| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prostate cancer disease progression |
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| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer that may develop from a low to intermediate risk form of the disease into a more aggressive form |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The principal research objective for this study is to demonstrate the acceptability and feasibility of recruiting 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. |
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| E.2.2 | Secondary objectives of the trial |
The secondary research objectives for this study are:
1. To report response to treatment as determined by magnetic resonance imaging (MRI) of the prostate and to assess consistency of reporting
2. To report cancer progression based on an increase in serum PSA (Prostate Specific Antigen)
3. To report cancer progression based on an increase in prostate cancer grade or volume, and to assess consistency of reporting
4. To report adverse reactions and/or allergy to aspirin and/or Vitamin D3
5. To assess various laboratory tests, both standard tests and specific research tests, to see how they may help us identify aggressive prostate cancer earlier
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. No previous treatment for prostate cancer (including surgery, hormone therapy, radiotherapy, cryotherapy)
4. All subjects must have Magnetic Resonance Imaging (MRI) of the prostate with targeted biopsy of any lesions identified
5. Histologically confirmed prostate cancer following prostate biopsy in men opting for Active Surveillance as their primary cancer therapy
6. Serum calcium (corrected) less than or equal to 2.65mmol/l
Prostate cancer criteria for inclusion:
1. Gleason score 6 or 7
2. Clinical and radiological stage <T3
3. Serum PSA < or = 15.0 ng/ml
4. Less than 10mm of cancer in a single core
Patients must have undergone a multiparametric MRI prior to study enrolment together with a prostate biopsy targeting any MRI observed lesions within 12 months of study enrolment. |
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| E.4 | Principal 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-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 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)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The PROVENT study is a feasibility study to determine whether men with prostate cancer managed with active surveillance are willing to be enrolled into a randomised placebo-controlled chemoprevention trial evaluating aspirin and Vitamin D.
Therefore the primary outcome measure of this feasibility study is patient recruitment over the 18 month study period. Screening logs and Case Report Forms (CRFs) will be utilised to measure patient recruitment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint of the study is the rate of patient recruitment. This will be captured by reporting the proportion of eligible patients that join the trial over the 18-month trial recruitment period.
After a recruitment period of 9 months, the Data Monitoring Committee will identify whether study recruitment has been adequate, i.e. an average recruitment rate of 6 patients per month, and if monitoring of 50% of the feasibility group shows minimal adverse effects in any arm of the trial, this information will be used to justify the main trial.
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| E.5.2 | Secondary end point(s) |
The secondary endpoints for PROVENT are:
To report response to treatment as determined by serial multi-parametric magnetic resonance imaging (MRI) of the prostate. Disease progression being defined as the development of a lesion on multi-parametric imaging where no MRI lesion was identified on screening MRI, or alternatively, an MRI scan that demonstrates that a lesion identified on screening MRI has increased or decreased in volume by greater than 33%.
To report biochemical disease progression - defined as a 50% increase in serum PSA at 12 months from baseline.
To report histological disease progression - 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)
To report toxicity and/or allergy to both aspirin and Vitamin D.
To evaluate an association between androgens and disease progression
To evaluate markers of disease progression
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MRI detected disease progression together with biochemical and histological disease progression will be captured 12 months after study entry.
All trial patients will undergo repeat MRI imaging and prostate biopsy at 12 months allowing comparison with baseline investigations.
All patients will undergo sequential PSA testing at 3 monthly intervals. To capture final outcome a mixed linear model will be applied on log (1+PSA) to test for dose-by-time interactions.
Toxicity and/or allergy will be captured continuously throughout the study period. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Recruitment feasibility and patient acceptability |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS - will be the end of the active phase
LPLDI - Last Patient Last Data Item will be the end of the non-interventional follow up period, which will be LVLS plus 10 years |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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