A Study to Examine the Effectiveness of Aspirin and/or Vitamin D3 to Prevent Prostate Cancer Progression (PROVENT)

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

To demonstrate the acceptability and feasibility of recruitment to a randomised chemoprevention study of standard (300mg) or low dose (100mg) aspirin vs. placebo and/or Vitamin D3 vs. placebo in patients enrolled on an Active Surveillance programme for prostate cancer.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: High dose Aspirin & Vitamin D; Drug: High dose Aspirin, Vitamin D placebo; Drug: Aspirin placebo, Vitamin D placebo; Drug: Low dose Aspirin , Vitamin D; Drug: Low dose Aspirin, Vitamin D placebo; Drug: Aspirin Placebo, Vitamin D

Detailed Description

The PROVENT study is 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

The main outcome measure of the trial is the rate of patient recruitment to a randomised chemoprevention study in men enrolled on an Active Surveillance programme for prostate cancer

Secondary outcomes include the response to treatment as determined by serial multi-parametric magnetic resonance imaging (MRI) of the prostate, biochemical disease progression and histological disease progression after 12 months of therapy and finally toxicity and/or allergy to both aspirin and Vitamin D3.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Dartford, United Kingdom, DA2 8DA
    • Darent Valley Hospital
  • London, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • London, United Kingdom, CV2 2DX
    • University Hospital UHCW NHS Trust
  • London, United Kingdom, EC1A 7BE
    • St Bartholomews Hospital London, Bart's and the London school of Medicine
  • London, United Kingdom, NW1 2B
    • University College Hospital London
  • London, United Kingdom
    • Homerton Hospital
  • Southampton, United Kingdom, S016 6YD
    • Southampton General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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. Must have undergone a multi-parametric MRI of the prostate, deemed assessable by the local radiologist, and any lesions seen must have undergone targeted biopsy, (transrectal or transperineal) within 12 months of study registration.

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. All must be met for Inclusion:

     • Gleason score 6 or 7 (Gleason 3+3 or 3+4)
     • Clinical and radiological stage <T3
     • Serum Prostate Specific Antigen (PSA) ≤15.0 ng/ml
     • Less than 10mm of cancer in a single core

Exclusion Criteria:

1. Previously treated prostate cancer (including radiotherapy, hormone therapy, brachytherapy or surgery)
2. Currently enrolled, or has been a participant within the last 30 days, in any other investigational drug or device study.
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 >400IU Vitamin D within two years of study enrolment
4. Current or previous use of 5-α 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 ( glucose-6-phosphate dehydrogenase) deficiency
17. Pre-existing macular degeneration
18. All contraindications to aspirin and Vitamin D3 (e.g. Sarcoidosis), including concomitant therapy with any medication that may interact with aspirin or Vitamin D3 (see section 4.10)
19. Tuberculosis
20. Regular consumption of alcohol units greater than the recommended daily limit of 3-4 units per day (men)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose Aspirin & Vitamin D; Aspirin high dose (300mgs) daily & Vitamin D 4,000 IU (0.1mg) per day	Drug: High dose Aspirin & Vitamin D; Aspirin 1 x 300mg tablet daily & Vitamin D 4,000IU daily. (8 drops).; Other Names: Aspirin - acetylsalicylic acid; Vitamin D - Vigantol® Oil
Experimental: High dose Aspirin, Vitamin D placebo; high dose aspirin (300mgs) daily and Vitamin D placebo (Miglyol®812 Oil)	Drug: High dose Aspirin, Vitamin D placebo; Aspirin 1 x 300mg tablet daily & Vitamin D placebo (8 drops).; Other Names: Aspirin - acetylsalicylic acid; Vitamin D placebo - Miglyol®812 Oil; Drug: Aspirin placebo, Vitamin D placebo; Aspirin 1 x 100mg placebo tablet daily & Vitamin D 4,000IU daily. (8 drops).; Other Names: Vitamin D placebo - Miglyol®812 Oil; Aspirin Placebo, Vitamin D
Experimental: Low dose Aspirin , Vitamin D; Low dose aspirin (100mgs) daily & Vitamin D 4,000 IU (0.1mg) per day	Drug: Low dose Aspirin , Vitamin D; Aspirin 1 x 100mg tablet daily & Vitamin D 4,000IU daily. (8 drops).; Other Names: Aspirin - acetylsalicylic acid; Vitamin D - Vigantol® Oil
Placebo Comparator: Low dose Aspirin, Vitamin D placebo; Low dose aspirin (100mgs) daily and Vitamin D placebo (Miglyol®812 Oil)	Drug: Low dose Aspirin, Vitamin D placebo; Aspirin 1 x 100mg tablet daily & Vitamin D placebo 8 drops daily.; Other Names: Aspirin - acetylsalicylic acid; Vitamin D placebo - Miglyol®812 Oil
Experimental: Aspirin Placebo, Vitamin D; Aspirin placebo and Vitamin D active ingredient - Vigantol® Oil	Drug: Low dose Aspirin , Vitamin D; Aspirin 1 x 100mg tablet daily & Vitamin D 4,000IU daily. (8 drops).; Other Names: Aspirin - acetylsalicylic acid; Vitamin D - Vigantol® Oil; Drug: Aspirin Placebo, Vitamin D; Aspirin 1 x 300mg placebo tablet daily & Vitamin D 4,000IU daily. (8 drops).; Other Names: Vitamin D - Vigantol® Oil
Experimental: Aspirin placebo, Vitamin D placebo; Aspirin placebo and Vitamin D placebo - Miglyol®812 Oil	Drug: Aspirin placebo, Vitamin D placebo; Aspirin 1 x 100mg placebo tablet daily & Vitamin D 4,000IU daily. (8 drops).; Other Names: Vitamin D placebo - Miglyol®812 Oil; Aspirin Placebo, Vitamin D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Patient Recruitment to a Randomised Chemoprevention Study in Men Enrolled on an Active Surveillance Programme for Prostate Cancer. Number Accrued Per Month.	The proportion of eligible patients that join the trial over the 12-month trial recruitment period.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to Treatment as Determined by Serial Multi-parametric Magnetic Resonance Imaging (MRI) of the Prostate. New Lesion Present or Existing Lesion + or - in Size.	Radiological progression was defined as 'development of a Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion (17) on mpMRI, where no lesion was identified before, 33% volume increase in the size of the lesion, or radiological upstaging to T3 or above based on local site reports.' Absence of these features represented radiologically stable disease. Lesion on multi-parametric imaging where no MRI lesion at screening. An MRI scan shows a screening + or - in volume by > 33%, or an upgrading of MRI stage of disease to ≥3.	3 years
Number of Participants With Biochemical (PSA) Disease Progression	50% increase in serum Prostate Specific Antigen at 12 months from baseline.	12 months
Number of Participants With Histological Disease Progression	Histological disease progression will be defined as an increase in Gleason scores from: Gleason 3+3 to Gleason score 7 or higher Gleason 3+4 (score 7) to 4+3 (score 7) or Gleason 4+3 to a higher score Or a 50% increase in maximum cancer core length (MCCL)	3 years
Number of Patients With Adverse With Toxicity, Allergy or Symptoms From Aspirin or Vitamin D	Aspirin toxicity: Haemorrhagic stroke, anaphylaxis following administration, gastrointestinal bleeding requiring intervention (both medical and surgical) Vitamin D3 toxicity: Hypercalcaemia, Anaphylaxis	18 months + 30 days

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: Cancer Research UK; Barts and the London School of Medicine and Dentistry
• Investigators: Principal Investigator: Greg Shaw, MD, Queen Mary London; Study Director: Jack Cuzick, PhD, Queen Mary London

Publications and helpful links

Helpful Links

• PROVENT STUDY WEBSITE

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): March 31, 2020
• Study Completion (Actual): March 31, 2020

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: April 5, 2017
• First Posted (Actual): April 6, 2017

Study Record Updates

• Last Update Posted (Actual): March 29, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Prostate Cancer; Active Surveillance; Chemo-prevention
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Aspirin; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: isrctn91422391

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO