E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006192 |
E.1.2 | Term | Breast cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To compare invasive disease-free survival (IDFS) in patients randomized
to standard (neo)adjuvant therapy plus placebo or standard
(neo)adjuvant therapy plus atorvastatin (80 mg/day for two years).
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E.2.2 | Secondary objectives of the trial |
- To compare overall survival (OS), recurrence-free interval (RFI),
distant recurrence-free interval (DRFI) including associations with first
site of recurrence, cardiac death-free interval, and overall
safety in the two treatment arms.
- To investigate morbidity endpoints as specified in the morbidity subprotocol.
- To address translational endpoints as specified in the translational subprotocol.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet ALL of the following criteria to be eligible for
randomization:
1. Women with estrogen receptor positive breast cancer who are
candidates for (neo)adjuvant systemic therapy OR have
received ≤3 years of adjuvant endocrine therapy.
2. Age > 18 years.
3. Performance status of ECOG ≤ 2.
4. Prior to patient registration, written informed consent must be
given according to ICH/GCP, and national/local regulations.
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E.4 | Principal exclusion criteria |
Patients meeting ANY one of the following criteria are not eligible:
1. History of any prior (ipsi- and/or contralateral) invasive breast
carcinoma.
2. Ongoing (prevalent) cholesterol-lowering therapy (statins,
fibrates, ezetimibe, PCSK9 inhibitors). If so, the patient can be
enrolled in the observational arm.
3. Evidence of hepatic dysfunction (alanine aminotransferase level
more than three times the upper limit of the normal range) or
renal dysfunction (creatinine level more than three times the
upper limit of the normal range).
4. Predisposing factors for rhabdomyolysis, including
hypothyroidism, reduced renal function, any muscle – or liver
disease, or excessive alcohol consumption AND creatine kinase
(CK) measured to less than five times the upper limit (CK only
measured in case of predisposing factors).
5. No current medication with potent CYP3A4-inhibitors (e.g.
ketokonazole, erythromycin) or gemfibrozile, cyclosporin or
danazol.
6. Pregnancy or breast-feeding.
7. Psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and
follow-up schedule; these conditions will be discussed with the
patient before registration in the trial.
8. History of allergic reactions attributed to compounds of similar
chemical or biological composition to atorvastatin.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is IDFS and is defined as the time
between randomization and date of first occurrence of an IDFS
event (as defined above in efficacy assessments).
The intention-to-treat (ITT) population will be used in the primary
analysis.
The stratified log-rank test will be used to compare IDFS between
the two treatment arms.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Recurrence-Free Interval
Distant Recurrence-Free Interval including associations with first
site of recurrence
Overall Survival
Death attributable to any cause, including non-breast cancer or
unknown cause, is considered a competing event.
Cardiac death-free interval. Cardiac death is defined as:
• Definitive cardiac death due to heart failure, myocardial
infarction or documented primary arrhythmia.
• Probable cardiac death defined as sudden, unexpected death
within 24 hours of a definite or probable cardiac event (e.g.,
syncope, cardiac arrest, chest pain, infarction, arrhythmia)
without documented etiology.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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) | Yes |
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 | 11 |
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 | No |
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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The trial will end 10 years after the last patient is included. |
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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 | 15 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |