Clinical trial NCT03137537
Conditions: Lymphoma Autonomic Imbalance Cancer Survivorship
Keywords: Lymphoma Abnormal resting heart rate Autonomic imbalance Cancer survivorship
Sponsor: Dana-Farber Cancer Institute
Start date: 2018-02-27; Completion date: 2020-11-18
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will explore whether ivabradine lowers heart rate, and thus improves exercise capacity, in survivors of lymphoma who have an elevated resting heart rate as a side effect of prior radiation treatment.

The drugs involved in this study are:

* Ivabradine
* Placebo

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

This research study is a Pilot Study, which is the first time investigators are examining this study intervention for this particular problem.

In this research study, the investigators are studying a drug called ivabradine. The investigators are exploring whether ivabradine can be used to reduce heart rate, increase exercise duration, and improve quality of life in survivors of lymphoma who received radiation to their chest as a part of their cancer treatment.

The U.S. Food and Drug Administration (FDA) has not approved ivabradine for this specific disease, but it has approved the drug as an oral medication to lower heart rate in heart failure patients.

Survivors of lymphoma who were treated with neck and/or chest radiation can have an elevated resting heart rate and an abnormal rate of decline in their heart rate after exercise, also known as cardiac autonomic dysfunction. These abnormalities can limit exercise duration and worsen quality of life in some radiation treated survivors of lymphoma

Arms: arm 1: * Ivabradine will be administered for a total of 6 weeks
* Ivabradine is taken orally twice daily
* Dosage will be adjusted according to physician determination arm 2: * Placebo will be administered for a total of 6 weeks
* Placebo is taken orally twice daily
* Dosage will be adjusted according to physician determination
Interventions: intervention 1: Ivabradine intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: lower heart rate in heart failure patients. intervention 2: Procedure prescribed to compare the active effect of a medicine.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 
 
 
DF/HCC Protocol #: 17-022 
 
TITLE:  Ivabradine in the management of cardiac autonomic dysfunction associated 
with thoracic radiation therapy.  
 
Coordinating Center: 
 
 
Brigham and Women’s Hospital 
*Principal Investigator (PI): 
Anju Nohria, MD 
 
Brigham and Women’s Hospital/DFCI 
 
75 Francis Street, Boston, MA 02115 
 
Telephone: (617) 525-7052 
 
Fax: (617) 264-5265 
 
E-mail address: anohria@partners.org 
 
Other Investigators: 
John Groarke, MD 
 
Brigham and Women’s Hospital/DFCI 
 
75 Francis Street, Boston, MA 02115 
 
Telephone: (617) 732-6632  
 
Fax: (617) 264-5265 
 
E-mail address: jgroarke@partners.org 
 
 
Ming Hui Chen, MD 
 
Boston Children’s Hospital 
 
300 Longwood Avenue, Boston, MA 02115 
 
Telephone: (617) 355-8366 
 
Fax: (617) 739-6282 
 
E-mail address: minghui.chen@cardio.chboston.org 
 
 
Peter Novak, MD 
 
Brigham and Women’s/Faulkner Hospital 
 
1153 Centre Street, Boston, MA, 02130 
 
Telephone: (617) 983-7580 
 
Fax: (781) 624-4165 
 
E-mail address: pnovak2@partners.org 
 
 
Tomas Neilan, MD 
 
Massachusetts General Hospital 
 
55 Fruit Street, Boston, MA, 02114 
 
Telephone: (617) 724-5351 
 
E-mail address: tneilan@mgh.harvard.edu  
 
 
  
  
 
 
 
 


NCI Protocol #: 
DF/HCC Protocol #: 17-022 
Protocol Version Date: 12/16/16 
 
2 
Other Agent(s):  Ivabradine, Amgen 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
Protocol Type / Version # / Version Date: 
Original/Version #1/December 16, 2016 


NCI Protocol #: 
DF/HCC Protocol #: 17-022 
Protocol Version Date: 12/16/16 
 
3 
 
SCHEMA 
 
 
 
 
 
Stratification
Beta-blocking agents
Randomization
Placebo
Ivabradine
Sophisticated 
autonomic testing
No autonomic testing
Placebo
Ivabradine
No beta-blocking agents
Screening Visit
Baseline Visit
•Obtain Informed Consent
•Review inclusion and exclusion criteria (perform EKG to assess eligibility)
•History and physical exam
•EKG, SF-36, cardiac autonomic test*, symptom limited exercise treadmill test , 24 
hour ambulatory holter monitoring
Randomization
Placebo
Ivabradine
Sophisticated 
autonomic testing
No autonomic testing
Placebo
Ivabradine
 
 
 
 
 
 
*Cardiac autonomic testing will be carried out in the 30 patients who are randomized to 
receive this component of the protocol.  
 
 
 
 
 
 
 
 
 
 
 
2 weeks 
 
6 weeks 
• 
Clinical safety review and EKG 
• 
Dose titration 
• 
History and physical exam 
• 
EKG, SF-36, sophisticated autonomic testing, symptom 
limited exercise treadmill test, 24 hour ambulatory 
holter monitor 
• 
Discontinue study drug 


NCI Protocol #: 
DF/HCC Protocol #: 17-022 
Protocol Version Date: 12/16/16 
 
4 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
 Study Design ...........................................................................................................7 
1.2 
Primary Objectives...................................................................................................7 
1.3 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease(s).......................................................................................................7 
2.2 
IND Agent(s): N/A ..................................................................................................8 
2.3 
Other Agents ............................................................................................................8 
2.4 
Rationale ..................................................................................................................9 
2.5 
Correlative Studies Background: N/A .....................................................................9 
3. 
PARTICIPANT SELECTION ...........................................................................................10 
3.1 
Eligibility Criteria ..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
REGISTRATION PROCEDURES ...................................................................................11 
4.1 
General Guidelines for DF/HCC Institutions ........................................................12 
4.2 
Registration Process for DF/HCC Institutions .......................................................12 
4.3 
General Guidelines for Other Investigative Sites: N/A .........................................12 
4.4 
Registration Process for Other Investigative Sites: N/A........................................12 
5. 
TREATMENT PLAN ........................................................................................................12 
5.1 
Treatment Regimen ................................................................................................12 
5.2 
Pre-Treatment Criteria ...........................................................................................13 
5.3 
Agent Administration.............................................................................................14 
5.4 
For Phase 1 Protocols Only: Definition of Dose-Limiting Toxicity (DLT): 
N/A .........................................................................................................................18 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................18 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................18 
5.7 
Duration of Follow Up ...........................................................................................19 
5.8 
Criteria for Taking a Participant Off Study ...........................................................19 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................19 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................20 
7.1 
For CTEP protocols only: Comprehensive Adverse Events and Potential 
Risks List(s) (CAEPRs): N/A ................................................................................20 
7.2 
For CTEP protocols only: Adverse Event Characteristics: N/A ............................20 
7.3 
For CTEP protocols only: Expedited Adverse Event Reporting: N/A ..................20 


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Protocol Version Date: 12/16/16 
 
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7.4 
For CTEP protocols only: Routine Adverse Event Reporting: N/A ......................20 
7.5 
For CTEP protocols only: Secondary Malignancy: N/A .......................................20 
7.6 
For CTEP protocols only: Second Malignancy: N/A ............................................20 
7.7 
Expected Toxicities ................................................................................................20 
7.8 
Adverse Event Characteristics ...............................................................................21 
7.9 
Expedited Adverse Event Reporting ......................................................................22 
7.10 
Expedited Reporting to the Food and Drug Administration (FDA): N/A .............22 
7.11 
Expedited Reporting to the NIH Office of Biotechnology Activities 
(OBA): N/A ...........................................................................................................22 
7.12 
Expedited Reporting to the Institutional Biosafety Committee (IBC): N/A..........22 
7.13 
Expedited Reporting to Hospital Risk Management .............................................22 
7.14 
Routine Adverse Event Reporting .........................................................................22 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................22 
8.1 
Ivabradine ..............................................................................................................23 
8.2 
IND Agent #2: N/A ................................................................................................25 
8.3 
Other Agent #1: N/A ..............................................................................................26 
8.4 
Other Agent #2: N/A ..............................................................................................26 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................26 
9.1 
Biomarker Studies: N/A .........................................................................................26 
9.2 
For IDE Protocols Only: Investigational Device Information: N/A ......................26 
9.3 
Laboratory Correlative Studies: N/A .....................................................................26 
9.4 
Other Agent #2: N/A ..............................................................................................26 
10. 
STUDY CALENDAR .......................................................................................................26 
11. 
MEASUREMENT OF EFFECT........................................................................................28 
11.1 
Antitumor Effect- Solid Tumors: N/A ...................................................................28 
11.2 
Antitumor Effect- Hematologic Tumors: N/A .......................................................28 
11.3 
Other Response Parameters ...................................................................................28 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................28 
12.1 
Data Reporting .......................................................................................................28 
12.2 
Data Safety Monitoring..........................................................................................29 
12.3 
Multicenter Guidelines: N/A..................................................................................29 
12.4 
Collaborative Agreements Language: N/A ............................................................29 
13. 
STATISTICAL CONSIDERATIONS...............................................................................29 
13.1 
Study Design/Endpoints.........................................................................................30 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................31 
13.3 
Stratification Factors ..............................................................................................32 
13.4 
Interim Monitoring Plan ........................................................................................32 
13.5 
Analysis of Primary Endpoint ................................................................................32 
13.6 
Analysis of Secondary Endpoints ..........................................................................33 
13.7 
Reporting and Exclusions ......................................................................................34 


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14. 
PUBLICATION PLAN .....................................................................................................34 
REFERENCES ..............................................................................................................................35 
APPENDIX A 
Birth Control Measures ..................................................................37 
APPENDIX B 
Drug Diary .....................................................................................38 
APPENDIX C 
Information On Possible Drug Interactions ...................................43 
 


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1. OBJECTIVES 
To evaluate whether ivabradine lowers resting heart rate and improves exercise duration in 
survivors of lymphoma with mediastinal involvement (including both Non-Hodgkin’s 
Lymphoma and Hodgkin’s Lymphoma) with evidence of radiation-induced autonomic 
dysfunction, manifested as a resting heart rate ≥ 80 bpm.   
 
1.1 
 
Study Design 
This is a single center Phase II/pilot study to evaluate the safety and efficacy of ivabradine in 
survivors of lymphoma with mediastinal involvement (including both Non-Hodgkin’s 
Lymphoma and Hodgkin’s Lymphoma) with post-radiation cardiac autonomic dysfunction, 
manifested as a resting heart rate ≥ 80 bpm. This study is a randomized, double-blind, placebo-
controlled, parallel design trial.   
 
1.2 
Primary Objectives 
To evaluate whether ivabradine reduces resting heart rate compared to placebo in survivors of 
lymphoma with mediastinal involvement (including both Non-Hodgkin’s Lymphoma and 
Hodgkin’s Lymphoma) who were treated with mediastinal/mantle radiation and have a resting 
heart rate ≥ 80 bpm.  
 
1.3 
Secondary Objectives 
To evaluate whether ivabradine improves exercise duration compared to placebo in survivors of 
lymphoma with mediastinal involvement (including both Non-Hodgkin’s Lymphoma and 
Hodgkin’s Lymphoma) who were treated with mediastinal/mantle radiation and have a resting 
heart rate ≥ 80 bpm.  
 
1.4  
Exploratory Objectives 
(i) To evaluate whether ivabradine improves additional markers of cardiac sympatho-vagal 
balance compared to placebo in survivors of lymphoma with mediastinal involvement 
(including both Non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma) who were 
treated with mediastinal/mantle radiation and have a resting heart rate ≥ 80 bpm. 
(ii)  To evaluate whether ivabradine improves health related quality of life compared to 
placebo in survivors of lymphoma with mediastinal involvement (including both 
Non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma) who were treated with 
mediastinal/mantle radiation and have a resting heart rate ≥ 80 bpm. 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
Thoracic radiation therapy (RT) is associated with an increased risk of cardiovascular morbidity 
and mortality.1, 2 In particular significant delayed cardiotoxicity has been observed among long-
term survivors of Hodgkin lymphoma (HL) treated with mantle/mediastinal radiation.3, 4 These 
patients also frequently report exercise intolerance. Elevated resting heart rate and abnormal 
heart rate recovery following exercise are established markers of cardiac autonomic dysfunction5 
and are strongly associated with cardiovascular morbidity and mortality in the general population 


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6-11 as well as in survivors of Hodgkin lymphoma treated with mediastinal RT.12 
 
Heart rate and rhythm are largely regulated by the autonomic nervous system.  Parasympathetic 
influence is mediated via acetylcholine release by the vagus nerve and sympathetic influences 
are mediated via the secretion of epinephrine and norepinephrine.  Acetylcholine reduces heart 
rate by increasing the potassium conductance of pacemaker cells in the sino-atrial node13 and 
inhibiting the hyperpolarization activated If channel to delay slow diastolic depolarization.14 
Conversely, sympathetic activation increases intracellular calcium15 and activates the If channel16 
to accelerate slow diastolic depolarization and increase heart rate.  We have previously shown 
that thoracic RT is associated with autonomic dysfunction, as measured by elevated resting heart 
rate and abnormal heart rate recovery.12 Furthermore, we were the first to report that these 
abnormalities are associated with impaired exercise tolerance among 263 Hodgkin lymphoma 
survivors treated with RT. Exercise duration was significantly reduced among RT patients with 
an elevated resting heart rate (9.2±2.9 versus 10.7±3.1 minutes, p<0.0001) and those with 
abnormal heart rate recovery (8.3±3.1 versus 10.6±2.9 minutes, p<0.0001).12 We hypothesize 
that this is related to depressed parasympathetic stimulation secondary to RT-induced injury to 
the vagus nerve.  
 
RT may also affect cardiovascular sympathetic function in Hodgkin lymphoma survivors.  We 
have previously shown that thoracic RT is associated with a blunted systolic blood pressure (BP) 
response to exercise (OR 1.88, 95% CI 1.25-2.81). 12  In unpublished data, we compared supine 
and standing systolic BPs of 200 RT patients and 517 age, sex and cardiovascular risk-score 
matched control patients. The mean ± SD postural decrease in SBP was significantly greater in 
the RT cohort compared to controls: -4.7 ± 9.9 versus -2.7 ± 10.8 mmHg, p= 0.02. The 
prevalence of orthostatic hypotension (defined as a postural decrease in SBP of ≥ 20 mmHg or a 
postural decrease in DBP of ≥ 10 mmHg) was 7.5% in the RT cohort.  Such BP abnormalities 
predispose to intolerance of traditional atrioventricular node blocking drugs such as beta-
blockers or calcium channel blockers that might be considered for this patient cohort with 
elevated resting heart rates who describe exercise intolerance. 
 
2.2 
IND Agent(s): N/A 
The FDA has deemed this study exempt from an IND (see attached FDA correspondence).  
 
2.3 
Other Agents 
Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces 
the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If 
current, resulting in heart rate reduction with no effect on ventricular repolarization and 
myocardial contractility. Ivabradine causes a dose-dependent reduction in heart rate. The size of 
the effect is dependent on the baseline heart rate (i.e., greater reduction occurs in subjects with 
higher baseline heart rate). At recommended doses (2.5-7.5 mg twice daily), HR reduction is 
approximately 10 bpm at rest and during exercise. Analysis of HR reduction vs. dose indicates a 
plateau effect at doses > 20 mg twice daily. Ivabradine increases the uncorrected QT interval 
with HR slowing but does not cause rate-corrected prolongation of QT. 
 
Following oral administration, peak levels of ivabradine are reached in approximately 1 hour 
under fasting conditions.  The oral bioavailability is about 40% due to first pass metabolism in 


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9 
the gut and liver.  Food delays absorption by 1 hour and increases plasma exposure by 20-40%.  
Therefore, it is recommended that ivabradine be taken with food.  It is about 70% plasma-protein 
bound with a volume of distribution of approximately 100 L at steady state.   
 
Ivabradine is metabolized by the liver and intestines via CYP3A4 mediated oxidation.  The 
major metabolite is the N-desmethylated derivative (S 18982), which is equipotent to ivabradine 
and circulates at concentrations approximately 40% that of ivabradine. The N-desmethylated 
derivative is also metabolized by CYP3A4. Ivabradine plasma levels decline with a distribution 
half-life of 2 hours and an effective half-life of approximately 6 hours. The total clearance of 
ivabradine is 24 L/h, and renal clearance is approximately 4.2 L/h, with ~ 4% of an oral dose 
excreted unchanged in urine. The excretion of metabolites occurs to a similar extent via feces  
and urine. No adjustment in dose is required for hepatic or renal dysfunction.  Due to the fact that 
it is metabolized by CYP3A4, concomitant administration of others drugs that are metabolized 
by CYP3A4, such as ketoconazole, diltiazem, verapamil, grapefruit juice and St. John’s wart is 
not recommended.  
 
Ivabradine is well tolerated with a similar incidence of adverse effects when compared to 
placebo in a large (n=6,505) clinical trial involving patients with chronic systolic heart failure 
(SHIFT: Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial).17 It is approved 
by the FDA to decrease heart failure related deaths and hospitalizations in patients with systolic 
heart failure (LVEF ≤ 35%) who have a resting HR ≥ 70 beats per minute despite maximal 
tolerated doses of beta-blockers. We wish to investigate whether ivabradine can achieve HR 
reduction in patients with a resting heart rate ≥ 80 bpm as a consequence of thoracic RT 
irrespective of baseline LVEF, and if so whether observed reductions in HR translate into 
improvements in exercise capacity. In addition, we wish to investigate whether ivabradine 
improves cardiac sympatho-vagal balance and patient-reported quality of life in this cohort. To 
date, this will be the first randomized trial of any therapeutic agent in the management of these 
patients.  We will use a dose scheme similar to that used in the SHIFT trial.17 
 
Matching placebo tablets will be manufactured and supplied by the Investigational Drug 
Pharmacy at Brigham and Women’s Hospital. 
 
2.4 
Rationale 
Survivors of mediastinal RT have increased cardiovascular morbidity and mortality.  We have 
previously shown that thoracic RT is associated with cardiac autonomic dysfunction, as 
manifested by elevated resting HR and abnormal HRR after exercise.12 Furthermore, we were the 
first to report that these abnormalities are associated with impaired exercise tolerance and 
increased mortality (for HRR only) among 263 HL survivors treated with RT.12  Furthermore, 
HL survivors treated with RT had a blunted BP response to exercise.12  Ivabradine is a drug that 
lowers HR without significantly impacting BP.  We hypothesize that ivabradine will lower HR in 
HL survivors treated with RT.  We further hypothesize that this reduction in HR will lead to 
increased exercise capacity, improved sympatho-vagal balance, and improved health related 
quality of life in these patients.   
 
2.5 
Correlative Studies Background: N/A 
 


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3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Survivors of mediastinal lymphoma (either Non-Hodgkin’s Lymphoma or Hodgkin’s 
Lymphoma) with no active malignancy 
 
3.1.2 Prior mediastinal or mantle radiation ≥ 5 years prior to enrollment in the study 
 
3.1.3 Age 18-80 years. Patients < 18 years will be excluded since ivabradine has not previously 
been studied in children.  Patients > 80 years will be excluded since patients have to be 
able to perform a treadmill exercise stress test as part of this study. 
 
3.1.4  ECOG performance status: N/A 
 
3.1.5 Life expectancy: N/A 
 
3.1.6 Participants must have normal organ function as defined below: 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
 
 
 
 
 
 
 
 
 
 
-     creatinine clearance ≥ 15 mL/min/1.73 m2 for participants with creatinine levels 
above institutional normal. 
 
3.1.7 Normal sinus rhythm with resting heart rate ≥ 80 bpm on screening EKG 
 
3.1.8 Based on findings in animals, ivabradine may cause fetal harm when administered to a 
pregnant woman.  For this reason, women of child-bearing potential must agree to use 
highly effective contraception (as described in Appendix A) prior to study entry and for 
at least 2 weeks after the last dose of ivabradine.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.   
 
3.1.9 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants who are receiving any other investigational agents. 
 
3.2.2 History of allergic reaction to ivabradine. Ivabradine is the first selective If channel sinus 
node inhibitor and therefore there are no other available drugs in this class.  
 


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3.2.3 Participants receiving any medications or substances that are inhibitors or inducers of 
cytochrome P450 3A4 are ineligible.  Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.   
 
3.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, acute coronary syndrome, symptomatic known 
coronary artery disease, severe valvular heart disease, active malignancy, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
3.2.5 Pregnant women are excluded from this study because ivabradine is an agent with the 
potential for teratogenic effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with ivabradine, 
breastfeeding should be discontinued if the mother is treated with ivabradine.   
 
3.2.6 HIV-positive participants on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with ivabradine.  
 
3.2.7 Patients with systolic blood pressure < 90 mm Hg. 
 
3.2.8 Patients with sick-sinus syndrome, sino-atrial block, third degree heart block, atrial 
fibrillation, and those with permanent pacemakers.   
 
3.2.9 Patients with other established indications for ivabradine: stable, symptomatic chronic 
HF with a left ventricular ejection fraction ≤ 35% and in sinus rhythm with a resting HR 
≥ 70 bpm, who are taking maximally tolerated doses of beta-blockers or have 
contraindications to beta-blocker use. 
 
3.2.10 Patients with severe hepatic dysfunction (Child Pugh Class C) 
 
3.2.11 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosureas or mitomycin C) prior to entering the study or those who have not recovered from 
adverse events due to agents administered more than 4 weeks earlier will be excluded.  
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
 


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4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
 
Following randomization by ODQ to ivabradine or placebo, ODQ will send subject registration 
information to the unblinded investigational pharmacy staff at bwhrxids@partners.org. 
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites: N/A 
 
4.4 
Registration Process for Other Investigative Sites: N/A 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
A total of 60 eligible patients will be randomized to ivabradine or placebo.  Ivabradine or 
placebo will be administered for a total of 6 weeks. Treatment will be administered on an 
outpatient basis. On assessment days, no dose holds will occur. Reported adverse events and 
potential risks are described in Section 7.   
 
Ivabradine will be started at a dose of 5 mg p.o. twice daily with meals.  The patient will then be 
assessed after 2 weeks and the dose will be adjusted as shown in the Table below: 
 
Heart Rate 
Dose Adjustment 
> 60 bpm 
Increase dose to 7.5 mg p.o. twice daily 
50-60 bpm 
Maintain dose at 5 mg p.o. twice daily 
< 50 bpm or signs and symptoms of bradycardia Decrease dose to 2.5 mg p.o. twice daily  
 
If the patient continues to have symptomatic bradycardia or HR < 50 on 2.5 mg twice daily, 
ivabradine will be discontinued.   


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If symptomatic bradycardia occurs on ivabradine 7.5 mg or 5 mg twice a day at any point in the 
study, without objective hemodynamic compromise (SBP > 80 mm Hg), the medication can be 
resumed at a lower dose (2.5 mg reduction) after a 24 hour drug-free interval (i.e. 1 missed 
dose).  If symptomatic bradycardia persists despite dose reduction, then the study drug will be 
further reduced by 2.5 mg or discontinued as per the discretion of the investigator. A maximum 
of 2 dose reductions would be allowed for patients on 7.5 mg twice daily and 1 dose reduction 
for those on 5 mg twice daily. Patients requiring dose reduction will not have a subsequent dose 
escalation at any point during the study.  
 
Placebo will be used in a similar manner. Patients will be maintained on the best tolerated dose 
for a total of 4 weeks.  
 
Patients randomized to either ivabradine or placebo will be asked to maintain a drug diary as 
detailed in Appendix B to assess compliance. 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 Screening Visit: After written informed consent is obtained, we will: 
 
a) Obtain a detailed history and physical examination 
 
b) Obtain an EKG to make sure that patients meet eligibility criteria i.e. are in sinus rhythm, 
have a resting HR ≥ 80 bpm, and do not have evidence of high grade AV block.  
 
c) Review laboratory values obtained within the last 12 months for liver and renal function 
as described in the inclusion/exclusion criteria.  
 
5.2.2 Baseline Visit: In addition to a detailed history and physical examination, we will: 
 
a) Obtain an EKG to make sure that patients are in sinus rhythm, have a resting HR ≥ 80 
bpm, and do not have evidence of high grade AV block prior to study drug 
randomization. 
 
b) Obtain a urine pregnancy test to ensure that women of child-bearing age are not pregnant 
prior to study drug randomization.  
 
5.2.3 2 week visit:  In addition to a detailed history to review side effects from study drug 
treatment, we will: 
 
a) Obtain an EKG to assess heart rate to determine dose adjustment as stated in section 5.1.  
 
5.2.4    6 week visit: In addition to study procedures outlined below, we will: 
 
       a) Obtain a pregnancy test to ensure that women of child bearing age are not pregnant.  
 


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5.3 
Agent Administration 
 
Patients will take ivabradine or placebo for a total of 6 weeks. Ivabradine will be started at a dose 
of 5 mg p.o. twice daily with food. Ivabradine or placebo must not be crushed, chewed, or 
dissolved in water. The dose will be adjusted as per the Table in section 5.1 at the 2 week visit.  
Patients will continue the maximal tolerated dose for an additional 4 weeks. Placebo will be 
administered in a similar manner.  
 
Ivabradine is FDA approved to reduce heart failure hospitalizations in patients with systolic heart 
failure (left ventricular ejection fraction ≤ 35%) who have resting HR > 70 bpm, despite maximal 
tolerated doses of beta-blockers.  This study is evaluating ivabradine for a non-FDA approved 
indication and the drug titration protocol is per the Table in section 5.1.  
 
Ivabradine is metabolized by the liver and intestines via CYP3A4 mediated oxidation.  
Therefore, patients will be instructed to avoid other drugs metabolized by the CYP3A4 system 
and grapefruit, star fruit, and pomegranate, in any form, for the duration of the study.  
 
Patients will be asked to maintain a drug diary to assess compliance during the study.  Patients 
will be instructed to note a missed or vomited dose and take the next dose as scheduled.   
 
5.3.1 CTEP and/or CIP IND Agent(s), or other IND agent: N/A 
 
5.3.2 Other Agent(s): N/A 
 
5.3.3 Other Modality(ies) or Procedures 
 
All patients will have a standard 12 lead EKG performed at the screening, baseline, 2 week and 6 
week visits. 
 
All patients will undergo exercise treadmill testing at the baseline and 6 week visits.   
 
All patients will have a 24 hour ambulatory Holter monitor placed at the baseline and 6 week 
visits.  
 
All patients will complete the SF-36 quality of life questionnaire at the baseline and 6 week 
visits.  
 
Due to cost constraints, a subset of patients (n=30) will undergo further sophisticated autonomic 
function testing at the baseline and 6 week visits. Depending on scheduling limitations, they may 
have to return for a second day at each of these visits to complete the additional autonomic 
function tests.  
 
a) Exercise treadmill testing 
 
All exercise stress tests will be performed in the cardiovascular stress testing laboratory at 
Brigham and Women’s Hospital by trained exercise physiologists under the supervision of a staff 


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15 
cardiologist.  Patients will avoid consumption of all caffeine containing products for 24 hours 
prior to exercise treadmill testing.  All patients will undergo exercise treadmill testing using a 
symptom-limited Bruce protocol according to established guidelines.18 Exercise will be 
continued until one or more of the following endpoints: exhaustion, symptom limitation, ≥ 85% 
of age-predicted maximal HR, ≥ 10 mmHg drop in systolic blood pressure (SBP) from baseline, 
sustained ventricular tachycardia, ST-segment depression ≥ 3 mm measured 80 msec after the J 
junction, or ST-segment elevation of ≥ 1 mm. 
 
b) 24 Hour Ambulatory Holter Monitor 
 
All patients will have a 24 hour ambulatory Holter monitor placed at baseline prior to study drug 
initiation and at the 6 week time point, prior to study drug termination.  Holter monitors will be 
placed by the cardiology department at Brigham and Women’s Hospital. Patients will be asked 
to return the Holter monitor in person or via mail to Brigham and Women’s Hospital.  
 
c) SF-36 Quality of Life Questionnaire 
 
All patients will be asked to complete short form 36 (SF-36) quality of life healthcare 
questionnaires at the baseline and 6 week visits.  
 
d) Sophisticated autonomic function testing 
 
All of the additional autonomic function tests will be performed by Dr. Peter Novak in the 
autonomic function testing laboratory at Faulkner Hospital.  Cardiac autonomic function will be 
assessed using:  
 
1. Deep breathing: 
Deep breathing tests cardiac parasympathetic functions. All subjects will be asked to 
avoid smoking, intake of caffeinated beverages, and strenuous exercise for 12 hours prior 
to the test. Subjects will be asked to empty their bladder before the test to prevent 
sympathetic over-activity.  They will then be asked to lie quietly in a temperature-
controlled room for 20 minutes.  A baseline EKG recording will be obtained for one 
minute to ensure a stable resting heart rate. Subjects will then be asked to inhale and 
exhale slowly at a rate of 6 breaths/minute and a continuous EKG will be recorded during 
deep breathing.  Respiratory sinus arrhythmia (RSA) amplitude, defined as the difference 
in heart rate between end expiration and end inspiration, will be recorded for each 
respiratory cycle and the average RSA will be reported.19  
 
2. Valsalva manuever: 
Valsalva maneuver evaluates sympathetic adrenergic function using the blood pressure 
responses and parasympathetic function using the heart rate responses. The Valsalva 
maneuver consists of forced expiration against resistance with an expiratory pressure 
during strain of 40 mm Hg for 15 seconds. The maneuver will be performed in the supine 
position. Patients will be asked to breath into a 10 ml plastic syringe that is connected to a 


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Protocol Version Date: 12/16/16 
 
16 
pressure gauge. They will be asked to take a deep breath and blow into the syringe and 
keep the pressure at 40 mm Hg for 15 seconds.  Subjects will be asked to practice the 
maneuver to ensure that they can do it correctly prior to the actual measurements. Once 
they have mastered the manuever, they will be asked to rest for 3-5 minutes before 
repeating the maneuver.  Heart rate and blood pressure will be recorded non-invasively 
using the Finapres NOVA system (Finapres Medical Systems, Netherlands). The 
Valsalva ratio, defined as the maximum heart rate during the maneuver divided by the 
lowest heart rate obtained within 30 seconds of the peak heart rate, will be measured.19  
 
3. Tilt Testing: 
 
Tilt tests predominantly evaluate adrenergic function by applying orthostatic stress.  
Patients will be placed in the supine position and baseline heart rate and blood pressure 
will be acquired over 5-10 minutes.  The patient will then be tilted up to an angle of 70 
degrees over 5-10 seconds.  Patients will be closely observed for chest pain, shortness of 
breath, dizziness, lightheadedness or syncope.  If they have no adverse reaction, the heart 
rate and blood pressure will be assessed every minute for 10 minutes.  The patient will 
then be placed back in the supine position.  The increase in heart rate and drop in blood 
pressure in response to the tilt will be recorded.19 
 
4. Heart rate variability: 
Heart rate variability with low frequency and high frequency oscillations in RR intervals 
assesses the balance of sympathetic and parasympathetic influences in the heart.  
Measures of overall heart rate variability and spectral analysis of heart rate variability 
will be performed with a Matlab based computer system.20  
 
5. Sudomotor testing  
 
Electrochemical skin conductance (ESC) is a new noninvasive test for measurement of 
sudomotor functions.21 ESC correlates with loss of small fiber skin nerves, and it is useful 
for evaluation of small fiber neuropathy.  Measurements using ESC will be performed as 
described previously.22 
 
The RSA and Valsalva ratio will be compared to age and gender based normative values (Tables 
1 and 2). The cardiovagal composite autonomic severity score (CASS) will be calculated (Table 
3).  The adrenergic CASS will be calculated (Table 4).19 
 
Table 1:  Normal Values for Deep Breathing Test 
Age range (years) 
Minimum Normal RSA (beats/min) 
10-29 
≥ 14 
30-39 
≥ 12 
40-49 
≥ 10 
50-59 
≥ 9 
60-69 
≥ 7 


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17 
 
Table 2: Normal Values for Valsalva Ratio 
Age range (years) 
Minimum Normal Valsalva Ratio 
 
Women 
Men 
10-29 
1.46 
1.59 
30-39 
1.5 
1.52 
40-49 
1.51 
1.44 
50-59 
1.47 
1.36 
60-69 
1.39 
1.29 
 
Table 3: Calculation of Cardiovagal Score 
Result 
Degree of 
Abnormality 
Cardiovagal 
Score  
Definition 
Normal 
 
0 
 
Abnormal Mild 
1 
RSA or Valsalva ratio reduced but 
≥ 50% of minimal normal values 
 
Moderate 
2 
RSA or Valsalva ratio < 50% of 
minimal normal values 
 
Severe 
3 
Both RSA and Valsalva ratio < 
50% minimal normal values 
 
Table 4: Calculation of Adrenergic Score: 
Result 
Degree of 
Abnormality 
Adrenergic 
Score 
Definition 
Normal 
0 
 
 
Abnormal Mild 
1 
Valsalva maneuver: 
Early phase 2 drop in BP: 20-40 
mmHg OR 
Late phase 2 BP does not return to 
baseline OR 
Pulse pressure reduction ≤ 50% of 
baseline OR 
Systolic pressure recovery time 4-5 
seconds 
 
Moderate 
2 
Valsalva maneuver: 
Early phase 2 drop in BP: 20-40 
mmHg AND 
Absent late phase 2 OR 
Absent phase 4 OR 
Systolic pressure recovery time 6-9 
seconds 
 
Severe 
3 
Tilt: 
SBP reduction ≥ 30 mmHg; MAP 
reduction ≥ 20 mmHg OR 
Valsalva maneuver: 


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Early phase 2 drop in BP ≥ 40 
mmHg 
AND 
Absent phase 2 AND 
Absent phase 4 OR 
Absent phases 2 and 4 systolic 
pressure recovery time = 10 
seconds 
 
Severe 
4 
Tilt AND Valsalva maneuver 
responses in #3 
 
 
 
5.3.4 Investigational Imaging Agent Administration: N/A 
 
5.4 
For Phase 1 Protocols Only: Definition of Dose-Limiting Toxicity (DLT): N/A 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of ivabradine with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Overall PI should 
be alerted if the participant is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes.  Appendix C presents guidelines for identifying 
medications/substances that could potentially interact with the study agent(s). 
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Patients will receive ivabradine or placebo for a total of 6 weeks.  Treatment may continue for 6 
weeks or until one of the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or procedure/documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 


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19 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Anju Nohria, MD at 617-732-5700 beeper 30350.  
 
5.7 
Duration of Follow Up 
 
Participants will be followed till the end of the study protocol.  Participants removed from 
protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff.  
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
All patients will be started on ivabradine 5 mg po twice daily or placebo. Dose modifications 
will be made at the 2 week visit as indicated in the following table(s).  
 
Heart Rate 
Dose Adjustment 
> 60 bpm 
Increase dose to 7.5 mg p.o. twice daily 
50-60 bpm 
Maintain dose at 5 mg p.o. twice daily 
< 50 bpm or signs and symptoms of bradycardia Decrease dose to 2.5 mg p.o. twice daily  
 
If the patient continues to have symptomatic bradycardia or HR < 50 on 2.5 mg twice daily, 


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ivabradine will be discontinued.  Placebo will be used in a similar manner. Patients will be 
maintained on the best tolerated dose for a total of 4 weeks.  
 
If symptomatic bradycardia occurs on ivabradine 7.5 mg or 5 mg twice a day at any point in the 
study, without objective hemodynamic compromise (SBP > 80 mm Hg), the medication can be 
resumed at a lower dose (2.5 mg reduction) after a 24 hour drug-free interval (i.e. 1 missed 
dose).  If symptomatic bradycardia persists despite dose reduction, then the study drug will be 
further reduced by 2.5 mg or discontinued as per the discretion of the investigator. A maximum 
of 2 dose reductions would be allowed for patients on 7.5 mg twice daily and 1 dose reduction 
for those on 5 mg twice daily. Patients requiring dose reduction will not have a subsequent dose 
escalation at any point during the study.  
 
Any patients with symptoms of bradycardia after drug titration will be brought in for an 
additional clinical evaluation and EKG. 
 
Overdosage of ivabradine may lead to severe and prolonged bradycardia. In the event of 
bradycardia with poor hemodynamic tolerance, the drug should be withdrawn.  Supportive 
treatment, including intravenous fluids, atropine, intravenous beta-stimulating agents 
(isoproterenol) or temporary pacing may be considered.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
For CTEP protocols only: Comprehensive Adverse Events and Potential Risks 
List(s) (CAEPRs): N/A 
 
7.2 
For CTEP protocols only: Adverse Event Characteristics: N/A  
 
7.3 
For CTEP protocols only: Expedited Adverse Event Reporting: N/A 
 
7.4 
For CTEP protocols only: Routine Adverse Event Reporting: N/A 
 
7.5 
For CTEP protocols only: Secondary Malignancy: N/A 
 
7.6 
For CTEP protocols only: Second Malignancy: N/A 
 
7.7 
Expected Toxicities 
 
7.7.1 Adverse Events List(s) 
 
7.7.1.1 
Adverse Event List(s) for Ivabradine 
 


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21 
a) Fetal toxicity 
b) Atrial fibrillation 
c) Bradycardia 
d) Conduction disturbances including heart block and sinus arrest 
e) Ventricular arrhythmias including torsades de pointes, ventricular fibrillation, and 
ventricular tachycardia 
f) Hypotension 
g) Syncope 
h) Hypertension 
i) Phosphenes (luminous phenomenon) 
j) Angioedema 
k) Erythema 
l) Rash 
m) Pruritis 
n) Urticaria 
o) Vertigo 
p) Diplopia 
q) Visual distrubance 
 
7.7.1.2 
Adverse Event List(s) for Other Agent(s): N/A 
 
7.8 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 


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7.9 
 Expedited Adverse Event Reporting 
 
7.9.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  Serious criteria includes: death, 
hospitalization, event that results in disability, life-threatening event, congenital anomaly, 
or any event determined to be medically significant by the investigator.  
 
7.9.2 N/A 
 
7.9.3    DF/HCC Expedited Reporting Guidlines 
             
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for   
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
7.9.4 N/A 
 
7.10 
Expedited Reporting to the Food and Drug Administration (FDA): N/A 
 
7.11 
Expedited Reporting to the NIH Office of Biotechnology Activities (OBA): N/A 
 
7.12 
Expedited Reporting to the Institutional Biosafety Committee (IBC): N/A 
 
7.13 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.14 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
The Overall PI must report all pregnancies and pregnancies occurring in the partner of a patient 
participating in the study or potential infant exposure through lactation within 10 calendar days 
of PI’s awareness to Amgen. Amgen will contact the investigator/study site and request the site 
attempt to obtain authorization from the pregnant or breast feeding woman to provide Amgen 
with pertinent information regarding the pregnancy and birth outcome or health of the breastfed 
infant.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.7. 
 


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23 
8.1 
Ivabradine 
 
8.1.1 Description 
 
Ivabradine is a hyperpolarization-activated cyclic nucleotide gated channel blocker that 
reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively 
inhibiting the If current, resulting in heart rate reduction with no effect on ventricular 
repolarization and no effects on myocardial contractility.   
 
The chemical name for ivabradine is 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-
1,3,5-trien-7 yl)methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-
benzazepin-2-one, hydrochloride. The molecular formula is C27H36N2O5, HCl, and the 
molecular weight (free base + HCl) is 505.1 (468.6 + 36.5).  
 
Ivabradine is extensively metabolized in the liver and intestines by CYP3A4-mediated 
oxidation. The major metabolite is the N-desmethylated derivative (S 18982), which is 
equipotent to ivabradine and circulates at concentrations approximately 40% that of 
ivabradine. The N-desmethylated derivative is also metabolized by CYP3A4. Ivabradine 
plasma levels decline with a distribution half-life of 2 hours and an effective half-life of 
approximately 6 hours. The total clearance of ivabradine is 24 L/h, and renal clearance is 
approximately 4.2 L/h, with ~ 4% of an oral dose excreted unchanged in urine. The 
excretion of metabolites occurs to a similar extent via feces and urine.  
 
The effects of coadministered drugs (CYP3A4 inhibitors, substrates, inducers, and other 
concomitantly administered drugs) on the pharmacokinetics of Corlanor were studied in 
several single- and multiple dose studies. Pharmacokinetic measures indicating the 
magnitude of these interactions are presented in the Figure below: 
 


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24 
 
 
8.1.2 Form 
 
Ivabradine is manufactured by Amgen under the trade Corlanor.  It is supplied as: 
Corlanor 5 mg: salmon-colored, oval-shaped, film-coated tablet, scored on both edges, 
debossed with “5” on one face and bisected on the other face. The tablet is scored and can 
be divided into equal halves to provide a 2.5 mg dose.  
Corlanor 7.5 mg: salmon-colored, triangular-shaped, film-coated tablet debossed with 
“7.5” on one face and plain on the other face.  
 
8.1.3 Storage and Stability 
 
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).  
 
8.1.4 Compatibility 
N/A 
 
8.1.5 Handling 
 
There are no special considerations for the handling of ivabradine. 
 
8.1.6 Availability 
 
Ivabradine, which is commercially available, will be provided free of charge for this 


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Protocol Version Date: 12/16/16 
 
25 
study by Amgen.  The study drug will be sent by Amgen to the principal investigator, Dr. 
Anju Nohria, and will be stored and dispensed by the Investigational Pharmacy at 
Brigham and Women’s Hospital.  Matching placebo tablets will also be manufactured 
and stored by the Investigational Drug Pharmacy at Brigham and Women’s Hospital.   
 
8.1.7 Preparation 
 
After randomization, ivabradine or matching placebo tablets will be supplied by the 
Investigational Drug Pharmacy at Brigham and Women’s Hospital.  
 
Active medication will be blinded using over-encapsulation in an empty gelatin capsule 
by the Investigational Drug Pharmacy at Brigham and Women’s Hospital. The matching 
placebo will be a capsule filled with microcrystalline cellulose also prepared by the 
Investigational Drug Pharmacy at Brigham and Women’s Hospital.  
 
 Both the patient and investigators will remain blinded to study drug assignment 
throughout the duration of the study.   
 
8.1.8    Administration: 
 
Medication will be taken P.O. twice daily with food. Medication will be taken outpatient. 
Pills should be swallowed whole. 
 
8.1.9 Ordering 
 
Ivabradine will be provided by Amgen prior to study initation. Placebo will be 
manufactured by the Investigational Drug Pharmacy.  Both ivabradine and placebo will 
be stored and dispensed by the Investigational Drug Pharmacy at Brigham and Women’s 
Hospital.   
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
Unused and expired supplies of ivabradine will be returned to Amgen at the end of the 
study.  
 
8.2 
IND Agent #2: N/A 
 


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26 
8.3 
Other Agent #1: N/A 
 
8.4 
Other Agent #2: N/A 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies: N/A 
 
9.2 
For IDE Protocols Only: Investigational Device Information: N/A 
 
9.3 
Laboratory Correlative Studies: N/A 
 
9.4 
Other Agent #2: N/A 
 
10. STUDY CALENDAR 
 
Baseline evaluations/tests are to be conducted within 1 week prior to start of protocol therapy.  In 
the event that the participant’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of therapy. 
 
2 week study evaluations and drug up-titration should be administered within + 3 days of the 
protocol-specified date, unless otherwise noted. 
 
Week 6 study evaluations/tests should be conducted within ± 7 days of the protocol-specified 
date and should be completed prior to termination of study drug.  


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27 
 
 
 
Screening 
visit 
Baseline  
Week 2 
Week 6 
Agents: 
 
Ivabradine vs. 
placebo 
Ivabradine or 
placebo dose 
titration 
Study End 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
X 
X 
Physical exam 
 
X 
X 
X 
Concurrent Meds 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Height 
 
X 
 
X 
Weight 
 
X 
 
X 
Serum chemistrya 
X 
 
 
 
EKG (as indicated) 
X 
X 
X 
X 
B-HCG 
 
Xb 
 
Xb 
Exercise stress test 
 
X 
 
X 
24-hr ambulatory Holter 
monitor 
 
X 
 
X 
SF-36 QOL 
questionnaire 
 
X 
 
X 
Sophisticated autonomic 
function testingc 
 
X 
 
X 
Adverse event evaluation 
 
X--------------------------------------------------------------X 
a: Review of SGOT [AST], SGPT [ALT], creatinine obtained within the last 12 months. 
b: Urine pregnancy test (women of childbearing potential). 
c: For subset of patients randomized to receive autonomic function testing 
 
 
 


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28 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect- Solid Tumors: N/A 
 
11.2 
Antitumor Effect- Hematologic Tumors: N/A 
 
11.3 
Other Response Parameters 
 
Primary end point: 
1. Change in HR from baseline to 6 weeks with ivabradine vs. placebo.17 
 
Secondary end point: 
1. Change in exercise duration from baseline to 6 weeks with ivabradine vs. placebo.23  
 
Exploratory end points: 
1. Change in markers of additional cardiac autonomic function: respiratory sinus arrhythmia 
amplitude, Valsalva ratio, heart rate variability, cardiovagal CASS and adrenergic CASS 
from baseline to 6 weeks.19   
 
2. Change in patient reported quality of life (as assessed using then SF 36 questionnaire) 
from baseline to 6 weeks with ivabradine compared to placebo.24   
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality according to the schedule set by the DF/HCC 
SOPs. 
 
12.1.3 Confidentiality Protections 
 
Data will be obtained from a complete history, physical examination, symptom limited 
exercise stress test, 24 hour ambulatory Holter monitor, cardiac autonomic testing, and a 
self-reported health related quality of life questionnaire (SF-36) before and after the 6 


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29 
week treatment period. Data will also be collected from the 14-day safety visit.  The data 
will be shared with investigators/personnel involved in the study and will be retained for 
at least 5 years after completion of the study.  The data source files will be kept in a 
locked room in the cardiovascular offices at Brigham and Women's Hospital.  The data 
will be stored in a de-identified manner in an encrypted Partners computer. 
 
The identifiable information will not be reused or disclosed except as consistent with this 
protocol and signed HIPAA Authorization for Research.  
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
12.3 
Multicenter Guidelines: N/A 
 
12.4 
Collaborative Agreements Language: N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a randomized double-blind, placebo-controlled study evaluating the effect of ivabradine 
on resting heart rate and exercise capacity in survivors of lymphoma with mediastinal 
involvement who were treated with mediastinal/mantle RT.   
 
Survivors of mediastinal RT have increased cardiovascular morbidity and mortality.  We have 
previously shown that thoracic RT is associated with cardiac autonomic dysfunction, as 
measured by elevated resting HR and abnormal HRR after exercise.12 Furthermore, we were the 
first to report that these abnormalities are associated with impaired exercise tolerance and 
increased mortality (for HRR only) among 263 HL survivors treated with RT.12  Furthermore, 
HL survivors treated with RT had a blunted BP response to exercise.12  Ivabradine is a drug that 
lowers HR without significantly impacting BP.  We hypothesize that ivabradine will lower HR in 
HL survivors treated with RT.  We further hypothesize that this reduction in HR will lead to 
increased exercise capacity, improved sympatho-vagal balance, and improved health related 
quality of life in these patients.   
 
The study will enroll adult survivors of lymphoma with mediastinal involvement (including both 


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Protocol Version Date: 12/16/16 
 
30 
Non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma) who have been treated with 
mediastinal/mantle radiation at least 5 years prior to enrollment and have a resting heart rate ≥ 80 
bpm.  The detailed eligibility criteria are outlined in sections 3.1 and 3.2 above.    
 
13.1 
Study Design/Endpoints 
 
Primary End point: 
 
The primary objective of this study is to investigate whether ivabradine lowers resting HR, 
compared to placebo, in survivors of lymphoma with mediastinal involvement who were treated 
with mediastinal/mantle radiation and have a resting HR ≥ 80 bpm. 
 
Secondary End-point: 
 
The secondary objective of this study is to evaluate whether ivabradine improves exercise 
duration, compared to placebo, in survivors of lymphoma with mediastinal involvement who 
were treated with mediastinal/mantle radiation and have a resting HR ≥ 80 bpm. 
 
Exploratory End-points: 
 
1) To evaluate whether ivabradine improves additional markers of cardiac sympatho-vagal 
balance, compared to placebo, in survivors of lymphoma with mediastinal involvement 
who were treated with mediastinal/mantle radiation and have a resting HR ≥ 80 bpm. 
2) To evaluate whether ivabradine improves health related quality of life, compared to 
placebo, in survivors of lymphoma with mediastinal involvement who were treated with 
mediastinal/mantle radiation and have a resting HR ≥ 80 bpm. 
 
• The patients will be accrued on a continuous basis from the out-patient survivorship, cardio-
oncology, and radiation oncology clinics at DFCI, Massachusetts General Hospital, Brigham 
and Women’s Hospital, and Boston Children’s Hospital till target accrual is completed.  
Eligible patients from sites other than the Brigham will be referred to the Brigham for all 
study procedures. 
 
• There are no explicit early stopping rules for this study.  However, the data will be reviewed 
periodically by the DFCI DSMB and the study will be terminated if the DSMB deems it 
necessary to do so.  
 
• The target sample size for this study is 54 patients.  We plan to enroll a total of 60 patients to 
account for screen failure, resting HR < 80 at baseline visit, withdrawals, or loss to follow up.  
Based on our clinical volume, we plan to recruit 2-3 patients per month over a cumulative 
accrual period of 24-36 months.  Each patient will be followed for the 6 week duration of the 
study.  There is no long-term follow-up planned in this study.   
 
• We hypothesize that ivabradine will lower resting HR, compared to placebo, in survivors of 
lymphoma with mediastinal involvement who were treated with mediastinal/mantle radiation 


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31 
and have a resting HR ≥ 80 bpm. We further hypothesize that this reduction in HR will be 
associated with increased exercise duration in these patients.   
 
• In the Ivabradine and chronic outcomes in heart failure (SHIFT) trial, the net reduction in 
heart rate with ivabradine was 10.9 (95% CI 10.4-11.4) bpm, with a standard deviation of 
10.5 bpm. Thus, with a sample size of 27 patients in each group, we will have 95% power to 
detect this net reduction in heart rate assuming a probability of making a type I error of 
0.05.12 To allow for incomplete primary end point data due to withdrawals or loss to follow 
up, we will aim to recruit 30 patients in each group.  
 
• With a sample size of 27 subjects in each group, we will have 90% power to detect a 
clinically meaningful improvement of 34% in exercise duration on treadmill testing assuming 
a probability of making a type I error of 0.05, an improvement in the placebo group of 12%, 
and a standard deviation of 24%. 
 
• All patients will first be stratified into two groups according to pre-randomization treatment 
with beta-blocking agents. Patients within each beta-blocker group will then undergo four 
way randomization using permuted blocks, dividing the two strata into four groups each: 
ivabradine with sophisticated autonomic testing, placebo with sophisticated autonomic 
testing, ivabradine with no sophisticated autonomic testing, placebo with no sophisticated 
autonomic testing. These four groups will be created in a 1:1:1:1 ratio. Randomization will 
be performed by the ODQ at Dana Farber Cancer Institute.  
 
• If patients are randomized into the sophisticated autonomic testing group and are not able to 
complete sophisticated autonomic function testing for any reason, but are willing to continue 
taking the study medication (ivabradine or placebo), they will be encouraged to continue 
taking part in all other study protocols for the duration of the study: twice daily ivabradine or 
placebo, history and physical exam, EKG, SF-36 questionnaire, exercise treadmill test, and 
24 hour ambulatory holter monitoring.  
 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
The target sample size for this study is 54 patients.  We plan to enroll a total of 60 patients to 
account for screen failure, resting HR < 80 at baseline visit, withdrawals, or loss to follow up.  
Based on our clinical volume, we plan to recruit 2-3 patients per month over a cumulative 
accrual period of 24-36 months.  Each patient will be followed for the 6 week duration of the 
study.  There is no long-term follow-up planned in this study.   
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
3 
+ 4 
= 7 
Not Hispanic or Latino 
24 
+ 29 
= 53 


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32 
Ethnic Category: Total of all 
subjects 
27 
(A1) + 33 
(B1) = 60 
(C1) 
Racial Category 
 
American Indian or Alaskan 
Native 
1 
+ 1 
= 2 
Asian 
1 
+ 1 
= 2 
Black or African American 
3 
+ 4 
= 7 
Native Hawaiian or other Pacific 
Islander 
1 
+ 1 
= 2 
White 
21 
+ 26 
= 47 
Racial Category: Total of all 
subjects 
27 
(A2) + 33 
(B2) = 60 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 
Stratification Factors 
 
All patients will first be stratified into two groups according to pre-randomization treatment 
with beta-blocking agents. Patients within each beta-blocker group will then undergo four 
way randomization using permuted blocks, dividing the two strata into four groups each: 
ivabradine with sophisticated autonomic testing, placebo with sophisticated autonomic 
testing, ivabradine with no sophisticated autonomic testing, placebo with no sophisticated 
autonomic testing. These four groups will be created in a 1:1:1:1 ratio. Randomization will 
be performed by the ODQ at Dana Farber Cancer Institute.  
 
Monitoring and efficacy determination will not be done separately for the different strata.  
An ANCOVA model (for normally distributed data) adjusting for the stratification factors 
(beta blocking agents [Yes, No], autonomic function testing [Yes, No]) or Quade test 
adjusting for the stratification factors (beta blocking agents [Yes, No], autonomic function 
testing [Yes, No]) (for non-normally distributed data) will be implemented to compare the 
change in various endpoint with ivabradine versus placebo.  
 
13.4 
Interim Monitoring Plan 
 
Patients will be enrolled continuously in this trial over the course of the trial.  Each patient 
will be followed for the 6 week duration of thestudy. There are no formal interim monitoring 
plans in this trial.  However, data will be submitted to the DFCI DSMB every 6 months and 
the recommendations of the DSMB regarding trial continuation will be followed accordingly.   
 
13.5 
Analysis of Primary Endpoint 
 
The primary end-point of this study is the change in resting HR with ivabradine, compared to 
placebo, in survivors of lymphoma with mediastinal involvement who were treated with 
mediastinal/mantle radiation and have a resting HR ≥ 80 bpm. 


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33 
 
We will calculate the change in resting HR (from EKGs) from baseline to 6 weeks for each 
patient in the study (n=60).  An ANCOVA model (for normally distributed data) adjusting for 
the stratification factors (beta blocking agents [Yes, No], autonomic function testing [Yes, No]) 
or Quade test adjusting for the stratification factors (beta blocking agents [Yes, No], autonomic 
function testing [Yes, No]) (for non-normally distributed data) will be implemented to compare 
the change in resting HR with ivabradine versus placebo.  A p value < 0.05 using a two-sided test 
will be considered statistically significant.   
 
13.6 
Analysis of Secondary Endpoints 
 
The secondary end-point of this study is the change in exercise duration with ivabradine, 
compared to placebo, in survivors of lymphoma with mediastinal involvement who were treated 
with mediastinal/mantle radiation and have a resting HR ≥ 80 bpm. 
 
We will calculate the change in exercise duration (from exercise treadmill stress tests) from 
baseline to 6 weeks for each patient in the study (n=60).  An ANCOVA model (for normally 
distributed data) adjusting for the stratification factors (beta blocking agents [Yes, No], 
autonomic function testing [Yes, No]) or Quade test adjusting for the stratification factors (beta 
blocking agents [Yes, No], autonomic function testing [Yes, No]) (for non-normally distributed 
data) will be implemented to compare the change in exercise duration with ivabradine versus 
placebo.  
 
We will then repeat the analysis with change in resting HR as an additional independent variable 
to assess whether change in resting HR affects exercise duration.  A p value < 0.05 using a two-
sided test will be considered statistically significant.   
 
Exploratory end-points of this study are: 
 
1) Change in additional markers of cardiac sympatho-vagal balance with ivabradine, 
compared to placebo, in survivors of lymphoma with mediastinal involvement who were 
treated with mediastinal/mantle radiation and have a resting HR ≥ 80 bpm.  
 
Since this is an exploratory end-point and due to cost constraints, it will only be 
conducted in half the patients enrolled in the trial (n=30) and no power calculation has 
been made.  The cardiovagal composite autonomic severity score (CASS) and adrenergic 
CASS will be calculated at baseline and at 6 weeks (as decribed in Section 5.3.3) for each 
patient in this substudy.  The change in CASS and adrenergic CASS will then be assessed 
for each patient.  Quade test adjusting for the stratification factors (beta blocking agents 
[Yes, No], autonomic function testing [Yes, No]) (for ordinal data) will be implemented 
to compare the change in CASS and adrenergic CASS in patients treated with ivabradine 
versus placebo.  A p value < 0.05 using a two-sided test will be considered statistically 
significant. 
 
2) Change in health related quality of life with with ivabradine, compared to placebo, in 
survivors of lymphoma with mediastinal involvement who were treated with 


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34 
mediastinal/mantle radiation and have a resting HR ≥ 80 bpm.  
 
All patients (n=60) will complete the SF-36 health survey at baseline and at 6 weeks.  
The SF-36 questionnaire consists of eight subsections; physical functioning, social role 
functioning, physical role functioning, emotional role functioning, mental health, vitality, 
bodily pain, and general health perceptions. For each section, item scores are coded from 
0 (worst health status) to 100 (best health status). Total scores are also obtained for two 
main domains: a physical component -consisting of physical function, role physical, 
bodily pain, and general health subscales- and a mental component -consisting of role 
emotional, social functioning, mental health, and vitality.  SF-36 has been used to assess 
quality of life in several cancer populations. Change in SF-36 scores from baseline to 6 
weeks will be calculated for each patient. An ANCOVA model (for normally distributed 
data) adjusting for the stratification factors (beta blocking agents [Yes, No], autonomic 
function testing [Yes, No]) or Quade test adjusting for the stratification factor (beta 
blocking agents [Yes, No], autonomic function testing [Yes, No]) (for non-normally 
distributed data) will be implemented to compare the change in quality of life with 
ivabradine versus placebo. A p value < 0.05 using a two-sided test will be considered 
statistically significant. 
 
13.7 
Reporting and Exclusions 
 
All patients who complete the baseline and 6 week assessments will be included in the analyses.   
 
13.7.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
Since the primary end-point is assessing change in HR from baseline to 6 weeks, we will 
only include those patients who complete both the baseline and 6 week visit for 
evaluation of the primary efficacy end-point.  However, we will have HR data at the 2 
week titration visit and will report this if there is a significant rate of study withdrawal or 
loss to follow up in the ivabradine group.  
 
14. PUBLICATION PLAN 
 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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35 
 
REFERENCES 
 
1. 
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, 
Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, 
Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer. The 
New England journal of medicine. 2013;368:987-998 
2. 
Jaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic 
irradiation. Journal of the American College of Cardiology. 2013;61:2319-2328 
3. 
Koh ES, Tran TH, Heydarian M, Sachs RK, Tsang RW, Brenner DJ, Pintilie M, Xu T, 
Chung J, Paul N, Hodgson DC. A comparison of mantle versus involved-field 
radiotherapy for hodgkin's lymphoma: Reduction in normal tissue dose and second 
cancer risk. Radiat Oncol. 2007;2:13 
4. 
Ng AK. Review of the cardiac long-term effects of therapy for hodgkin lymphoma. 
British journal of haematology. 2011;154:23-31 
5. 
Rosenwinkel ET, Bloomfield DM, Arwady MA, Goldsmith RL. Exercise and autonomic 
function in health and cardiovascular disease. Cardiology clinics. 2001;19:369-387 
6. 
Lauer MS. Autonomic function and prognosis. Cleveland Clinic journal of medicine. 
2009;76 Suppl 2:S18-22 
7. 
Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal 
exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Annals of 
internal medicine. 2000;132:552-555 
8. 
Shetler K, Marcus R, Froelicher VF, Vora S, Kalisetti D, Prakash M, Do D, Myers J. 
Heart rate recovery: Validation and methodologic issues. Journal of the American 
College of Cardiology. 2001;38:1980-1987 
9. 
Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS. Heart-rate recovery 
immediately after exercise as a predictor of mortality. The New England journal of 
medicine. 1999;341:1351-1357 
10. 
Morshedi-Meibodi A, Larson MG, Levy D, O'Donnell CJ, Vasan RS. Heart rate recovery 
after treadmill exercise testing and risk of cardiovascular disease events (the framingham 
heart study). The American journal of cardiology. 2002;90:848-852 
11. 
Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic 
risk factor in patients with coronary artery disease and left-ventricular systolic 
dysfunction (beautiful): A subgroup analysis of a randomised controlled trial. Lancet. 
2008;372:817-821 
12. 
Groarke JD, Tanguturi VK, Hainer J, Klein J, Moslehi JJ, Ng A, Forman DE, Di Carli 
MF, Nohria A. Abnormal exercise response in long-term survivors of hodgkin lymphoma 
treated with thoracic irradiation: Evidence of cardiac autonomic dysfunction and impact 
on outcomes. Journal of the American College of Cardiology. 2015;65:573-583 
13. 
Sakmann B, Noma A, Trautwein W. Acetylcholine activation of single muscarinic k+ 
channels in isolated pacemaker cells of the mammalian heart. Nature. 1983;303:250-253 
14. 
DiFrancesco D, Tromba C. Muscarinic control of the hyperpolarization-activated current 
(if) in rabbit sino-atrial node myocytes. The Journal of physiology. 1988;405:493-510 
15. 
Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature. 
1979;280:235-236 
16. 
DiFrancesco D, Ferroni A, Mazzanti M, Tromba C. Properties of the hyperpolarizing-


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36 
activated current (if) in cells isolated from the rabbit sino-atrial node. The Journal of 
physiology. 1986;377:61-88 
17. 
Swedberg K, Komajda M, Bohm M, Borer J, Robertson M, Tavazzi L, Ford I. Effects on 
outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: Is 
there an influence of beta-blocker dose?: Findings from the shift (systolic heart failure 
treatment with the i(f) inhibitor ivabradine trial) study. Journal of the American College 
of Cardiology. 2012;59:1938-1945 
18. 
Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, Mark 
DB, McCallister BD, Mooss AN, O'Reilly MG, Winters WL, Gibbons RJ, Antman EM, 
Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, 
Smith SC. Acc/aha 2002 guideline update for exercise testing: Summary article. A report 
of the american college of cardiology/american heart association task force on practice 
guidelines (committee to update the 1997 exercise testing guidelines). Journal of the 
American College of Cardiology. 2002;40:1531-1540 
19. 
Novak P. Quantitative autonomic testing. Journal of visualized experiments : JoVE. 2011 
20. 
Heart rate variability: Standards of measurement, physiological interpretation and clinical 
use. Task force of the european society of cardiology and the north american society of 
pacing and electrophysiology. Circulation. 1996;93:1043-1065 
21.  
Novak P. Electrochemical skin conductance: a systematic review. Clin Auton Res 2017 
Sep 26. doi: 10.1007/s10286-017-0467-x. [Epub ahead of print] 
22. 
Novak P. Electrochemical skin conductance correlates with skin nerve fiber density. 
Front Aging Neurosci. 2016;8:199-206. 
23. 
Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, 
Tavazzi L. Ivabradine and outcomes in chronic heart failure (shift): A randomised 
placebo-controlled study. Lancet. 2010;376:875-885 
24. 
Van Tulder MW, Aaronson NK, Bruning PF. The quality of life of long-term survivors of 
Hodgkin’s disease. Ann Oncol. 1994;5:153-158. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A 
Birth Control Measures 
 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy 
• Premature ovarian failure confirmed by a specialist 
• Pre-pubescence, XY genotype, Turner Syndrome, uterine agenesis 
• Post-menopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause 
 
Women of Childbearing potential must use a reliable method of contraception during treatment 
with ivabradine and for an additional 2 weeks after the last dose of ivabradine. The use of the 
following options is regarded as highly effective contraception: 
 
    Option #1 
 
 
 
       Option #2 
One method from this list: 
 
 
Combined (estrogen and 
progesterone containing) hormonal 
contraception: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 
- 
OR 
Progesterone-only hormonal 
contraception: 
- 
Oral 
- 
Injectable 
- 
Transdermal 
One method from this list: 
 
Intrauterine device (IUD) 
Intrauterine hormone-releasing 
system (IUS) 
 
Option #3 
One method from this list: 
 
Partner’s vasectomy with medical 
confirmation of surgical success 
Bilateral tubal occlusion 
Sexual abstinence 
 


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APPENDIX B 
Drug Diary 
 
 
  
  
Study Participant 
  
  
  
Self-Administration 
  
  
Study Drug Diary 
  
  
  
Dana-Farber/Harvard Cancer 
Center 
  
  
 
Participant Identifier: ____________________ 
Protocol # 
Study MD ____________________ Phone ____________________ 
STUDY DRUG INSTRUCTIONS: 
Study Drug: Ivabradine 
How Much:  a) 2.5 milligrams, 
b) 5 milligrams, OR 
c) 7.5 milligrams 
How Often: Twice daily 
When: With breakfast and with dinner 
SPECIAL INSTRUCTIONS: 
i) do not consume grapefruit, grapefruit juice, or any other form of grapefruit 
ii) do not consume starfruit 
iii) do not consume pomegranate, pomegranate juice or any other form of pomegranate  
iv) Store drug at room temperature and keep drug in provided pill bottle 
v) a dose should be considered missed if it has not been taken within 6 hours prior to the 
next scheduled dose. If you miss a dose or vomit after taking the medication, please 
make a note of this in your drug diary. Take your next dose at your regularly schedule 
time 
vi) if you experience any side effects, please note this in your drug diary. If these side 
effects interfere with your ability to carry out your daily activities, please contact the 
study staff. 
vii) please keep drug in provided pill bottle 
viii) bring any unused drug, your pill bottle, and this diary to your next clinic visit 
ix) do not crush, chew, or dissolve drug in water 
x) do not skip drug on days where you come to see your doctor 
xi) please update this diary daily 
 
 
 


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39 
OTHER MEDICATIONS TAKEN 
If you take a daily medication or supplement (prescribed or otherwise), please use one 
line per drug and indicate the start and stop dates under the "Date(s)  
Taken" section (i.e., 6/2/09 - 6/5/09).  
Drug Name 
Dose 
Dates Taken 
Reason Taken 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study Participant Initials __________ 
Date _________ 
  
  
FOR STUDY TEAM USE 
ONLY 
  
  
  
  
  
  
  
Staff Initials: 
  
  
  
Date Dispensed: 
  
Date 
Returned: 
  
# pills/caps/tabs 
dispensed: 
  
# pills/caps/tabs returned: 
  
  
  
  
  
# pills/caps/tabs that should have been taken: 
  
  
  
  
  
  
Discrepancy Notes: 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 


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DOSING LOG 
Ivabradine 
For each AM dose take: 1 pill 
For each PM dose take: 1 pill 
Please indicate the date, time, amount taken and any comments.  
Date 
Amount Taken 
Comments 
AM 
dose 
PM dose 
Ex: 
6/1/2009 
8 am - 1 
7:30 pm - 1 
forgot PM pill 
Day 1 
  
  
  
  
Day 2 
  
  
  
  
Day 3 
  
  
  
  
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Day 17 
  
  
  
  
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Day 20 
  
  
  
  
Day 21 
  
  
  
  
Day 22 
  
  
  
  
Day 23 
  
  
  
  
Day 24 
  
  
  
  
Day 25 
  
  
  
  
Day 26 
  
  
  
  
Day 27 
  
  
  
  
Day 28 
  
  
  
  


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Day 29 
  
  
  
  
Day 30 
  
  
  
  
Day 31 
  
  
  
  
Day 32 
  
  
  
  
Day 33 
  
  
  
  
Day 34 
  
  
  
  
Day 35 
  
  
  
  
Day 36 
  
  
  
  
Day 37 
  
  
  
  
Day 38 
  
  
  
  
Day 39 
  
  
  
  
Day 40 
  
  
  
  
Day 41 
  
  
  
  
Day 42 
  
  
  
  
Day 43 
  
  
  
  
Day 44 
  
  
  
  
Day 45 
  
  
  
  
Day 46 
  
  
  
  
Day 47 
  
  
  
  
Day 48 
  
  
  
  
Day 49 
  
  
  
  
Day 50 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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42 
SYMPTOMS/SIDE EFFECTS 
Please record any side effects experienced during this cycle. 
Include the date the particular symptom started and when it 
ended. Please evaluate the severity of the symptom according to 
the following scale: 
Mild: Awareness of sign or symptom; easily tolerated and did  
not affect ability to perform normal daily activities. Symptom  
did not require medication or therapeutic intervention. 
Moderate: Significant  discomfort which interfered with ability  
to perform normal daily activities. Symptom was easily resolved   
with at home medication or simple therapeutic intervention. 
Severe: Marked discomfort with an inability to carry out  
normal daily activities. Symptom required new medication  
and/or therapeutic intervention in order to resolve. 
Please Note: The severity should reflect the most severe level  
experienced during the time period.  
    
    
  
  
  Symptom 
  Start Date 
End 
Date 
Severity 
    
    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


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43 
APPENDIX C 
Information On Possible Drug Interactions 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
Ivabradine interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
 
Ivabradine interacts with a specific enzyme in your liver. The enzyme in question is known as 
Cytochrome P450 3A4, also known as CYP 3A4. Ivabradine is broken down and metabolized 
by CYP 3A4. 
 
Ivabradine must be used very carefully with other medicines that need CYP3A4 to be effective 
or to be cleared from your system.   
 
Substances that increase CYP3A4 activity (known as “inducers”) could reduce the effectiveness 
of ivabradine, while substances that decrease the CYP3A4 activity (known as “inhibitors”) could 
result in high levels of the active drug, increasing the chance of harmful side effects. 
 
You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category. 
 
Before you start the study, your study doctor will work with your regular prescriber to switch 
any medicines that are considered “strong inducers/inhibitors or substrates of CYP3A4. 
 
Your prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
or consult a medical reference to see if any medicine they want to prescribe is on a list of drugs 
to avoid.   
 
Please also avoid any grapefruit products, star fruit, or pomegranate products for the duration of 
the study since these foods are inhibitors of CYP3A4 activity.  
 
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually big 
and catches your eye.  They also have a generic name—it’s usually small and located above or 
below the brand name, and printed in the ingredient list.  Find the generic name and determine, 
with the pharmacist’s help, whether there could be an adverse interaction.   
 


NCI Protocol #: 
DF/HCC Protocol #: 17-022 
Protocol Version Date: 12/16/16 
 
44 
 
 
 
Be careful to avoid the following drugs, foods, and supplements while taking ivabradine: 
• CYP3A4 inhibitors: ketoconazole, itraconazole, voriconazole, clarithromycin, 
telithromycin, nefazodone, ritonavir, saquinavir, boceprevir, telaprevir, iopinavir, 
fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, idinavir, 
verapamil, diltiazem, erythromycin, grapefruit, pomegranate, and star fruit, 
• CYP3A4 inducers:  carbamazepine, rifampicin, rifabutin, phenytoin, St. John’s Wort,  
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is Dr. Anju Nohria and she can be contacted at (617) 525-
7052. 
 

ICF_001.pdf: 
 
 
Research Consent Form 
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 1 of 20 
 
DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
Protocol Title:  Ivabradine in the management of cardiac autonomic dysfunction 
associated with thoracic radiation therapy 
 
DF/HCC Principal Research Doctor / Institution:  Anju Nohria, MD/BWH/DFCI 
 
DF/HCC Site-Responsible Research Doctor(s) / Institution(s):   
BWH/DFCI: Anju Nohria, MD 
BCH: Ming Hui Chen, MD 
MGH: Tomas Neilan, MD  
A. INTRODUCTION 
 
You are invited to take part in a clinical trial, a type of research study, because 
you have a history of lymphoma that was treated with neck and/or chest 
radiation. Prior radiation treatment can cause abnormalities of the cardiac 
autonomic nervous system. The autonomic nervous system regulates changes in 
heart rate, the pumping efficiency of the heart, and blood pressure during 
exercise. Radiation induced abnormalities of the cardiac autonomic system can 
lead to decreased exercise tolerance and decreased survival in some people. 
This research study is studying a drug called Ivabradine. Our study will explore 
the effect that ivabradine treatment has on survivors of lymphoma who have 
cardiac autonomic dysfunction as a side effect of prior radiation treatment. 
 
The names of the study drugs involved in this study are: 
• Ivabradine and 
• Placebo 
 
For purposes of this research, you will be referred to as a “participant”.   
 
It is expected that about 60 people will take part in this research study.  
 
Amgen, a pharmaceutical company, is supporting this research study by 
providing funding for the research study and the study drug. 
 
This research consent form explains why this research study is being done, what 
is involved in participating in the research study, the possible risks and benefits 
of participation, alternatives to participation, and your rights as a research 
participant.  The decision to participate is yours.  If you decide to participate, 
please sign and date at the end of this form. We will give you a copy so that you 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 2 of 20 
 
DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
can refer to it while you are involved in this research study. If you choose not to 
participate in this research study, the research doctors will discuss other 
treatment options with you and/or refer you back to your primary doctor.  
 
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future. 
 
 
B. WHY IS THIS RESEARCH STUDY BEING DONE?  
 
This research study is a Phase II clinical trial.  Phase II clinical trials test the 
safety and effectiveness of an investigational intervention to learn whether the 
intervention works in treating a specific disease.  “Investigational” means that the 
intervention is being studied.   
 
This research study is a Pilot Study, which is the first time investigators are 
examining this study intervention for this particular problem. 
 
In this research study, we are studying a drug called ivabradine. We are 
exploring whether ivabradine can be used to reduce heart rate, increase exercise 
duration, and improve quality of life in survivors of lymphoma who received 
radiation to their chest as a part of their cancer treatment.  
 
The U.S. Food and Drug Administration (FDA) has not approved ivabradine for 
your specific disease, but it has approved the drug as an oral medication to lower 
heart rate in heart failure patients.  
  
 
Survivors of lymphoma who were treated with neck and/or chest radiation can 
have an elevated resting heart rate and an abnormal rate of decline in their heart 
rate after exercise, also known as cardiac autonomic dysfunction. These 
abnormalities can limit exercise duration and worsen quality of life in some 
radiation treated survivors of lymphoma.  
 
C. WHAT OTHER OPTIONS ARE THERE? 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following: 
 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 3 of 20 
 
DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
• Lifestyle measures that include avoiding medications, food (e.g. 
chocolate) and beverages (e.g. coffee) that contain stimulants that 
increase heart rate. 
• Participate in a regular exercise training program. 
• Receive other drugs that lower resting heart rate and blood pressure, 
including beta-blockers and calcium channel blockers.  However, these 
have also not been specifically studied in lymphoma survivors with 
radiation induced autonomic dysfunction.  
• No treatment. 
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 
 
 
D. WHAT IS INVOLVED IN THE RESEARCH STUDY? 
 
Because no one knows which of the study options is best, you will be 
“randomized” into one of two study groups: ivabradine or placebo. Ivabradine is 
the active drug we are studying and placebo is a pill that contains no active 
medicine. Randomization means that you are put into a group by chance. It is 
like flipping a coin. Neither you nor the research doctor will choose what group 
you will be in. Neither you nor the research doctor will know what group you are 
in.  You will have an equal chance of being placed in any of the following groups:  
 
• Arm A: Ivabradine for 6 weeks 
• Arm B: Placebo for 6 weeks 
 
You will be given a study medication and it will contain either ivabradine or 
placebo. 
 
You will be asked to maintain a diary to record your drug usage throughout the 
study. If you miss or vomit a study drug dose during the study, we will ask you to 
record the reason that you missed the dose in the diary.  Please take your next 
study drug dose as scheduled.   
 
Since ivabradine is currently not FDA approved for lymphoma survivors with 
radiation induced autonomic dysfunction, it may not be available after the study 
ends. 
 
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for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
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DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
Sometimes it is hard to keep track of all of the details and procedures that are 
part of a research study.  We will describe them in this consent form and you can 
refer to this at any time during the research study. 
 
Before the research starts (screening):   
After signing this consent form, you will be asked to undergo some screening 
tests or procedures to find out if you can be in the research study.  This visit will 
last approximately 1 hour. 
 
• A medical history, which includes questions about your health, prior 
illnesses and testing, current medications, and any allergies. We will also 
review any liver and kidney function tests that you may have had within 
the previous year.  
 
• Physical Examination, to ensure that you do not have any clinical 
findings that would exclude you from this study.  
 
• Urine pregnancy test, if you are a female of child bearing age and are 
not menopausal or have not undergone surgery to prevent childbearing.  
 
• Electrocardiogram (EKG), to quantify your resting heart rate. This test 
checks the electrical activity of your heart.  We will place several small, 
sticky pads on your chest, arms, and legs.  Each pad has a wire attached.  
The wires connect to a machine that makes a recording of your heart 
rhythm.  This painless test takes about 15 minutes.   
 
• Laboratory testing, to assess liver and kidney function tests if you have 
not had them within the past year.  
 
If these tests show that you are eligible to participate in the research study, you 
may begin the study intervention.  If you do not meet the eligibility criteria, you 
will not be able to participate in this research study. 
 
Study Visit 1: This visit involves baseline testing to assess your resting heart 
rate, your exercise capacity, and quality of life prior to starting the study drug. 
This visit will last approximately 2-3 hours.   
 
Participants will also be randomized to undergo additional tests to assess their 
heart rate and blood pressure response to certain special maneuvers (cardiac 
autonomic function testing). Therefore, there is a 50-50 chance that you may 
undergo these additional tests that will last approximately 2-3 hours.   
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
Page 5 of 20 
 
DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
 
This visit will involve the following: 
• Clinical Exam:  During this visit you will have a physical exam and you 
will be asked questions about your general health and specific questions 
about any problems that you might be having and any medications you 
may be taking.  
  
• Treadmill exercise stress test: This test will be conducted by trained 
professionals in the exercise stress testing laboratory at Brigham and 
Women’s Hospital.  The treadmill exercise test includes walking and/or 
jogging on a moving belt for the purpose of testing the function of the heart 
and the blood supply to the heart. Preparation for the test includes shaving 
the chest (if needed), rubbing the chest with alcohol and abrasive material 
(which may cause some skin irritation) in order to attach EKG leads to 
evaluate the electrical activity of your heart while you are exercising.  You 
will start exercising slowly with frequent EKGs and blood pressure 
measurements.  The speed and incline of the treadmill will be increased 
every 3 minutes.  You will be encouraged to exercise until you get 
exhausted or if the exercise technologist/physician feels that you have 
symptoms or EKG changes that suggest that you should stop.  
 
• SF-36 Questionnaire: You will be asked to fill out a 36 question form 
about your general health and well-being, quality of life, mental health, 
emotional health, mood, and memory. 
 
• 24 hour holter monitor: This test measures your average heart rate over 
24 hours.  A holter monitor, which is a small, portable digital recorder that 
records your EKG (your heart's electrical activity) for 24 hours, will be 
placed on you in the cardiology clinic at Brigham and Women’s Hospital. 
Electrodes will be placed on your chest after it has been cleaned to 
remove oils and shaved, if required. The recorder will be placed in a 
holding pouch with a strap so that you can carry it easily. You will be given 
a diary to list any symptoms noticed during the test. The recorder is also 
equipped with an event marker to be pressed when symptoms occur. You 
will return after 24 hours to have the monitor removed. The monitor will 
be connected to a special computer to scan your EKG.  
 
• Cardiac Autonomic Function Testing: If you are randomized to have 
this test, it will be performed in the autonomic function testing laboratory at 
Faulkner Hospital and lasts approximately 2 hours.  This test involves 3 
parts: 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
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DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
1) Deep breathing: You will be asked to avoid smoking, caffeinated 
beverages, and strenuous exercise for 12 hours before the test. You 
will be asked to empty your bladder before the test. You will then be 
asked to lie quietly for 20 minutes.  A baseline EKG recording will be 
obtained for one minute to ensure a stable resting heart rate. You will 
then be asked to breathe in and out slowly at a rate of 6 
breaths/minute and a continuous EKG will be recorded during deep 
breathing. This tests the parasympathetic system which is responsible 
for slowing down your heart rate. 
2) The Valsalva maneuver: You will be asked to lie down quietly. You will 
then be asked to breathe into a 10 cc plastic syringe that is connected 
to a pressure gauge.  You will be asked to take a deep breath and 
blow into the syringe and keep the pressure at 40 mm Hg for 15 
seconds.  You will asked to practice this until you can do it correctly. 
Once you have mastered the maneuver, you will be asked to rest for 3-
5 minutes before performing the maneuver.  Your heart rate and blood 
pressure will be recorded by a machine that will be connected to your 
finger. The heart rate response to the Valsalva maneuver tests your 
parasympathetic system which is responsible for slowing down your 
heart rate and your blood pressure response to the Valsalva maneuver 
tests your sympathetic system which is responsible for speeding up 
your heart rate and increasing your blood pressure.  
3) Tilt tests predominantly evaluate the body’s heart rate and blood 
pressure response to change in body position from lying to standing.  
You will be asked to lie down and your heart rate and blood pressure 
will be measured over 5-10 minutes.  You will then be tilted up to an 
angle of 70 degrees over 5-10 seconds.  You will be monitored closely 
for chest pain, shortness of breath, dizziness, or fainting. If you have 
no adverse reaction, your heart rate and blood pressure will be 
recorded every minute for 10 minutes.  You will then be returned to a 
lying position. 
4) Sudomotor Testing: You will be asked to complete a short 
questionnaire asking whether you have nerve pain symptoms.  You will 
also be asked to place both palms and soles on large area stainless-
steel electrodes for 3-minutes.  A low voltage (<4 V) current will be 
applied incrementally to the electrodes to measure your skin 
conductance.  
 
Study Intervention Overview:  After the baseline evaluation is completed, you 
will be given study drug to take home with you.  
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
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DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
• Oral Study Drug(s):  Each study intervention lasts 6 weeks during which 
time you will be taking the study drug 2 times per day.  It is important for 
you to follow our instructions about how to take the study drug.  After 
approximately 14 days, the dose of the study drug may be adjusted based 
on your heart rate. Please bring your drug diary with you to your 
subsequent visits.  Please also bring any unused study drug with you to 
your subsequent visits.  
 
Study Visit 2:  This visit will occur approximately 14 days after starting the study 
drug. The purpose of this visit is to adjust the dose of your study medication 
based on your resting heart rate and symptoms. This visit will take approximately 
30 minutes. At this visit, you will have the following: 
 
• Clinical Exam:  During this visit you will have a physical exam and you 
will be asked questions about any side effects to the study drug or health 
problems since your last visit.  
 
• EKG: To measure your resting heart rate.   
 
If you are tolerating the medication at the current dose without significant side 
effects and your resting heart rate is greater than or equal to 60 beats per 
minute, we will increase the dose of the study medication.  If your heart rate is 
less than or equal to 50 beats per minute or you are experiencing side effects 
related to a slow heart rate, we will decrease the dose of your study medication.    
 
Study Visit 3:  This visit will occur approximately 6 weeks after starting taking 
the study drug.  This visit is exactly the same as Visit 1. If you are a female of 
child bearing age and are not menopausal or have not undergone surgery to 
prevent childbearing, you will be asked to undergo a urine pregnancy test. This 
visit will take approximately 2-3 hours if you are not randomized to undergo 
autonomic function testing.  If you are randomized to undergo autonomic function 
testing, this visit will take an additional 2-3 hours.  You will take the final dose of 
the study drug on the morning of this visit.  You will be asked to bring any unused 
study drug to this visit. 
 
After You Complete the Study: 
After you complete the study, we will refer you back to your own doctor for your 
ongoing medical care.  
 
Research Study Plan: 
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Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 09.23.16a 
 
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DFCI Protocol Number: 
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Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
 
 
 
Visit 1 Visit 2 Visit 3 
 
Screenin
g 
Day 1 Day 14 Day 42 
Medical History & 
Physical Exam 
X 
X 
X 
X 
EKG 
X 
X 
X 
X 
Pregnancy Test 
X 
 
 
X 
Autonomic 
Function Tests 
 
X 
 
X 
Treadmill 
exercise stress 
test 
 
X 
 
X 
SF-36 
questionaire 
 
X 
 
X 
24 Holter monitor 
 
X 
 
X 
Receive study 
drug 
 
X 
 
 
Adjust study drug 
dose 
 
 
X 
 
Return study 
drug 
 
 
 
X 
 
 
 
 
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY? 
 
You will be in this research study for approximately 6 weeks. 
 
You may be taken off the research study drug for many reasons including if: 
• It is considered to be in your best interest 
• The study intervention or procedures are found to be unsafe or ineffective 
• There is any problem with following study interventions and procedures 
• Your condition worsens 
• You are a female and become pregnant or plan to become pregnant 
• A decision is made to close the study 
• Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study 
 
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BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
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DFCI Protocol Number: 
17-022 
Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
If you are removed from the research study, the research doctor will explain to 
you why you were removed. 
 
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.  If you decide to stop participating in this 
research study, we encourage you to talk to the research doctor and your 
primary doctor first. 
 
 
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY? 
 
There are risks to taking part in any research study. One risk is that you may get 
a study drug or study dose of a drug that does not help treat your disease or that 
makes your condition or disease worse.  Another risk is that there may be side 
effects.   
 
All medical treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different medications and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects.  
 
Everyone in the research study will be watched carefully for side effects.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away. Some may be life-threatening or fatal.  
 
 
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study. 
 
Risks Associated with Ivabradine: 
 
Occasional (1-10%): 
• Slow heart rate  
• High blood pressure  
• Atrial fibrillation (an irregular heart rate)  
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DFCI Protocol Number: 
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Date DFCI IRB Approved this Consent Form: 
09/04/2019 
Date Posted for Use: 
09/18/2019 
  
 
• Phosphenes or visual brightness 
• Shortness of breath  
Rare (less than 1%): 
• Syncope (fainting) 
• Hypotension (low blood pressure) 
• Angioedema (swelling of the face and throat) 
• Rash 
• Itching 
• Urticaria (hives) 
• Vertigo (sensation that the room is spinning) 
• Diplopia (double vision) 
• Visual impairment 
 
Risks Associated with Sophisticated Autonomic Function Testing:  
While you are in this research study, you will undergo a tilt table test to evaluate 
the degree of radiation induced autonomic dysfunction before and after taking 
study drug.  A rapid change in body position can occasionally cause: 
• Dizziness 
• Fainting 
• Chest pain 
• Shortness of breath 
If these occur, you will be immediately returned to a lying position. 
You may experience a slight buzzing sensation in your palms and soles during 
sudomotor testing.   
 
Risks Associated with Exercise Treadmill Tests:  
While you are in this research study, exercise treadmill tests will be done to 
assess your exercise capacity. During the test, you can occasionally develop: 
• Abnormal blood pressure (low or high) 
• Rhythm disturbances of the heart  
• Chest pain  
• Shortness of breath 
Rarely, you can have a: 
• Heart attack.  
 
In addition, there is a chance of having an abnormal stress test. This could 
require further testing or treatment. If you have an abnormal stress test, you may 
be withdrawn from the study and will be referred for further care to your primary 
physician.  If one of the research doctors is involved in your clinical care, they 
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DFCI Protocol Number: 
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Date Posted for Use: 
09/18/2019 
  
 
may decide what additional testing and/or treatment is required after reviewing 
your stress test results.  
 
Reproductive Risks:  
The drugs used in this research study may affect a fetus.  While participating in 
this research study, you should not become pregnant or father a baby, and 
should not nurse a baby while you are taking the study drug and for 2 weeks 
after the last dose of the study drug. We will provide counseling about preventing 
pregnancy for either male or female study participants. We will check a urine 
pregnancy test in all women of child bearing age who are not post-menopausal 
or do not have a documented history of surgery to prevent conception before you 
start study drug and at the end of the study.  
 
 
 
 
 
 
 
 
 
Let your doctor know immediately if you become pregnant or find out that you are 
going to be the father of a child during the study or within 2 weeks of study 
completion. 
 
In the event that your partner becomes pregnant, it may be critical to share 
information regarding your participation in this research study with that person.  
Your research doctor should also be told if this happens.  The study sponsor may 
want to collect data on your partner’s pregnancy.    
 
Non-Physical Risks:  
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities.  
 
The questionnaires used in this study may be upsetting. If you find the 
questionnaires upsetting, you may speak with the research doctor or ask to be 
referred for additional emotional support. 
 
 
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY? 
 
Taking part in this study may or may not help you. Taking part in this research 
study may help us learn more about ivabradine as a treatment for radiation 
induced autonomic dysfunction that may help other people in the future. 
   
 
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DFCI Protocol Number: 
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Date DFCI IRB Approved this Consent Form: 
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H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS? 
 
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study.  
 
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.   
 
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled.  
 
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping ivabradine. Another 
reason to tell your research doctor that you are thinking about stopping is to 
discuss what follow-up care and testing could be most helpful for you. 
 
 
I. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
 
The study sponsor will reimburse you for travel/parking costs incurred during 
each of your study visits ($25 per visit).  Study staff will review the 
reimbursement plan and any requirements for reimbursement with you. 
 
 
J. WHAT ARE THE COSTS? 
 
Taking part in this research study might lead to added costs to you or your 
insurance company. 
 
You will not be charged for ivabradine or the tests described above that are done 
as part of this study.  
 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are:   
• Boston Children’s Hospital: (617) 355-7188 
• Brigham and Women’s Hospital: (617) 732-5524 or (617) 732-7485 
• Dana-Farber Cancer Institute: (617) 632-3455 
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DFCI Protocol Number: 
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Date DFCI IRB Approved this Consent Form: 
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Date Posted for Use: 
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• Dana-Farber Cancer Institute/Faulkner Hospital: (617) 632-3455 
 
 
 
K. WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN THIS 
RESEARCH STUDY? 
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The 
research doctor’s name and phone number are listed in this consent form. 
 
The treating hospital will offer you the care needed to treat injuries directly 
resulting from taking part in this research.  These treatments will be billed to your 
insurance company. You will be responsible for deductibles and co-payments. 
There are no plans to pay you or give you other compensation for the injury. You 
do not give up your legal rights by signing this form.  
 
 We will need to collect certain personal information about you for insurance or 
payment reporting purposes, such as your name, date of birth, gender, social 
security number or Medicare identification number and information related to this 
research study. We may be required to report this information to the Centers for 
Medicare & Medicaid Services. We will not use this information for any other 
purpose. 
 
 
L. WHAT ABOUT CONFIDENTIALITY? 
 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file.  It may also become part of a DF/HCC research database.   
 
The results of this research study may be published. You will not be identified in 
publications without your permission. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
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identify you.  At most, the Web site will include a summary of the results.  You 
can search this Web site at any time. 
 
 
M. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY? 
 
If you have questions about the study, please contact the research doctor or 
study staff as listed below: 
 
Brigham and Women’s Hospital/Dana Farber Cancer Institute 
 
• Anju Nohria, MD: (617) 525-7052 
• John Groarke, MD: (617) 732-6632 
• Peter Novak, MD: (617) 983-7580 
 
If you need to contact study staff outside normal business hours, please page 
either Drs. Nohria or Groarke through the Brigham and Women’s page operator:  
 
24-hour contact: Anju Nohria, MD at (617) 525-7052 beeper 30350 or John 
Groarke, MD at 617-732-6632 beeper 31692 
 
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at DFCI (617) 632-
3029. This can include questions about your participation in the study, concerns 
about the study, a research related injury, or if you feel/felt under pressure to 
enroll in this research study or to continue to participate in this research study.  
 
Massachusetts General Hospital Boston Children’s Hospital 
 
• Shawn Clinton Pun, MD: (617) 726-3453 
• Tomas Neilan, MD: (617) 724-5351 
 
Boston Children’s Hospital 
 
• Ming Hui Chen, MD: (617) 355-8366 
 
 
N. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to 
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protect the privacy of information that identifies you and relates to your past, 
present, and future physical and mental health conditions (“protected health 
information”).  If you enroll in this research study, your “protected health 
information” will be used and shared with others as explained below. 
 
1. What protected health information about me will be used or shared with 
others during this research? 
 
• Existing medical records, including mental health records. 
• New health information created from study-related tests, procedures, 
visits, and/or questionnaires 
 
2. Why will protected information about me be used or shared with others? 
 
The main reasons include the following: 
• To conduct and oversee the research described earlier in this form; 
• To ensure the research meets legal, institutional, and accreditation 
requirements;  
• To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and 
• To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug for the 
purpose of this or other research related to the study drug;  
• To better understand the diseases being studied and to improve the 
design of future studies; and, 
• Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.) 
 
3. Who will use or share protected health information about me? 
 
• DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information. 
 
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4. With whom outside of DF/HCC may my protected health information be 
shared? 
 
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities: 
 
• Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors). 
• The sponsor(s) of the study, its subcontractors, representatives, business 
partners, and its agent(s): Amgen 
• Other research doctors and medical centers participating in this research, 
if applicable 
• Federal and state agencies (for example, the Department of Health and 
Human Services, the FDA, the National Institutes of Health, and/or the 
Office for Human Research Protections), or other domestic or foreign 
government bodies if required by law and/or necessary for oversight 
purposes. A qualified representative of the FDA and the National Cancer 
Institute may review your medical records. 
• Hospital accrediting agencies 
• A data safety monitoring board organized to oversee this research, if 
applicable 
 
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission.  
 
5. For how long will protected health information about me be used or 
shared with others? 
 
• There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.   
 
 
 
 
 
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6. Statement of privacy rights: 
 
• You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?” 
• You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?” 
 
 
 
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O. DOCUMENTATION OF CONSENT 
 
My signature below indicates: 
• I have had enough time to read the consent and think about 
participating in this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at 
any time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
 
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To be completed by person obtaining consent: 
 
Adult Participant 
 
 
The consent discussion was initiated on   
 (date). 
 
Signature of individual obtaining consent:  
 
 
Printed name of above:  
 
 
 
Date:  
 
 
 A copy of this signed consent form will be given to the participant or legally 
authorized representative. 
 1)  The participant is an adult and provided consent to participate. 
 
 1a)  Participant (or legally authorized representative) is a non-English 
speaker and 
 
signed the translated Short Form in lieu of English consent document: 
 
As someone who understands both English and the language spoken by 
the participant, I interpreted and/or witnessed, in the participant’s 
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language, the researcher’s presentation of the English consent form.  The 
participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed Name of Interpreter/Witness:  
 
Date:  
 
 
 
 1b)  Participant is physically unable to sign the consent form because:  
 
 
 
 The participant is illiterate. 
 
 
 
 The participant has a physical disability. 
 
 
 
 Other (please describe): 
_________________________________________ 
 
The consent form was presented to the participant who was given the 
opportunity   
to ask questions and who communicated agreement to 
participate in the research.  
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:  
 
 
 2)  The participant is an adult who lacks capacity to provide consent and 
his/her legally authorized representative: 
 2a) gave permission for the adult participant to participate  
 2b) did not give permission for the adult participant to participate  
 
 
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