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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: High dose Aspirin & Vitamin D
* Drug: High dose Aspirin, Vitamin D placebo
* Drug: Low dose Aspirin , Vitamin D
* Drug: Low dose Aspirin, Vitamin D placebo
* Drug: Aspirin Placebo, Vitamin D
* Drug: Aspirin placebo, Vitamin D placebo


Participation Criteria
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Eligibility Criteria
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Male subjects aged 16 years or over with an estimated life expectancy of more than three years Willing and able to provide written informed consent Corrected serum calcium ≤ 2.65mmol/l No previous treatment for prostate cancer (including surgery, hormone therapy, radiotherapy, cryotherapy) 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. 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: Previously treated prostate cancer (including radiotherapy, hormone therapy, brachytherapy or surgery) Currently enrolled, or has been a participant within the last 30 days, in any other investigational drug or device study. 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 Current or previous use of 5-α reductase inhibitors such as finasteride or dutasteride Not willing to comply with the procedural requirements of this protocol including repeat prostate biopsies Known allergy/sensitivity to or intolerance of aspirin, other salicylates or NSAIDs e.g. ibuprofen/ naproxen Prior history of gastro-intestinal bleeding or ulceration, severe dyspepsia or inflammatory bowel disease Haemophilia or other bleeding diatheses Prior history of renal stone disease Chronic renal disease (≥stage 4) Known hypercalcaemia (corrected serum calcium >2.65 mmol/l) or untreated hyperparathyroidism 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. Any malignancy (other than non-melanoma skin cancer) that has not been in complete remission for five years Any serious co-existent medical condition that would make repeat prostate biopsy hazardous e.g. anti-coagulation requiring continuous administration Severe Asthma G6PD ( glucose-6-phosphate dehydrogenase) deficiency Pre-existing macular degeneration 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) Tuberculosis Regular consumption of alcohol units greater than the recommended daily limit of 3-4 units per day (men)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Active Surveillance, Chemo-prevention