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Trial registered on ANZCTR


Registration number
ACTRN12619000520134
Ethics application status
Approved
Date submitted
22/02/2019
Date registered
2/04/2019
Date last updated
12/02/2020
Date data sharing statement initially provided
2/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to investigate if aspirin reduces the risk of developing ovarian cancer in high risk women with abnormalities in their BRCA1 or BRCA2 gene (or both).
Scientific title
A Randomized Phase II Double-Blind Placebo-Controlled Trial of Acetylsalicylic Acid (ASA) in Chemoprevention of Ovarian Cancer in Women with BRCA 1 and 2 Mutations.
Secondary ID [1] 297112 0
OV.25
Secondary ID [2] 297113 0
ANZGOG 1413/2018
Secondary ID [3] 297117 0
CTC 0157
Secondary ID [4] 297496 0
ClinicalTrials.gov ID: NCT03480776
Universal Trial Number (UTN)
Trial acronym
STICs and STONEs
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian cancer 311133 0
Condition category
Condition code
Cancer 309760 309760 0 0
Ovarian and primary peritoneal
Human Genetics and Inherited Disorders 310355 310355 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants randomized to Group A will be given aspirin in the form of a pill, to be taken by mouth every day for between 6 months to a maximum of 2 years, before you have your scheduled risk-reducing surgery. Participants in the intervention group will have an equal chance to receive either low dose of aspirin 81 mg or high dose of aspirin is 325 mg once per day.
Participants will return aspirin containers to study sites to enable check for adherence.

Intervention code [1] 313380 0
Prevention
Comparator / control treatment
Participants randomized to Group B will be given a placebo in the form of a pill, to be taken by mouth every day for between 6 months to a maximum of 2 years, before you have your scheduled risk-reducing surgery. A placebo is a medication with no active ingredients that is identical in appearance to the real medication.
The placebo is a glucose tablet.


Control group
Placebo

Outcomes
Primary outcome [1] 318725 0
The primary outcome measure of this study is the frequency of pre- and malignant lesions (serous tubal intraepithelial carcinomas (STICs) or serous tubal occult neoplasias - early (STONEs) - high grade serous carcinoma) in the fallopian tube/ovary, at the time of risk-reducing surgery (bilateral salpingo-oophorectomy or bilateral salpingectomy inclusive of fimbria), in women carriers of BRCA1/2 mutations who have been treated with a minimum of 6 months and a maximum of 2 years of daily ASA/placebo.
Timepoint [1] 318725 0
All subjects who receive at least one dose of ASA/placebo and undergo risk reducing surgery (bilateral salpingo-oophorectomy or bilateral salpingectomy inclusive of fimbria) will be evaluable for the diagnosis of pre- and malignant lesions in the fallopian tube/ovary determined by central pathology review. Risk reducing surgery can occur up to 2 years post randomisation.
Secondary outcome [1] 365822 0
A composite secondary outcome of subject acceptance of the ASA (aspirin) intervention, includes credibility of ASA as a prevention agent and compliance with ASA/placebo.

Timepoint [1] 365822 0
Credibility will be assessed using a questionnaire Aspects of credibility, i.e. how much the subject believes that the therapy will help to reduce risk of ovarian cancer, will be assessed using modified questions from the self-report Credibility/Expectancy Questionnaire validated by Devilly G. J. and Borkovec T. D. [Devilly 2000] at the following time points:
1. Before commencing treatment (within 7 days before randomization)
2. 6 months following randomization

Compliance will be assessed by serum monitoring of ASA levels, evaluation of treatment completion rates and reasons for early discontinuation of protocol intervention.
Serum monitoring of ASA levels will occur within 72 hours of randomisation and at the first visit (at 6 months) during protocol treatment,
Secondary outcome [2] 365823 0
Tertiary outcomes include characterization of HGSOC tumourigenesis and examination of the link between tumourigenesis and microenvironment.
Timepoint [2] 365823 0
Sample analyses for characterization of effect of ASA (aspirin) on HGSOC Tumourigenesis and examination of link between Tumourigenesis and Microenvironment will occur regularly (every 50 cases). Findings will be batched and presented to the team annually, at trial interim when 200 subjects have been accrued, and trial completion.
Secondary outcome [3] 365824 0
Tertiary outcomes include exploration of the feasibility of using ctDNA/cfDNA as a detection method for pre- & malignant tubal and ovarian lesions, comparing the blood samples to biopsies taken at surgery.
Timepoint [3] 365824 0
Additional blood samples will be collected at baseline, 12 months and within 24 hours prior to the risk-reducing surgery to evaluate the feasibility of ctDNA/cfDNA as a detection method for pre- and malignant lesions.
Secondary outcome [4] 365825 0
Tertiary outcomes include biobanking for future correlative studies.
Timepoint [4] 365825 0
Blood samples will be collected at baseline, 6 and 12 months and within 24 hours prior to the risk-reducing surgery. Tissue collection will be completed at the time of risk reducing surgery i.e. within 6 months to 2 years from randomization.

Eligibility
Key inclusion criteria
1. Previously documented germline BRCA1/2 pathogenic mutation or likely pathogenic variant based on the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines
2. Risk-reducing surgery (bilateral salpingo-oophorectomy or bilateral salpingectomy inclusive of fimbria) scheduled for within 6 months to 2 years after the date of randomization as standard of care, for women who have completed their families. Surgery should not be delayed to allow subjects to participate in the trial. Subjects must have been deemed suitable for the trial participation including surgical interventions by the qualified health care professionals who will oversee the study subjects. Subjects with a previous unilateral salpingectomy/oophorectomy for other reasons will be eligible.
3. ECOG performance status 0 or 1
4. Aged equal to or greater than 18 years old
5. Subject is able (i.e. sufficiently literate) and willing to complete the Credibility/Expectancy questionnaire in English or French. The baseline assessment must be completed within required timelines, prior to randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency or literacy) to complete the questionnaire will not make the subject ineligible for the study. However, ability but unwillingness to complete the questionnaire will make the subject ineligible
6. Subject consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each subject must sign a consent form prior to enrollment in the trial to document their willingness to participate.
7. Subjects must be accessible for treatment and follow-up. Subjects randomized on this trial must be treated and followed at the participating centre. Investigators must assure themselves that subjects randomized to this trial will be available for complete study participation
8. In accordance with CCTG policy, protocol treatment is to begin within 2 working days after subject randomization
9. Women of childbearing potential must have agreed to use a highly effective contraceptive method for the duration of the study treatment and for 30 days post last dose of study medication. Women of childbearing potential are defined as those who are not surgically sterile (i.e. bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
* Women less than 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent hysterectomy
* Women aged 50 years of age or older would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses greater than 1 year ago, had chemotherapy-induced menopause
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subjects with history of other malignancies, except:
Adequately treated non-melanoma skin cancer
Curatively treated in-situ cancer of the cervix
Previously diagnosed (at any point) breast cancer, treated with curative intent; prior
chemotherapy is allowed and the last dose must be equal to or greater than 12 months
prior to randomization
Other solid tumours curatively treated with no evidence of disease for less than 5 years
2. Subjects who have been treated with any PARP-inhibitors (e.g. olaparib) at any time
3. Subjects with active bleeding or bleeding diathesis
4. Subjects with active peptic ulcer
5. Subjects with renal, hepatic or congestive heart failure
6. Subjects with concurrent use of anti-coagulants
7. Subjects with prior bilateral salpingectomy
8. Subjects with history of chronic daily use of ASA (aspirin) or NSAIDs
9. Subjects with intolerance of ASA (aspirin) including subjects with a history of asthma induced by or substances with a similar action, notably non-steroidal-anti-inflammatory drugs
10. Ongoing or planned pregnancy
11. Subjects who are breastfeeding.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All randomizations will be done through a central web-based, password-operated Electronic Data Capture (EDC) system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation will be used for random order generation.
Stratification factors include:
1. Age (less than 40 versus 40 – 50 versus greater than 50 years old )
2. Current (defined as last dose equal to or less than 6 months prior to randomization) combined oral contraceptive use (Yes versus No)
3. BRCA status* (BRCA1 versus BRCA2)
Note: * the carriers of both BRCA1 and BRCA2 mutations will be stratified as BRCA1
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
Intervention assignment
Parallel
Other design features
The ratio of subjects treated with ASA (aspirin) to those with placebo will be 2:1.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
From published findings, we estimate that 15% occurrence of occult carcinomas (6%) and STICs (7-10%) in RRSO specimens in an untreated population [George 2014]. Following upon Trabert et al. [Trabert 2014], restricting analyses to a defined high-risk population such as women with BRCA mutations, we posit that expected magnitude of benefit of ASA should be 40% [Tsoref 2014]. To detect this magnitude of reduction in proportion of malignant precursor lesions (i.e. from 15% in placebo group to 9% in ASA group) with a 80% power and at one-sided 20% alpha level, a sample size of n=372 (n=248 in the ASA group and n=124 in the placebo group) will be required with a 2:1 ratio between ASA and placebo groups.
By allowing a 10% drop out rate, the final sample size will be 414 subjects. It is estimated that accrual of these subjects would take 3 years. The final analysis will be analyzed when the last subject accrued completes her treatment and risk reducing surgery, which would be between 6 months and 2 years. Therefore, the total duration of the study would be between 3.5 and 5 years.

Recruitment
Recruitment status
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,WA,VIC
Recruitment hospital [1] 12944 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 12952 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [3] 12953 0
Prince of Wales Hospital - Randwick
Recruitment hospital [4] 12954 0
Westmead Hospital - Westmead
Recruitment hospital [5] 12955 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [6] 13910 0
King Edward Memorial Hospital - Subiaco
Recruitment postcode(s) [1] 25419 0
3000 - Melbourne
Recruitment postcode(s) [2] 25421 0
2031 - Randwick
Recruitment postcode(s) [3] 25422 0
2145 - Westmead
Recruitment postcode(s) [4] 25425 0
6008 - Subiaco
Recruitment postcode(s) [5] 25426 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 301677 0
Government body
Name [1] 301677 0
National Health and Medical Research Council (NHMRC)
Address [1] 301677 0
16 Marcus Clarke St
Canberra ACT 2601
Country [1] 301677 0
Australia
Funding source category [2] 302059 0
Other Collaborative groups
Name [2] 302059 0
Canadian Clinical Trials Group (CCTG)
Address [2] 302059 0
Queen's University,
10 Stuart Street,
Kingston, Ontario, K7L 3N6
Country [2] 302059 0
Canada
Primary sponsor type
University
Name
University of Sydney
Address
NSW 2006
Country
Australia
Secondary sponsor category [1] 301394 0
None
Name [1] 301394 0
Address [1] 301394 0
Country [1] 301394 0
Other collaborator category [1] 280496 0
Other Collaborative groups
Name [1] 280496 0
Canadian Clinical Trials Group (CCTG)
Address [1] 280496 0
Queen's University,
10 Stuart Street,
Kingston, Ontario, K7L 3N6
Country [1] 280496 0
Canada
Other collaborator category [2] 280497 0
Other Collaborative groups
Name [2] 280497 0
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Address [2] 280497 0
Level 6, Lifehouse
119-143 Missenden Road
Camperdown NSW 2050
Country [2] 280497 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302396 0
Sydney Local Health District (RPAH Zone)
Ethics committee address [1] 302396 0
Research Ethics and Governance Office
Royal Prince Alfred Hospital
Camperdown NSW 2050
Ethics committee country [1] 302396 0
Australia
Date submitted for ethics approval [1] 302396 0
17/07/2018
Approval date [1] 302396 0
16/10/2018
Ethics approval number [1] 302396 0
X18-0289 and HREC/18/RPAH/404

Summary
Brief summary
This study is testing if taking aspirin (also known as acetylsalicylic acid or ASA for short) may help prevent ovarian cancer in women with a high-risk gene mutation, BRCA1 or BRCA2, who plan to have the standard risk-reducing surgery.

Who is it for?
You may be eligible to join this study if you are a woman aged 18 years or above, and you have a gene change or mutation called BRCA1 or BRCA2, which puts you at high risk for getting ovarian cancer. Also you are scheduled, sometime in the next 6 months to 2 years, to have a surgery to reduce your risk by removing your fallopian tubes and ovaries.

Study details
Patients will be randomly allocated to one of two groups, Group A or Group B.

Patients in Group A will be given aspirin in the form of a pill, to be taken by mouth every day for between 6 months to 2 years, before you have your scheduled risk-reducing surgery. You will have an equal chance of receiving either the low or the high dose of aspirin; low dose of aspirin is 81 mg per day and high dose of aspirin is 325 mg per day.

Patients in Group B will be given a placebo in the form of a pill, to be taken by mouth every day for between 6 months to 2 years, before you have your scheduled risk-reducing surgery. A placebo is a medication with no active ingredients that is identical in appearance to the real medication.

The purpose of the study is to find out whether taking aspirin (also known as acetylsalicylic acid or ASA for short) may help prevent ovarian cancer in women with a high-risk gene mutation, BRCA1 or BRCA2, who plan to have surgery to reduce the risk of developing cancer.

Trial website
https://www.ctc.usyd.edu.au/our-research/clinical-trials/oncology/gynaecological-cancer/active-trials.aspx
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90094 0
Prof Kelly-Anne Phillips
Address 90094 0
c/o NHMRC Clinical Trials Centre
Level 6 COB Lifehouse
119-1443 Missenden Rd
Camperdown
NSW 2050
Country 90094 0
Australia
Phone 90094 0
+61 02 9562 5000
Fax 90094 0
Email 90094 0
stics@ctc.usyd.edu.au
Contact person for public queries
Name 90095 0
Ms STICs and STONEs Trial Coordinator
Address 90095 0
c/o NHMRC Clinical Trials Centre
Level 6 COB Lifehouse
119-1443 Missenden Rd
Camperdown
NSW 2050
Country 90095 0
Australia
Phone 90095 0
+61 02 9562 5000
Fax 90095 0
Email 90095 0
stics@ctc.usyd.edu.au
Contact person for scientific queries
Name 90096 0
Prof Kelly-Anne Phillips
Address 90096 0
c/o NHMRC Clinical Trials Centre
Level 6 COB Lifehouse
119-1443 Missenden Rd
Camperdown
NSW 2050
Country 90096 0
Australia
Phone 90096 0
+61 02 9562 5000
Fax 90096 0
Email 90096 0
stics@ctc.usyd.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
Please contact the CTC for publication and data sharing SOP
What supporting documents are/will be available?
No other documents available
Summary results
No Results