Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000097448
Ethics application status
Approved
Date submitted
23/12/2003
Date registered
23/12/2003
Date last updated
14/12/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomised trial investigating the effect on biomedical (PSA) control and survival of different durations of adjuvant androgen deprivation in association with definite radiation treatment for localised carcinoma of the prostate (RADAR)
Scientific title
Trans Tasman Radiation Oncology Group (TROG) 03.04 - A randomised trial investigating the effect on biomedical (Prostate Specific Antigen- PSA) control and survival of different durations of adjuvant androgen (Leuprorelin acetate and zoledronic acid)deprivation in association with definite radiation treatment for localised carcinoma of the prostate (The RADAR trial)
Secondary ID [1] 72 0
National Clinical Trials Registry: NCTR491
Secondary ID [2] 73 0
ClinicalTrials.gov: NCT 00193856
Universal Trial Number (UTN)
Trial acronym
TROG 03.04 - RADAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Localised carcinoma of the prostate 48 0
Condition category
Condition code
Cancer 54 54 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Androgen deprivation: artificial drugs create a depression in the production of sex hormones.
Arm A: Androgen deprivation (AD): 6 months Luteinising Hormone - Releasing Hormone (LH-RH) analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months, at 0 and 3 months. Radiation begins after 5 months AD.
Arm B: Androgen deprivation: 6 months LH-RH analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months, at 0 and 3 months. Radiation begins after 5 months AD. Bisphosphonate therapy (Zoledronic acid 4mg) every 3 months for 18 months by IV.
Arm C: Androgen deprivation: 18 months LH-RH analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months at 0, 3, 6, 9, 12 and 15 months. Radiation treatment begins after 5 months AD.
Arm D: Andorgen deprivation: 18 months LH-RH analogue (Leuprorelin acetate 22.5mg) depot injected every 3 months at 0, 3, 6, 9, 12 and 15 months. Radiation treatment begins after 5 months AD. Bisphosphonate therapy (Zoledronic acid 4mg) every 3 months for 18 months by IV.
Radiation will be 66Gy in 33 fractions of 2gy in all cases for a period of 8 weeks.
Intervention code [1] 1497 0
Treatment: Drugs
Comparator / control treatment
LH-RH analogue for 5 months prior to and during first month of radiation treatment (total 6 mths)
Control group
Active

Outcomes
Primary outcome [1] 103 0
Prostate cancer-specific mortality.

Prostate cancer specific mortality will be assessed by estimation of cumulative incidence (1). After ensuring that the hazards of prostate cancer specific mortality (PCSM) are proportional for each trial arm, the primary analysis comparing short (6 months) and intermediate (18 months) androgen deprivation with respect to PCSM will be performed using the method of Fine and Gray (cumulative incidence competing hazards estimation), adjusting for presenting PSA level (< 10, 10 - 20, > 20), Gleason score (2 - 6, 7, 8 - 10) and stage (T2, 3 - 4). If the hazard rates are not proportional then the primary analysis will be performed by comparing the cumulative incidence rates at fixed time points, namely five and ten years. These comparisons will be performed adjusting for presenting PSA level, Gleason score and stage as before. Within each stratum, the 5-year and 10-year cumulative incidences of PCSM estimates and their standard errors will be determined over the 12 strata calculated and tested for significance.

1. Fine JP, Gray R. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association. 1999;94:496-509.
Timepoint [1] 103 0
Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.
Secondary outcome [1] 214 0
1. Cumulative incidence of PSA progression

PSA is measured at each follow-up and is measured more frequently on progression. Cumulative incidence of PSA progression will be compared between treatment arms using the method of Fine and Gray (1), adjusting for PSA level, Gleason score and stage.

1. Fine JP, Gray R. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association. 1999;94:496-509.
Timepoint [1] 214 0
Measured until a death from any cause. Follow up is 3 monthly up to 30 months . Then 6 monthly for 5 years post randomisation and then annually until death.
Secondary outcome [2] 215 0
2. Cumulative incidence of local, distant and bony progression and associated patterns of clinical progression

The effect of androgen deprivation on risk of local and distant progression will be tested using competing risks methodology to compare the short term and intermediate term arms as a first event in a competing risks analysis of clinical progression data. In a separate analysis the data will be examined to see if there is an interaction between androgen deprivation arm and dose of radiotherapy (=< 70 Gy versus > 70 Gy) using Cox regression (ie to see if the effect of duration of androgen deprivation depends on the radiation dose used).
Timepoint [2] 215 0
Measured until local progression, distant progression, rising PSA, or death from any cause. Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.
Secondary outcome [3] 216 0
3. All-cause mortality (5 years)
Timepoint [3] 216 0
Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.
Secondary outcome [4] 217 0
4. Changes in bone mineral density and osteopenic Fracture

Risk of osteoporotic fracture: Any fracture occuring during follow-up is reported, each incidence will be investigated and cause attributed by the investigator. All patients will have a thoracor-lumbar x-ray at 0 and 3 years to assess vertebral fracture. The effect of bisphosphonate (BP) on the risk of osteoporotic and sporadic fractures will be tested by comparing the proportions of patients at three years with new fractures, between the arms, no BP and BP, using an exact test of proportions, stratifying for type of androgen deprivation arm (Short or intermediate term) and age (<60, 60 - 70, 70+). Patients eligible for this analysis will be those alive and who have been examined for presence of fracture by plain radiograph at baseline and at three years. The proportions of patients in each arm who have died before three years or who are otherwise not included in the comparison will be taken into account in the interpretation of the results. A test for interaction between bisphosphonate arm and androgen deprivation arm will be performed; if there is a significant interaction (ie if the effect of BP depends importantly on the AD arm) the BP arms may be tested separately within short-term AD patients and within intermediate term AD patients.

Loss of Bone mineral density: BMD will be measured in a subset of patients at 0, 2 and 4 years by DEXA scan. The primary analysis for the effect of bisphosphonate on loss of BMD will be tested using multiple linear regression analysis on the change from baseline at two years of BMD, with a further analysis at 4 years, adjusting for baseline BMD and length of androgen deprivation received. It is intended to log-transform data prior to analysis, however the pooled data will be examined prior to analysis to see whether a different transformation or the use of a nonparametric test is appropriate. Patients eligible for these analyses are those alive and who are tested for BMD by DEXA scan at baseline and at two years. The proportions of patients in each arm who have died before two years or are otherwise not included in the comparison will be taken into account in the interpretation of the results. Testing for, and interpretation of, interaction between BP and AD will be as for fracture risk.
Timepoint [4] 217 0
Measured until death. Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.
Secondary outcome [5] 297900 0
5. Quality of life self-assessment

Patient reported outcomes will be measured using the EORTC QLQ C-30 and PR 25 questionnaires at baseline, 3 months, at end of RT and at 12, 18, 24, 36 and 60 months. Mean change from baseline in global and domain scores will be plotted by time and by treatment arm. The primary analysis of QOL will be a comparison between treatments of the change from baseline of the global QOL score at three years, adjusted for baseline QOL score, using multiple linear regression. Patients included in this analysis will be those who are alive at three years and who have completed both baseline and three-year questionnaires. Pooled data will be examined prior to analysis to see whether transformation or use of a nonparametric test is appropriate.
Timepoint [5] 297900 0
Performed at baseline, 3 months, end of radiation therapy treatment, 12 months, 18 months, 24 months, 36 months, 60 months and then yearly.
Secondary outcome [6] 297901 0
1. Treatment related morbidity

Radiation induced toxicity: Patient reported outcomes will be measured using the EORTC QLQ C-30 and PR25 questionnaires, the International Prostate Symptom Score (IPSS) for urinary function and pharmaceutical intervention (PI) questionnaire for androgen deprivation and bisphosphonate side effects at baseline, 3 months, end of RT, 12 months, 18 months, 24 months, 36 months, 60 months and then yearly.

Urinary and rectal function will be analysed at four cross-sectional time points: 1. At baseline prior to any treatment; 2. At the end of radiotherapy; 3. At 24 months (ie approximately 18 months post radiation); 4. At 36 months (ie 30 months post radiation). Individual function scores and composite scores will be compared between trial arms using non-parametric uni-variable and multi-variable techniques.

Hormone deprivation induced toxicity: Pre-morbidity data and serial testosterone measures will be collected; reported cardiac and other adverse events will be thoroughly reviewed and classified. Cumulative incidence (CI) of myocardial infarction or other serious adverse event will be derived by competing risk methodology and multi-variable models to determine contributing factors. Data will be analysed at 5 years post randomisation.
Timepoint [6] 297901 0
Follow up is 3 monthly for up to 30 months. Then 6 monthly for 5 years post randomisation and then annually until death.

Eligibility
Key inclusion criteria
Histological confirmation of adenocarcinoma of the prostate in the three months prior to randomisation- Gleason primary and secondary pattern reported. If the volume of tumour in biopsies is too small for the pathologist to allocate a secondary pattern, the primary pattern alone is sufficient.- Primary tumour stage T2b - 4 (UICC 2002), or T2a providing biopsies demonstrate Gleason score 7 or more, and presenting PSA 10 or more- PSA value obtained within one month of randomisation- No evidence of lymphatic or haematogenous metastases, as determined by negative chest x-ray, CT scan of abdomen and pelvis, and bone scan in the 3 months prior to randomisation- ECOG performance status 0 - 1- No concurrent medical conditions likely to significantly reduce prospects of 5 year survival- Patient accessible to follow up at intervals specified in protocol- Written informed consent given (signed by both patient and investigator prior to randomisation)
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Previous or concurrent malignancy within previous 5 years except for non-melanomatous skin cancer- Prostatectomy- Prior pelvic radiotherapy- Prior hormone treatment for prostate cancer- Inability to complete self administered QOL questionnaire- Prior bisphosphonate therapy- Serum creatinine > 2 x ULN- Osteoporosis resulting in >30% loss in vertebral height in one or more thoraco-lumbar vertebrae- Liver disease resulting in ALT or AST levels >3 x ULN- Prolonged continuous glucocorticoid therapy > 10 mg/day of prednisone equivalent (>6 months)- Current treatment with bisphosphonate

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)
Central randomisation by phone / computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation. Factors: Treatment centre, presenting Prostate Specific Antigen, Gleason score, stage. Simple randomisation by computer.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
23/10/2003
Actual
23/10/2003
Date of last participant enrolment
Anticipated
29/08/2007
Actual
29/08/2007
Date of last data collection
Anticipated
Actual
Sample size
Target
1000
Accrual to date
Final
1071
Recruitment in Australia
Recruitment state(s)
NSW,VIC,QLD,WA,TAS
Recruitment outside Australia
Country [1] 443 0
New Zealand
State/province [1] 443 0

Funding & Sponsors
Funding source category [1] 77 0
Government body
Name [1] 77 0
National Health & Medical Research Council Project Grant
Country [1] 77 0
Australia
Funding source category [2] 78 0
Government body
Name [2] 78 0
Health Research Council New Zealand
Country [2] 78 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Trans Tasman Radiation Oncology Group (TROG)
Address
TROG Central Operations, Department of Radiation Oncology, Calvary Mater Newcastle, Locked Bag 7, Hunter Regional Mail Centre, NSW 2310
Country
Australia
Secondary sponsor category [1] 64 0
Individual
Name [1] 64 0
Professor Jim Denham
Address [1] 64 0
Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308
Country [1] 64 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287436 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 287436 0
Ethics committee country [1] 287436 0
Australia
Date submitted for ethics approval [1] 287436 0
Approval date [1] 287436 0
17/07/2003
Ethics approval number [1] 287436 0
03/06/11/3.02

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 27431 0
Prof Jim Denham
Address 27431 0
Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308
Country 27431 0
Australia
Phone 27431 0
+61 2 4985 4017
Fax 27431 0
Email 27431 0
[email protected]
Contact person for public queries
Name 10686 0
Allison Steigler
Address 10686 0
Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308
Country 10686 0
Australia
Phone 10686 0
+61 2 4985 4019
Fax 10686 0
N/A
Email 10686 0
[email protected]
Contact person for scientific queries
Name 1614 0
Jim Denham
Address 1614 0
Prostate Cancer Trials Group, University of Newcastle, Callaghan NSW 2308
Country 1614 0
Australia
Phone 1614 0
+61 2 4985 4018
Fax 1614 0
N/A
Email 1614 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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