pill bottle containing oral capsules containing active drug to take at home. This arm will require the subject to take the study medication BID for the duration of the study period. Neither study team nor subject will know if the pill bottle contains active drug or placebo. intervention 2: At discharge from the observation unit, subjects will receive a pill bottle containing oral capsules not containing active drug to take at home. This arm will require the subject to take the study medication BID for the duration of the study period. Neither study team nor subject will know if the pill bottle contains active drug or placebo.

Protocol documents:
SAP_003.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN: 
OBSERVE-IVA 
A Randomized, Double-Blind, Placebo-Controlled Trial 
Assessing the Efficacy of Ivabradine Initiated at the 
Time of Discharge from the Observation Unit 
Phillip Levy 
plevy@wayne.edu 
NCT: 03168529 
8/1/2021 


Statistical Analysis Plan:  
A Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Eﬃcacy of Ivabradine 
Initiated at the Time of Discharge from the Observation Unit. 
(OBSERVE-IVA) 
NCT: 03168529 
 
The original plan detailed in the protocol is as follows: 
13.0 Statistical Analysis The primary outcome (change in heart rate i.e. the value at Day 28 (+/-2) - the 
value at baseline) will be analyzed as two sample t-test. Secondary outcomes that are continuous 
variables will be analyzed as two sample t-test. The safety endpoint of unplanned visits will be compared 
as the number of unplanned medical visits over the study period tested using Poisson regression.  
14.0 Sample Size And Power Based on the SHIFT1 study, the mean heart rate reduction with IVA is 8 
bpm with a standard deviation of 13 bpm. A sample size of 57 in each group will have 90% power to 
detect a diﬀerence in means of 8.0 assuming that the common standard deviation is 13.0 using a two 
group t-test with a 0.05 two-sided signiﬁcance level. To account for a projected dropout rate of 15%, 66 
subjects will be enrolled in each group (132 total for the study over a 2-year period). Furthermore, we 
expect that our centers will recruit a cohort that is 75% self-identiﬁed African Americans. This number 
(n=99) will provide 80% power to detect the same eﬀect size when analyzed in African Americans only. 
 
Unfortunately, formal statistical analysis was not completed due to low sample size.  Unfortunately, 
OBSERVE IVA fell far short of its enrollment goal with just 19 out of a targeted 132 subjects included in 
the ﬁnal study cohort. Because of this, we have not developed any abstracts, manuscripts or other 
publications to date, though we may do so in the future. Of the 19 enrollments, 6 were at Detroit 
Receiving Hospital, 8 at Sinai-Grace Hospital, 2 at Harper University Hospital, and 3 at Henry Ford 
Hospital. A total of 13 subjects (68%) received ivabradine (IVA) and 6 received matching placebo. 
Baseline data for the overall study cohort and by randomization are provided in the accompanying Table 
with corresponding notation regarding the approach to statistical analysis. While no formal comparison 
has been performed, data showing heart rate at each of the 3 study visits for the 19 subjects enrolled 
and by study group are provided in the accompanying Figure.  
 
 


Table: Baseline data for OBSERVE IVA study cohort 
 
 
 
 
 
 
 
 


Figure: Heart rate trends by study visit (1= baseline, 2 = 15 days, 3 = 30 days) 
 
 
 
 
 

Prot_000.pdf: 
 
 
Title: A Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy of Ivabradine 
Initiated at the Time of Discharge from the Observation Unit. 
(OBSERVE-IVA) 
 
 
Principal Investigators: 
 
Phillip D. Levy, MD, MPH, FACEP, FAHA, FACC 
Professor of Emergency Medicine 
Associate Chair for Research, Department of Emergency Medicine 
Wayne State University School of Medicine 
4201 St. Antoine, UHC Suite 6G, Detroit, MI 48201 
 
David E. Lanfear, MD, MS, FAHA, FACC, FHFSA 
Section Head, Advanced Heart Failure and Cardiac Transplantation 
Heart and Vascular Institute, Henry Ford Hospital 
Associate Professor of Medicine, Wayne State University 
2799 West Grand Blvd, Suite K14,Detroit, MI 48202 
 
Funding Source: Amgen Inc. 
 
Version Number:  7.0 
Date of Protocol: July 23, 2018 
 
Authors: David Lanfear, Syed Imran Ayaz and Phillip Levy 
 
 


    
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Table of Contents: 
 
1.0 
Summary 
 
2.0 
Rationale 
 
3.0 
Setting 
 
4.0 
Eligibility Criteria 
 
5.0 
Endpoints 
 
6.0 
Study Design & Timeline 
 
7.0 
Post-Discharge Management 
 
8.0 
Schedule Of Events 
 
9.0 
IP Dosage And Titration 
 
10.0 
Beta Blockers Dosage And Titration 
 
11.0 
Adverse Events or Unanticipated Problems involving Risk to Participants 
 
12.0 
Biomarker Assessments 
 
13.0 
Statistical Analysis 
 
14.0 
Sample Size and Power 
 
15.0 
Institutional Review Board 
 
16.0 
Informed Consent Process 
 
17.0 
Participant Confidentiality 
 
18.0 
Data Management and Source Documentation 
 
19.0 
References 
 
 
 


    
                                                                                                                              Protocol v7.0, 23-JUL-2018 
 
 
 
 
 
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1.0 
Summary 
 
Prospective, randomized (1:1), placebo-controlled, double blind, study of ivabradine (Corlanor®) begun 
at the time of discharge from the hospital or observation unit after a stay of < 48 hours from the time of 
admission, for a total of 28 (+/-2) days in a cohort of predominantly (but not exclusively) African 
American patients with acute heart failure (HF). The primary endpoint will be change in heart rate from 
discharge to 28 (+/-2) days. Secondary endpoint will be heart rate change in African Americans from 
discharge to 28 (+/-2) days. Exploratory endpoints include change in NT-proBNP, change in hs-cTnT each 
comparing baseline to 28 (+/-2) days. Key safety endpoints will be the rate of unplanned medical care 
(presentation to ED or urgent care, unplanned hospitalization, unplanned medical office visit) and days 
alive and out of hospital over the 28 (+/-2) days of treatment.   
 
2.0 
Rationale 
 
Ivabradine (IVA) has been shown to decrease the risk of hospitalizations for worsening HF and was 
associated with a trend towards improved mortality in the SHIFT1 trial. SHIFT1 excluded patients within 4 
weeks of hospital discharge, so the efficacy and safety of IVA in this setting is less clear.  In today’s 
health care environment more and more patients that present to the ED for mild AHF are being placed 
into observation unit and subsequently discharged, or discharged outright from the ED.  This is not only 
a growing segment of patients, but also represents an important window of opportunity to intervene 
with a potentially effective therapy.   
 
Moreover, at this point in a patient’s experience (being discharged after getting treated for exacerbation 
of HF), its not clear that beta blockers (BB) should yet be increased/started due to the recent state of 
exacerbation. Standard treatment of worsened heart failure presenting to the ER or urgent care includes 
diuresis and vasodilators (e.g. ACE-I), but according to usual standard of care, titration of beta blockade 
is often reserved for outpatient follow up after a period of demonstrated stability (in the ambulatory 
setting). This is in contradistinction to hospitalized patients, where patients have been observed by the 
treating team for days, presumably show stability and improvement, and starting low dose BB at the 
time of hospital discharge has been shown to be safe (IMPACT-HF2 trial). As such these ED/Observation 
discharge patients are often not optimal candidates for intensification of BB at the time of release, and 
could be considered to be at maximally tolerated BB dose (for at least for 2-4 weeks). This may 
represent a vulnerable period for these patients; it’s unknown in the setting of Observation discharge 
but evidence from hospitalized patients indicates that the highest daily risk of rehospitalization is in the 
days just after discharge.  IVA may be effective post observation unit management (where lower risk HF 
patients are typically placed), to reduce heart rate (without decreasing contractility, such as a BB would) 
to help reduce the risk of hospitalization or emergency care, but safety and efficacy (in terms of heart 
rate lowering) in this setting has not been previously explored. 
 
Additionally, the SHIFT1 trial lacked African Americans and this unique patient population has not been 
previously studied with IVA. The investigating sites serve a predominantly African American patient 


    
                                                                                                                              Protocol v7.0, 23-JUL-2018 
 
 
 
 
 
Page 4 of 11 
population. Therefore the proposed study represents an important opportunity to gather data on IVA 
effect in this understudied group of patients. 
 
3.0 
Setting 
 
Four medical centers in Detroit (Henry Ford Hospital, Detroit Receiving Hospital, Sinai Grace Hospital, 
and Harper University Hospital) with a single coordinating center (Wayne State University). The 
emergency departments of these two hospitals treat >100,000 patients annually each. The patient 
population is majority African American. This makes a perfect setting to execute the proposed study. In 
addition, both hospitals are affiliated with Wayne State University, which has a highly functional Clinical 
Research Service Center that is under the direction of one of the co-investigators (Dr. Levy), enabling 
facilitated outpatient follow-up.  
 
4.0 
Eligibility Criteria 
 
Inclusion Criteria: 
 
1) Age >18 and <90. 
2) Established HF with reduced ejection fraction (EF ≤35 %), assessment done within 12 months of 
index visit.  
3) Admitted to the observation unit or inpatient ward for management of AHF. 
4) Heart rate ≥70 beats per minute, with sinus rhythm. 
5) Receiving guideline based medical therapy in the judgement of the treating physician.   
6) Patient currently on a Beta Blocker regimen. 
7) Achieved clinically determined stabilization during treatment under observation unit or during 
hospital admission within 48 hours from the time of admission. 
 
Exclusion Criteria: 
 
1) Known intolerance to study drug. 
2) End stage renal disease. 
3) Plan to titrate BB at the time of discharge from the observation unit. 
4) Any condition that in the opinion of the investigators will interfere with the ability to complete 
the study (e.g. history of extreme non-adherence, extreme psychosocial instability). 
5) Inability to provide written informed consent. 
6) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test (women of childbearing age will be included only if they agree to use adequate 
contraceptive methods or engage in sexual abstinence). 
7) Systolic Blood pressure less than 100 mmHg. 
8) Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand 
pacemaker is present. 


    
                                                                                                                              Protocol v7.0, 23-JUL-2018 
 
 
 
 
 
Page 5 of 11 
9) Severe hepatic impairment. 
10) Pacemaker dependence (i.e. heart rate maintained exclusively by the pacemaker). 
11) Concomitant use of strong CYP3A4 inhibitors. Examples of strong CYP3A4 inhibitors include 
azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g., clarithromycin, telithromycin), 
HIV protease inhibitors (e.g., nelfinavir), and nefazodone. 
12) Concomitant use of diltiazem or verapamil that are not planned for discontinuation. 
13) Severe, left sided valvular abnormalities (severe aortic stenosis, severe mitral stenosis, severe 
aortic insufficiency or severe mitral regurgitation.  
14) Documented, prior to or at the time of randomization, restrictive amyloid cardiomyopathy, or 
acute myocarditis, or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.   
 
5.0 
Endpoints 
 
Efficacy: 
§ 
Primary - Change in heart rate (Day 28 (+/-2) - baseline), measured by 12-lead ECG 
and Zio® patch (Day 14 (+/-1) - baseline). 
§ 
Secondary - Change in heart rate in self-identified African Americans (Day 28 (+/-2) – 
baseline), measured by 12-lead ECG and Zio® patch3(Day 14 (+/-1) - baseline). 
§ 
Exploratory: 
1) Change in NT-proBNP (Day 28 (+/-2) – baseline)  
2) Change in hs-cTnT (Day 28 (+/-2) – baseline)  
 
Safety: Presentation for unplanned medical care in any setting within 28 (+/-2) days. 
 


    
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6.0 
Study Design & Timeline 
 
 
 
 
 
 
Ivabradine 
Placebo 
Screen patients in Hospital or 
Observation Unit and randomize 
at discharge  
Screening 
Randomized Treatment 
 
Day 14±1  
(Visit 2) 
uptitrate BB  
(if necessary) 
 
 
Day 28±2  
(Visit 3) 
 
Baseline/Randomization 
(Visit 1) 


    
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7.0 
Post-Discharge Management 
Subjects will be enrolled at the time of discharge from the hospital or observation unit (visit 1), all 
baseline procedures will be performed at this time, these would include blood draw for biomarker 
assessments, vitals, physical examination, Zio patch3 placement and IP dispensation. At the baseline visit, 
the study team will schedule a follow-up appointment post Day 28 +/- 2 (Visit 3) with the subject’s 
primary care physician(PCP)/cardiologist, if the subject does not have their own PCP/cardiologist the 
study team will schedule and facilitate this appointment with the Gateway Clinic. A list of current 
medications and doses will be provided. At Day 14 +/-1 (visit 2) the subject will return for a follow up 
visit for IP accountability and titration (if needed), BB uptitration (if needed), collection of the HR 
monitor (Zio patch3), assessment of any adverse events, ECG, vital signs, and will undergo a physical 
examination. At Day 28 +/-2 (visit 3), the patient will return for study exit procedures, which include 
blood draw for biomarker assessments, vitals, physical examination, assessment of adverse events (if 
any), and IP return.  
 
As with any clinical trial, no un-blinding will occur unless there is a concern for patient safety, as this 
could affect the integrity of data. We will provide the patient and their PCP/cardiologist a clinical 
summary, inclusive of ECGs. On-going management for the patient’s condition will be at the discretion 
of their PCP/cardiologist and will not be influenced directly by participation in this study. 
 
8.0 
Schedule of Events 
 
 
Baseline - Visit 1a 
Day 14 (+/- 1) - Visit 2 
Day 28 (+/- 2) - Visit 3 
Screening (I/E) 
X 
 
 
Informed consent 
X 
 
 
Medical History 
X 
 
 
Medication History 
X 
 
 
Concomitant Medications 
X 
X 
X 
Physical Exam  
X 
X 
X 
Vitals, including Height and Weight  
X 
X 
X 
12-lead ECG 
X 
X 
X 
Zio® XT patch HR monitoring 
X 
X 
 
Echocardiogram  
Xb 
 
 
Biomarker Assessment  
(NT-proBNP and hs-cTnT) 
X 
 
X 
Urine Pregnancy Test 
X 
 
 
Randomization 
X 
 
 
IP Dispensation 
X 
 
 
IP Titration (if needed) 
 
X 
 
IP Accountability 
 
X 
X 
Beta Blocker uptitration (if needed) 
 
X 
 
Assessment of AEs 
X 
X 
X 
aBaseline procedures will be done at discharge from the hospital or observation unit. 
bAssessment done at index visit or within 12 months of index visit. 


    
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9.0 
IP Dosage and Titration 
 
At Randomization the initial Ivabradine dose will be 5 mg BID. If at any time during the study the 
patient’s HR <50 AND suggestive symptoms such as lightheadedness or hypotension are present: 
Discontinue study drug immediately. 
 
At Day 14 (+/-1) follow up, medication adjustments will be made based on the following criteria: 
1) If patient has signs or symptoms of continued volume overload diuretic dose will be doubled 
for 3 days and vasodilators (ACEi/ARB/H+N) reassessed for potential increase, and BB 
continued at current dose. Regarding IP: 
a. If HR <50 bpm decrease study dose by 2.5 mg BID. 
b. If HR between 50-60 AND possible signs/symptoms of bradycardia (i.e. light 
headedness or hypotension), decrease study dose by 2.5 mg BID.  
c. Otherwise (i.e. neither above criteria present) no adjustment to study drug. 
2) If patient appears stable and euvolemic: 
a. If HR >60 bpm and patient on target BB dose (i.e. total daily of 50mg carvedilol OR 
200mg metoprolol succinate OR 10mg Bisoprolol): Increase study drug dose by 2.5 
mg BID, to the maximum dose of 7.5 mg BID. 
b. If HR >60 bpm and patient receiving less than target BB dose: Double BB daily dose. 
c. If HR 50-60 bpm: Maintain study drug dose at 5 mg BID (and no BB change). 
d. If HR <50 bpm: Decrease study drug by half (2.5 mg BID). If IP is at the lowest dose 
i.e. 2.5mg BID, it will be stopped. 
 
At Day 28 (+/-2) follow up, IP will be permanently stopped and no unblinding will occur unless for safety 
reasons. Other medications dose adjustments (if needed) will be made according to standard of care 
practice (GDMT).   
 
10.0 
Beta Blockers Dosage and Titration 
 
Subjects will be assessed for BB therapy uptitration at Day 14 (+/-1) follow up. 
 
11.0 
Adverse Events or Unanticipated Problems involving Risk to Participants 
 
All incidence of AE, AE leading to withdrawal of IP, and SAE will be reported to the IRB per institutional 
policies and procedures. IP will be stopped in treatment emergent clinically relevant events such as 
hypotension, significant dizziness, loss of consciousness, atrial fibrillation, 3rd degree AV block, and QTc 
prolongation. If IP is stopped, no re-challenging will be done. In case of any events between the 
scheduled study visits, subjects will be instructed to call the 24/7 phone number of the study team, and 
if clinically relevant, subjects will be asked to come in to follow up clinic for an unscheduled visit. 
 
 


    
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11.1 
Unblinding Procedure 
 
In the case of an emergent medical event, where the unblinding of a subject is deemed medically 
necessary by the study PIs, the unblinded study personnel will consult the randomization key to unblind 
study treatment. Once a subject has been unblinded, the date, time and reason(s) for un-blinding will be 
recorded in the source documents and eCRF. 
 
11.2 
MedWatch Reporting 
 
If in the study PIs assessment, an unexpected SAE is related to subject’s participation in the study, the 
event will be reported to MedWatch. 
 
11.3 
Data Safety and Monitoring Board 
 
A safety analysis and review by an independent 3-member data safety and monitoring board (DSMB) 
will be done halfway through recruitment (after 66 subjects have been enrolled). Based on the 
outcomes of the review, the DSMB may propose amendments to the study protocol. The study PIs will 
review these proposals prior to amending the protocol and submitting to the IRB. 
 
12.0 
Biomarker Assessments 
 
Once patients have been enrolled they will have their blood drawn using proper phlebotomy 
procedures. Standard gold top serum vacutainer and green top Lithium Heparin gel vacutainer, 
approximately 10mL (about 2 tsp) of blood, will be drawn at baseline as well as at the day 28 (+/- 2) (visit 
3) follow-up. Plasma vacutainers will be placed in the refrigerator (2°-8°C) while serum sample is 
coagulating for 30-60 minutes. Immediately after the serum sample has coagulated for at least 30 
minutes the vacutainers will be centrifuged in a swing bucket horizontal centrifuge for 10 minutes at 
1100 to 1300 g. Samples will be qualitatively assessed for hemolysis after centrifugation. These 
characteristics will be recorded in the source documents. Plasma and serum will be aliquoted using 
transfer micro pipettes into as many 0.5 mL aliquots possible; aseptic techniques will be utilized 
throughout processing. These aliquoted samples will be frozen in a -80°C freezer onsite within three 
hours of blood draw. Samples will be batch shipped on dry ice in thermally-insulated containers to the 
University of Maryland. Good Laboratory Practices and national regulations regarding biohazardous 
materials will be followed. NT-proBNP and hs-TnT levels will be quantified.  
 
13.0 
Statistical Analysis 
 
The primary outcome (change in heart rate i.e. the value at Day 28 (+/-2) - the value at baseline) will be 
analyzed as two sample t-test.  Secondary outcomes that are continuous variables will be analyzed as 
two sample t-test. The safety endpoint of unplanned visits will be compared as the number of 
unplanned medical visits over the study period tested using Poisson regression.  
 
 
 


    
                                                                                                                              Protocol v7.0, 23-JUL-2018 
 
 
 
 
 
Page 10 of 11 
14.0 
Sample Size And Power 
 
Based on the SHIFT1 study, the mean heart rate reduction with IVA is 8 bpm with a standard deviation of 
13 bpm. A sample size of 57 in each group will have 90% power to detect a difference in means of 8.0 
assuming that the common standard deviation is 13.0 using a two group t-test with a 0.05 two-sided 
significance level. To account for a projected dropout rate of 15%,  66 subjects will be enrolled in each 
group (132 total for the study over a 2-year period). Furthermore, we expect that our centers will recruit 
a cohort that is 75% self-identified African Americans. This number (n=99) will provide 80% power to 
detect the same effect size when analyzed in African Americans only.  
 
For the safety endpoint (unplanned presentation for medical care), assuming an event rate of 25% at 1 
month (estimated based on local hospital readmission rates), our sample size will provide 80% power to 
detect a doubling of the relative risk. If the Control group event rate is higher there will be greater 
power; for example, with an event rate of 35% we would have 98% power for risk ratio of 2.0 and 83% 
power for risk ratio of 1.75.  
 
15.0 
Institutional Review Board 
 
The conduct of this study will conform to the International Conference on Harmonization Good Clinical 
Practice (ICH-GCP) guidelines and applicable regulations. A copy of the protocol (including protocol 
amendments), and all versions of informed consent forms will be sent to IRB for approval of both of the 
participating centers prior to implementation of the study. The investigator will also obtain IRB approval 
of the annual continuing review throughout the duration of the study and will notify the IRB of 
deviations from the protocol. 
 
16.0 
Informed Consent Process 
 
All participants or their family members will be given detailed oral and written information about the 
study. Consent forms describing in detail the study procedures and risks will be given to each participant 
or their family members and written documentation of informed consent is required prior to 
enrollment. Participants or their family members must sign an informed consent document that has 
been approved by the IRB. The informed consent form will be signed and dated by the participant, and 
the person who conducted the informed consent discussion. The original signed informed consent form 
will be retained in the participant’s study file and a copy will be provided to the participant. Participants 
may withdraw consent at any time during the course of the study. Deciding to not be part of the study 
will not change the patient’s regular medical care in any way.   
 
17.0 
Participant Confidentiality 
 
All subject related information including Case Report Forms, and biological specimens will be kept 
strictly confidential. All records will be kept in a secure, locked location and only research staff will have 
access to the records. Subjects will be identified only by means of a coded number specific to each 


    
                                                                                                                              Protocol v7.0, 23-JUL-2018 
 
 
 
 
 
Page 11 of 11 
subject. All computerized databases will identify subjects by numeric codes only, and will be password 
protected. 
 
18.0 
Data Management and Source Documentation 
 
Research staff will collect data on study specific case report forms (CRFs). Source documentation will 
support the data collected on the CRFs. Source documents include all recordings of observations or 
notations of clinical activities and all reports in the EMR. All de-identified data will be entered in the 
password-protected, HIPAA compliant, REDCap database (Research Electronic Data Capture 
http://project-redcap.org/).  
 
19.0 
References 
 
1. Böhm M, Robertson M, Borer J, et al. Effect of Visit-to-Visit Variation of Heart Rate and Systolic 
Blood Pressure on Outcomes in Chronic Systolic Heart Failure: Results from the Systolic Heart 
Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) Trial. Journal of the American 
Heart Association: Cardiovascular and Cerebrovascular Disease. 2016;5(2): e002160. 
doi:10.1161/JAHA.115.002160. 
2. Gattis W, O'Connor C, Gallup D, et al. Predischarge initiation of carvedilol in patients hospitalized 
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