E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of cardiac dysfunction during adjuvant breast cancer treatment with anthracycline containing chemotherapy, with or without radiation or trastuzumab. |
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E.1.1.1 | Medical condition in easily understood language |
Heart failure occurring during modern breast cancer treatment. The breast cancer treatment consists of anthracycline containing chemotherapy with or without radiation or immunotherapy. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10057654 |
E.1.2 | Term | Breast cancer female |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10050528 |
E.1.2 | Term | Ejection fraction decreased |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In patients with early breast cancer scheduled for anthracycline-containing anti-cancer therapy, to assess whether the administration of Entresto can prevent or is associated with attenuation of the reduction in left ventricular systolic function measured by cardiovascular magnetic resonance (CMR) |
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E.2.2 | Secondary objectives of the trial |
To assess whether the administration of Entresto is associated with:
(1) prevention of reduction in left ventricular systolic function measured by echocardiography or CMR
(2)reduced incidence of a significant reduction in left ventricular systolic function measured by CMR or echocardiography
(3) reduced incidence of cardiotoxicity measured by CMR or echocardiography
(4) reduced early, acute and late, chronic cardiotoxic injury measured by cardiac biomarkers |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Women with histological evidence of invasive early breast cancer scheduled for adjuvant therapy with anti-cancer regimens that include anthracyclines
- Eastern Cooperative Oncology Group performance status 0-1
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E.4 | Principal exclusion criteria |
- Age <18 years
- Renal failure, i.e. serum creatinine greater than 133 umol/L (1,5 mg/dl) or estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2
- Hyperkalemia, i.e. serum potassium greater than 5.0 mmol/L
- Systolic blood pressure < 100 mg Hg
- Uncontrolled hypertension
- Acute myocardial infarction within the last three months
- Contraindication to angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) or sacubitril/valsartan, including previous hypersensitivity reaction, angioedema and renal artery stenosis
- ACEI, ARB, or aldosterone antagonist use within 4 weeks of study start
- Clear indication for ACEI, ARB, or aldosterone antagonist therapy, including symptomatic heart failure
- History of hemodynamically significant valvular disease
- Active liver disease, i.e. alanine aminotransferase or aspartate aminotransferase greater than 1.5 times the upper limit of normal
- Participation in another pharmaceutical clinical trial of an investigational medicinal product less than 4 weeks prior to inclusion or use of other investigational drugs within 5 half-lives of enrollment, whichever is longer
- Psychiatric or mental disorders, alcohol abuse or other substance abuse
- Language barriers or other factors which makes adherence to the study protocol difficult
- Suspected poor drug compliance
- Contraindication or inability to undergo CMR examination. Patients who are unable to complete the baseline CMR investigation will be excluded
- Pregnancy or breastfeeding
- Life expectancy < 12 months |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in left ventricular ejection fraction (LVEF), as determined by CMR from randomization to end of blinded therapy (18 months). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
In addition to Visit 1, main scheduled visits are as following:
Visit 2: at a minimum 5 days and maximum 3 weeks after completion of anthracycline containing chemotherapy but before initiation of additional therapy
Visit 3: at a minimum 18 months and maximum 19 months after initiation of chemotherapy. If trastuzumab treatment exceeds this time frame, visit 3 should be at a minimum 5 days and maximum 4 weeks after completion of trastuzumab
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E.5.2 | Secondary end point(s) |
Secondary endpoints:
(1) a. Change in left ventricular ejection fraction (LVEF), as determined by echocardiography from randomization to end of blinded therapy (18 months)
b. Change in GLS, as determined by echocardiography from randomization to end of blinded therapy (18 months)
c. Change in end-systolic volume measured by CMR
(2) Incidence of clinically significant reduction in left ventricular systolic function expressed as
a. A reduction in LVEF equal or more than 5% by CMR or
b. A relative percentage reduction of global longitudinal strain (GLS) > 15%
(3) Incidence of cardiotoxicity expressed as:
a. Reduction in LVEF 10% to a value below 50% as measured either by CMR or Echocardiography or
b. Incidence of clinical heart failure
(4) Cardiotoxic injury expressed as change in circulating concentrations of cardiac troponins I and T measured by high sensitivity assays (hs-TnI and hs-TnT) and N-terminal proB-type natriuretic peptide (NT-proBNP)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
In addition to Visit 1, main scheduled visits are as following:
Visit 2: at a minimum 5 days and maximum 3 weeks after completion of anthracycline containing chemotherapy but before initiation of additional therapy
Visit 3: at a minimum 18 months and maximum 19 months after initiation of chemotherapy. If trastuzumab treatment exceeds this time frame, visit 3 should be at a minimum 5 days and maximum 4 weeks after completion of trastuzumab
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |