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Trial registered on ANZCTR


Registration number
ACTRN12618000267257
Ethics application status
Approved
Date submitted
29/01/2018
Date registered
21/02/2018
Date last updated
6/09/2019
Date data sharing statement initially provided
23/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of targeted screening in high risk melanoma patients using: 3D full body imaging, genomic risk assessment and functional testing of gene variants.
Scientific title
Evaluation of the consumer acceptability and economic efficacy of targeted screening in high risk melanoma patients using: 3D full body imaging, genomic risk assessment and functional testing of gene variants.
Secondary ID [1] 293792 0
None
Universal Trial Number (UTN)
U1111-1207-8069
Trial acronym
Linked study record
This study is linked to previous studies, ACTR ref 12616000450415 and 12616000272493, as we will be recruiting previous participants from these studies to joint the current study.

Health condition
Health condition(s) or problem(s) studied:
Melanoma 306195 0
Condition category
Condition code
Skin 305305 305305 0 0
Other skin conditions
Cancer 305557 305557 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a targeted screening program for people who are at high risk to melanoma.
This screening program involves visits to the Clinical Research Facility at Princess Alexandra Hospital every 6 months for a period of 2 years (5 visits in total). At these visits participants will complete questionnaires (clinical examination form and 'melanoma surveillance - a patients perspective' questionnaire), they will donate a saliva sample for genetic sequencing (baseline visit only), and they will have 3D full body imaging done with further dermoscopic imaging of all naevi larger than 3mm.
Participants will be seen by either a Dermatologist or a clinical research assistant trained by a dermatologist. A second Research Assistant will also be present at participant visits. Patient visits should take between 1-2 hours, depending on the amount of moles the participant has. All images taken at patient visits will be reviewed by a dermatologist.
The saliva sample will be used for genetic analysis that will be used to identify genes associated with high risk of melanoma. This information will be used for further research into melanoma risk, but will not affect the intervention, i.e. participant visits will be the same regardless of genetic findings.
We will also collect healthcare data for cost/benefit analysis
A substudy will evaluate the feasibility of using telehealth services to review 3D full body imaging remotely for a clinical skin examination. Both the technical feasibility of the telehealth network, including interoperability with hospital image repositories and integrated electronic medical records will be evaluated, with addition to the accuracy and concordance of skin examinations between a in-person clinical skin check compared with a teledermatological diagnosis.
Intervention code [1] 300048 0
Early detection / Screening
Comparator / control treatment
Participants randomised to the control group will still be asked to attend an initial baseline visit at the Clinical Research Facility at Princess Alexandra Hospital, where they will complete their first questionnaires (Clinical Examination and Patient's perspective on melanoma surveillance). A research assistant, trained by the Principal Investigator (Dermatologist), will conduct the participant visit. If randomised the control group, participants will then be asked to continue with their standard care for skin checks, i.e. continue to see whoever they were previously for skin checks, e.g. their GP or attending skin check clinics. They will be counseled that they are considered 'high risk' and recommended that they are reviewed every 6 months, however it will be their decision as to who they see and when they do this.
We will contact the control group every 6 months for 2 years, via email or post to complete follow up questionnaires on 'patient's perspective on melanoma surveillance'.
We will also collect healthcare data for cost/benefit analysis.
Control group
Active

Outcomes
Primary outcome [1] 304465 0
All skin excisions/biopsies and their histopathological categorisation, including the number and thickness of melanomas (including in situ). As confirmed by clinical records and pathology reports.
Timepoint [1] 304465 0
Months 6, 12, 18 and 24 (primary endpoint) post baseline visit
Primary outcome [2] 304466 0
An economic evaluation of the surveillance program consisting of a cost benefit analysis, assessed by using data linkage.
Participant healthcare services utilisation relating to skin surveillance and managment will be collected. Participant claims through the Medicare Benefits Schedule (MBS) and the Pharmaceutical Benefits Scheme (PBS), will be collected from all consenting participants at the end of the two year study. Data will also be collected from the Queensland Hospital Admitted Patient Data Collection (GHAPDC) Database, Healthcare Purchasing & System Performance data (HPSP), HHS Funding Models for clinical case-mix and costing. we will capture the whole journey of health service contacts, patient skin cancer outcomes and be able to estimate the related costs of skin cancers within this high risk population. A range of economic outcomes will be measured to determine the feasibility and cost of widespread implementation. Cost savings (earlier detection), additional costs (unnecessary naevi excision/biopsy – measured by number of benign and dysplastic naevi), time taken for in-person review, and number of ‘call backs’ will be recorded.
Timepoint [2] 304466 0
Data collected at the completion of the study, to cover the 2 year study period for each participant.
(timepoint is 0 to 24 months)
Primary outcome [3] 304610 0
This is a composite primary outcome to explore and report on consumer outcomes, by evaluating:
- Satisfaction and acceptability (of 3D imaging technology) will be measured using self-administered, validated questionnaires adapted from the Technology Acceptance Model. Additional questions will capture satisfaction with travel, waiting times, appointment length, convenience and perceived financial value of the surveillance program. Recruitment and retention will contribute to analysis.
- Health behaviours are evaluated with self-administrated, validated questionnaires to capture sub protective behaviours and relevant demographics.
- Psychological well-being of high risk study participants is evaluated using the Euro-QoL-5D, to capture quality of life index
- Health Beliefs of study participants is measured using the validated Health Beliefs Survey, to evaluate knowledge, perceived severity of melanoma, perceived personal risk and perceived worthiness of surveillance programs.
Timepoint [3] 304610 0
Months 6, 12, 18 and 24 (primary endpoint) post baseline visit
Secondary outcome [1] 342047 0
Feasibility of using a Telehealth network to transfer 3D full body images for remote dermatological review of images, including the interoperability with hospital image repositories and integrated electronic medical records (iEMR),
This will include:
• Investigate subsystems for image acquisition, storage and display by measuring network throughput (bandwidth) and latency between subsystems
• Measure data volume, and transmission time per 3D full body examination.
• Assess the compression ratio of transmitted image files necessary to achieve adequate functionality.
• Evaluate success of transmission and integrity of data.
.
Timepoint [1] 342047 0
0-24 Months.
This assessment is continuous and not dependent on individual participant visits.
Secondary outcome [2] 374614 0
Evaluating the Accuracy of telehealth skin examinations (composite outcome).
The safety and accuracy of teledermatology review of 3D full body images will be evaluated by:
• Review the concordance between provisional diagnosis and clinical management decisions of the teledermatologist to the gold standard of in-person dermatological assessment.
• Assess comparative diagnostic accuracy between in-person clinical diagnosis, teledermatological diagnosis and histopathological diagnoses.


Timepoint [2] 374614 0
These assessment will occur randomly at any participant visits at 6, 12, 18 or 24 months.
Secondary outcome [3] 374615 0
Development of a holistic melanoma risk stratification score for a high risk populations is a composite outcome, and based on combining genetic results, self reported sun-behaviour, and deep phenotyping by using the following sources:

Genetic results: saliva samples collected at baseline using the Oragene DNA self-collection kit. Whole Exome Sequencing (WES) or Sanger sequencing used to identify rare, pathogenic, germline variants in known melanoma genes. Common variants associated with melanoma risk will be genotyped using Illumina CoreExomev24 chip array.

Sun Behaviour: Self-administered, previously validated sun behaviour questionnaire (Koh et al, 2018; Olsen et al, 2012) to record sun protective behaviour, sun exposure, sunburn history, personal and family skin cancer history, and relevant demographic information

Deep Phenotyping:
• Documentation of eye, hair and skin colour.
• Spectrophotometer readings for skin colour on the right arm including; the proximal anterior bicep, proximal anterior forearm, and proximal posterior forearm, using Spectrometer CM-600d (Konica Minolta inc., Osaka, Japan).
• Digital photographs of participant’s irises using a Nikon D3400 Digital Single-Lens Reflex (DSLR) camera
• Freckling on the face, dorsum of right hand and shoulders are rated 0 to 4 (=none, mild, moderate, severe) to produce an overall freckling score.

Multivariable logistic regression will be used to assess what combinations of genetic, phenotypic and demographic risk factors are associates with an increased odds of melanoma within a high risk population. Variables with p < 0.2 in univariate regression will be included in the model, and backwards step-wise regression will be used, with variables in the model remaining statistically significant at the 5% level. Validation of the resulting risk stratification algorithms will be performed on larger collaborative cohorts.

References:
Koh U, Janda M, Aitken JF, et al. 'Mind your Moles' study: protocol of a prospective cohort study of melanocytic naevi. BMJ open. 2018;8(9):e025857
Olsen CM, Green AC, Neale RE, et al. Cohort profile: the QSkin Sun and Health Study. Int J Epidemiol. 2012;41(4):929-i.
Timepoint [3] 374615 0
Assessment will be conducted using data collected from all visits: baseline, 6, 12, 18 and 24 months.

Eligibility
Key inclusion criteria
1st round of recruitment:
- diagnosed with multiple melanomas before the age of 40
2nd round of recruitment:
- aged 40-65 with multiple melanomas
3rd round of recruitment:
- diagnosed with single melanoma before the age of 40
4th round of recruitment;
- Individuals considered high risk by a Dermatologist due to strong family history of melanoma, genetic status, and/or dysplastic naevi syndrome

The different inclusion criteria at different rounds of recruitment are to ensure that those at highest risk to melanoma are given the opportunity to participate in the study.

Other inclusion criteria includes:
-ability to provide informed consent
-willingness and ability to commit to a 24 months study including attending 5 visits to the CRF facility at Princess Alexandra Hospital
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Receiving current treatment for melanoma

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)
Central randomisation by computer
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
STATISTICAL METHODS

Sample size
The study aims to recruit 330 high risk participants over a 12-18 month period, to be powered to compare excision rates between groups. This sample size is based on previously reported difference in excision rates in a high risk sample, between those monitored by TBP (mean=0.81, SD=0.75), and a standard care group (mean=2.55, SD=2.01). The definition of high risk is broader in this study, and approximately a third of participants are likely to be already monitored using TBP, therefore the difference between routine clinical care and monitoring with 3D TBP is likely to be smaller. Given this, the study was powered to observe a 50% smaller difference in excision rates than observed previously, including an increase in standard deviation of 50% within each group (mean intervention 0.81 (SD=1.13), mean control 1.68 (SD=3.02)). Given these estimates, with a power of 90% and a significance level of 5%, 153 participants will be required for each arm of the trial. Allowing for participant withdrawal, we will aim to recruit a total 330 participants.

Baseline demographic
Descriptive statistics will be used to summarise demographic and clinical characteristics for both the control and intervention groups. Chi-square tests will be used to estimate difference in proportions of categorical variables between the two groups, and t-tests will be used for continuous variables. Non-parametric equivalents will be used if the assumptions of the parametric tests are violated. Results will be considered statistically significant if p <0.05.

Clinical outcomes
A non-parametric Mann-Whitney test will be used to assess the clinical primary outcome to test if there is a difference in mean annual rate of lesion excisions/biosies between the intervention and control groups, given the primary outcome is based on counts and therefore unlikely to follow a normal distribution. The primary outcome will be analysed as intention to treat, with a per protocol analysis as a secondary outcome. This outcome will also be re-evaluated on a subset excluding those from both the intervention and control groups who are receiving 2D TBP. The benign to malignant ratio for excisions of pigmented lesions and non-melanoma skin cancers will be calculated for both groups. Chi-square or fisher’s exact test (as appropriate) will be used to compare the difference in proportions of pathology confirmed melanoma, melanoma in-situ, BCCs and SCCs dignosed between the two groups with diagnosis. Logistic regression analyses will be used to investigate the relationship between baseline demographic and phenotypic information, and past melanoma history. A subgroup analysis of participants diagnosed with melanoma excluding in-situ, and melanoma including in-situ will investigate the differences in staging, Breslow thickness and body site and other parameters of interest, between the two groups, using linear, logistic and generalised regression models as appropriate. As above, results will be considered statistically significant if p <0.05.

Economic outcomes
Data from Medicare and Queensland Health sources will be linked and aggregated for each patient covering the surveillance period of the study. Skin cancer related resource use will be identified and coded according to ICD-10, procedure and MBS/PBS items. Cost data are typically skewed so generalised linear models will be used with a gamma family and log link (if appropriate) to assess differences between the intervention and control groups. Non-parametric bootstrapping methods will also be applied for verification of differences in costs between groups. Subgroup cost analyses of hospital versus out-of-hospital, melanoma stage, age, phenotypes or other patient characteristics will be explored.

Telehealth review outcomes
The main telehealth outcome is the level of agreement in clinical decision between the teledermatologist and the dermatologist carrying out an in-person skin examination assessment. Four decision outcomes will be considered: No action (no suspicious lesion), follow up in 3-6 months, excision of lesion/s, and treatment of lesion. Weighted Cohen’s kappa coefficient will be calculated to measure agreement.

Melanoma risk score development
Multivariable logistic regression will be used to assess what combinations of genetic, phenotypic and demographic risk factors are associates with an increased odds of melanoma within a high risk population. Variables with p < 0.2 in univariate regression will be included in the model, and backwards step-wise regression will be used, with variables in the model remaining statistically significant at the 5% level. Validation of the resulting risk stratification algorithms will be performed on larger collaborative cohorts.

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)
QLD
Recruitment hospital [1] 9895 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 18702 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 298410 0
University
Name [1] 298410 0
The University of Queensland
Address [1] 298410 0
Translational Research Institute, 37 Kent Street
Woolloongabba, QLD 4102
Country [1] 298410 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Translational Research Institute, 37 Kent Street
Woolloongabba, QLD 4102
Country
Australia
Secondary sponsor category [1] 297546 0
None
Name [1] 297546 0
Address [1] 297546 0
Country [1] 297546 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299407 0
Metro South Health
Ethics committee address [1] 299407 0
Translational Research Institute, 37 Kent Street
Woolloongabba, QLD 4102
Ethics committee country [1] 299407 0
Australia
Date submitted for ethics approval [1] 299407 0
17/11/2017
Approval date [1] 299407 0
19/12/2017
Ethics approval number [1] 299407 0
HREC/17/QPAH/816
Ethics committee name [2] 299506 0
The University of Queensland HREC
Ethics committee address [2] 299506 0
Cumbrae-Stewart Building #72
The University of Queensland
St Lucia, QLD 7072
Ethics committee country [2] 299506 0
Australia
Date submitted for ethics approval [2] 299506 0
15/01/2018
Approval date [2] 299506 0
17/01/2018
Ethics approval number [2] 299506 0
2018000074

Summary
Brief summary
This study will evaluate the effectiveness of targeted screening of people at high-risk of melanoma using 3D full body imaging and genomic risk assessment.

Who is it for?
You may be eligible to join this study if you have been diagnosed with melanoma before the age of 40 years old.

Study details
Participants in this study are randomly allocated (by chance) to one of two groups. Participants in one group will receive standard care at the participants’ discretion which may involve regular skin checks from their own doctor. Participants in the other group will attend a screening program involving 6-monthly 3D full body imaging for 24 months and a once-off genetic testing for high-risk melanoma genes.

We hypothesise our surveillance program using 3D whole body photography and genomic testing will be cost-effective, and will result in fewer excisions of benign lesions and earlier/smaller excision of malignant lesions than the control standard care group
Trial website
n/a
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80294 0
Prof H. Peter Soyer
Address 80294 0
Dermatology Research Centre
Translational Research Institute, 37 Kent Street
Woolloongabba, QLD 4102
Country 80294 0
Australia
Phone 80294 0
+61 07 3443 8017
Fax 80294 0
+61 07 3443 7779
Email 80294 0
p.soyer@uq.edu.au
Contact person for public queries
Name 80295 0
Mrs Clare Primiero
Address 80295 0
Dermatology Research Centre
Translational Research Institute, 37 Kent Street
Woolloongabba, QLD 4102
Country 80295 0
Australia
Phone 80295 0
+61 07 3443 7496
Fax 80295 0
+61 07 3443 7779
Email 80295 0
c.bover@uq.edu.au
Contact person for scientific queries
Name 80296 0
Mrs Clare Primiero
Address 80296 0
Dermatology Research Centre
Translational Research Institute, 37 Kent Street
Woolloongabba, QLD 4102
Country 80296 0
Australia
Phone 80296 0
+61 07 3443 7496
Fax 80296 0
+61 07 3443 7779
Email 80296 0
c.bover@uq.edu.au

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?
Only researchers who provide a methodologically sound proposal, case-by-case basis at the discretion of Primary Sponsor.
Available for what types of analyses?
Only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access subject to approvals by Principal Investigator. May require to sign data access agreement.
What supporting documents are/will be available?
No other documents available
Summary results
No Results