ANZCTR - Registration

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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

6/03/2023

Date data sharing statement initially provided

17/06/2019

Date results provided

6/03/2023

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]

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

Condition category

Condition code

Cancer

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]

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]

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]

The outcome will be assessable 6 months from randomisation

Secondary outcome [1]

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]

prior to second-line imaging (within 35 days of randomisation)

Secondary outcome [2]

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]

6 months from randomisation

Secondary outcome [3]

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]

6 months from randomisation

Secondary outcome [4]

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]

after second-line imaging and prior to any confirmatory tests (within 12 weeks of randomisation)

Secondary outcome [5]

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]

assessed at 18, 30, 42 and 54 months from randomisation of the last patient

Secondary outcome [6]

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]

6 months from randomisation

Secondary outcome [7]

To compare patient radiation exposure between imaging strategies, defined as the total patient radiation exposure (millisieverts) in each arm.

Timepoint [7]

6 months from randomisation

Secondary outcome [8]

To assess inter-reporter agreement of PSMA-PET/CT by comparing blinded independent core lab interpretations to onsite clinical care interpretations

Timepoint [8]

6 months from randomisation

Secondary outcome [9]

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]

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

Sex

Males

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

14/03/2017

Actual

22/03/2017

Date of last participant enrolment

Anticipated

20/01/2020

Actual

2/11/2018

Date of last data collection

Anticipated

24/07/2023

Actual

22/07/2022

Sample size

Target

300

Accrual to date

Final

302

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [2]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [4]

Calvary Mater Newcastle - Waratah

Recruitment hospital [5]

Royal North Shore Hospital - St Leonards

Recruitment hospital [6]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [7]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [8]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [9]

South Australian Health and Medical Research Institute (SAHMRI) - Adelaide

Recruitment hospital [10]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [11]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment postcode(s) [1]

3000 - Melbourne

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

3168 - Clayton

Recruitment postcode(s) [4]

2298 - Waratah

Recruitment postcode(s) [5]

2065 - St Leonards

Recruitment postcode(s) [6]

4029 - Herston

Recruitment postcode(s) [7]

6009 - Nedlands

Recruitment postcode(s) [8]

5000 - Adelaide

Recruitment postcode(s) [9]

4102 - Woolloongabba

Recruitment postcode(s) [10]

3065 - Fitzroy

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Prostate Cancer Foundation of Australia

Address [1]

Level 5, 437 St Kilda Road, Melbourne VIC 3004

Country [1]

Australia

Primary sponsor type

Hospital

Name

Peter MacCallum Cancer Centre

Address

305 Grattan Street
Melbourne, Victoria
3000 Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Peter MacCallum Cancer Centre HREC

Ethics committee address [1]

305 Grattan Street
Melbourne VIC 3000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

10/10/2016

Approval date [1]

07/03/2017

Ethics approval number [1]

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

A/Prof Michael Hofman

Address

Peter MacCallum Cancer Centre
Cancer Imaging Department
305 Grattan Street
Melbourne VIC 3000

Country

Australia

Phone

+61 3 8559 6914

Fax

[email protected]

Contact person for public queries

Name

Michael Hofman

Address

Peter MacCallum Cancer Centre
Cancer Imaging Department
305 Grattan Street
Melbourne VIC 3000

Country

Australia

Phone

+61 3 8559 6914

Fax

[email protected]

Contact person for scientific queries

Name

Michael Hofman

Address

Peter MacCallum Cancer Centre
Cancer Imaging Department
305 Grattan Street
Melbourne VIC 3000

Country

Australia

Phone

+61 3 8559 6914

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

All of the individual participant data collected during the trial, after de-identification

When will data be available (start and end dates)?

Immediately following publication, no end date.

Available to whom?

Available to the researchers who provide a methodologically sound proposal.

Available for what types of analyses?

To achieve the aims in the approved proposal.

How or where can data be obtained?

Proposal should be directed to [email protected] to gain access. Data requestors will sign a data access agreement.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
18512	Informed consent form			[email protected]
18513	Study protocol			[email protected]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Prostate-specific membrane antigen ligands for imaging and therapy.	2017	https://dx.doi.org/10.2967/jnumed.116.186767
Dimensions AI	Meeting report from the Prostate Cancer Foundation PSMA-directed radionuclide scientific working group	2018	https://doi.org/10.1002/pros.23642
Embase	Multimodality imaging of prostate cancer.	2019	https://dx.doi.org/10.2967/jnumed.119.228320
Embase	Molecular Imaging of Newly Diagnosed Prostate Cancer.	2020	https://dx.doi.org/10.1097/PPO.0000000000000427
Embase	Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.	2020	https://dx.doi.org/10.1016/S0140-6736%2820%2930314-7
Embase	Management and treatment options for patients with de novo and recurrent hormone-sensitive oligometastatic prostate cancer.	2021	https://dx.doi.org/10.1016/j.prnil.2020.12.003
Embase	The Role of Magnetic Resonance Imaging and Positron Emission Tomography/Computed Tomography in the Primary Staging of Newly Diagnosed Prostate Cancer: A Systematic Review of the Literature.	2021	https://dx.doi.org/10.1016/j.euo.2020.11.002
Dimensions AI	Evaluation of PSMA-PET Biology-Guided Radiotherapy Sequential Boost to the PSMA-avid Subvolume in the Prostate Region in Low-Volume Advanced Prostate Cancer	2021	https://doi.org/10.1016/j.ijrobp.2021.07.136
Dimensions AI	Prognostic Significance of the Risk of Non-localized Disease on PSMA/PET: Comparative Performance of a Novel, PSMA/PET-Derived Risk Stratification Tool for High-Risk Prostate Cancer in a Large, Multi-Institutional Cohort	2021	https://doi.org/10.1016/j.ijrobp.2021.07.135
Dimensions AI	Small Non-Rigid Variations Can Assist Robust IMPT Plan Selection for Head and Neck Patients	2021	https://doi.org/10.1016/j.ijrobp.2021.07.137

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically