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

• ClinicalTrials.gov Identifier: NCT03137537
• Recruitment Status: Terminated
• First Posted: May 2, 2017
• Results First Posted: February 10, 2022
• Last Update Posted: February 10, 2022
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Amgen
• Information provided by (Responsible Party): Anju Nohria, Dana-Farber Cancer Institute

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 (Clinical Trial)
• 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: February 27, 2018
• Actual Primary Completion Date: November 18, 2020
• Actual Study Completion Date: November 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 Name: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Boston Children Hospital

Boston, Massachusetts, United States, 02115

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)

Documents provided by Anju Nohria, Dana-Farber Cancer Institute:

Study Protocol and Statistical Analysis Plan  [PDF] December 16, 2016

Informed Consent Form  [PDF] September 18, 2019

More Information

• 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
• Results First Posted: February 10, 2022
• Last Update Posted: February 10, 2022
• Last Verified: January 2022

Individual Participant Data (IPD) Sharing Statement:

• 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, Dana-Farber Cancer Institute:

Lymphoma; Abnormal resting heart rate; Autonomic imbalance; Cancer survivorship

Additional relevant MeSH terms:

Autonomic Nervous System Diseases; Primary Dysautonomias; Nervous System Diseases