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Trial registered on ANZCTR


Registration number
ACTRN12615000571572
Ethics application status
Approved
Date submitted
20/05/2015
Date registered
3/06/2015
Date last updated
22/05/2020
Date data sharing statement initially provided
1/04/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Randomised Double-Blind Controlled Trial of Metformin and Atorvastatin – with treatment commenced following prostatic biopsy and ceasing just before radical prostatectomy - to guide subsequent patient management
Scientific title
The effectiveness of a combination of Metformin and Atrovastatin compared with each drug alone and placebo in modulating tumour aggressiveness in men with high risk prostate cancer undergoing radical prostatectomy
Secondary ID [1] 286613 0
Nil Known
Universal Trial Number (UTN)
U1111-1169-7401
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate cancer 294929 0
Condition category
Condition code
Cancer 295179 295179 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group 1
Participants randomised to Group 1 will receive Metformin 500mg twice a day and placebo once a day as oral capsules from randomisation until 6 weeks later when they give their second blood and urine samples for the trial just prior to radical prostatectomy.

Group 2
Participants randomised to Group 2 will receive Atorvastatin 20mg once a day and placebo twice a day as oral capsules from randomisation until 6 weeks later when they give their second blood and urine samples for the trial just prior to radical prostatectomy.

Group 3
Participants randomised to Group 3 will receive Metformin 500mg twice a day + Atorvastatin 20mg once a day as oral capsules from randomisation until 6 later when they give their second blood and urine samples for the trial just prior to radical prostatectomy.

Intervention adherence will be monitored through drug tablet return at the end of the intervention.
Intervention code [1] 291744 0
Treatment: Drugs
Comparator / control treatment
Group 4
Participants randomised to Group 3 will receive placebo three times a day as oral capsules from randomisation until 6 weeks later when they give their second blood and urine samples for the trial just prior to radical prostatectomy.

Intervention adherence will be monitored through drug tablet return at the end of the intervention
Control group
Placebo

Outcomes
Primary outcome [1] 294966 0
Response in histology results between initial targeted prostatic biopsy and radical prostatectomy specimen through a change in the Gleason Score of the cancer
Timepoint [1] 294966 0
Baseline (shortly after initial screening) and at the time of radical prostatectomy (6-8 weeks after commencement of intervention)
Primary outcome [2] 294967 0
Detectable metabolic changes to ejaculate assessed via molecular and metabolomic profiling with nuclear magnetic resonance (ex-vivo, all patients)
Timepoint [2] 294967 0
Initial screening and 6 weeks after commencement of intervention
Primary outcome [3] 295120 0
Findings from ejaculate profiling (Primary Outcome 2) will be mirrored in-vivo by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) with a 7 Tesla machine in a small group of randomised patients (selected from each intervention group as part of the randomisation process)
Timepoint [3] 295120 0
Just before biopsy and just before prostatectomy
Secondary outcome [1] 314481 0
Changes in serum PSA (prostate specific antigen) and biochemical/lipid profiles in blood and urine pathology as indirect indicators of metabolic changes
Timepoint [1] 314481 0
Initial screening, 6 weeks after commencement of the intervention, 3-4 months post radical prostatectomy
Secondary outcome [2] 314630 0
Tolerability of medications will be assessed by questionnaire assessment (International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF), Expanded Prostate cancer Index Composite (EPIC), SF-36, Sexual Health Inventory for Men (SHIM), Distress Thermometer, Brief Symptom Inventory (BSI-18)) (composite outcome)
Timepoint [2] 314630 0
Initial screening, 6 weeks after commencement of the intervention, 3-4 months post radical prostatectomy

Eligibility
Key inclusion criteria
Patients will be eligible for the trial if they are adult men aged 40 to 80 years who have a PI-RADSv2 (Prostate Imaging-Reporting and Data System) score of 4 or 5 and proceed to prostate biopsy with an intention of having a prostatectomy for confirmed high-risk prostate cancer
Minimum age
40 Years
Maximum age
80 Years
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be ineligible for the trial if they:
- have been taking any lipid (fats) or cholesterol-lowering medication or blood-glucose (sugar level)-lowering drugs
- have experienced any unwanted effects with lipid or glucose-lowering drugs previously
- have been considered by their urologist to be unsuitable for the research programme or involvement in the study is not consistent with the patient’s best interests
- are taking medications that could cross-react with medications used in the trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Potentially eligible patients who are seeing a recruiting urologist for this trial and who have had a multiparametric MRI (magenetic resonance imaging) with a commercially-operated 3 Tesla machine for an elevated serum PSA will be given the Participant Information Sheet and Consent Form for this trial with their request for the MRI.

Patients who have the MRI and subsequently have a PI-RADSv2 (Prostate Imaging-Reporting and Data System) score of 4 or 5 and indicate a preparedness to have a radical prostatectomy if significant cancer is detected by biopsy, will then discuss the trial with their urologist and sign the consent form at their leisure should they wish to participate and be eligible. The urologist will then pass the consent form on to the Trial Coordinator along with the participant's biopsy date.

The participant will then complete the baseline questionnaires and provide blood and urine samples prior to their prostate biopsy. Randomly selected participants will have an additional MRI and magnetic resonance spectroscopy (MRS) with a 7 Tesla machine prior to their prostate biopsies.

The trial coordinator will then use a randomisation list to randomise participants into one of the four treatment groups and arrange for the appropriate medication to be dispensed. This list will not reveal the group to which participants have been assigned to the Trial Coordinator, urologist or participant, only their randomisation number (R001, R002, etc.), which will also be used to label their medication. The Trial Coordinator will also have opaque Code Break Envelopes containing the group assignment of each randomisation number, should unblinding be required due to an adverse event. With the exception of unblinding being required due to an adverse event, unblinding will not take place until statistical analysis has been completed.

The morning after biopsy the participant will commence the 6 weeks of medication. Medication will be supplied to patients in three bottles (morning, mid-day and evening) and each bottle will contain pills of identical appearance (although they will be coloured depending on the time of day they should be taken, but not their content).

In the unlikely event that a participant's biopsy reveals no prostate cancer or should a participant later elect not to undergo a radical prostatectomy he will cease the trial medication and any further assessments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be computer-generated externally to the research team with no blocking resulting in 20 participants being allocated to each trial group across the 80 participants involved.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
As a phase I/II study, a number of 20 per group was considered appropriate for provision of baseline data. If evidence of favourable parameter changes and acceptable tolerability of the combination regimen of atorvastatin and metformin is forthcoming, the results may justify a larger study with these drugs, although not necessarily at this stage in tumour development.

A multivariable model for prognostication of the risk for experiencing either of the primary end points will be developed. The model will incorporate baseline measures in blood and SF as well as metabolomic and proteomic markers. Each marker tested independently that achieves a significance level of P<0.20 will be selected for testing in this multivariable stepwise (backward elimination) logistic regression model. Variables associated with P<0.2 will be retained in the final multivariable model. Maximum likelihood estimates of the parameter coefficients will be obtained using Stata (StataCorp, College Station, TX). The goodness of fit of the model will be evaluated by calculating the Hosmer-Lemeshow statistic and the ability of the model to classify patients (ie, its predictive performance) will be evaluated using the C statistic, a term equivalent to the area under a receiver operating characteristic curve for dichotomous outcomes. The beta coefficients of selected markers will be used to create the composite scores that can then be used for clinical risk stratification.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Other reasons/comments
Other reasons
Difficulty recruiting, patients did not have surgery in accordance with the protocol and the drugs expired and were prohibitively expensive to replace
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3744 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 3746 0
Urologist's Private Rooms (John Yaxley, Geoff Couglin, Troy Gianduzzo, Rachel Esler)

Funding & Sponsors
Funding source category [1] 291186 0
Charities/Societies/Foundations
Name [1] 291186 0
RBWH Foundation
Address [1] 291186 0
Block 20
Royal Brisbane and Women’s Hospital
Butterfield Street
Herston QLD 4006
Country [1] 291186 0
Australia
Primary sponsor type
University
Name
University of Queensland Centre for Clinical Research
Address
University of Queensland Centre for Clinical Research
Building 71/918
Royal Brisbane & Women's Hospital Campus
Herston QLD 4029
Country
Australia
Secondary sponsor category [1] 289885 0
Hospital
Name [1] 289885 0
Royal Brisbane and Women's Hospital
Address [1] 289885 0
Butterfield Street
Herston QLD 4006
Country [1] 289885 0
Australia
Other collaborator category [1] 278457 0
Commercial sector/Industry
Name [1] 278457 0
Q-Pharm Pty Ltd
Address [1] 278457 0
Level 5 (Clinic and Recruitment & Outpatients)
Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Road
Herston QLD 4006
Country [1] 278457 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292757 0
Royal Brisbane & Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 292757 0
Human Research Ethics Office
Level 7, Block 7
Royal Brisbane and Women's Hospital
Metro North Health Service District
Ethics committee country [1] 292757 0
Australia
Date submitted for ethics approval [1] 292757 0
28/04/2014
Approval date [1] 292757 0
04/07/2014
Ethics approval number [1] 292757 0
HREC/14/QRBW/153
Ethics committee name [2] 292758 0
The University of Queensland Medical Research Ethics Committee
Ethics committee address [2] 292758 0
The University of Queensland
St Lucia QLD 4072
Ethics committee country [2] 292758 0
Australia
Date submitted for ethics approval [2] 292758 0
28/04/2014
Approval date [2] 292758 0
22/07/2014
Ethics approval number [2] 292758 0
2014000944

Summary
Brief summary
The primary purpose of this study is to determine whether Metformin and Atorvastatin (taken alone or together) improve outcomes for men with prostate cancer in terms of the aggressiveness and the biology of their cancer

Who is it for?
You may be eligible to join this study if you are aged 40 to 80 years, have a PI-RADSv2 (Prostate Imaging-Reporting and Data System) score of 4 or 5 and proceed to prostate biopsy with an intention of having a prostatectomy for confirmed high-risk prostate cancer.

Study details
Metformin is a medication commonly used in the treatment of Type 2 Diabetes to lower blood sugar levels and Atorvastatin is a common cholesterol lowering medication. Previous research has found that people who take these Metformin are less likely to have prostate cancer and those who take Atorvastatin are more likely to have less dangerous prostate cancers. Participants in this study will be randomly allocated (by chance) to one of four groups. The four groups will be divided as: 1) Placebo; 2) Metformin; 3) Atorvastatin; and 4) Metformin and Atorvastatin. You will have to take oral capsules three times a day for 6 weeks and all parties will be blinded regarding patient treatment allocation.

Patient outcomes will then be assessed through blood, urine and tissue samples provided before the treatment starts and 6-8 weeks after as well as through medical imaging for some patients.

It is hoped that the findings of this pilot trial will serve to help other men after they have had diagnostic prostatic biopsies showing prostate cancer, through providing evidence for a treatment that reduces the aggressiveness of their cancer, although this will need to be established in larger studies.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 56862 0
Prof Robert ('Frank') Gardiner AM
Address 56862 0
University of Queensland Centre for Clinical Research
Building 71/918
Royal Brisbane & Women's Hospital Campus
Herston, QLD, 4029
Country 56862 0
Australia
Phone 56862 0
+61 7 3346 5555
Fax 56862 0
Email 56862 0
f.gardiner@uq.edu.au
Contact person for public queries
Name 56863 0
Ms Aine Farrell
Address 56863 0
University of Queensland Centre for Clinical Research
Building 71/918
Royal Brisbane & Women's Hospital Campus
Herston, QLD, 4029
Country 56863 0
Australia
Phone 56863 0
+61 7 3346 6100
Fax 56863 0
+61 7 3346 5599
Email 56863 0
a.farrell@uq.edu.au
Contact person for scientific queries
Name 56864 0
Prof Robert ('Frank') Gardiner AM
Address 56864 0
University of Queensland Centre for Clinical Research
Building 71/918
Royal Brisbane & Women's Hospital Campus
Herston, QLD, 4029
Country 56864 0
Australia
Phone 56864 0
+61 7 3346 5555
Fax 56864 0
Email 56864 0
f.gardiner@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results