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Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline Pilot Study (SPARE-HF)

Primary Purpose

Cancer, Heart Failure, Cardiotoxicity

Status

Active

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Atorvastatin

Placebo oral tablet

About this trial

This is an interventional prevention trial for Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with one of the following malignancies requiring anthracycline based chemotherapy with a curative intent: breast cancer; aggressive lymphomas; leukemia (acute myelogenous leukemia, acute lymphoblastic leukemia, mixed phenotype acute leukemia) or; sarcoma
Patients with high cardiovascular risk defined as:
I. ≥60 years and at least one of the following:
i. Compromised cardiac function based on baseline LVEF <55% measured by echocardiography or MUGA or moderate left sided valvular heart disease (moderate mitral or aortic regurgitation or stenosis) ii. Planned cumulative doxorubicin dose equivalent 200mg/m² or more iii. Prior anthracycline therapy at any cumulative dose or prior chest/mediastinal radiation therapy iv. Any one of hypertension, smoking, obesity (BMI≥30), history of cardiomyopathy or heart failure but with recovered LVEF to ≥ 50%
OR
II. Age <60 years with one of the following:
i. and at least 2 of the risk factors listed above (I i-iv) ii. type 2 diabetes with age <40 iii. type 1 diabetes duration <15 years
OR
III. High anthracycline dose defined as ≥250mg/m² of doxorubicin, ≥600mg/m² epirubicin, or other isoequivalent dose
Living within geographic area conducive to repeated clinical and imaging follow-up

Exclusion Criteria:

Participating in another clinical research study where randomization would be unacceptable
Previous history of statin intolerance
Already on statin therapy or known statin indicated condition:
I. atherosclerosis i. myocardial infarction ii. acute coronary syndrome iii. stable angina iv. documented coronary disease by angiography (>10% stenosis) v. stroke vi. TIA vii. documented carotid disease viii. peripheral arterial disease ix. claudication and/or ABI <0.9
II. abdominal aortic aneurysm (>3.0cm or previous aneurysm surgery)
III. chronic kidney disease (>3 months duration and ACR >3.0mg/mmol or eGFR <60mL/min/1.73m²)
CK level >3x upper limit of normal
Evidence of hepatic dysfunction (ALT level >2x upper limit of normal)
On a drug that is a strong inhibitor of cytochrome P450 3A4 or may require such treatment during the treatment period (because atorvastatin is metabolized by this pathway)
Significant valvular heart disease defined as severe stenotic or regurgitant lesions of any of the cardiac valves
Life expectancy less than 12 months
Contraindication to cardiac MRI (e.g. implanted pacemakers, ICDs, other implanted ferromagnetic objects unsafe for cardiac MRI or will result in significant artifact, eGFR <30)
Creatinine >177umol/L
Known history of uncontrolled hypothyroidism (TSH level >1.5x upper limit of normal)

Sites / Locations

Toronto General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebos

Statin

Arm Description

Placebos

Atorvastatin 40mg

Outcomes

Primary Outcome Measures

Cardiac MRI measured LVEF within 4 weeks of anthracycline completion

Cardiac MRI LVEF at the end of treatment will be measured before cancer treatment and within 4 weeks after completion of anthracycline-based treatment. The pre-treatment measurement will facilitate a baseline adjusted comparison between placebo and statin treated groups.

Secondary Outcome Measures

Full Information

NCT ID

NCT03186404

First Posted

June 9, 2017

Last Updated

February 4, 2022

Sponsor

University Health Network, Toronto

Collaborators

Mount Sinai Hospital, Canada, Unity Health Toronto, Sunnybrook Health Sciences Centre, Scarborough General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03186404

Brief Title

Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline Pilot Study

Acronym

SPARE-HF

Official Title

Randomized Double Blind Placebo Controlled Trial of Statins for the Primary pREvention of Heart Failure in Patients With Cancer Receiving Anthracycline Based Chemotherapy

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Active, not recruiting

Study Start Date

May 10, 2018 (Actual)

Primary Completion Date

December 21, 2021 (Actual)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Health Network, Toronto

Collaborators

Mount Sinai Hospital, Canada, Unity Health Toronto, Sunnybrook Health Sciences Centre, Scarborough General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Anthracycline (AC) chemotherapy has substantially reduced the mortality rate from several common cancers globally. Unfortunately, AC treatment is associated with up to 19% risk of heart failure (HF). Current standard of care for preventing AC induced HF (AIHF) is cardiac surveillance followed by initiation of treatment once HF is diagnosed. With this approach 89% of patients fail to recover heart function and 46% will experience adverse cardiac events. Therefore there is a need for effective preventive therapy to reduce the risk of AIHF. Based on small human studies, animal studies, and our own pilot data, statins are an ideal class of drug for this purpose. We will conduct a pilot double blinded, placebo controlled, randomized controlled trial to assess whether pre-treatment with statins before AC can prevent heart dysfunction. Eligible patients with cardiovascular risk factors scheduled to receive AC will be recruited. They will be randomized to statin therapy or placebo and followed until the end of cancer treatment. Primary outcome is the difference in cardiac MRI-determined left ventricular ejection fraction between pre-AC and end of treatment.

Detailed Description

STUDY DESIGN: This is a double blind, placebo controlled randomized controlled trial (RCT). We will also use stratification to ensure that the proportion of patients with different malignancies is balanced between the study arms. PATIENT RECRUITMENT: Patients will be recruited from respective oncology clinics at Princess Margaret Hospital, Mount Sinai Hospital, St. Michael's Hospital, Sunnybrook Health Sciences Centre and Scarborough General Hospital. INTERVENTION: Patients will receive treatment with 40mg/day of atorvastatin or placebo started 2-10 days prior to the initiation of AC and continued for up to one month after completion of the AC portion of cancer treatment. CARDIAC MRI (CMR): Studies will be performed on a 3.0T scanner (Siemens) and will include complete function and tissue characterization. CMR studies will be performed pre-therapy, after completion of AC, and 2 years after completion of AC. After de-identification and randomization, a research assistant blinded to all clinical data will perform all CMR analysis using commercially available software. ECHOCARDIOGRAPHY: Routine echocardiography studies will be performed at baseline, post-anthracycline completion, and at 6 months, 1 year, and 2 years follow up. SERUM BIOMARKERS: Blood work will be obtained on the day of baseline imaging, immediately after each cycle of anthracycline, on the day of post treatment imaging, and at the 6 months, 1 year and 2 year follow up. At each time point, optional samples of bio-banking may be collected. Blood sample collection will be done locally at the participant's respective site and transferred to University Health Network (UHN) biobank for future analysis or analysis of markers that are not available at all sites (e.g. high sensitivity troponin I and BNP).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cancer, Heart Failure, Cardiotoxicity

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

112 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebos

Arm Type

Placebo Comparator

Arm Description

Placebos

Arm Title

Statin

Arm Type

Experimental

Arm Description

Atorvastatin 40mg

Intervention Type

Drug

Intervention Name(s)

Atorvastatin

Other Intervention Name(s)

Statin

Intervention Description

Atorvastatin 40mg OD

Intervention Type

Drug

Intervention Name(s)

Placebo oral tablet

Other Intervention Name(s)

Placebo

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

Cardiac MRI measured LVEF within 4 weeks of anthracycline completion

Description

Time Frame

Within 4 weeks of cancer therapy completion

Other Pre-specified Outcome Measures:

Title

Cardiac MRI measured LV end diastolic volume (LVEDV) and end systolic volume (LVESV) at the end of treatment

Description

these measures will be obtained at the same time as the LVEF measures with pre-treatment measurements facilitating a baseline adjusted comparison between placebo and statin treated groups

Time Frame

Within 4 weeks of anthracycline completion

Title

The incidence of cardiotoxicity

Description

defined by LVEF fall >10% from pre-cancer treatment assessment to <53%

Time Frame

From start of anthracycline therapy to upto 4 weeks of anthracycline completion

Title

Interruption of study drug due to side effects or permanent cessation of study drug or cancer treatment due to cardiac dysfunction

Description

as defined by reduction in drug dose or delay of cancer treatment by more than 1 week or permanent cessation

Time Frame

From start of anthracycline therapy to upto 4 weeks of anthracycline completion

Title

Troponin I

Description

Maximal increase in troponin I

Time Frame

Maximal increase in Troponin I between pre-anthracycline therapy to within 4 weeks of anthracycline completion

Title

BNP

Description

Maximal increase in BNP

Time Frame

From start of anthracycline therapy to within 4 weeks of cancer therapy completion

Title

Myocardial strain

Description

Maximal change in myocardial strain

Time Frame

From start of anthracycline therapy to within 4 weeks of cancer therapy completion

Title

MRI tissue characterization parameters

Description

Maximal change in myocardial tissue characterization parameters as measured by cardiac MRI from pre-anthracycline treatment to within 4 weeks of anthracycline completion

Time Frame

Within 4 weeks of anthracycline completion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with one of the following malignancies requiring anthracycline based chemotherapy with a curative intent: breast cancer; aggressive lymphomas; leukemia (acute myelogenous leukemia, acute lymphoblastic leukemia, mixed phenotype acute leukemia) or; sarcoma Patients with high cardiovascular risk defined as: I. ≥60 years and at least one of the following: i. Compromised cardiac function based on baseline LVEF <55% measured by echocardiography or MUGA or moderate left sided valvular heart disease (moderate mitral or aortic regurgitation or stenosis) ii. Planned cumulative doxorubicin dose equivalent 200mg/m² or more iii. Prior anthracycline therapy at any cumulative dose or prior chest/mediastinal radiation therapy iv. Any one of hypertension, smoking, obesity (BMI≥30), history of cardiomyopathy or heart failure but with recovered LVEF to ≥ 50% OR II. Age <60 years with one of the following: i. and at least 2 of the risk factors listed above (I i-iv) ii. type 2 diabetes with age <40 iii. type 1 diabetes duration <15 years OR III. High anthracycline dose defined as ≥250mg/m² of doxorubicin, ≥600mg/m² epirubicin, or other isoequivalent dose Living within geographic area conducive to repeated clinical and imaging follow-up Exclusion Criteria: Participating in another clinical research study where randomization would be unacceptable Previous history of statin intolerance Already on statin therapy or known statin indicated condition: I. atherosclerosis i. myocardial infarction ii. acute coronary syndrome iii. stable angina iv. documented coronary disease by angiography (>10% stenosis) v. stroke vi. TIA vii. documented carotid disease viii. peripheral arterial disease ix. claudication and/or ABI <0.9 II. abdominal aortic aneurysm (>3.0cm or previous aneurysm surgery) III. chronic kidney disease (>3 months duration and ACR >3.0mg/mmol or eGFR <60mL/min/1.73m²) CK level >3x upper limit of normal Evidence of hepatic dysfunction (ALT level >2x upper limit of normal) On a drug that is a strong inhibitor of cytochrome P450 3A4 or may require such treatment during the treatment period (because atorvastatin is metabolized by this pathway) Significant valvular heart disease defined as severe stenotic or regurgitant lesions of any of the cardiac valves Life expectancy less than 12 months Contraindication to cardiac MRI (e.g. implanted pacemakers, ICDs, other implanted ferromagnetic objects unsafe for cardiac MRI or will result in significant artifact, eGFR <30) Creatinine >177umol/L Known history of uncontrolled hypothyroidism (TSH level >1.5x upper limit of normal)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paaladinesh Thavendiranathan

Organizational Affiliation

University Health Network, Toronto

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Eitan Amir

Organizational Affiliation

University Health Network, Toronto

Official's Role

Principal Investigator

Facility Information:

Facility Name

Toronto General Hospital

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2N2

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline Pilot Study

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