Condition category
Cancer
Date applied
14/07/2005
Date assigned
12/09/2005
Last edited
09/12/2014
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Mr Paul Abel

ORCID ID

Contact details

Block B
Department of Surgery
Hammersmith Hospital
Du Cane Road
London
W12 0NN
United Kingdom
+44 (0)20 8383 2268
p.abel@imperial.ac.uk

Additional identifiers

EudraCT number

2005-001030-33

ClinicalTrials.gov number

NCT00303784

Protocol/serial number

MRC PR09

Study information

Scientific title

A randomised controlled trial of transcutaneous oestrogen patches versus luteinising hormone-releasing hormone (LHRH) analogues in prostate cancer

Acronym

PATCH

Study hypothesis

Current 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).

On 16/02/2009 the overall trial end date was changed from 01/09/2010 to 01/06/2009.

On 15/02/2011 the overall trial end date has again been updated from 01/06/2009 to 30/09/2013.

On 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

Ethics approval

Leeds (East) REC, 23/11/2005, ref: 05/Q1206/168

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Prostate cancer

Intervention

LHRH analogues versus transdermal oestrogen patches.

Intervention type

Drug

Phase

Phase III

Drug names

Transdermal oestrogen

Primary outcome measures

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 trial start date

01/09/2005

Overall trial end date

31/03/2021

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Mixed

Gender

Male

Target number of participants

2150

Participant 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.

Recruitment start date

01/09/2005

Recruitment end date

31/03/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Hammersmith Hospital
London
W12 0NN
United Kingdom

Sponsor information

Organisation

Imperial College London (UK)

Sponsor details

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

Sponsor type

University/education

Website

http:\\www.ic.ac.uk

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Medical Research Council (MRC) (UK)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2008 results in: http://www.ncbi.nlm.nih.gov/pubmed/18422771
2009 planned interim analysis results in: http://meetinglibrary.asco.org/content/20418-64
2011 results in: http://meetinglibrary.asco.org/content/72277-104
2011 results in: Langley RE, Jinks RC, Sundaram SK, Clarke NC, Kynaston HG, Alhasso AA, Rosen SD, Kockelbergh R, Parmar MK, Pollock P, Cafferty FH and Abel PD. Hormone responses in prostate cancer patients treated with transcutaneous oestrogen patches: Results from a randomised phase II Trial (MRC PR09 PATCH). EAU Annual Congress 2011 Abstract #1097.
2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23465742

Publication citations

  1. Results

    Langley RE, Godsland IF, Kynaston H, Clarke NW, Rosen SD, Morgan RC, Pollock P, Kockelbergh R, Lalani el-N, Dearnaley D, Parmar M, Abel PD, Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer., BJU Int., 2008, 102, 4, 442-445, doi: 10.1111/j.1464-410X.2008.07583.x.

  2. Planned interim analysis results

    Langley RE, Kynaston H, Clarke NW, Godsland IF, Rosen SD, Morgan RC, Pollock P, Parmar MK, Abel PD, PATCH, a randomised phase II trial of oestrogen patches versus LHRH as first-line hormonal therapy for prostate cancer: Planned interim analysis results, Genitourinary Cancers Symposium 2009, Abstract #173.

  3. Results

    Abel PD, Sundaram SK, Kynaston HG, Clarke N, Alhasso AA, Rosen SD, Jinks RC, Pollock P, Cafferty FH, Langley RE, Cardiovascular events and clinical responses in prostate cancer patients treated with transcutaneous oestrogen patches compared with LHRH analogues: Results from a randomized phase II trial (MRC PR09 PATCH), Genitourinary Cancers Symposium 2011 , Abstract #201.

  4. Results

    Langley RE, Jinks RC, Sundaram SK, Clarke NC, Kynaston HG, Alhasso AA, Rosen SD, Kockelbergh R, Parmar MK, Pollock P, Cafferty FH, Abel PD, Hormone responses in prostate cancer patients treated with transcutaneous oestrogen patches: Results from a randomised phase II Trial (MRC PR09 PATCH), EAU Annual Congress 2011, Abstract #1097.

  5. Results

    Langley RE, Cafferty FH, Alhasso AA, Rosen SD, Sundaram SK, Freeman SC, Pollock P Jinks RC, Godsland IF, Kockelbergh R, Clarke NW, Kynaston HG, Parmar MKB, Abel PD, Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09), Lancet Oncol., 2013, 14, 4, 306-316, doi: 10.1016/S1470-2045(13)70025-1.

Additional files

Editorial Notes