Prostate Adenocarcinoma: TransCutaneous Hormones versus luteinising hormone-releasing hormone (LHRH) analogues

ISRCTN	ISRCTN70406718
DOI	https://doi.org/10.1186/ISRCTN70406718
EudraCT/CTIS number	2005-001030-33
ClinicalTrials.gov number	NCT00303784
Secondary identifying numbers	MRC PR09

Submission date: 14/07/2005
Registration date: 12/09/2005
Last edited: 13/05/2024

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

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

http://www.cancerhelp.org.uk/trials/a-trial-looking-at-hormone-patches-for-prostate-cancer

Study website

Contact information

Prof Ruth Langley
Scientific

MRC Clinical Trial Unit at UCL
Institute of Clinical Trials and Methodology
90 High Holborn, 2nd Floor
London
WC1V 6LJ
United Kingdom

Phone	+44 (0)20 7670 4700
Email	mrcctu.pr09@ucl.ac.uk

Study information

Study design	Randomised controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
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	A randomised controlled trial of transcutaneous oestrogen patches versus luteinising hormone-releasing hormone (LHRH) analogues in prostate cancer
Study acronym	PATCH
Study objectives	Current hypothesis as of 17/04/2023: The primary objective of the trial is to confirm that transdermal oestradiol is a safe and efficacious therapy for patients with locally advanced and metastatic prostate cancer. The final phase III evaluation of efficacy will test the hypothesis that transdermal oestradiol is non-inferior to standard ADT in terms of progression-free survival and overall survival. However, there is a possibility that transdermal oestradiol may improve overall survival compared to standard ADT. First, transdermal oestradiol may reduce treatment-associated morbidity and could potentially benefit overall survival. Second, up to 30% of people with castrate-resistant prostate cancer respond to oral oestrogen as post-relapse therapy, suggesting oestradiol therapy may potentially have additional direct anti-tumour effects. Hence, if transdermal oestradiol is shown to be non-inferior compared to LHRHa in terms of overall survival, it will also be assessed for superiority. _____ Previous hypothesis as of 09/12/2014: The primary objective of the trial is to confirm that transdermal oestrogen is a safe and efficacious therapy for patients with locally advanced and metastatic prostate cancer. The final phase III evaluation of efficacy will test the hypothesis that patches are non-inferior to LHRH in terms of overall survival and progression-free survival. _____ Previous hypothesis: The primary objective of this study is to confirm that oestrogen patches are a safe and efficacious therapy for patients with locally advanced and metastatic prostate cancer. Transcutaneous oestrogen avoids first-pass hepatic metabolism and therefore is not expected to be associated with the same level of cardiovascular system (CVS) toxicity as oral oestrogen. Patients with locally advanced or metastatic prostate cancer will be randomised between transcutaneous oestrogen patches and luteinising hormone-releasing hormone (LHRH) analogues in a 2:1 ratio in order to maximise experience with the patches. The primary endpoint of the study is CVS toxicity. For a summary of a systematic review on the use of parenteral oestrogens in prostate cancer undertaken to inform the design of this study please see Appendix H or access the following link: http://www.york.ac.uk/inst/crd/pdf/parentoestrogen.pdf).
Ethics approval(s)	Leeds (East) REC, 23/11/2005, ref: 05/Q1206/168
Health condition(s) or problem(s) studied	Prostate cancer
Intervention	LHRH analogues versus transdermal oestrogen patches.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	Transdermal oestrogen
Primary outcome measure	Current primary outcome measures as of 09/12/2014: The primary outcome measures for the final phase III evaluation of the patches are overall survival (OS) and progression-free survival (PFS). The outcome measure which will be used to assess efficacy of the patches during interim analyses is PFS. Previous primary outcome measures: CVS morbidity and mortality. Criteria for differing CVS events will be defined as follows: 1. Heart Failure: New clinical signs/symptoms and/or CXR changes of heart failure requiring the use or change of diuretics and/or angiotensin-converting enzyme inhibitors 2. Ischaemic Heart Disease: Myocardial infarction diagnosed by at least two of the following: 2.1. Typical cardiac chest pain for 30 minutes or more 2.2. Cardiac enzymes greater than 2 times upper limit of normal 2.3. Typical ECG changes: 2.3.1. Unstable angina (typical cardiac chest pain at rest) for greater than 15 minutes 2.3.2. Stable angina-exercise induced pain with increasing frequency of attacks lasting greater than 15 minutes or a long-lasting attack (greater than 15 minutes) with newly developed ST-changes or T wave inversion 3. Cerebral ischaemic event: cerebral infarction seen on computerised tomography (CT) or magnetic resonance imaging (MRI). Transient ischaemic attacks with clear neurological symptoms from regions of the internal carotid or vertebral arteries. 4. Intermittent Claudication: severe intermittent claudication at a maximum walking distance of 200 metres 5. Venous thromboembolism: thromboses to be confirmed radiologically. Pulmonary embolism to be confirmed by means of ventilation/perfusion scans or angiography. 6. Death attributed to any of the above All cardiovascular events will be reviewed by two blinded reviewers.
Secondary outcome measures	Current secondary outcome measures as of 09/12/2014: The secondary outcome measures include prostate cancer specific survival, hormone levels, CVS and other toxicity, and quality of life (QL). In the first stage of the trial (completed in 2010), the primary outcome measure was CVS toxicity. Previous secondary outcome measures: 1. Activity (castrate levels of hormones): luteinishing hormone (LH) and follicle-stimulating hormone (FSH) will be measured pre-randomisation and then at 12 weeks, 6 months and then at 1 and 2 years post randomisation. Testosterone will be measured pre-randomisation and then at 4 and 12 weeks, 6 months and then at 1 and 2 years post randomisation to confirm that castrate levels are achieved and maintained. Adjustments to the dose of the patches will be made if necessary. Sex hormone binding globulin (SHBG) will be measured at pre-randomisation and then at 4 and 12 weeks, 6 months and then at 1 year post randomisation. Oestrone and oestradiol levels will be measured at baseline and at 4, 8 and 12 weeks, 6 months and then at 2 years. Fasting glucose, insulin and lipids will be measured at baseline, 6 months and 1 and 2 years. Urinary metabolites (hydroxyproline) will also be measured at baseline, 1 and 2 years. Clotting studies will include measurement of INR, APTT, Von Willebrand Factor, fibrinogen, and platelets at baseline, 6 months and 1 year. 2. Failure-free survival (FFS) (including biochemical failure) 3. Other toxicity (osteoporosis, hot flushes, gynaecomastia, anaemia): bone scans, CXR and CT/MRI scans of abdomen, pelvis and chest will be performed as clinically appropriate. Toxicity resulting in the patient stopping treatment will be measured, as will grade 3 or 4 toxicity at pre-specified time points using the NCI Common Toxicity Criteria (CTCv3). 4. Quality of life (QoL): QoL will be measured using patient-completed questionnaires (EORTC QLQ-C30 and PR25 which is prostate specific).
Overall study start date	01/09/2005
Completion date	01/02/2026

Eligibility

Participant type(s)	Patient
Age group	Mixed
Sex	Male
Target number of participants	2500
Total final enrolment	1854
Key inclusion criteria	Current inclusion criteria as of 09/12/2014: Newly diagnosed patients with one of the following: 1. Stage T3/4 NO or NX M0 histologically confirmed prostate adenocarcinoma with PSA ≥20 ng/ml or Gleason sum score ≥6 2. Stage Tany N+ M0 or Tany Nany M+ histologically confirmed prostate adenocarcinoma 3. Multiple sclerotic bone metastases with a PSA ≥50 ng/ml without histological confirmation of prostate cancer OR Patients with histologically confirmed prostate adenocarcinoma previously treated with radical surgery and/or radiotherapy who are now relapsing, with at least one of the following: 1. PSA ≥4 ng/ml and rising with doubling time less than 6 months 2. PSA ≥20 ng/ml 3. Documented evidence of metastatic disease with PSA >4 ng/ml Note: Prior hormone therapy for localised disease must have been completed at least 12 months previously and have been no longer than 12 months in duration. It can have been given as adjuvant or neoadjuvant therapy. Patients who have started bicalutamide or flutamide (up to 4 weeks prior to date of randomisation) are eligible. Patients who have started cyproterone acetate prior to randomisation are not eligible. AND For all patients 1. Intention to treat with continuous long-term ADT (> 3 years) 2. Fit for all protocol treatment and follow-up, WHO performance status 0-2 3. Should have completed the appropriate investigations prior to randomisation 4. Normal testosterone level prior to hormone treatment (>6 nmol/L) 5. Written informed consent 6. Willing and expected to comply with follow-up schedule 7. For newly diagnosed N0M0 patients only - Intention to treat with radical radiotherapy Previous inclusion criteria: Newly diagnosed patients with one of the following: 1. Stage T3/4 NX M0 histologically confirmed prostate adenocarcinoma with prostate specific antigen (PSA) greater than or equal to 20 ng/ml or Gleason sum score greater than or equal to 6 2. Stage Tany N+ M0 or Tany Nany M+ histologically confirmed prostate adenocarcinoma 3. Multiple sclerotic bone metastases with a PSA greater than or equal to 50 ng/ml without histological confirmation OR Patients with histologically confirmed prostate adenocarcinoma previously treated with radical surgery or radiotherapy who are now relapsing with one of: 1. PSA greater than or equal to 4 ng/ml and rising with doubling time less than 6 months 2. PSA greater than or equal to 20 ng/ml Note: Prior hormone therapy for localised disease must have been completed at least 12 months previously and have been no longer than 12 months in duration. It can have been given as adjuvant or neoadjuvant therapy. For all patients: 1. Intention to treat with long-term androgen deprivation therapy (ADT) 2. Fit for all protocol treatment and follow-up, World Health Organization (WHO) performance status 0 - 2 3. Have completed the appropriate investigations prior to randomisation 4. Normal testosterone level prior to hormone treatment 5. Written informed consent 6. Willing and expected to comply with follow-up schedule
Key exclusion criteria	Current exclusion criteria as of 09/12/2014: 1. Prior systemic therapy for locally advanced or metastatic prostate cancer except as listed in participant inclusion criteria 2. Any other previous or current malignant disease or CVS disease which is thought likely to compromise the patient’s ability to tolerate therapy or affect assessment 3. Cardiovascular exclusions: 3.1. Any history of cerebral ischaemia (e.g. stroke or TIA) within 2 years of randomisation 3.2. Any history of DVT or PE confirmed radiologically or a known thrombophilic disorder (e.g. Protein C, protein S, or antithrombin deficiency) 3.3. History of myocardial infarction/acute coronary syndrome: 3.3.1. Within the last 6 months 3.3.2. Greater than 6 months with evidence of q-wave anterior infarct on ECG 3.4. Unstable angina (typical cardiac chest pain at rest lasting more than 15 minutes) within the last year 3.5. Angina that occurs on walking 100 metres on the level or after climbing one flight of stairs at a normal pace and in normal condition, or angina that causes marked limitation of ordinary physical activity or occurs at rest 3.6. Heart failure: if patients have symptoms such as shortness of breath or oedema that are attributable to heart failure and this causes marked limitation of activity and/or they are comfortable only at rest then they should be excluded from the study 3.7. BP ≥160/100 (if either systolic or diastolic BP is greater than or equal to these values then the patient is not eligible) 3.8. Pulmonary oedema on CXR 4. Known porphyria Previous exclusion criteria: 1. Prior systemic therapy for locally advanced or metastatic prostate cancer 2. Any other previous or current malignant disease or CVS disease which, in the judgement of the responsible physician, is likely to interfere with PATCH treatment or assessment. 3. Cardiovascular exclusions: 3.1. Any history of cerebral ischaemia (e.g. stroke or transient ischaemic attack [TIA]) 3.2. Any history of deep vein thrombosis (DVT) or pulmonary embolism (PE) confirmed radiologically 3.3. History of myocardial infarction 3.3.1. Within the last 6 months 3.3.2. Greater than 6 months with evidence of q-wave anterior infarct on electrocardiogram (ECG) (right lead [RL]) 3.4. Unstable angina (typical cardiac chest pain at rest lasting more than 15 minutes) within the last year 3.5. Angina that occurs on walking 100 metres on the level or after climbing one flight of stairs at a normal pace and in normal condition, or angina that causes marked limitation of ordinary physical activity or occurs at rest 3.6. Heart failure: If patients have symptoms such as shortness of breath or oedema that are attributed to heart failure and this causes marked limitation of activity and/or they are comfortable only at rest then they should be excluded from the study 3.7. Blood pressure (BP) greater than or equal to 160/100 (if either systolic or diastolic BP greater than these values then the patient is not eligible) 3.8. Pulmonary oedema on chest x-ray (CXR) Patients that have a history of ischaemic heart disease or heart failure are required to have an Echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA). Patients with left ventricular ejection fraction less than 40% will be excluded.
Date of first enrolment	01/09/2005
Date of final enrolment	01/04/2020

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Hammersmith Hospital

London
W12 0NN
United Kingdom

Sponsor information

Imperial College London (UK)
University/education

c/o Mr Gary Roper
Imperial College London
Faculty of Medicine
Level 2, Faculty Building
South Kensington Campus
London
SW7 2AZ
England
United Kingdom

Website	http:\\www.ic.ac.uk
"ROR"	https://ror.org/041kmwe10

Funders

Funder type

Charity

Cancer Research UK
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Medical Research Council (MRC) (UK)
Government organisation / National government

Alternative name(s): Medical Research Council (United Kingdom), UK Medical Research Council, MRC
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Other publications	Early hormonal data	01/08/2008		Yes	No
Other publications	Cardiovascular outcomes	01/04/2013		Yes	No
Other publications	1-yr change in lumbar spine bone mineral density in a subset of participants	01/06/2016		Yes	No
Other publications	Long-term cardiovascular mortality and morbidity	13/02/2021	15/02/2021	Yes	No

Editorial Notes

13/05/2024: The overall study end date has been changed from 01/09/2024 to 01/02/2026
17/04/2023: The following changes have been made:
1. The recruitment end date has been changed from 31/03/2018 to 01/04/2020.
2. The overall trial end date has been changed from 31/03/2021 to 01/09/2024.
3. The study website has been updated.
4. The scientific contact has been changed.
5. The study hypothesis has been changed.
6. The target number of participants has been changed from 2150 to 2500.
7. The final enrolment number has been changed from 1694 to 1854.
15/02/2021: Publication reference and total final enrolment number added.
02/08/2017: publication reference added.
09/12/2014: The following changes were made to the trial record:
1. The trial was changed from Phase II to Phase III.
2. The overall trial end date was changed from 30/09/2013 to 31/03/2021.
3. The target number of participants was changed from 200 to 2150.
15/02/2011: The overall trial end date has been updated from 01/06/2009 to 30/09/2013.
16/02/2009: The overall trial end date was changed from 01/09/2010 to 01/06/2009.