To examine the clinical effectiveness of aspirin and/or Vitamin D3 to prevent disease progression in men on active surveillance for prostate cancer

ISRCTN	ISRCTN91422391
DOI	https://doi.org/10.1186/ISRCTN91422391
EudraCT/CTIS number	2014-001784-13
ClinicalTrials.gov number	NCT03103152
Secondary identifying numbers	PROVENT: Version 5.0

Submission date: 06/04/2014
Registration date: 16/04/2014
Last edited: 23/05/2023

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

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-of-active-surveillance-aspirin-and-vitamin-d-in-men-with-prostate-cancer-provent#undefined

Study website

Contact information

Ms Roseann Kealy
Public

Centre for Cancer Prevention
Wolfson Institute of Preventive Medicine
Charterhouse Square
London
EC1M 6BQ
United Kingdom

Phone	+44 20 7882 3520
Email	provent@qmul.ac.uk

Mr Greg Shaw
Scientific

St Bartholomew's Hospital
Urology Department
West Smithfield
London
EC1A 7BE
United Kingdom

Phone	+44 (0)20 3594 2671
Email	gregshaw@nhs.net

Study information

Study design	Randomised double blind placebo-controlled feasibility study
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Other
Study type	Prevention
Participant information sheet	IRSCTN91422391_PIS_05May16_V3.pdf
Scientific title	PROVENT: A randomised, double blind, placebo-controlled feasibility study to examine the clinical effectiveness of aspirin and/or Vitamin D3 to prevent disease progression in men on active surveillance for prostate cancer
Study acronym	PROVENT
Study objectives	That men enrolled onto an active surveillance programme for the management of prostate cancer will actively participate in a randomised chemoprevention study of standard (300mg) or low dose (100mg) aspirin vs placebo and/or Vitamin D vs placebo.
Ethics approval(s)	London-Hampstead Committee London, 18/11/2014, ref: 14/LO/2033
Health condition(s) or problem(s) studied	Prostate cancer
Intervention	The principal method of randomisation will be by means of a purpose designed web-based application, developed by Barts CTU, which will be accessible to all relevant research staff. Staff will be trained in the use of this application. The applications' Case Report Forms will reaffirm the patient's eligibility and require confirmation that the consent form has been satisfactorily signed and countersigned. Eligible participants will be randomised into one of 6 arms of the study to receive one of the following: 1. Aspirin 300mg + Vitamin D3 2. Aspirin 300mg + Vitamin D3 placebo 3. Aspirin 100mg + Vitamin D3 4. Aspirin 100mg + Vitamin D3 placebo 5. Aspirin placebo + Vitamin D3 6. Aspirin placebo + Vitamin D3 placebo Randomised blocks will be used to maintain balance amongst these 6 arms. In addition, the aspirin placebo groups will be block randomised to either small or large aspirin placebo tablets. The allocated study number will correspond to pre-labelled pots of trial medication held in pharmacy. In the event that the web application is unavailable, a paper backup system will be available, and randomisations may be made using a FAX backup system. Once a patient has been successfully randomised, the enrolment of the patient will be documented on the PROVENT Screening Log. Dosage: Vitamin D3: 4,000IU/0.1mg (6 drops) orally daily or matched placebo Aspirin: 100mg daily orally or matched placebo Aspirin: 300mg daily orally or matched placebo
Intervention type	Supplement
Primary outcome measure	Rate of patient recruitment to a randomised chemoprevention study in men enrolled on an Active Surveillance programme for prostate cancer. This will be determined by screening logs and screening/randomisation case report forms.
Secondary outcome measures	1. To report response to treatment as determined by serial multi-parametric magnetic resonance imaging (MRI) of the prostate - measured by performing repeat prostate MRI imaging 2. To report biochemical disease progression - measured by measuring serum PSA levels 3 monthly 3. To report histological disease progression - measured by measuring serum PSA levels 3 monthly 4. To report toxicity and/or allergy to both aspirin and Vitamin D. Toxicity will be evaluated 3 monthly using the Adverse Events Case Report Form and the patient diary cards on which patients will record side effects and adverse reactions 5. To evaluate an association between androgens and disease progression. Blood will be taken to measure serum androgen levels every 6 months - at baseline, 6 months, 12 months and 18 months 6. To evaluate markers of disease progression. Urinary markers of disease progression (PCA3 and TMPRSS2-ERG) will be evaluated at baseline and 12 months. Tissue will be collected from the baseline and 12 month prostate biopsies for Cell Cycle Progression scores.
Overall study start date	01/10/2014
Completion date	31/03/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	16 Years
Sex	Male
Target number of participants	102
Total final enrolment	130
Key inclusion criteria	Current inclusion criteria as of 10/12/2018: 1. Male subjects aged 16 years or over with an estimated life expectancy of more than three years 2. Willing and able to provide written informed consent 3. Corrected serum calcium <2.65 mmol/l 4. No previous treatment for prostate cancer (including surgery, hormone therapy, radiotherapy, cryotherapy) 5. All subjects must have had Magnetic Resonance Imaging (MRI) of the prostate with targeted biopsy of any lesions identified 6. Histologically confirmed prostate cancer* following prostate biopsy (including at least 10 cores of prostate tissue) in men opting for Active Surveillance as their primary cancer therapy PROVENT Prostate Cancer Criteria for Inclusion: 1. Gleason score 6 or 7 (Gleason 3+3 or 3+4) 2. Clinical and radiological stage <T3 3. Serum PSA of 15.0 ng/ml or below Less than 10 mm of cancer in a single core 7. Patients must have undergone a multi-parametric MRI deemed assessable by the local radiologist, and any lesions seen must have undergone targeted biopsy (transrectal or transperineal) within 12 months of study enrolment. Previous inclusion criteria: 1. Male subjects aged 16 years or over with an estimated life expectancy of more than three years 2. Willing and able to provide written informed consent 3. Corrected serum calcium <2.65mmol/l 4. No previous treatment for prostate cancer (including surgery, hormone therapy, radiotherapy, cryotherapy) 5. All subjects must have had Magnetic Resonance Imaging (MRI) of the prostate with targeted biopsy of any lesions identified 6. Histologically confirmed prostate cancer following prostate biopsy (including at least 10 cores of prostate tissue) in men opting for Active Surveillance as their primary cancer therapy *PROVENT Prostate Cancer Criteria for Inclusion: 1. Gleason score 6 or 7 2. Clinical and radiological stage <T3 3. Serum PSA of 15.0 ng/ml or below Less than 10mm of cancer in a single core 7. Patients must have undergone a multi-parametric MRI deemed assessable by the local radiologist, and any lesions seen must have undergone targeted biopsy (transrectal or transperineal) within 12 months of study enrolment.
Key exclusion criteria	Current exclusion criteria as of 10/12/2018: 1. Previously treated prostate cancer (including radiotherapy, hormone therapy, brachytherapy or surgery) 2. Current enrolment in an investigational drug, device or other clinical research study or participation in such a study within 30 days of randomisation 3. Current daily use of aspirin or NSAIDs; or daily dietary supplements/medication containing more than 400 IU (10 micrograms per day)Vitamin D; or chronic use (defined as > 6 months continuous daily use) of either aspirin or Vitamin D within two years of study enrolment 4. Current or previous use of 5-alpha-reductase inhibitors such as finasteride or dutasteride 5. Not willing to comply with the procedural requirements of this protocol including repeat prostate biopsies 6. Known allergy/sensitivity to or intolerance of aspirin, other salicylates or NSAIDs e.g. ibuprofen/ naproxen 7. Prior history of gastro-intestinal bleeding or ulceration, severe dyspepsia or inflammatory bowel disease 8. Haemophilia or other bleeding diatheses 9. Prior history of renal stone disease 10. Chronic renal disease (≥ stage 4) 11. Known hypercalcaemia (corrected serum calcium >2.65 mmol/l) or untreated hyperparathyroidism 12. Any bowel condition that would make repeat transrectal biopsy hazardous or difficult to perform e.g. recto-urethral fistula, or prior bowel surgery such as abdomino-perineal resection. 13. Any malignancy (other than non-melanoma skin cancer) that has not been in complete remission for five years 14. Any serious co-existent medical condition that would make repeat prostate biopsy hazardous e.g. anti-coagulation requiring continuous administration 15. Severe Asthma 16. G6PD deficiency 17. Pre-existing macular degeneration 18. All contraindications to aspirin and Vitamin D (e.g. Sarcoidosis), including concomitant therapy with any medication that may interact with aspirin or Vitamin D 19. Tuberculosis 20. Regular consumption of alcohol units greater than the recommended daily limit of 3-4 units per day (men) Previous exclusion criteria: 1. Previously treated prostate cancer (including radiotherapy, hormone therapy, brachytherapy or surgery) 2. Current enrolment in an investigational drug, device or other clinical research study or participation in such a study within 30 days of randomisation 3. Current daily use of aspirin or NSAIDs; or daily dietary supplements/medication containing more than 400 IU (10 micrograms per day)Vitamin D; or chronic use (defined as > 6 months continuous daily use) of either aspirin or Vitamin D within two years of study enrolment 4. Current or previous use of 5-alpha-reductase inhibitors such as finasteride or dutasteride 5. Not willing to comply with the procedural requirements of this protocol including repeat prostate biopsies 6. Known allergy/sensitivity to or intolerance of aspirin, other salicylates or NSAIDs e.g. ibuprofen/ naproxen 7. Prior history of gastro-intestinal bleeding or ulceration, severe dyspepsia or inflammatory bowel disease 8. Haemophilia or other bleeding diatheses 9. Prior history of renal stone disease 10. Chronic renal disease (¡Ýstage 4) 11. Known hypercalcaemia (corrected serum calcium >2.65 mmol/l)or untreated hyperparathyroidism 12. Any bowel condition that would make repeat transrectal biopsy hazardous or difficult to perform e.g. recto-urethral fistula, or prior bowel surgery such as abdomino-perineal resection. 13. Any malignancy (other than non-melanoma skin cancer) that has not been in complete remission for five years 14. Any serious co-existent medical condition that would make repeat prostate biopsy hazardous e.g. anti-coagulation requiring continuous administration 15. Severe Asthma 16. G6PD deficiency 17. Pre-existing macular degeneration 18. All contraindications to aspirin and Vitamin D, including concomitant therapy with any medication that may interact with aspirin or Vitamin D (see section 4.10) 19. Regular consumption of alcohol units greater than the recommended daily limit of 3-4 units per day (men)
Date of first enrolment	16/12/2016
Date of final enrolment	16/12/2017

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Centre for Cancer Prevention

London
EC1M 6BQ
United Kingdom

Sponsor information

Queen Mary University of London (UK)
University/education

Representative of Sponsor:
Mays Jawad
Research & Development Operations Manager
Joint Research Management Office
QM Innovation Building
5 Walden Street
London
E1 2EF
England
United Kingdom

Phone	+44 207 882 7275
Email	sponsorsrep@bartshealth.nhs.uk
"ROR"	https://ror.org/026zzn846

Funders

Funder type

Charity

Bart's and the London Charity (UK) - Clinical Trials Awards and Advisory Committee (CTAAC) endorsed

No information available

Results and Publications

Intention to publish date	31/03/2021
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal. Any information used for publication in peer reviewed journals will be anonymised and presented at aggregate, and not individual, level. Barts & the London Charity, and CR-UK will be informed of the results. In addition, they will be disseminated to the participants via the PROVENT website.
IPD sharing plan	The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	version V3	05/05/2016	03/04/2017	No	Yes
Participant information sheet	version V4.0	16/02/2017	26/01/2018	No	Yes
Protocol file	version V4.0	16/02/2017	26/01/2018	No	No
Protocol file	version V5.0	18/08/2018	10/12/2018	No	No
Basic results		16/12/2020	20/05/2022	No	No
Results article		11/06/2022	08/07/2022	Yes	No
Plain English results			23/05/2023	No	Yes
HRA research summary			28/06/2023	No	No

Additional files

IRSCTN91422391_PIS_05May16_V3.pdf: Uploaded 03/04/2017
ISRCTN91422391_PIS_V4.0_16Feb17.pdf: Uploaded 26/01/2018
ISRCTN91422391_PROTOCOL_V4.0_16Feb17.pdf: Uploaded 26/01/2018
ISRCTN91422391_Protocol _V5.0_18Aug2018.pdf: Uploaded 10/12/2018

Editorial Notes

23/05/2023: A link to plain English results on CRUK was added.
08/07/2022: Publication reference and total final enrolment added.
20/05/2022: EU Clinical Trials Register results added.
11/03/2021: Contact details updated.
06/01/2021: Contact details updated, IPD sharing statement added.
18/12/2020: Internal review.
04/11/2020: The following changes were made to the trial record:
1. The overall end date was changed from 31/10/2019 to 31/03/2020.
2. The intention to publish date was changed from 30/06/2020 to 31/03/2021.
05/08/2019: ClinicalTrials.gov number added.
10/12/2018: The following changes have been made:
1. Uploaded protocol version 5.0 18 August 2018 (not peer-reviewed)
2. The participant inclusion criteria have been changed.
3. The participant exclusion criteria have been changed.
4. The Representative of Sponsor has been changed from Coleen Colechin to Mays Jawad.
5. The protocol/serial number has been changed from "PROVENT: Version 4.0" to "PROVENT: Version 5.0".
06/06/2018: The following changes have been made:
1. Dr Adedayo Oke has been added as a scientific contact.
2. The Representative of Sponsor has been changed from Sally Burtles to Coleen Colechin.
26/01/2018: The protocol has been updated from Version 3 to Version 4. Uploaded protocol Version 4 16 February 2017 (not peer-reviewed). The fourth version of the patient information sheet has been uploaded. The trial website has been added. The PI confirmed that recruitment has finished.
03/04/2017: Primary study contact changed from Mr Paul Cathcart to Ms Roseann Kealy. Cancer Help UK lay summary link added to plain English summary field. Updated ethics approval. Added publication and dissemination plan. Study end date was updated from 01/10/2017 to 31/10/2019. Recruitment dates changed from 01/10/2017 - 01/10/2017 to 16/12/2016 - 16/12/2017. Sponsor representative changed from Gerry Leonard to Sally Burtles. Protocol version was updated from Version 1.0 to Version 3.0
06/02/2017: Internal review.