Ivabradine in the Management of Cardiac Autonomic Dysfunction Associated With Thoracic Radiation Therapy.

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03137537
• Collaborator: Amgen (Industry)
• Enrollment: 23
• Locations: 3
• Arms: 2
• Actual Duration (Months): 32.7
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Lymphoma; Autonomic Imbalance; Cancer Survivorship	Drug: Ivabradine; Drug: Placebo Oral Tablet	Phase 2

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Ivabradine in the Management of Cardiac Autonomic Dysfunction Associated With Thoracic Radiation Therapy.
• Actual Study Start Date: Feb 27, 2018
• Actual Primary Completion Date: Nov 18, 2020
• Actual Study Completion Date: Nov 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ivabradine Ivabradine will be administered for a total of 6 weeks Ivabradine is taken orally twice daily Dosage will be adjusted according to physician determination	Drug: Ivabradine; lower heart rate in heart failure patients.; Other Names: Corlanor
Placebo Comparator: Placebo Oral Tablet Placebo will be administered for a total of 6 weeks Placebo is taken orally twice daily Dosage will be adjusted according to physician determination	Drug: Placebo Oral Tablet; Procedure prescribed to compare the active effect of a medicine.

Outcome Measures

Primary Outcome Measures

1. To Investigate Whether Ivabradine Lowers Resting HR, Compared To Placebo, In Survivors Of Lymphoma [6 weeks]

   Calculate the change in resting HR (from Holter monitor data) from baseline to 6 weeks for each patient in the study. Then compare the median change with ivabradine to the median change with placebo.

Secondary Outcome Measures

1. To Evaluate Whether Ivabradine Improves Exercise Duration, Compared To Placebo, In Survivors Of Lymphoma [6 weeks]

   Calculate the change in exercise duration (from exercise treadmill stress tests) from baseline to 6 weeks for each patient in the study. Then compare the median change in exercise duration with ivabradine to the median change in exercise duration with placebo.

Other Outcome Measures

1. To Evaluate Whether Ivabradine Improves Additional Markers of Cardiac Sympatho-vagal Balance, Compared To Placebo, In Survivors Of Lymphoma [6 weeks]

   Calculate the change in cardiac autonomic function (from cardiac autonomic function testing) from baseline to 6 weeks in one half of the patients in the study (n=30)

2. To Evaluate Whether Ivabradine Improves Health Related Quality Of Life Compared To Placebo, In Survivors Of Lymphoma [6 weeks]

   Calculate the change in health related quality of life (from SF-36 quality of life surveys) from baseline to 6 weeks for each patient in the study (n=60)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Survivors of mediastinal lymphoma (either Non-Hodgkin's Lymphoma or Hodgkin's Lymphoma) with no active malignancy

• Prior mediastinal or mantle radiation ≥ 5 years prior to enrollment in the study

• Age 18-80 years.

• 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.

• Normal sinus rhythm with resting heart rate ≥ 80 bpm on screening EKG

• 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 adequate contraception.

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Participants who are receiving any other investigational agents.

• History of allergic reaction to ivabradine.

• Participants receiving any medications or substances that are inhibitors or inducers of cytochrome P450 3A4 are ineligible.

• 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.

• 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.

• HIV-positive participants on combination antiretroviral therapy.

• Patients with systolic blood pressure < 90 mm Hg.

• Patients with sick-sinus syndrome, sino-atrial block, third degree heart block, atrial fibrillation, and those with permanent pacemakers.

• 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.

• Patients with severe hepatic dysfunction (Child Pugh Class C).

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Boston Children Hospital	Boston	Massachusetts	United States	02115
3	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Amgen

Investigators

• Principal Investigator: Anju Nohria, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 16, 2016
• Informed Consent Form - Sep 18, 2019

More Information

Publications

None provided.

• Responsible Party: Anju Nohria, Assistant Professor in Internal Medicine, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03137537
• Other Study ID Numbers: 17-022
• First Posted: May 2, 2017
• Last Update Posted: Feb 10, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Anju Nohria, Assistant Professor in Internal Medicine, Dana-Farber Cancer Institute: Lymphoma; Abnormal resting heart rate; Autonomic imbalance; Cancer survivorship
• Additional relevant MeSH terms: Autonomic Nervous System Diseases; Primary Dysautonomias

Study Results

Participant Flow

Arm/Group Title	Ivabradine	Placebo Oral Tablet
Arm/Group Description	Ivabradine will be administered for a total of 6 weeks Ivabradine is taken orally twice daily Dosage will be adjusted according to physician determination Ivabradine: lower heart rate in heart failure patients.	Placebo will be administered for a total of 6 weeks Placebo is taken orally twice daily Dosage will be adjusted according to physician determination Placebo Oral Tablet: Procedure prescribed to compare the active effect of a medicine.
Period Title: Overall Study
STARTED	12	11
COMPLETED	12	10
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Ivabradine	Placebo Oral Tablet	Total
Arm/Group Description	Ivabradine will be administered for a total of 6 weeks Ivabradine is taken orally twice daily Dosage will be adjusted according to physician determination Ivabradine: lower heart rate in heart failure patients.	Placebo will be administered for a total of 6 weeks Placebo is taken orally twice daily Dosage will be adjusted according to physician determination Placebo Oral Tablet: Procedure prescribed to compare the active effect of a medicine.	Total of all reporting groups
Overall Participants	12	11	23
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	52	56
Sex: Female, Male (Count of Participants)
Female	9 75%	10 90.9%	19 82.6%
Male	3 25%	1 9.1%	4 17.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 16.7%	0 0%	2 8.7%
Not Hispanic or Latino	10 83.3%	11 100%	21 91.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	12 100%	11 100%	23 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Beta-blocker at baseline (Count of Participants)
Count of Participants [Participants]	6 50%	6 54.5%	12 52.2%
Ejection Fraction, % (%) [Median (Full Range) ]
Median (Full Range) [%]	61	63	63
Resting heart rate (bpm) [Median (Full Range) ]
Median (Full Range) [bpm]	90	93	91

Outcome Measures

1. Primary Outcome

Title	To Investigate Whether Ivabradine Lowers Resting HR, Compared To Placebo, In Survivors Of Lymphoma
Description	Calculate the change in resting HR (from Holter monitor data) from baseline to 6 weeks for each patient in the study. Then compare the median change with ivabradine to the median change with placebo.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Analyzed all patients who had data available at baseline and at 6 weeks

Arm/Group Title	Ivabradine	Placebo Oral Tablet
Arm/Group Description	Ivabradine will be administered for a total of 6 weeks Ivabradine is taken orally twice daily Dosage will be adjusted according to physician determination Ivabradine: lower heart rate in heart failure patients.	Placebo will be administered for a total of 6 weeks Placebo is taken orally twice daily Dosage will be adjusted according to physician determination Placebo Oral Tablet: Procedure prescribed to compare the active effect of a medicine.
Measure Participants	12	10
Median (Full Range) [bpm]	-13	-1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo Oral Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	To Evaluate Whether Ivabradine Improves Exercise Duration, Compared To Placebo, In Survivors Of Lymphoma
Description	Calculate the change in exercise duration (from exercise treadmill stress tests) from baseline to 6 weeks for each patient in the study. Then compare the median change in exercise duration with ivabradine to the median change in exercise duration with placebo.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ivabradine	Placebo Oral Tablet
Arm/Group Description	Ivabradine will be administered for a total of 6 weeks Ivabradine is taken orally twice daily Dosage will be adjusted according to physician determination Ivabradine: lower heart rate in heart failure patients.	Placebo will be administered for a total of 6 weeks Placebo is taken orally twice daily Dosage will be adjusted according to physician determination Placebo Oral Tablet: Procedure prescribed to compare the active effect of a medicine.
Measure Participants	12	10
Median (Full Range) [minutes]	0.4	-0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ivabradine, Placebo Oral Tablet
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Other Pre-specified Outcome

Title	To Evaluate Whether Ivabradine Improves Additional Markers of Cardiac Sympatho-vagal Balance, Compared To Placebo, In Survivors Of Lymphoma
Description	Calculate the change in cardiac autonomic function (from cardiac autonomic function testing) from baseline to 6 weeks in one half of the patients in the study (n=30)
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	To Evaluate Whether Ivabradine Improves Health Related Quality Of Life Compared To Placebo, In Survivors Of Lymphoma
Description	Calculate the change in health related quality of life (from SF-36 quality of life surveys) from baseline to 6 weeks for each patient in the study (n=60)
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	6 weeks
Arm/Group Title	Ivabradine		Placebo Oral Tablet
Arm/Group Description	Ivabradine will be administered for a total of 6 weeks Ivabradine is taken orally twice daily Dosage will be adjusted according to physician determination Ivabradine: lower heart rate in heart failure patients.		Placebo will be administered for a total of 6 weeks Placebo is taken orally twice daily Dosage will be adjusted according to physician determination Placebo Oral Tablet: Procedure prescribed to compare the active effect of a medicine.
All Cause Mortality
	Ivabradine		Placebo Oral Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/11 (0%)
Serious Adverse Events
	Ivabradine		Placebo Oral Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Ivabradine		Placebo Oral Tablet
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/12 (25%)		1/11 (9.1%)
Cardiac disorders
heart failure	1/12 (8.3%)	1	0/11 (0%)	0
sinus bradycardia	1/12 (8.3%)	1	0/11 (0%)	0
Ear and labyrinth disorders
Dizziness	0/12 (0%)	0	1/11 (9.1%)	1
General disorders
fatigue	1/12 (8.3%)	1	0/11 (0%)	0
Musculoskeletal and connective tissue disorders
Ankle pain	1/12 (8.3%)	1	0/11 (0%)	0
Respiratory, thoracic and mediastinal disorders
dyspnea	0/12 (0%)	0	1/11 (9.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.