Navigate: A study protocol for a randomized controlled trial of an online treatment decision aid for men with low risk prostate cancer and their partners

Background Active surveillance (AS) is the disease management option of choice for low risk prostate cancer. Despite this, men with low risk prostate cancer (LRPC) nd management decisions distressing and confusing. We developed Navigate, an online decision aid to help men and their partners make management decisions consistent with their values. The aims are to evaluate the impact of Navigate on: uptake of AS; decision-making preparedness; decisional conict, regret and satisfaction; quality of illness communication; and prostate cancer-specic quality of life and anxiety. In addition, the healthcare cost impact, cost-effectiveness and patterns of use of Navigate will be assessed. This paper describes the study protocol. Methods 304 men and their partners are randomly assigned one-to-one to Navigate or to the control arm. Randomisation is electronically generated and stratied by site. Navigate is an online decision aid that presents up-to-date, unbiased information on LRPC tailored to Australian men and their partners including each management option and potential side-effects; and an interactive values clarication exercise. Participants in the control arm will be directed to the website of Australia’s peak national body for prostate cancer. Eligible patients will be men within three months of being diagnosed with LRPC, aged 18 years or older and who are yet to make a treatment decision and who are deemed eligible for AS by their treating clinician, and who have internet access and sucient English to participate. The primary outcome is self-reported uptake of AS as the rst-line management option. Secondary outcomes include self-reported preparedness for decision-making; decisional conict, regret and satisfaction; quality of illness communication; and prostate cancer-specic quality of life. Uptake of AS one month after consent will be determined through patient self-report. Men and their partners will complete study outcome measures before randomisation, and one, three and six months after study consent. delaying radical associated side partners’

detection strategies can reduce the risk of disease progression, they can also result in overtreatment, particularly in men diagnosed with low risk prostate cancer (LRPC).
Men diagnosed with LRPC may be offered curative treatment options, including radical prostatectomy (RP), radiotherapy (RT) and brachytherapy (BT), or may be managed with routine monitoring called active surveillance (AS). It is estimated that up to 50% of all prostate cancer cases do not require curative treatment up to 12 years post-diagnosis (4). Indeed, evidence suggests that there is no survival bene t in providing curative treatments for LRPC at least up to 10 years after diagnosis (5,6). Moreover, these curative treatment options are commonly associated with both short-and long-term side effects such as erectile dysfunction, urinary and bowel incontinence, and reduced quality of life (6)(7)(8). This underscores the importance of patient involvement in decision-making regarding the commencement of curative treatment during early-stage disease (9).
AS is now recommended as a preferred management strategy for LRPC (9)(10)(11)(12)(13), although rates of AS uptake vary widely around the world (14). AS is a proactive approach which aims to delay or avoid radical treatments through close monitoring of both the patient and the tumour (15). AS is now widely accepted as an effective management strategy for LRPC and clinicians are encouraged to offer AS to eligible patients (9,13,16,17). AS has also been shown to be the least costly option for LRPC and increased uptake of AS would lead to substantial cost-savings to the health system (18).

Comparisons in outcomes between management options for LRPC
A recent examination of cancer mortality statistics revealed a 15-year survival rate of 95% for men with LRPC on AS (19). In terms of age-speci c outcomes for AS, 15-year cancer-speci c mortality has been shown to be 5.7% for men aged 65-74 years, and 10% for those over 75 (20). Indeed, 10-year prostate cancer-speci c mortality rates have been shown to be similar regardless of whether men undergo AS, RT or RP (6). However, recent data has raised concerns about compliance with AS protocols, reporting that 75% of patients do not meet minimum requirements for PSA testing and biospies to ensure that their cancer is adequately monitored (21).
While survival rates remain similar across management options, impacts on urinary, bowel and sexual function vary signi cantly. Two recent studies demonstrated signi cantly greater urinary incontinence and poorer sexual function in men treated with RP compared with those managed by AS (7,22). Importantly, men receiving AS report similar outcomes in relation to sexual, urinary and bowel function as men who are not diagnosed with LRPC (7).

Treatment decision making in LRPC
Management decision making is di cult for men with LRPC. Decision-related distress and confusion are high (23)(24)(25), due largely to the variety of management options with no clear best choice and the fact that management decisions are highly dependent on men's individual preferences and lifestyle (26). For those contemplating AS, anxiety about not receiving radical (i.e. curative) treatment is common (24). Most men do not consider all management options nor do they make decisions concordant with their personal preferences and values (27,28). Partners of men with LRPC also experience high decisional distress and confusion (15,29) and some pressure their partner towards curative treatment (24,28). The study anticipates that both men and their partners would bene t from decision-making support, particularly regarding their understanding of the bene ts and risks associated with each management option, the risk of the LRPC spreading outside the prostate and the concordance of each option with their personal values and preferences (27).
Decision aids for LRPC Decision aids are textual, audio, visual and web-based tools that provide evidence-based information to assist patients to consider management options within the context of their own preferences and values. Decision aids guide patients through a deliberative process of actively weighing-up the bene ts/costs of available treatment options, thus enabling decision-making that is both evidence-based and considerate of patient preferences and life circumstances (30). A 2017 Cochrane systematic review demonstrated that decision aids improve knowledge of available treatment options and outcomes, and accuracy of risk perceptions, decrease decisional con ict, increase decisional satisfaction, increase congruency between treatment choice and patient values, and improve patient-clinician communication (31). Level I evidence shows that decision aids reduce the proportion of those who choose surgery in favour of less invasive management options (13).
Several decision aids for LRPC exist, and some of these have shown promise in assisting in decision making and reducing decisional regret (32)(33)(34)(35). However, two systematic reviews have concluded that none comprehensively addresses the needs of men with LRPC (26,27). The major de cits include incomplete or biased content, lack of consideration of patient values, inadequate partner involvement, lack of clari cation between AS and watchful waiting (WW), lack of theoretical framework, too few examples of patient experiences, and inadequate systematic evaluation (26,27). Both reviews highlighted an urgent need for high-quality decision aids, which accurately portray AS and are developed in line with International Patient Decision Aid Standards (IPDAS) (26,27). Moreover, none of the currently available decision aids have been tailored to the local health care context or are easily accessible by Australian men.
Navigate -an Australian online treatment decision aid for LRPC Besides doctors, the internet is the primary source of information for men with prostate cancer (36). In 2017, 86% of Australian households had internet access at home (37) while 88% of Australian adults aged 18-75 owned or had access to a smartphone (37). Provision of an online decision aid enables access from home, promotes rapid and widespread dissemination, and enables easy updating to ensure currency of content.
We have developed the Navigate online decision aid which presents up-to-date, unbiased information tailored to Australian men with LRPC in written, graphical and video formats. The Navigate decision aid was informed by a qualitative study which explored the experiences of 21 men with LRPC who had been on AS for at least 3 months, and 14 of their partners (24). The ndings con rmed that partners were highly involved in management decision-making and highlighted the need for consistent and accurate discourse surrounding LRPC diagnosis and management options. Men and their partners emphasised the need for balanced information to facilitate informed and values-based treatment decisions (24). Navigate was co-designed by consumers and a multidisplinary team, is evidenced-based and theoretically underpinned and complies with IPDAS criteria. Box 1 displays the key features of the website and example graphic images.

Study aims and hypotheses
The aims of this study are to evaluate the impact of Navigate for men with low risk prostate cancer and their partners on: uptake of AS as a rst-line management option; men's preparedness for decisionmaking; men's decisional con ict, regret and satisfaction; the quality of men's illness communication; and men's prostate cancer-speci c quality of life. The secondary aims are to: estimate study arm differences in men's anxiety; explore the impact of Navigate on partner's decisional con ict, regret and satisfaction, and quality of illness communication; assess the healthcare cost impact and cost-effectiveness of Navigate (economic sub-study); and determine the speci c patterns of use of Navigate (web analytic substudy).
Speci c hypotheses are that: a higher proportion of men randomised to Navigate will select AS as a rstline management option when compared with men randomised to the control group; and men randomised to Navigate will feel better prepared for decision-making, experience lower levels of decisional con ict and regret and higher levels of decisional satisfaction, report better quality of illness communication and better prostate cancer-speci c quality of life when compared to men randomised to the control group.
Research questions, rather than hypotheses, were developed for secondary aims, since no speci c predictions were made. Research questions relevant to the main study include: Do men randomised to Navigate report higher or lower levels of anxiety than men in the control group?
Do the partners of men randomised to Navigate experience lower levels of decisional con ict and regret, and higher levels of decisional satisfaction when compared with the partners of men randomised to the control group?
The research question for the economic sub-study is: What is the cost-effectiveness of the decision-aid intervention compared with usual care for men newly diagnosed with prostate cancer?
The research questions for the web analytic study include: What are the general patterns of use of the website; are there any identi able areas for improvement from a user experience perspective? Do men diagnosed with prostate cancer use the website differently compared with partners of these men?
What are the patterns of use across individuals relating to the values clari cation exercise?
Do patterns of use relate to the primary and secondary outcome variables?
Trial design and randomisation This study will use a parallel group, prospective randomised controlled trial (RCT) with one baseline and three post-baseline assessments (i.e. follow-ups 1, 2 and 3), along with economic and web analytics substudies. In this study, 'partner' refers to the support person nominated by the patient. Both patients and their partners (if one is nominated) will be invited to participate. Following informed consent and completion of baseline study measures, participating patients and their partners will be randomly assigned to Navigate or the usual care arm with a one-to-one allocation, strati ed by recruitment site. Randomisation will be undertaken remotely and independently by the trial coordinator using a purposebuilt Microsoft Access randomisation database. After a participant (patient/partner) has been enrolled and completed baseline measures, the trial coordinator uses the randomisation database to assign the participant to the intervention or usual care arm and informs them via email of the experimental allocation. Post-baseline assessments will occur approximately one, three and, six months after consent. Participants will be informed of their allocation after completing baseline questionnaires. Researchers involved in data collection will be blinded to group allocation. Statisticians will be unblinded to allocation before preparation of the participant ow diagram and outcome analysis. Ethical approval was received from the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC16 PMCC114).

Participants and study setting
Australian patients will be eligible to participate regardless of whether or not their partners participate, whereas partners are not eligible without a participating patient.

Eligibility criteria
Men will be eligible to participate in this trial if they: are 18 years or older; have been diagnosed with LRPC in the last three months and have yet to make a treatment decision; have been deemed eligible for AS by their treating clinician; and have internet access and su cient English to complete study requirements and use the Navigate website. Men will be ineligible if they have a severe psychiatric or cognitive disorder or are too unwell to participate as deemed by their treating clinican, self-report or the research team at the time of approach.
Partners are eligible to participate in this trial if they: are 18 years or older, are the designated partner identi ed by the consenting patient; and have internet access and su cient English to complete study requirements and use the Navigate website.

Participating sites include ve Australian treatment centres within Victoria (Peter MacCallum Cancer
Centre, Western Hospital, Cabrini Hospital, Alfred Hospital, Austin Hospital), and two in Queensland (Royal Brisbane and Women's Hospital, Redcliffe Hospital). Men with LRPC and their partners from either public or private health care settings are also be able to self-refer online to the trial.
Intervention: Intervention participants are emailed login details to access the Navigate online decision aid which is hosted on the Prostate Cancer Foundation of Australia website. Using Navigate, men and their partners are led through information on each treatment option for LRPC with its potential bene ts and side-effects. An interactive values clari cation exercise assists the men with weighing up the advantages and disadvantages of each management option to clarify what matters to them and to guide their preferences.
Usual care: Usual care participants are provided with minimal information to ful l ethical obligations and emailed a link to the Prostate Cancer Foundation of Australia website page for LRPC treatments. This website provides brief information on LRPC and treatment options, but differs from the Navigate website in that it does not include comparisons of the pros and cons of each management option; a values clari cation exercise nor the presentation of material in graphical or multimedia formats.

Recruitment and consent
Potentially eligible men will: i) are identi ed by their treating clinician/nurse or the site investigator using screening clinic lists; or ii) self-refer to the website via digital marketing strategies. The treating clinician can also refer interested patients directly to the study team. Once men and their partners provide consent and complete baseline questionnaires, they are provided with the appropriate website link as per their group allocation. Non-consenters are asked for de-identi ed demographic and clinical details. Attrition will be monitored and reasons for withdrawal recorded.

Hospital recruitment and consent
Eligible men are approached after their diagnosis by research nurse/assistant, consistent with the agreement of those patients' treating doctors. The research nurse/assistant reviews the Patient Information and Consent Form (PICF) with interested patients and patients provide online consent via the Qualtrics survey platform. Using the same consent procedure, partners are invited to participate. Consenting patients are also asked to provide written consent for the study team to obtain data from the Medicare Bene ts Scheme and Pharmaceutical Bene ts Scheme databases.
For patients or partners who are unsure about participating or do not have time to complete the PICF in clinic, a research team member is able to contact the patient/partner by telephone within a week to determine participation status. If the patient/partner agrees to participate, they are emailed a personalised PICF link.

Self-referral, recruitment and consent
The study is being promoted using digital marketing and community engagement strategies (Google Ads, Facebook, social media, blogs, commentary articles). Men who self-refer to the study are asked to complete an online Expression of Interest form including the details of their treating clinician who will be contacted by the study team to con rm eligibility. If eligible, a research nurse/assistant will undertake the consent process with the patient over the telephone.

Clinician referral, recruitment and consent
The treating clinician can also refer their patients directly the study con rming they meet the eligibility criteria and they have discussed the trial with his/her patient who is happy to be contacted. A research nurse/assistant is then available to undertake the consent process with the patient over the telephone.

Procedure and Assessments
After consent, the research team emails a link to access this questionnaire to be completed at home. The online questionnaires were created by the research team within Qualtrics, an online program which prevents skipping questions. A reminder telephone call is made if the study measures have not been completed within 48 hours. However, if the participant exits the form without completing the entire questionnaire, they are not followed up to obtain the remaining data.
Follow-ups 1, 2, and 3 are emailed to participants respectively at 1, 3 and 6 months post-consent. If follow-up questionnaires have not been completed within two weeks, a reminder telephone call is made. After completion of follow-up 3, participants are contacted via email and telephone to con rm trial completion, and to thank the participant for their time. The trial ow chart is presented in Figure 2.

Main study measures
Demographic and clinical information Demographic information collected from patients and partners includes: age (in years), marital status, postcode, highest education level, occupation and ethnic origin.
Clinical information (Gleason score and PSA) is obtained from the referring site; the referring clinician, or collected via a medical record audit.

Primary outcome
The primary outcome is self-reported uptake of AS as the rst-line management option for LRPC assessed as a percentage (AS or curative treatment option) at follow-up 1.

Secondary outcomes
Preparedness for decision-making is assessed at follow-up 1 with the preparedness for decision-making scale (PrepDM). The PrepDM total scale measures the perceived usefulness of the decision aid in preparing the patient to communicate with his doctor(s) to make a health decision and has shown acceptable internal consistency (Cronbach's α=0.92 to 0.96), and Item Response Theory analyses demonstrated that all ten scale items function well (38).
Decisional con ict is assessed at follow-up 1 with the 16-item Decisional Con ict Scale (DCS). The DCS measures patients' perceptions of uncertainty, being uninformed, unsupported and having unclear values in decision making. The DCS is suitable for use with cancer patients and has shown acceptable internal consistency (Cronbach's α=0.78-0.92), test-retest reliability (r=0.81), and responsiveness (longitudinal validity) (39).
Decisional satisfaction is assessed at follow-up 2 and, for patients only, follow-up 3 with the 6-item Satisfaction with Decision (SWD) measure. The SWD has shown acceptable internal consistency (Cronbach's α=0.86), discriminant validity and responsiveness (31,40).
The quality of men's and partners' illness communication is assessed at baseline and follow-up 1 with the 4-item Couples' Illness Communication Scale (CICS). The CICS was adapted for use in prostate cancer populations. The original scale has shown acceptable internal consistency (Cronbach's α= 0.80) and convergent validity with other measures of dyadic adjustment (41).
Anxiety is assessed at baseline and follow-up 1 with the 7-item PROMIS Emotional distress-Anxiety 7a short-form. The Anxiety 7a is a standardised, valid and precise measure speci cally developed for use in clinical oncology research (42).
Prostate cancer-speci c quality of life is assessed at baseline and every follow-up with the 26-item Expanded Prostate Cancer Index Composite short-form (EPIC-26). The EPIC-26 comprises four subscales: urinary, bowel, sexual and hormonal. The hormonal subscale is not relevant in this context, so will not be administered. Subscales have shown acceptable internal consistency (all Cronbach's α >0.70), test-retest reliability (all r>0.69) and responsiveness when used independently (43).

Sample size
The sample size calculation was based on 80% power, a two-sided α=0.05 test and a difference in uptake of the AS treatment option of 15%. Assuming 65% uptake in the usual care group (3) and 80% uptake in the intervention group (a conservative assumption), the required sample size is 272 patients (136 in each study arm). Our sample size calculation was performed with PASS version 16. Allowing for 10% attrition a total sample size of 304 participants is required.

Statistical analysis
All analyses will be performed using Stata 16. Prior to formal analysis, descriptive statistics and graphical displays will be used to identify missing and out-of-range values, assess distributional assumptions and identify outliers.
Recruitment bias will be assessed by comparing demographic and clinical characteristics of consenters and non-consenters using t-tests (or Mann-Whitney) and chi-squared (or Fisher's exact) tests as appropriate. Differential attrition will be assessed by comparing baseline characteristics of drop-outs and continuing participants using the same statistical tests.

Outcome analysis
The primary analysis will follow the intention-to-treat principle and all study participants will be analysed as part of the study arm to which they were randomised in all outcome analysis. Missing data will be imputed using multiple imputation, redrawing 50 samples. Pearson's chi squared test will be used to analyse study arm differences in the primary outcome. Linear regression will be used to analyse study arm differences for preparedness for decision-making at follow-up 1, illness communication at follow-up 1, and anxiety at follow-up. Each model will be adjusted for baseline and group assignment. Decisional con ict (follow-up 1), satisfaction (Follow-ups 2 and 3) and regret (follow-ups 2 and 3) will be analysed using linear regression with group assignment as the independent covariate (equivalent to a test). The effect between groups and signi cance will be assessed using the beta-coe cent and p-value corresponding to the group assignment term. Finally, prostate cancer-speci c quality of life will be analysed with a random effects mixed model. The independent variables will be group assignment, time (coded 0/1) and the interaction term group assignment BY time. The effect and between groups and signi cance will be assessed using the beta-coe cient and p-value corresponding to the interaction term. All results will be presented with 95% con dence intervals and a p-value less than 0.05 (two-sided) will be deemed to be statistically signi cant.

Exploratory analyses
Participants will be analysed as part of the study arm to which they were randomized in all exploratory analysis. Regression (similar to the above) will be used to analyse study arm differences in the following exploratory outcomes: men's anxiety (at follow-up 1); partners' illness communication with men (at follow-up 1); partners' decisional con ict (follow-up 1); partner's satisfaction (follow-up 2 and 3); and partner's regret (follow-up 2 and 3). The effect between groups and signi cance will be assessed using the beta-coe cient and p-value corresponding to the group assignment term.

Health-economic sub-study
The aim of the economic sub-study is to assess the nancial burden and cost-effectiveness of the Navigate online decision aid in the Australian context. This will compare the costs and patient outcomes of intervention versus usual care aligning to the goals of the planned RCT. The analysis will take a societal perspective and include Medicare data for all patient participants to assess healthcare costs to government and patient out-of-pocket expenses from participant surveys.
Health utility data will be collected at baseline and follow-ups 2 and 3. The 5-item EuroQol-5D (EQ-5D-5L) will be used, which is a standardised measure of health status developed speci cally for economic evaluation and is suitable for cancer patients. It has shown acceptable internal consistency (Cronbach's α=0.71), test-retest reliability (kappa=0.7), convergent validity (r>0.49), discriminant validity and responsiveness (47,48).
Patient health care costs will be reported by patients at follow-ups 2 and 3. These include out-of-pocket expenses for all medical services, as well as costs for travel, accommodation and income lost from interrupted employment. The Patient Costs Questionnaire (PCQ) is purpose-built for Australian men with prostate cancer (49) and includes items such as general practice and specialist visits, counselling and support services, as well as sexual and incontinence aids. Follow-up 3 will also include the COST-FACIT questionnaire (50) capturing nancial hardship and additional questions used previously by men with prostate cancer relating to early retirement and nancial situation.
At the end of the data collection period, Medicare data on all services and medicines for all consenting participants will be accessed. With this data, the types and dollar amounts exchanged for health services, community services and medicines for prostate cancer and other diseases will be assessed, including medical services for privately-insured patients. The main economic outcome will be incremental cost per quality-adjusted life year for the Navigate tool versus usual care. Methods for this economic evaluation will be governed by standardised guidelines in modelling studies and economic evaluations (51,52).
Web analytics sub-study Website analytics will be used to indicate: preferred modes of interaction; which aspects users (participants) nd most engaging; and how users prefer to access information on the Navigate website. This provides indicative answers to speci c questions, such as how comprehensively users consume the information regarding the different management options before submitting preferences on decisions.
Analysis of user behaviour may lead to a better understanding of the effectiveness of the decision tool, as well as potentially identifying areas for improvement. Planned data capture includes: click information; pages visited; time spent on each page; information viewed and/or downloaded; and values clari cation exercise responses. Since data is associated with user ID, behaviours can be linked to demographic characteristics such as age, sexual orientation, or user type (i.e. patient or partner).
Analysis will be restricted to the intervention group of the randomised study since the focus of this substudy is the characteristics and effectiveness of the web-based decision tool. Effects to be investigated include informational value of pages (determined by number of visits and time spent), as well as complex behavioural effects such as the amount of information consumed before coming to decisions. Variance across demographic sub-groups will be measured using appropriate statistical metrics (e.g., ANOVA, chisquared) to determine demographic-based preferences. Data mining techniques (e.g., association-rule mining) will be applied to attempt to determine other associations between behaviour characteristics (e.g., consuming certain information leading to certain decisions and/or outcomes).
Data storage, management and future use.
All data is kept in password protected databases. Non-identi able participant data is separated from databases linking names with participant identi able details. Once the study is completed, this database with identi able details will be destroyed; the remaining data will be retained inde nitely. With the exception of the Medicare data, participants who consent to this study will also be consenting to the use of their data for future unspeci ed research. To obtain access to the data obtained through this project, investigators will have to have their projects approved by the HREC of their host institution and by Peter Mac Cancer Centre HREC.

Discussion
With the increase in diagnoses of LRPC (1,53), there is an urgent need for resources to support patients and their partners in their management decision making and, speci cally, to reduce the choice of potentially unnecessary radical treatments with inherent signi cant side effects (26,27). Confusion, anxiety, distress and decisional regret are common in men with LRPC (23)(24)(25) and in their partners which may be enduring (15,24,28,29). Indeed, men with LRPC and their partners express the need for unbiased information about potential bene ts and risks of their management options, to help them informed decisions which are aligned their own personal preferences and values (24).
The Navigate online decision aid has the potential to increase the choice of AS to manage LRPC, thereby avoiding or delaying radical treatments. In addition, Navigate has the potential to reduce patients' and partners' confusion and distress in management decision making, reduce decisional regret and increase decision-making preparedness, decisional satisfaction, and improve prostate cancer-speci c quality of life. Navigate will be made available to all Australian men diagnosed with LRPC to support their management decision making.
Besides the potential rami cations on quality of life for men who receive treatment with curative intent, management of LRPC exerts a substantial nancial burden to governments, hospitals and men affected by this condition which is increasing annually (18). Approximately 25% of Australian prostate cancer patients diagnosed have LRPC (3,11): approximately 5,500 per year. If this intervention is successful in achieving the minimal expected difference of 15%, which represents 825 men selecting AS in preference to the most common de nitive treatment approach (i.e. radical prostatectomy), this could present an annual cost saving of at least AU$6.1 million to Australians (difference in average cost per patient of AU$1,400 for government and AU$2,300 for out of pocket) (18). As prostate cancer diagnoses and health care costs escalate, these projected cost savings will grow. Therefore, this project has the potential to reduce both the nancial costs to the government and personal costs to the large and growing population of men with LRPC.
The ndings of this study will be disseminated via publications in peer-reviewed journals and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this study amongst the broader medical and consumer community to improve treatment paradigms and approaches to supportive care for patients with LRPC and their partners. This will include providing the Navigate online decision aid as standard care for patients diagnosed with prostate cancer via the Prostate Cancer Foundation of Australia website, if ultimately proved effective.

Trial Status
The protocol version number is HREC16PMCC114_NAVIGATE_Protocol_V8_27/03/2020. Patient recruitment opened on May 2017 and it is estimated that it will cease in December 2020.