Aim 2 is to explore the role of each of the CM modules and whether the intervention is associated with changes in module-specific target outcomes (see Table 1 for CM modules and their associated outcomes).

If the CM intervention improves emotion dysregulation, we will assess whether changes in emotion dysregulation mediate the effects of CM versus CL on anxiety and depressive symptoms. Hypothesis 2 states that improvements in anxiety and depressive symptoms for CM compared with CL participants —after the treatment will be mediated by greater reductions in emotion dysregulation in CM participants than in CL participants.

Participants comprise individuals who have completed their primary cancer treatment (ie, cancer survivors; Textbox 1).

No minimum criterion was included for the primary outcomes of emotion dysregulation, as it is not certain that this UP-adaption is only effective in highly dysregulated cancer survivors. By excluding participants based on a minimum cut-off, we would not be able to assess the intervention effects on cancer survivors experiencing high and low difficulties.

Participants are recruited using multiple methods, including social media platforms (eg, Facebook groups), web-based community forums (eg, Cancer Council), and via organizers of cancer support groups. Embedded within each of these advertisements, participants can access a link to the study’s written explanatory statement and consent form hosted on the Research Electronic Data Capture (REDCap) tool [43,44]. Informed consent is obtained by submission of a consent form on the web.

Consenting participants are automatically redirected to a web-based screening survey to assess eligibility. Subsequently, eligible participants complete the baseline survey and are telephoned to administer the Mini International Neuropsychiatric Interview (MINI) [45] and conduct a risk assessment. Individuals deemed high risk (ie, probable risk of harming themselves) are excluded over the phone and referred to relevant psychiatric services. Eligible participants are randomized to either CM or CL. This group allocation and a summary of their intervention are conveyed to participants over the phone.

Randomization to CM or CL is conducted using a stratified, block randomization scheme generated in advance and uploaded to REDCap. Variable block sizes (4, 6, or 8) are used to ensure allocation concealment and prior guessing of the allocation sequence at the end of each block. Randomization is stratified by baseline depressive and anxiety symptoms as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety and Depression scales (2 strata: ≥60 for either depression or anxiety, <60 for both depression and anxiety) and the Difficulties in Emotion Regulation Scale–Short Form (2 strata: <45 and ≥45). The randomization scheme is generated and set up in REDCap by a member of the research staff who is not involved in the recruitment or delivery of the intervention nor in the subsequent statistical analysis. The participants are aware of their intervention allocation (ie, CM or CL); thus, they are not blinded. However, participants remain unaware of the study hypotheses regarding which group will improve more on outcomes, and both treatments are presented as potentially effective.

CM is a web-based version of the UP’s Transdiagnostic Treatment for Emotional Disorders [15]. The overall goal of the UP is to help individuals understand and recognize their emotions and respond to uncomfortable emotions in a more adaptive manner. Participants allocated to CM receive four UP-adapted modules titled (1) understanding emotions, (2) mindful emotion awareness, (3) flexible thinking, and (4) doing things differently. CM is a reduced format of the UP, as 2 core UP modules (modules 6 and 7) have been excluded from CM owing to their sole focus on exposure therapy, which was deemed inappropriate for remote delivery for individuals experiencing chronic health conditions. In CM, each module comprises 14 daily activities on the web (3-10 minutes each), which allow participants to apply what they have learned from the psychoeducational readings and videos. Participants are not expected to complete every daily activity, although they must complete at least 1 to 2 core activities per module before they could move on to the subsequent module. This format aims to mirror a more real-life, clinician-led intervention, where clients would not prematurely progress to a subsequent and more advanced module without first being exposed to fundamental skills from the previous modules (ie, in CM, participants must first learn about what an emotion is [module 1] before they can begin to mindfully engage with their emotional experiences [module 2] and change them [modules 3 and 4]). As a result, participants who reach the end of the entire intervention have been exposed to all core skills. Each module is outlined in subsequent sections, and a summary overview is provided in Table 1.

Module 1 aims to build an awareness and understanding of emotions through 3 psychoeducational readings, 2 summary videos, and 14 daily activities. Part 1 explains that emotions are neither good nor bad, and it outlines the various adaptive functions of common emotions. For instance, anxiety elicits fight-or-flight responses, which is important in times of threat. During the daily activities, participants are encouraged to reflect on their own emotions and their adaptive functions in their lives. Part 2 describes common unhelpful beliefs or misconceptions around emotions (eg, “showing emotions is a sign of weakness” and “I ‘should’ feel a certain way in particular situations”). The daily activities encourage participants to explore their own unhelpful beliefs about their emotions. Part 3 describes the three interrelated components that constitute an emotional experience: (1) thoughts, (2) feelings or bodily sensations, and (3) behaviors. During the daily activities, participants are encouraged to bring awareness to these 3 components in their lives.

Module 2 aims to increase mindful awareness of emotions through 2 psychoeducational readings, 2 summary videos, and 14 activities. In part 1, participants are encouraged to adopt an accepting and nonjudgmental stance toward primary emotions, as critical judgment of primary emotional responses can perpetuate negative affective states. Participants are provided with 2 emotion-focused guided mindfulness audios and are encouraged to listen to one of them every day for 7 days. Part 2 teaches a four-step mindful anchoring exercise: (1) paying attention to a cue, such as the breath; (2) identifying their thoughts, feelings, and behaviors; (3) considering whether their response is consistent with the present moment; and (4) shifting their response to align with the demands of the present moment. For 7 days, participants are encouraged to practice anchoring in real time, when experiencing uncomfortable emotions.

Module 3 aims to increase skills in flexible thinking (ie, cognitive flexibility). Flexible thinking involves the ability to (1) identify automatic and unhelpful thoughts and interpretations and subsequently (2) identify an alternative, more balanced appraisal of the given situation. The module comprises 1 reading, 1 summary video, and 14 activities that outline the bidirectional relationship between thoughts and emotions. Participants are taught about common and unhelpful thinking traps (ie, cognitive distortions), including catastrophizing, jumping to conclusions, tunnel vision, “should” statements, and all-or-nothing thinking. The daily activities on the web encourage participants to (1) identify their thinking traps, (2) answer multiple questions to challenge the thinking trap (eg, “What evidence supports my negative belief?” “Am I 100% sure these negative outcomes will occur?”), and (3) generate an alternative and more balanced appraisal of the situation.

The final module aims to build skills in identifying and altering unhelpful emotion-driven behaviors (EDBs) through 2 psychoeducational readings, 2 summary videos, and 14 activities. Unhelpful EDBs are defined as maladaptive ways to try to manage one’s emotions, often with the purpose of eliminating an emotion or preventing oneself from feeling an emotion in the first place. Part 1 focuses on overt and covert avoidance-oriented EDBs (eg, avoiding certain situations or people, procrastinating, denial, ruminating, suppression, and safety behaviors) and their paradoxical effect in increasing negative emotions, such as anxiety. Two other broad categories of EDBs are discussed: reassurance-seeking behaviors (eg, excessive bodychecking for signs of cancer recurrence or excessively seeking external validation and compliments) and defensive behaviors (eg, directing anger and frustration toward others). In activities on the web, participants are encouraged to identify and reflect on these EDBs throughout their lives. Part 2 teaches participants about alternative actions, value-consistent and healthier behaviors that can replace unhelpful EDBs (eg, engaging in conversations with loved ones regarding their cancer journey as opposed to avoiding cancer-related discussions owing to anxiety). In daily activities on the web, participants are encouraged to practice replacing their EDBs with alternative actions.

Rationale for Choice of Control Group

To assess the effects of CM on an appropriate comparator, we consulted the National Institute of Health’s Pragmatic Model for Comparator Selection in Health-Related Behavioral Trials [46]. According to the model, the best comparator is one that suits the goals of the research trial. Given that (1) the CanCope modules have demonstrated promising results when trialed independently in pilot studies and (2) this is the first efficacy trial to assess the effectiveness of the CM program in its entirety, this trial remains within the preliminary phases of the research process. We defined the goal of this trial as establishing how well CM compares to information currently readily available to cancer survivors seeking support to improve their general well-being.

Currently, patients with cancer and cancer survivors have access to a host of resources that aim to promote general QoL, often with a focus on diet, physical exercise, relaxation, and sleep. These resources are often disseminated freely on the web by cancer-specific (eg, Cancer Council, National Breast Cancer Foundation, Prostate Cancer Foundation Australia) and noncancer-specific (eg, Mind UK, Beyond Blue, and Black Dog Institute) community and government organizations. Therefore, two possible comparator options were considered: (1) a wait-list control condition versus (2) a basic lifestyle and well-being intervention targeting diet, exercise, sleep, and relaxation using free and highly accessible web-based resources.

Both options were evaluated against 7 key characteristics identified in the National Institute of Health model [46], which are summarized in Table 2. On the basis of these considerations, a 4-module web-based well-being or lifestyle comparator was chosen (ie, CL). CL is expected to be widely accepted by participants in comparison to a wait-list control group, which may result in high attrition rates, especially given the number of between-module surveys. Furthermore, a basic well-being program is deemed relevant and highly feasible, as we can draw on information available on the web and preexisting sleep resources used in sleep trials by researchers at Monash University. Most importantly, an active comparator controls for nonspecific components of the intervention, such as contact with researchers and expectancy or placebo effects, allowing for greater stringency in measuring the outcomes of interest. The primary limitation of using CL as a comparator is that improvements in diet, physical exercise, relaxation, and sleep may lead to sizeable improvements in secondary outcomes (ie, anxiety and depressive symptoms and QoL). However, the primary outcome of interest is emotion regulation. Given that the CL intervention does not focus specifically on emotions, we expect that any significantly meaningful improvements in emotion regulation will be smaller than those observed in the CM group.

In parallel to the CM modules, the CL group receives four internet-delivered modules that focus on different lifestyle domains: (1) diet, (2) physical activity, (3) relaxation, and (4) sleep. Throughout each 2-week module, participants are sent 2 activity links via email, whereby they are asked to apply what they have learned from the module (eg, describe how you applied the module material to your life over the past week and describe how you plan to apply the module material to your life over the next week). Participants may take 3 to 10 minutes to complete each reflective activity on the web. Although the CL participants are sent fewer application activities on the web than the CM participants, they are still encouraged to apply the module material to their daily lives over the 2-week module duration. The content included in CL is publicly available, except for sleep hygiene information, which was developed by the Monash University sleep research group. The content of each module is outlined in the subsequent sections.

Module 1 comprises 1 video and 3 readings. The video was developed by the organization Mind (a mental health charity in the United Kingdom established by the National Association for Mental Health) and outlines 8 tips to improve well-being through healthy diet habits (eg, eat regularly, eat healthy fats, keep hydrated, and eat a variety of healthy vegetables). All the 3 readings were developed by the Cancer Council. The readings promote eating a healthy diet rich in fruits, vegetables, and whole grains to maintain well-being and reduce cancer risk and provide healthy recipes. Participants are encouraged to apply the healthy eating habits across the 2-week module.

Module 2 comprises 1 video and 1 reading. The video was developed by the organization Mind and outlines tips to encourage physical activity (eg, starting small and adhering to a consistent routine). Participants are directed to the Cancer Council’s reading; “Exercise for people living with cancer,” which provides various exercises related to strength training, aerobic exercise, flexibility, and strengthening the pelvic floor. Participants are encouraged to choose 2 exercises listed in the reading (eg, strength training) to apply throughout the module.

Module 3 comprises educational material (1 video and 1 reading) and a link to various guided relaxation audios. The 5-minute YouTube video was developed by the organization Mind and outlines 8 tips to aid relaxation (eg, scheduling regular breaks, diaphragmatic breathing, visualization techniques, and listening to music). The reading, titled “Learning to relax,” was developed by the Cancer Council and discusses healthy ways to manage emotional stress and aid relaxation (eg, exercising, massage, and yoga). Finally, participants are sent a link to access Beyond Blue’s guided relaxation audio clips. Participants could choose from (1) breathing exercises, (2) muscle relaxation, and (3) guided visualizations. Participants are encouraged to listen to any of these audio clips as many times as they would like across the 2-week module.

The final module comprises 2 readings focused on sleep and fatigue. The first reading was developed by the Cancer Council and explains fatigue in the context of cancer and ways to manage fatigue. The second reading provides education on sleep (eg, what is sleep, stages of sleep, and the importance of sleep) and various sleep hygiene tips (eg, reducing caffeine intake, reducing light exposure at night, and increasing light exposure in the morning). This informational sheet was developed by researchers at Monash University. Participants are encouraged to apply the sleep hygiene tips across the 2-week module.

The MINI [45] is conducted in an initial phone call and used as a diagnostic tool to assess the presence of a major depressive episode (module A) and generalized anxiety disorder (module N), ruling out organic causes (module O). MINI interviews are recorded, allowing for the assessment of reliability and team discussion of complex cases. Any participant who endorses the criteria for a psychiatric illness is provided with relevant mental health and emergency support numbers.

The Difficulties in Emotion Regulation Scale–Short Form (DERS-SF) [47] will be used to assess six domains of emotional regulation (ie, acceptance of emotional responses, emotional awareness, emotional clarity, engagement in goal-directed behaviors, impulse control, and access to emotion regulation strategies). The DERS-SF is an 18-item self-report questionnaire that asks participants to indicate the frequency of emotion-focused behaviors and thoughts on a Likert-type rating scale, with possible responses ranging from 1 (“Almost never”) to 5 (“Almost always”). Example items include “I have difficulty making sense of my feelings” and “When I’m upset, I become out of control.” Scores can range from 18 to 90, with higher scores indicating greater emotional dysregulation. The DERS-SF indicates good concurrent validity for depression, anxiety, and self-harm measures and demonstrates good internal consistency reliability for both the overall scale (Cronbach α=.90) and each individual subscale (Cronbach α ranging from .78 to .89) [48,49]. Moreover, the full version of the Difficulties in Emotion Regulation Scale has been used in prior research to assess emotion dysregulation in oncology populations [50].

The PROMIS–computer [51,52] adaptive tests for the Anxiety and Depression scales will be used to measure symptom changes. The computer-adaptive test algorithm requires a minimum of 4 items and a maximum of 12, and the test stops when the SE is less than 0.30 [51]. The scales present the statement “over the past 7 days...” followed by items, such as “I felt uneasy” (PROMIS Anxiety) and “I felt helpless” (PROMIS Depression). Each item response is rated on a 5-point Likert-type frequency scale, ranging from 1 (“Never”) to 5 (“Always”). Raw scores for each item are summed and converted into a T score (population mean 50, SD 10). Higher scores indicate greater depressive or anxiety symptoms (T<65 = normal-to-mild; T≥65 = moderate to severe symptoms [53]).

The PROMIS QoL Health Utility Score [54] will be calculated using preference-based weights in PROMIS−29+2 Profile (version 2.1) [55] based on computer-adaptive testing to assess QoL. The QoL outcome score is a composite of the following seven domains captured by PROMIS: physical function, pain interference, cognitive function, depression, fatigue, sleep disturbance, and the ability to participate in social roles and activities. The QoL score ranges from −0.022 (“Dead”) to 1.0 (“Full health”) and has achieved good construct validity when measured against the Health Utility Index and the EQ-5D [56].

All the module-specific target outcomes and their respective modules are listed in Table 1. The Beliefs About Emotions Scale [39] will be used to assess negative beliefs about emotions and the impact of CM’s module 1. The Southampton Mindfulness Questionnaire [40] will be used to assess mindfulness and the impact of CM’s module 2. The Unified Protocol–Cognitive Skills Questionnaire [32] will be used to assess cognitive reappraisal skills and the impact of CM’s module 3. In addition, the Cognitive Emotional Regulation Questionnaire [41] “Catastrophizing” and “Refocus on Planning” subscales will also be used to assess the impact of CM’s module 3. The Multidimensional Experiential Avoidance Questionnaire-30 [42] will be used to assess levels of emotional (experiential) avoidance and to assess the impact of CM’s module 4.

The Credibility Expectancy Questionnaire [57] will be administered to assess the perceived credibility and expectancy of CM versus CL before commencing the intervention. The Client Satisfaction Questionnaire [58] will be used to assess the participants’ level of satisfaction with CM and CL. Questions will assess factors such as whether the intervention has met participants’ needs and whether participants would return to the service. Higher scores indicate greater satisfaction. With regard to evaluation of treatment fidelity and reliability, because both interventions are delivered in a standardized way via the internet, no additional measures of treatment fidelity or reliability are collected. With regard to adherence, for CM, adherence is measured objectively via the number of completed application activities on the web per module. For CL, adherence is measured via self-reports of whether participants indicate that they have applied the intervention content to their lives that week in the weekly web-based activities.

The Depression Risk Questionnaire-7 [59] is a brief self-reported questionnaire developed as a clinical screening tool for patients with breast cancer at risk of depression. The Positive Affect Subscale from the Positive and Negative Affect Scales [60] will be used to assess positive emotional states (eg, attentiveness, enthusiasm, pride, and interest). Two items assessing (1) impact and (2) distress caused by COVID-19 will be administered, with participants’ self-reported responses indicated on a sliding scale from 0 to 100 (0=no distress or no impact, 100=a lot of distress or a lot of impact).

The primary end point for the trial is the immediate postintervention assessment (T₄). As all primary and secondary outcomes are continuous, the primary analyses will be linear regressions with group as a predictor and outcome scores at baseline included as a covariate. We set the type 1 error at Cronbach α=.05 (2-tailed). A Monte Carlo simulation study was conducted to determine the power analysis and required sample size. In the simulation, we varied (1) the correlation between baseline and postintervention outcome scores (r) across four values (0.3, 0.4, 0.5, and 0.6) selected from the literature and our pilot research [18] and (2) the standardized mean difference (SMD) between the CM and CL groups at post intervention on outcome scores (primary end point) across 2 values (SMDs of 0.5 and 0.6). The SMDs were selected based on our pilot work [18] where we observed SMDs from before to after the intervention of approximately 0.5 to 1.0 for our primary and secondary outcomes. Our pilot did not include a control group (likely inflating the SMDs) but only tested individual modules separately (likely reducing the SMDs); therefore, we believe that a moderate SMD was reasonable, on average. The code for this Monte Carlo study is publicly available [61]. Results from 10,000 Monte Carlo simulations for each of the conditions and varying sample sizes showed that participants (n=100) with complete data at T₄ will provide more than 80% power to detect a medium (SMD=0.5) group difference—after the intervention, even with only a moderate correlation (r=0.3) between baseline and postintervention outcome scores with Cronbach α=.05.

Analyses will be conducted in R on an intention-to-treat basis with statistical significance set at Cronbach α=.05 for type 1 error. The tests for primary and secondary outcomes will be 2-sided. The data will be assessed for outliers. If outliers are present, we will use quantile regression to calculate a median estimate or evaluate removing or winsorizing outliers.

Missing data are ubiquitous in research, and dropout and incomplete data (eg, dropout) are particularly common in web-only trials [62]. For aim 1 analyses, we will address missing data using multiple imputation with a fully conditional specification [63] and predictive mean matching [64]. A total of 20 imputed data sets will be generated. The primary outcome of the trial is the Difficulties in Emotion Regulation Scale (DERS-SF). The primary end point is immediately after the intervention, immediately following module 4 (T₄). Anxiety and depression symptoms as well as overall QoL are secondary outcomes. All outcomes are continuous measures.

The primary analyses will consist of linear regressions on multiple imputed data. Each outcome variable at the primary end point (T₄) will be included as the outcome variable in a linear regression, with group as the main predictor and the outcome variable at baseline (T₀) and stratification factors included as covariates. Adjusted means in each group, as well as the adjusted mean difference, will be calculated. In the event of outliers, quantile regression will be used in place of linear regression and adjusted median differences at the primary end point (T₄), and as exploratory analyses, the other time points will be estimated. Following recent research suggestions [65], we chose to provide randomization-based inferences; that is, statistical significance will be based on Fisher exact P values [66] from 100,000 permutations for the adjusted mean differences and uncertainty intervals will be based on 95% Fisher intervals. The sharp null hypothesis tested will be that being randomized to CM has an identical effect on participants’ outcomes as being randomized to CL.

Given the conceptual overlap between stratification factors and the outcome measured at baseline, only the stratification factors for anxiety and depression will be included in the linear regression assessment of the primary outcome (DERS-SF). For the linear regression assessment of depression and anxiety symptoms, only the DERS-SF stratification factor will be included. For the linear regression assessing QoL, both stratification factors will be included.

In addition to testing for group differences at the primary end point (T₄), we will explore group differences at T₁, T₂, T₃, and T₅ on the primary and secondary outcomes. The overall sample mean at T₀ will be presented for comparison.

The adjusted SMDs will be calculated as the adjusted group mean difference (CM–CL) divided by the residual SD estimated from the model. In the case of outliers, standardized median difference will be calculated. By using the residual adjusted for baseline outcome scores, this is effectively an effect size on the difference scores or for repeated measures [67].

The same analyses, significance tests, sharp null hypothesis, and result reporting described for the primary aim will be used to assess aim 2, the effect of CM versus CL on module-specific target outcomes. The model-specific target outcomes are presented in Table 1. Using regressions (linear if no outliers and quantile if outliers), adjusted differences between CM and CL in module-specific outcome scores will be assessed after each module and at the intervention end point (T₄) adjusted for the score before completing the module.

If intervention effects are observed on the DERS-SF, aim 3 will involve conducting mediation analyses to assess whether greater improvements on the DERS-SF (primary outcome), in the CM versus CL condition, mediate the effects of CM versus CL on anxiety and depression symptoms (secondary outcomes).

Planned sensitivity analyses will include (1) calculating parametric and asymptotic P values and CIs, (2) generalized additive models to examine whether results differ when allowing nonlinear associations between baseline and postintervention symptoms, (3) per-protocol analyses based only on participants who completed all core intervention components, and (4) assessing group differences in intervention duration and the impact of intervention completion time on outcomes.