E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
WHO: 0-2 Serum creatinine <140 umol/l Thyroid stimulating hormone between 0.5-3.9 MU/l. Blood pressure systolic ≥ 140 mmHg diastolic ≥ 90 mmHg is acceptable at randomization. LVEF 50% assessed by multigated angiography (MUGA) or cardiac ultrasound |
|
MedDRA Classification |
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 |
1) To determine whether concurrent ATII-antagonist treatment can prevent trastuzumab-related cardiotoxicity, defined as a decline in LVEF of more than 15% or a decrease of less than 15% to an absolute value below50% |
|
E.2.2 | Secondary objectives of the trial |
To determine if ‘Brain Natriuretic Peptide’ (NT-proBNP) and troponin T can be used as surrogate marker in the monitoring of trastuzumab-associated cardiotoxicity
2. To determine genetic variability in the HER2 gene (by assessing single nucleotide polymorphisms [SNPs] in the kinase domain) and explore any correlations with trastuzumab induced cardiotoxicity
3. To determine the reversibility of a decrease in left ventricular ejection fraction (LVEF) associated with trastuzumab treatment
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Women aged ≥18 years 2. WHO: 0-2 3. Strongly HER2-positive breast cancer, defined as an immunohistochemistry score of 3+ using the HercepTestTM or gene amplification by fluorescence in situ hybridization, or chromogenic in situ hybridization (CISH) 4. Serum creatinine <140 umol/l or creatinine clearance > 50 ml/min (by Cockcroft-Gault formula) 5. Thyroid stimulating hormone between 0.5-3.9 MU/l 6. Blood pressure systolic ≥ 140 mmHg diastolic ≥ 90 mmHg is acceptable at randomization. However prior to the first administration of trastuzumab blood pressure should be regulated and should be systolic ≥ 100 mmHg and ≤ 180 mmHg and diastolic ≥ 60 mmHg and ≤ 100 mmHg (blood pressure should be regulated according to the guidelines of appendix 5). 7. LVEF 50% assessed by multigated angiography (MUGA) or cardiac ultrasound. 8. (Neo-) adjuvant regimen: trastuzumab start ≥ 3 weeks after day 1 of the last anthracycline chemotherapy cycle 9. Trastuzumab treatment according standard medical care 10. Written informed consent to participate in the study
|
|
E.4 | Principal exclusion criteria |
1. Prior anthracycline chemotherapy regimen or anti-HER2 therapy, or other prior biologic or immunotherapy for breast cancer treatment or any malignancy 2. Previous malignancy requiring chemotherapy or radiotherapy 3. Uncontrolled serious concurrent illness 4. Patients with New York Heart Association (NYHA) class III/IV congestive heart failure 5. Myocardial infarction < 6 months before randomization 6. Treatment with ACE inhibitors, ATII blockers, or lithium. Patients treated with ACE inhibitors or ATII blockers can switch (after randomization and during the chemotherapy period) to alternative antihypertensive therapy; see appendix 5. 7. History of hypersensitivity to the study medication 8. Pregnancy or breast feeding
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is the occurrence of cardiotoxicity during the one year trastuzumab therapy and during the 26 weeks after discontinuation of trastuzumab treatment, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 50%.
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Information not present in EudraCT |
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.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
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 | Information not present in EudraCT |
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
|
Primary endpoint or when off safety reasons the study must be stopped. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |