Thrombin inhibition preoperatively in early breast cancer

ISRCTN	ISRCTN14785273
DOI	https://doi.org/10.1186/ISRCTN14785273
EudraCT/CTIS number	2014-004909-33
Secondary identifying numbers	19731

Submission date: 05/11/2015
Registration date: 05/11/2015
Last edited: 16/04/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-a-blood-thinning-drug-for-women-with-breast-cancer-tip

Study website

Contact information

Mr Greg Gibson
Public

Cancer Research UK Liverpool Cancer Trials Unit
Block C, Waterhouse Building
1-3 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Phone	+44 (0)151 795 5289
Email	tiptrial@liverpool.ac.uk

Ms Helen Scott
Public

Cancer Research UK Liverpool Cancer Trials Unit
Block C
Waterhouse Building
1-3 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Phone	+44 (0)151 795 8209
Email	tiptrial@liverpool.ac.uk

Study information

Study design	Randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Other
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	Thrombin Inhibition Preoperatively in early breast cancer (TIP study)
Study acronym	TIP
Study hypothesis	Current study hypothesis as of 20/09/2018: The aim of this study is to determine whether preoperative oral Factor Xa inhibitor (Rivaroxaban) in oestrogen receptor negative early breast cancer patients results in inhibition of tumour proliferation markers as determined by a reduction in tumour Ki67 from baseline (pretreatment) to post treatment (at time of surgical excision/research core biopsy). Previous study hypothesis: The aim of this study is to determine whether preoperative oral Factor Xa inhibitor (Rivaroxaban) in oestrogen receptor negative early breast cancer patients results in inhibition of tumour proliferation markers as determined by a reduction in tumour Ki67 from baseline (pretreatment) to post treatment (at time of surgical excision).
Ethics approval(s)	First Medical Research Ethics Committee, 13/07/2015, ref: 15/NW/0406
Condition	Breast cancer
Intervention	Current interventions as of 20/09/2018: Patients will be randomised into 2 groups in a 1:1 ratio as follows: Group 1: Preoperative Rivaroxaban 20mg od and excisional approx 14 days later Group 2: No Preoperative therapy with surgery/research core biopsy approx 14 days later Patients should have their surgery/neoadjuvant chemotherapy booked prior to randomisation and scheduled for around two weeks ahead. All surgery will be completed to standard care. Patients will return 2 weeks following the date of surgery for post-op complications and adverse events review. All further follow-up will be as per standard NHS practice with annual clinical and mammographic examination. Previous interventions: Patients will be randomised into 3 groups in a 1:1:1 ratio as follows (with the Rivaroxaban treatment groups being combined for primary endpoint analysis creating a 2:1 randomisation for Rivaroxaban vs. no treatment): Group 1: Preoperative Rivaroxaban 20mg od and excisional approx 14 days later Group 2: Preoperative Rivaroxaban 10mg od and excisional approx 14 days later Group 3: No Preoperative therapy with surgery approx 14 days later Patients should have their surgery booked prior to randomisation and scheduled for around two weeks ahead, as long it is within 31 days from diagnosis. All surgery will be completed to standard care. Patients will return 2 weeks following the date of surgery for post-op complications and adverse events review. All further follow-up will be as per standard NHS practice with annual clinical and mammographic examination.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Rivaroxaban
Primary outcome measure	Current primary outcome measure as of 20/09/2018: Percentage reduction in tumour Ki67 expression is measured using tumour core biopsies at baseline (pre-rivaroxaban), surgery/research core biopsy (post-rivaroxaban). Previous primary outcome measure: Percentage reduction in tumour Ki67 expression is measured using tumour core biopsies at baseline (pre-rivaroxaban), surgery (post-rivaroxaban).
Secondary outcome measures	Current secondary outcome measure as of 20/09/2018: In post Rivaroxaban compared to pre- Rivaroxaban patient samples: 1. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 2. Reduction in tumour tissue expression of CD31 is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 3. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 4. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 5. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 6. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 7. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) In post Rivaroxaban compared to post placebo patient samples: 1. Reduction in MFE is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 3. Reduction in tumour tissue expression of CD31 is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 5. Reduction in CTCs is measured using patient samples at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 7. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) 8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery/research core biopsy (post-rivaroxaban) Previous secondary outcome measure: In post Rivaroxaban compared to pre- Rivaroxaban patient samples: 1. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 2. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 3. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 4. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 5. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 6. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 7. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) In post Rivaroxaban compared to post placebo patient samples: 1. Reduction in MFE is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 3. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 5. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 7. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) In post 20mg od Rivaroxaban compared to post 10mg Rivaroxaban patient samples (subgroup analysis): 1. Reduction in MFE is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 3. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 5. Reduction in CTCs is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 7. Reduction in plasma d-dimer, TF and TAT is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban) 8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre-rivaroxaban) and the time of surgery (post-rivaroxaban)
Overall study start date	26/06/2015
Overall study end date	30/09/2021

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Female
Target number of participants	Planned Sample Size: 88; UK Sample Size: 88; Description: The study is powered on a change in Ki67 from baseline to post treatment. A sample size of 44 patients in the Rivaroxaban arm can achieve 80% power to detect a 0.6 standard deviation (SD) geometric mean Ki67-difference with a two-sided test at the alpha-level of 0.05.
Participant inclusion criteria	Current inclusion criteria as of 20/09/2018: 1. Provision of written informed consent. 2. World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks 3. Patients must be able to swallow and retain oral medication 4. Female patients, age over 18, with histological confirmation of ER negative (ER Quick Score / Allred ≤5) invasive breast carcinoma 5. Any Her2 status 6. AJCC Stage 1- 3 with primary tumour in the breast amenable to biopsies 7. Scheduled to have definitive breast surgery 11 or more days after commencement of treatment or are able to take 11 or more days of rivaroxaban and have an additional core biopsy prior to starting neoadjuvant therapy. 8. Tumour size ≥10mm (large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy (free-hand or under ultrasound guidance as per local protocols)). 9. As judged by the Investigator, no evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. 10. No clinically significant abnormalities in the full blood count, renal or liver biochemistry, as decided by the PI, and where the PI is unsure they should contact the CI or Clinical Coordinator for a final decision. 11. Estimated Glomerular Filtration Rate (eGFR) above 50 ml/min. Previous inclusion criteria: 1. Female patients with histological confirmation of ER negative invasive breast carcinoma 2. Provision of written informed consent. 3. World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks 4. Patients must be able to swallow and retain oral medication 5. AJCC Stage 1-3 with primary tumour in the breast amenable to biopsies 6. Scheduled to have definitive breast surgery 11 or more days after study entry 7. Tumour size =10mm (large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy (freehand or under ultrasound guidance as per local protocols). 8. As judged by the site's Principal Investigator, no evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV) 9. Full blood count, renal and liver biochemistry (within 10% of laboratory normal limits) 10. EGFR above 50 11. Aged 18 or over
Participant exclusion criteria	Current exclusion criteria as of 20/09/2018: 1. Tumour size <10mm 2. Prior treatment for breast or other cancer (excluding non-melanoma skin cancer) 3. Concurrent anticoagulant therapy (excluding antiplatelet therapy such as aspirin or clopidogrel) 4. Concurrent treatment with azole-antimycotics (such as, ketoconazole, itraconazole, voriconazole and posaconazole); clarithromycin; HIV protease inhibitors; dronedarone; strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort); strong CYP3A4 or P-gp inhibitors 5. Major surgery within 4 weeks before the first dose of study treatment. 6. Conditions associated with an increased risk of bleeding: 6.1. Major surgery or trauma within the previous month 6.2. Haemorrhagic disorder or bleeding diathesis 6.3. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra‐articular bleeding 6.4. Gastrointestinal haemorrhage within the past year 6.5. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days 6.6. Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm 6.7. Need for anticoagulant treatment of disorders other than atrial fibrillation 6.8. Fibrinolytic agents within 48 hours of study entry 6.9. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg 7. Known hypersensitivity or allergy to rivaroxaban and/or excipients 8. Participation in another interventional trial 9. Pregnant or lactating women 10. All women of reproductive potential, unless using at least one contraceptive precaution, which must be a condom for at least two weeks after the end of their treatment Previous exclusion criteria: 1. Tumour size <10mm 2. Prior treatment for breast or other cancer (excluding non-melanoma skin cancer) 3. Concurrent anticoagulant therapy (excluding antiplatelet therapy such as aspirin or clopidogrel) 4. Concurrent treatment with azole-antimycotics (such as, ketoconazole, itraconazole, voriconazole and posaconazole); clarithromycin; HIV protease inhibitors; dronedarone; strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort); strong CYP3A4 or P-gp inhibitors 5. Major surgery within 4 weeks before the first dose of study treatment. 6. Conditions associated with an increased risk of bleeding: 6.1. Major surgery or trauma within the previous month 6.2. Haemorrhagic disorder or bleeding diathesis 6.3. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra‐articular bleeding 6.4. Gastrointestinal haemorrhage within the past year 6.5. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days 6.6. Any of the following intracranial pathologies: neoplasm, arteriovenous malformation or aneurysm 6.7. Need for anticoagulant treatment of disorders other than atrial fibrillation 6.8. Fibrinolytic agents within 48 hours of study entry 6.9. Uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg 7. Known hypersensitivity or allergy to rivaroxaban and/or excipients 8. Participation in another interventional trial 9. Pregnant or lactating women 10. All women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom for at least two weeks after the end of their treatment
Recruitment start date	01/01/2016
Recruitment end date	30/06/2021

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

University Hospital of South Manchester

Wythenshawe Hospital
Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom

Macclesfield District General Hospital

Victoria Road
Macclesfield
SK10 3BL
United Kingdom

North Manchester General Hospital

Delaunays Road
Manchester
M8 5RB
United Kingdom

The Royal Liverpool University Hospital

Prescot Street
Liverpool
L7 8XP
United Kingdom

The Royal Bolton Hospital

Minerva Road
Farnworth
Bolton
BL4 0JR
United Kingdom

Leeds Teaching Hospitals

Beckett Street
Leeds
LS9 7TF
United Kingdom

Clatterbridge Hospital

Wirral University Teaching Hospitals NHS Foundation Trust
Clatterbridge Road
Bebington
Wirral
CH63 4JY
United Kingdom

Churchill Hospital

Oxford Health NHS Foundation Trust
Old Road
Headington
Oxford
OX3 7LJ
United Kingdom

Sponsor information

Manchester University NHS Foundation Trust
Hospital/treatment centre

Southmoor Road
Wythenshawe
Manchester
M23 9LT
England
United Kingdom

"ROR"	https://ror.org/00he80998

Funders

Funder type

Government

National Institute for Health Research
Government organisation / National government

Alternative name(s): National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
Location: United Kingdom

Results and Publications

Intention to publish date	30/09/2022
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
Publication and dissemination plan	The results from different centres will be analysed together and published in a peer reviewed journal.
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	27/08/2020	02/09/2020	Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

16/04/2021: The following changes have been made:
1. The recruitment end date has been changed from 30/09/2019 to 30/06/2021.
2. The overall trial end date has been changed from 30/09/2019 to 30/09/2021.
3. The intention to publish date has been changed from 30/09/2020 to 30/09/2022.
02/09/2020: Publication reference added.
02/04/2019: The condition has been changed from "Topic: Cancer; Subtopic: Breast Cancer; Disease: Breast" to "Breast cancer" following a request from the NIHR.
21/09/2018: The following changes have been made:
1. The recruitment end date has been changed from 01/02/2018 to 30/09/2019.
2. An IPD sharing statement has been added.
20/09/2018: The following changes have been made:
1. Helen Scott has been added as a public contact.
2. The study hypothesis has been changed.
3. The intervention has been changed.
4. The primary outcome measures have been changed.
5. The secondary outcome measures have been changed.
6. The participant inclusion criteria have been changed.
7. The Participant inclusion criteria: Target number of participants has been changed from "Planned Sample Size: 81; UK Sample Size: 81; Description: The study is powered on a change in Ki67 from baseline to post treatment. A sample size of 43 patients, in the Rivaroxaban can achieve 90 % power to detect a 0.5 standard deviation (SD) geometric mean Ki67-difference with a two-sided test at the alpha-level of 0.05." to "Planned Sample Size: 88; UK Sample Size: 88; Description: The study is powered on a change in Ki67 from baseline to post treatment. A sample size of 44 patients in the Rivaroxaban arm can achieve 80% power to detect a 0.6 standard deviation (SD) geometric mean Ki67-difference with a two-sided test at the alpha-level of 0.05."
8. The total target enrolment has been changed from 81 to 88.
9. The participant exclusion criteria have been changed.
10. Leeds Teaching Hospitals, Clatterbridge Hospital and Churchill Hospital have been added as trial centres.
11. The sponsor name has been changed from University Hospital of South Manchester NHS Foundation Trust to Manchester University NHS Foundation Trust.
12. The intention to publish date has been changed from 31/01/2020 to 30/09/2020.
04/05/2018: The following changes have been made:
1. The overall trial end date has been changed from 01/03/2018 to 30/09/2019.
2. The intention to publish date has been changed from 30/06/2018 to 31/01/2020.
3. The public contact has been changed.
24/08/2016: Cancer Help UK lay summary link added.