Exclusion Criteria (section 6.2, page 22): the word ‘invasive’ has been added to the third exclusion criteria to clearly specify ‘invasive breast cancer’ Treatment Details (section 8.1, page 24): clarification has been made to explain until when patients should continue their trial treatment (also mentioned on page 28) Two stratification variables have been removed (page 23): ‘clinical nodal involvement’ and ‘participation in translation sub protocol’ Schedule of Assessments (section 9, page 26): updated to make clearer when samples are required Pharmacy/drug distribution contact details (throughout the protocol) have been modified to direct the reader to refer to the trial-specific Investigator Site Files for detailed information Trial management/data collection section (section 10, page 29): minor modifications have been made to reflect updates in CRFs required Administrative changes have been made throughout eg. replacing ‘Centre’ by ‘Site’, replacing/removing the abbreviation CRCTU and updating contact details where applicable

Changes to Clinical Trial agreement

• TRANS Neo-excel sub-study has been made optional, removing the requirement for tissue and blood sample collection and the additional 14 day biopsy. A new version of the PIS and ICF (Version A) has been created for use at sites that choose not to participate in this optional sub-study. • The existing PIS and ICF (Version B) have been simplified, although the basic information regarding the trial remains the same, so the intent is not to re-consent patients for this study. • The Breast Biopsy- PIS and Pathology ICF have been amended and renamed and are now called the PIS - Donating Tissue for Research and Research Tissue ICF respectively. • An optional PIS has been created which provides a very brief and simple summary about the trial, which sites can choose to give to patients prior to the PIS. • Statistical analysis and sample size sections have been rewritten to indicate that a meaningful analysis can be preformed between the celecoxib and placebo arms if only 434 patients are recruited. • Additional instructions regarding unbinding outside of office hours. • Section 15.2 patient confidentiality has been reworded in line with CRCTU procedures and also to indicates that from now on patient’s signed and dated ICFs will be returned to the CRCTU. The PIS and consent has also been updated to include this information. • Appendix 3 has been updated with the 1996 version of the Declaration of Helsinki as specified by The Medicines for Human Use (Clinical Trials) Regulations 2004. • PIS, ICF, GP letter have been removed from appendix 7-11 and separate documents have been created. • In eligibility criteria, the breast tumour size now includes postmenopausal women with ER positive tumours ≥ 2 cm. Also tumours must be measured clinically as ≥ 2cm and not measured on ultrasound. • Changes to the definition of serious adverse event to bring it in line with current CRCTU definitions.

Sample size reduced from 1000 to 256 subjects Changes to trial objectives. New objective is to whether the activity of aromatase inhibitors as primary neo-adjuvant endocrine therapy for early stage ER positive breast cancer in postmenopausal women may be enhanced by the addition of the selective COX 2 inhibitor celecoxib. Changes to trial design and statistical analysis. Prospective phase III, multicentre, randomised clinical trial, with placebo-controlled comparisons.

The recruitment target has been reduced to 256 patients. The statistical analysis and sample size sections of the protocol have been rewritten to highlight this change. Other major changes to the protocol include: • Modification to the RECIST criteria. The RECIST is irrelevant to the trial as we are not reviewing target lesions and non-target lesions. • Introduction of Patient Contact Cards, which will be given to all patients randomised into the trial on which the patient trial number, allocated treatment and contact details for emergency unblinding will be recorded.

In summary, the duration of treatment period (16 weeks) has been clarified throughout the protocol. In addition, Patient Information Sheets (A and B) and Informed Consent Forms (A and B) have also been amended to include subheadings “excludes Trans NEO-EXCEL sub-study” and “includes Trans NEO-EXCEL sub-study” to further clarify their separate uses within NEO-EXCEL study. Other major changes to the protocol include: • Changes to the Randomisation telephone an fax number • Changes to the SAE Reporting fax number • Unit for creatinine measurement corrected to µmol/l • Recruitment target amended from 1000 to 256 patients on Patient Information Sheet A and B • Changes in Principal Investigator at two sites: o Dr Tahir Farooq has taken over the role of Principal Investigator instead of Dr Alan Jewkes at Good Hope Hospital o Mr Simon Smith has taken over the role of Principal Investigator instead of Prof Paul Sauven at Broomfield Hospital (formerly known as Chelmsford and Essex County Hospital) We would also like to extend the recruitment period for this trial to 1 May 2014 and therefore the duration of the ethical approval for this trial from 1 May 2012 to 1 May 2019, which includes an extended recruitment phase and 5 years follow-up.

In summary, due to the current Celecoxib/placebo stock expiring in the end of October 2013 and the recruitment period continuing until May 2014, we require a new stock of Celecoxib/placebo treatment packs. The current stock of Celecoxib is of 400mg strength but it is only possible to purchase 200mg strength for the new stock. Therefore the following changes have been made: • Protocol o Change from “celecoxib 400mg, one capsule twice daily” to “celecoxib 200mg, two capsules twice daily”. o The drug distribution company has changed its name to Sharp Clinical Services. • GP Letter o Change from “Celecoxib 400mg bd” to “Celecoxib 2 x 200mg bd”. In addition the following changes will occur: • Addition of four new sites: o Dr Karen McAdam will be the Principal Investigator at Peterborough City Hospital. o Mr Jibril Jibril will be the Principal Investigator at Lincoln County Hospital, Grantham and District Hospital, and Pilgrim Hospital. • Changes in Principle Investigator at one site: o Dr Diane Ritchie has taken over the role of Principal Investigator instead of Dr Peter Canney at Beatson West of Scotland Cancer Centre. • Protocol: o Dr Susanna Kallioinen has taken over from Dr Jaspreet Babrah as the Trial Co-ordinator. o Mrs Cassandra Brookes has taken over from Dr Laura Buckley as the Statistician.

Change in principal Investigator

Changes to end of trial definition, Chief Investigator and Trial Management Group