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Trial registered on ANZCTR


Registration number
ACTRN12617000005358
Ethics application status
Approved
Date submitted
24/10/2016
Date registered
3/01/2017
Date last updated
17/06/2019
Date data sharing statement initially provided
17/06/2019
Date results information initially provided
17/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A prospective study to assess the diagnostic accuracy and management impact of Prostate Specific Membrane Antigen (PSMA) PET scanning in men with prostate cancer being considered for surgery or radiotherapy.
Scientific title
A prospective randomised multi-centre study of the impact of Ga-68 PSMA-PET/CT imaging for staging high risk prostate cancer prior to curative-intent surgery or radiotherapy
Secondary ID [1] 290345 0
Nil known
Universal Trial Number (UTN)
U1111-1188-7770
Trial acronym
ProPSMA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate cancer 300623 0
Condition category
Condition code
Cancer 300468 300468 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Experimental arm: Ga-68 PSMA-PET/CT imaging in place of standard care conventional imaging scan
Patients randomised to the experimental arm will undergo PET/CT imaging following a single intravenous bolus administration of 150 MBq (+/- 50 MBq) of Ga-68-PSMA-11.
Prior to injection, qualified site personnel will assay the dose in the dose calibrator and
record the assay reading and time. The CT and PET imaging session will begin approximately 45 to 75 minutes after injection. The total time in the scanner is around 20 minutes.
The result of the scan will be provided to the treating physician who may modify patient management based on the result
All patients will cross-over to second-line DI (crossover to other arm) within 14 days from the first line DI unless the disease status for distant metastases was positive (ie. not equivocal or negative) with >2 sites of disease demonstrated.
Repeat imaging at 6 months will be performed if (1) initial staging was N1 or M1 (ie. positive for disease in pelvic lymph nodes or distant disease) or (2) Biochemical or clinical suspicion of residual / recurrent disease for those initial N0 M0.
After completion of first and second-line imaging, at pre-defined sites, 50 participants will also undergo a whole body MRI . The scan takes around 45 minutes and involves no preparation. In the MRI scanner there is a high magnetic field and all patients need to undergo a thorough safety questionnaire and assessment to ensure that any metallic implants or devices (such as pacemakers, stents, joint replacements or even shrapnel) are compatible and safe within the scanner. The diagnostic accuracy of whole body MRI will be then compared to that of PSMA PET/CT
Intervention code [1] 296159 0
Diagnosis / Prognosis
Comparator / control treatment
Control arm. Conventional imaging (CT + bone scan)

Each patient randomised to the conventional imaging will undergo a whole body bone scan with SPECT/CT following injection of 99mTc-MDP or 99mTc-HDP, and multi-slice CT scan of the abdomen and pelvis following injection of intravenous contrast.
All patients will cross-over to second-line DI (crossover to other arm) within 14 days from the first line DI unless the disease status for distant metastases was positive (ie. not equivocal or negative) with >2 sites of disease demonstrated.
Control group
Active

Outcomes
Primary outcome [1] 299904 0
To compare the diagnostic accuracy of PSMA-PET/CT to that of conventional imaging (CI) for detecting nodal or distant metastatic disease.
To define accuracy, diagnostic findings will be compared to the ground truth which will be established using all data available to the six-month follow-up time-point (+/-30 days). Cases will be considered positive by ground truth if they satisfy at least 1 hard criterion or at least 3 soft criteria amongst the pre-defined criteria listed in the protocol as evidence for one or more metastases. Where feasible, biopsy confirmation of disease is strongly encouraged.
Timepoint [1] 299904 0
The outcome will be assessable 6 months from randomisation
Secondary outcome [1] 328464 0
To compare the first-line management impact of PSMA-PET/CT to that of conventional imaging DI. This outcome is assessed by a prospective questionnaire completed by the clinician before and after first-line imaging. The questionnaire has been designed for this trial and available through the secure electronic data capture system.
Timepoint [1] 328464 0
prior to second-line imaging (within 35 days of randomisation)
Secondary outcome [2] 328465 0
To compare the number of equivocal study results using PSMAPET/CT to the number using CI. This outcome is determined by the local radiologist or nuclear medicine specialist when reading the study.
Timepoint [2] 328465 0
6 months from randomisation
Secondary outcome [3] 328466 0
To assess incremental accuracy of PSMA-PET/CT or conventional imaging as a second-line imaging modality by their ability to detect additional metastases in subset of patients who cross-over and have both tests. This is defined as the proportion of M0 patients (ie. patients without distant metastatic disease) who were upstaged to M1 by second-line imaging, and the separately, the proportion of N0 patients (ie. patients without pelvic nodal metastases) who were upstaged to N1 by second-line imaging.
Timepoint [3] 328466 0
6 months from randomisation
Secondary outcome [4] 328467 0
To assess the incremental management impact of PSMAPET/CT or CI as a second-line imaging modality in the subset of patients who cross-over and have both tests. This outcome is assessed by a questionnaire designed for this study and completed by the clinician after second-line imaging.
Timepoint [4] 328467 0
after second-line imaging and prior to any confirmatory tests (within 12 weeks of randomisation)
Secondary outcome [5] 328468 0
To evaluate the prognostic value of PSMA-PET/CT with regards to disease-free status. Kaplan-Meier curves will be plotted for each of the following time to event endpoints, namely: (1) time until the first of i) biochemical failure or ii) metastatic disease or iii) salvage therapy, (2) time until biochemical failure (3) time until metastatic disease and (4) time until salvage therapy.
Timepoint [5] 328468 0
assessed at 18, 30, 42 and 54 months from randomisation of the last patient
Secondary outcome [6] 328469 0
To compare the cost of each imaging staging strategy. Data on utilisation of each relevant resource type at each timepoint will be combined (as a mean) across sites and over time. This outcome will be assessed with the assistance of the Centre for Health Economics Research and Evaluation (CHERE) at the University of Technology Sydney.
Timepoint [6] 328469 0
6 months from randomisation
Secondary outcome [7] 328470 0
To compare patient radiation exposure between imaging strategies, defined as the total patient radiation exposure (millisieverts) in each arm.
Timepoint [7] 328470 0
6 months from randomisation
Secondary outcome [8] 328471 0
To assess inter-reporter agreement of PSMA-PET/CT by comparing blinded independent core lab interpretations to onsite clinical care interpretations
Timepoint [8] 328471 0
6 months from randomisation
Secondary outcome [9] 328472 0
To report the acute adverse events for PSMA-PET/CT graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) version v4.03 (based on current information no adverse related to Ga-PSMA11 are expected)
Timepoint [9] 328472 0
Experienced by the patient a the time of radiotracer administration and during the two hours following

Eligibility
Key inclusion criteria
1. Untreated, biopsy-proven adenocarcinoma of the prostate
2. Patient is being considered for curative-intent treatment with radical prostatectomy or radiotherapy
3. Patients must have high-risk features including at least one of the following features:
- PSA greater than or equal to 20.0 ng/ml within 12 weeks prior to randomisation
- Gleason group 3, 4 or 5
- Clinical stage greater than or equal to T3
4. Age greater than or equal to 18 years
5. Patient has provided written informed consent for participation in this trial
6. In the opinion of investigator, willing and able to comply with required study procedures
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participant has had any prior therapy for prostate cancer
2. Participant has undergone, within 8 weeks prior to randomisation, imaging for the primary purpose of staging nodal or distant metastatic disease of prostate cancer (MRI
performed for primary purpose of assessing T-stage or to guide biopsy is acceptable)
3. A history of other active malignancy within the last 5 years with exception of non-melanoma skin cancer or melanoma insitu
4. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components
5. Significant intercurrent morbidity that, in the judgment of the investigator, would limit compliance with study protocols

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer. Participants will be randomised in the ratio of 1:1 between the two arms as follow:
Arm A – PSMA-PET/CT – experimental arm
Arm B – CT + Bone Scan – control arm
The assigned diagnostic arm will not be known to any person prior to eligibility criteria being established and the intention to randomise the patient being declared
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary analysis will be diagnostic accuracy, assessed by the AUC. For a binary valued diagnostic instrument, the AUC is equal to the mean of the sensitivity and specificity. The power of the trial is dependent on the sensitivity and specificity of both diagnostic tools, as well as the ratio of cases (positives as assessed by ground truth) to controls (negatives as assessed by ground truth). A sample size of 270 (135 patients per arm) will achieve a power of 0.85 using the following pragmatic assumptions:
1) Conventional imaging (CI) has a true underlying AUC of 0.65, consisting of a sensitivity of 0.65 and a specificity of 0.65.
2) PSMA-PET/CT has a true underlying AUC of 0.9, consisting of a sensitivity of 0.9 and a specificity of 0.9.
3) The proportion of cases (as opposed to controls) is 25%.
4) Margin of 10% improvement (absolute) in AUC requirement to declare PSMA superior
5) Two-sided type I error of 10%.
To allow for patient drop out of up to 10%, 300 patients will be accrued to the study.

Recruitment
Recruitment status
Active, not recruiting
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)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 6832 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 6833 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 6834 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 6835 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [5] 6836 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [6] 6837 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 6838 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [8] 10394 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [9] 10395 0
South Australian Health and Medical Research Institute (SAHMRI) - Adelaide
Recruitment hospital [10] 10396 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [11] 10397 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 14497 0
3000 - Melbourne
Recruitment postcode(s) [2] 14498 0
3084 - Heidelberg
Recruitment postcode(s) [3] 14499 0
3168 - Clayton
Recruitment postcode(s) [4] 14500 0
2298 - Waratah
Recruitment postcode(s) [5] 14501 0
2065 - St Leonards
Recruitment postcode(s) [6] 14502 0
4029 - Herston
Recruitment postcode(s) [7] 14503 0
6009 - Nedlands
Recruitment postcode(s) [8] 22075 0
5000 - Adelaide
Recruitment postcode(s) [9] 22076 0
4102 - Woolloongabba
Recruitment postcode(s) [10] 22077 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 294728 0
Charities/Societies/Foundations
Name [1] 294728 0
Prostate Cancer Foundation of Australia
Address [1] 294728 0
Level 5, 437 St Kilda Road, Melbourne VIC 3004
Country [1] 294728 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan Street
Melbourne, Victoria
3000 Australia
Country
Australia
Secondary sponsor category [1] 293574 0
None
Name [1] 293574 0
Address [1] 293574 0
Country [1] 293574 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296146 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 296146 0
305 Grattan Street
Melbourne VIC 3000
Ethics committee country [1] 296146 0
Australia
Date submitted for ethics approval [1] 296146 0
10/10/2016
Approval date [1] 296146 0
07/03/2017
Ethics approval number [1] 296146 0

Summary
Brief summary
The primary purpose of this trial is to evaluate the accuracy of PSMA-PET/CT scans for determining the stage of prostate cancer and planning treatment.

Who is it for? You may be eligible to participate in this trial if you are aged 18 or over and have been diagnosed with prostate cancer for which you have not yet received treatment, but it is planned that you will undergo surgery or radiotherapy.

Study details: All participants enrolled in this trial will be randomly allocated (by chance) to receive either the conventional scans (CT + bone scan), or the PSMA-PET/CT scan which is being evaluated. All patients will cross-over to second-line DI (crossover to other arm) unless the disease status for distant metastases was positive (ie. not equivocal or negative) with >2 sites of disease demonstrated. The results of the scan will be made available to your doctors to help them to plan the most suitable treatment course.

The accuracy of the scans will be determined by using follow-up information available up to 6 months after entering the study. If the scans showed abnormalities or your doctor has clinical suspicion of prostate cancer, the scans will be repeated at 6 months.

In patients with normal PSMA PET/CT scans, follow-up data may be collected at 18 30, 42 and 54 months (the study will stop 3 years after randomisation of the last patient).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69734 0
A/Prof Michael Hofman
Address 69734 0
Peter MacCallum Cancer Centre
Cancer Imaging Department
305 Grattan Street
Melbourne VIC 3000
Country 69734 0
Australia
Phone 69734 0
+61 3 8559 6914
Fax 69734 0
Email 69734 0
Michael.Hofman@petermac.org
Contact person for public queries
Name 69735 0
A/Prof Michael Hofman
Address 69735 0
Peter MacCallum Cancer Centre
Cancer Imaging Department
305 Grattan Street
Melbourne VIC 3000
Country 69735 0
Australia
Phone 69735 0
+61 3 8559 6914
Fax 69735 0
Email 69735 0
Michael.Hofman@petermac.org
Contact person for scientific queries
Name 69736 0
A/Prof Michael Hofman
Address 69736 0
Peter MacCallum Cancer Centre
Cancer Imaging Department
305 Grattan Street
Melbourne VIC 3000
Country 69736 0
Australia
Phone 69736 0
+61 3 8559 6914
Fax 69736 0
Email 69736 0
Michael.Hofman@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary