# The effectiveness and implementation of a STEpwise program to promote INGeniouS ONline supportive solutions for self-management of cancer-related fatigue: The STEPPING-STONe digitally enabled randomized trial

Maria Alice Franzoi, Arnaud Pages, Cecile Charles, Marcio Debiasi, Emma Gillanders, Arlindo Ferreira, Fanny Jacques, Sibille Everhard, Guillaume Garybobo, Cesarine Sambou, et al.

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Maria Alice Franzoi, Arnaud Pages, Cecile Charles, Marcio Debiasi, Emma Gillanders, et al. The effectiveness and implementation of a STEpwise program to promote INGeniouS ONline supportive solutions for self-management of cancer-related fatigue: The STEPPING-STONe digitally enabled randomized trial. Contemporary Clinical Trials, 2025, 155, pp.107993. 10.1016/j.cct.2025.107993. inserm-05148566

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# The effectiveness and implementation of a STEpwise program to promote INGeniouS ONline supportive solutions for self-management of cancer-related fatigue: The STEPPING-STONe digitally enabled randomized trial

Maria Alice Franzoi<sup>a,*</sup>, Arnaud Pages<sup>b</sup>, Cecile Charles<sup>c</sup>, Marcio Debiasi<sup>d</sup>, Emma Gillanders<sup>a</sup>, Arlindo Ferreira<sup>e</sup>, Fanny Jacques<sup>e</sup>, Sibille Everhard<sup>f</sup>, Guillaume GaryBobo<sup>f</sup>, Cesarine Sambou<sup>g</sup>, François Alla<sup>g</sup>, Amandine Quivy<sup>h</sup>, Sophie Morin<sup>i</sup>, Ines Vaz-Luis<sup>a,j</sup>

## ARTICLE INFO

### Keywords:

- Cancer-related fatigue

- Digital health

- Self-management support

- Hybrid effectiveness-implementation clinical trial

- Digitally enabled research

- Decentralized clinical trials

## ABSTRACT

**Background:** Fatigue is one of the most common and disturbing symptoms patients face throughout the cancer care continuum, and it is sub optimally addressed in routine care. Developing effective and scalable tools for symptom management is a central unmet need for achieving comprehensive and patient-centric cancer care delivery. This study aims to evaluate the effectiveness of three digital aid modalities for cancer related fatigue (CRF) focusing on patient empowerment and self-management.

**Methods:** Hybrid type 2 effectiveness-implementation randomized clinical trial. A total of 372 patients diagnosed with cancer and moderate to severe self-reported CRF will be randomized 1:1:1 into one of three intervention arms: educational mobile app, educational mobile app powered with a self-guided fatigue self-management program, or educational mobile app powered with the fatigue self-management program and interactive coaching. Clinical trial procedures will benefit from a pragmatic online platform for digitally enabled research allowing eligibility screening, electronic consent, randomization and collection of patient-reported outcomes and clinical data. The primary endpoint is the difference in fatigue scores measured by the EORTC QLQ-C30 questionnaire between baseline and three months after the end of the program. Secondary endpoints include short and long-term impact on fatigue scores including fatigue subdomains, self-efficacy, overall quality of life, use of health resources, as well a detailed implementation evaluation of both the study intervention and the digitally enabled trial procedures.

**Discussion:** This study will provide high-level evidence on the effectiveness and implementation of digital interventions for CRF. It will also demonstrate the feasibility of using technology to streamline clinical trial procedures.

**Trial Registration:** [ClinTrials.gov](https://ClinicalTrials.gov) NCT06505590

<footnote><sup>a</sup> Cancer Survivorship Group, Inserm Unit 981, Gustave Roussy, Villejuif, France</footnote>

<footnote><sup>b</sup> OncoStat, Gustave Roussy, Villejuif, France</footnote>

<footnote><sup>c</sup> Direction general de la Cohesion sociale (DGCS), Paris, France</footnote>

<footnote><sup>d</sup> Champalmaud Hospital, Lisbon, Portugal</footnote>

<footnote><sup>e</sup> Resilience Care, Paris, France</footnote>

<footnote><sup>f</sup> WeShare Platform, Data Department, UNICANCER, Paris, France</footnote>

<footnote><sup>g</sup> Équipe PHARES, Centre de recherche Bordeaux Population Health, Inserm Unit 1219, Université de Bordeaux, France</footnote>

<footnote><sup>h</sup> Supportive Care Department, CHU Bordeaux, Bordeaux, France</footnote>

<footnote><sup>i</sup> Supportive Care Department, Institut Bergonié, Bordeaux, France</footnote>

<footnote><sup>j</sup> Department for the Organization of Patient Pathways, Gustave Roussy, Villejuif, France</footnote>

<footnote>* Corresponding author at: Cancer Survivorship Group, Inserm Unit 981, Gustave Roussy, Villejuif, France.
*E-mail address:* Mariaalice.borinelli-franzoi@gustaveroussy.fr (M.A. Franzoi).</footnote>
# 1. Introduction

Fatigue is one of the most common and disturbing symptom patients face during and after cancer treatment, affecting up to 90 % of patients [1,2]. Although most patients will experience an improvement in their fatigue over time, about 30 % of them experience persistent or chronic fatigue for years after the completion of primary treatments [2-5]. Cancer-related fatigue (CRF) is defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer and/or cancer treatment that is not proportional to recent activity and interferes with usual functioning [2]. Compared with the fatigue experienced by healthy individuals, CRF is more severe, more distressing, and less likely to be relieved by rest [2].

Fatigue's physical and psychological mechanisms remain only partially understood [6]. Research in individuals without cancer suggests that fatigue results from a complex interplay of biological, psychosocial, behavioral, and situational factors [7]. In patients with cancer, tumor and treatment-related disruptions, along with the psychological strain of the diagnosis, may also amplify perception of fatigue [4,8]. Cancer-related fatigue (CRF) affects daily functioning, coping abilities, and social roles, while also hindering treatment adherence and increasing healthcare resource use [2,9].

Despite evidence-based management recommendations [10], CRF remains under recognized, underdiagnosed, and undertreated [11]. Misconceptions and the trivialization of the issue by both patients and healthcare professionals, along with systemic constraints such as time pressure and limited supportive care resources, collectively act as barriers that perpetuate this situation [12-16]. As this situation has been recognized as an outstanding unmet medical need for patients, current international clinical practice guidelines promote systematic screening and evaluation of CRF as part of standard routine care [2,11]. As per the most updated recommendations, information, education, and counseling on CRF must be delivered to patients and their families as early as possible and repeatedly throughout the patient journey in their care pathway [17].

Physical activity and cognitive behavioral approaches are the most efficacious interventions to CRF [3]. Empowering patients to recognize, track and self-manage their fatigue alongside other comorbid conditions is essential in the optimal treatment of this multifactorial condition [18] [19]. As such, digital health interventions represent a pragmatic and scalable strategy, enabling health systems to allocate scarce resources efficiently and to extend the benefits of these interventions to a wide range of patients [18,20,21]. However, a prior pragmatic evaluation of both effectiveness and implementation of different digital health modalities (self-guided vs. supervised by healthcare professional) for managing CRF is lacking [10].

Pragmatic randomized clinical trials investigating strategies for symptom management and quality of life improvement are essential. However, clinical trials often face operational difficulties, including barriers related to eligibility screening, recruitment, data collection, and intervention delivery [22-24]. Technology has the potential to refine and expand the reach of pragmatic clinical trials by streamlining in-person procedures [25]. This could make symptom management trials faster, more effective, engaging, and accessible for both patients and researchers [25]. Nevertheless, the use of such technologies for dematerialized trial procedures is not yet straightforward and evidence evaluating the implementation of such benefits in the oncology setting remains immature [26-28].

The STEPPING-STONE trial is a hybrid type 2 randomized controlled trial [29] assessing both the effectiveness and implementation of three digital aid modalities for patients suffering from moderate to severe CRF, regardless of cancer type or stage. The trial will also evaluate the implementation of digital technology for clinical trial procedures at the patient, health care provider and research team level.

# 2. Objectives

## 2.1. Primary objective

The study's primary objective is to compare the effectiveness of three stepwise digital aid modalities in addition to the standard supportive care delivered in oncology cancer: ([1] educational mobile app (Resilience®); [2] educational mobile app (Resilience®) plus self-guided fatigue self-management program; or [3] educational mobile app (Resilience®) plus fatigue self-management program and interactive coaching with a healthcare provider in reducing patients' perceived burden of CRF, measured as an improvement of at least 6 points from baseline to three months after the end of the program in the fatigue scores yielded by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 fatigue subscale.

## 2.2. Secondary objectives

The study's secondary objectives are to compare the effectiveness of the three aid modalities on additional patient-reported outcomes: CRF at immediately after the intervention and at long-term, self-efficacy, overall quality of life and specific domains, different dimensions of CRF (including the physical, cognitive, and emotional fatigue), description of intervention effectiveness according to baseline electronic health (eHealth) literacy and health literacy levels, and use of health resources. Another key secondary endpoint is to study implementation barriers and facilitators at the patient, health care provider and research team level of the three digital health intervention modalities as well as the use of innovative digital methods for clinical trial procedures, this analysis will be guided by the RE-AIM [30,31] framework using quantitative and qualitative methods.

# 3. Methods

## 3.1. Study design

STEPPING-STONE is a national, pragmatic, hybrid type 2 effectiveness/implementation randomized clinical trial leveraging digitally enabled clinical trial procedures. Participants will be randomized 1:1:1 into one of the three intervention arms: educational mobile app, educational mobile app powered with a self-guided fatigue self-management program, or educational mobile app powered with fatigue self-management program and interactive coaching - Fig. 1.

## 3.2. Patient eligibility

### 3.2.1. Inclusion criteria

Patients eligible for the study must be aged 18 years or older, with a clinical diagnosis of cancer (all primary sites allowed) and have self-reported moderate to severe CRF for at least one week, defined as the worst level of fatigue scoring 4 or more on a 10 point numerical scale (cutoff retained in international guidelines as an optimal cutoff for identifying clinically significant CRF) [32]. Patients also have to be able to read and understand French, and have access to internet, e-mail and a smartphone.

### 3.2.2. Exclusion criteria

Patients currently engaging in cognitive-behavioral therapy or participating in another clinical trial evaluating a behavioral intervention are not eligible. According to physician's judgment, patients suffering from any potentially reversible and/or treatable cause of fatigue (such as anemia, electrolyte imbalance, infections, renal dysfunction, active metastases causing fatigue, hormonal imbalances, hypothyroidism, adrenal insufficiency, etc.) are not eligible.
<figure><img src="image_4.png" /><figcaption>Fig. 1. STEPPING STONE trial design.</figcaption></figure>

### 3.3. Clinical trial operational procedures

#### 3.3.1. Development of the web platform for digitally enabled clinical trial procedures

This trial will benefit from the availability of a secure, FISMA, HIPAA, GDPR and HDS compliant web platform dedicated to digitally enabled clinical trials (WeShare Platform – www.weshare.unicancer.com) for the following procedures: online eligibility screening, electronic consent, randomization, and electronic data collection of patient reported outcomes (ePRO) and clinical data (ClinRO). Traditional in-paper procedures will also be available for centers or patients who prefer them or as a mitigation plan for potential technical challenges.

The WeShare platform was co-designed by a team of researchers, oncologists, technical developers, patient representatives, and experts in legal, ethical, and regulatory matters [33]. The STEPPING STONE project served as one of the pilot studies for the platform’s development. The design implementation of the platform followed the Exploration/Preparation, Implementation, and Sustainability (EPIS) Framework [34]. During the Exploration/Preparation phase, user stories and specifications were developed by the technical team and researchers, addressing the specific needs of the STEPPING STONE trial. This phase was followed by multiple rounds of prototype testing and refinement in a sandbox environment, using agile development methodology – Fig. 2. In addition, specific tutorials, along with digital navigation support and counseling, were created to guide both patients and research teams in

using the platform during the trial. Details on WeShare Web Development Process and the stakeholders involved are available in the Supplementary Material under “WeShare Web Development Process and Stakeholder Involvement.” The platform’s implementation will be evaluated during the STEPPING STONE clinical trial, with the sustainability evaluation expected by 2026.

#### 3.3.2. Recruitment and consent

Patients will be recruited in 3 cancer centers in France during routine medical consultations. Flyers and posters with a QR code will be available in the consultation room and in waiting rooms inviting patients to self-screen for eligibility by completing a quick online evaluation of their fatigue levels through a visual analogic numerical rating scale from 0 to 10 on a dedicated space for the trial within the WeShare platform website. Patients whose scores indicate moderate to severe CRF (score equal or greater than 4) will receive an automated standard message from the study website asking them if they agree to be contacted by phone by the research team to receive further information. If the patient accepts to participate in the trial, they will be invited to create an online account in the WeShare platform to launch the electronic consent procedures for patient and provider. After consent signature, patients will be able to access the reserved area in the web platform containing the study’s online questionnaires (ePROs).

<figure><img src="image_5.png" /><figcaption>Fig. 2. WeShare development and implementation process for the STEPPING STONE trial.</figcaption></figure>
### 3.3.3. Randomization

Once the study baseline questionnaires have been completed, randomization will automatically be performed on the WeShare platform and patients will receive a phone call from the research team with

instructions on how to access their digital aid modality according to the study arm they have been assigned to.

Randomization will be stratified based on the level of fatigue (moderate [numerical scale 4–6] vs. severe [numerical scale 7–10]),

<table><caption>**Table 1**
Content of the fatigue self-management program (arms 2 and 3).</caption><thead><tr><th>Week</th><th>Content</th></tr></thead><tbody><tr><td>Week 1</td><td><p>Psychoeducation</p><ul><li>Video presenting the learning objectives and the content of the program for the week.</li><li>Practical sessions in the format of articles, videos and podcasts dissecting the following themes:<ul><li>What is cancer related fatigue? o What are the symptoms and effects in daily life?</li><li>What are the medical causes and mechanisms behind cancer related fatigue?</li><li>Introduction to self-management with fatigue diary technique (what is it and how to use it) - Learning more: o More specific and refined content on fatigue biology and medical causes to explore if the patient wishes so.</li><li>Patient & healthcare provider testimonials</li></ul></li></ul></td></tr><tr><td>Week 2</td><td><p>Motivation</p><ul><li>Video presenting the learning objectives and the content of the program for the week.</li><li>Practical sessions in the format of articles, videos and podcasts dissecting the following themes:<ul><li>How to set goals and achieve them o Presentation of the setting goals methods: SMART (specific, measurable, attainable, relevant, and time-based), Kaizen (one small step at a time), 5-min</li><li>Learn how to manage time (offer yourself time, find time, enjoy time) o Fatigue diary technique - Learning more: o What is procrastination and how to deal with it o Learn how to keep a retroplanning and manage tasks.</li><li>Tips from the "25 h"</li></ul></li><li>Patient & healthcare provider testimonials</li></ul></td></tr><tr><td>Week 3</td><td><p>Cognitive restructuring</p><ul><li>Video presenting the learning objectives and the content of the program for the week.</li><li>Practical sessions in the format of articles, videos and podcasts dissecting the following themes:<ul><li>Identifying negative thoughts and using a Beck table o Finding alternative thoughts more adapted and effective for action o Podcasts for energy conservation and recovery techniques.</li><li>Learning more: o The vicious circle of anticipatory anxiety related to fatigue.</li><li>The false beliefs about cancer and fatigue</li><li>Patient & healthcare provider testimonials.</li></ul></li></ul></td></tr><tr><td>Week 4</td><td><p>Managing everyday life</p><ul><li>Video presenting the learning objectives and the content of the program for the week.</li><li>Practical sessions in the format of articles, videos and podcasts dissecting the following themes:<ul><li>Managing tasks at home: cooking, dishes, laundry, cleaning o Managing work</li><li>Physical activity and exterior activities o Beloved ones and kids o Fatigue journal technique - Learning more: o Evidence-based key recommendations for healthy diet o Evidence-based key recommendations for physical activity</li><li>Patient & healthcare provider testimonials.</li></ul></li></ul></td></tr><tr><td>Week 5</td><td><p>The environment</p><ul><li>Video presenting the learning objectives and the content of the program for the week.</li><li>Practical sessions in the format of articles, videos and podcasts dissecting the following themes:<ul><li>Learning how to say no o Learning how to ask a favor or how to ask for help (method DESC) o Talking about your fatigue to others (family, friends, kids, colleagues) - Learning more: o Self-confidence and self-esteem: what is it and how to build it o The notion of schemes</li></ul></li><li>Patient & healthcare provider testimonials</li></ul></td></tr><tr><td>Week 6 and 7</td><td><p>Sleeping troubles</p><ul><li>Video presenting the learning objectives and the content of the program for the next 7 days which will be focused on sleep, and important driver of fatigue.</li><li>Practical sessions in the format of articles, videos and podcasts dissecting the following themes:<ul><li>Sleep physiology (melatonin, sleep cycle, SNC aspects, and causes of insomnia)</li><li>Having a sleep diary o Sleep hygiene recommendations o Sleep restriction o Relaxation exercises for sleep troubles o Meditation exercises for sleep troubles o Breathing exercises for sleep troubles</li><li>Self-confidence and self-esteem: what are they and how to build them.</li><li>Learning more: o False beliefs about sleep o Other sleep restauration techniques</li><li>Patient & healthcare provider testimonials</li></ul></li></ul></td></tr><tr><td>Week 8</td><td><p>Recap</p><ul><li>Video recapitulating the learning points of the program and motivating the patient to keep progress.</li></ul></td></tr></tbody></table>
educational level (less than bachelor's degree vs. equal to or above bachelor's degree), active receipt of chemotherapy treatment (yes vs. no) and the presence of metastatic disease (M0 versus M1). Educational level will be regarded as a proxy measurement for both, the socioeconomic condition, and the health literacy level of the patient. All collected data will be anonymized.

### 3.3.4. Data collection procedures

Regarding patient-generated data, ePROs evaluating primary and secondary study outcomes will be collected electronically via the WeShare platform at four preestablished time points: (T0) immediately before randomization; (T1) immediately after the end of the intervention [Week 8]; (T2) three months after the end of the intervention; and (T3) six months after the end of the intervention – Table 1. Participants will not be able to view or edit their answers to the ePROs once submitted. To avoid missing data, up to three automatic reminders will be emailed to participants to complete questionnaires at the due date, seven and ten days after the due date (if needed).

Regarding clinical data, ClinROs will be completed by the research team in each cancer center through the WeShare platform at the time-points specified in Table 1.

Qualitative assessments will be carried out via videoconference through key informative interviews with patients and focus groups with health care providers, technology providers and researchers aiming to evaluate the implementation of each aid modality and the digitalized trial procedures [13,35].

## 3.4. Study intervention

The intervention consists in the use of a mobile app (Resilience®) designed for patients with cancer, already used for remote symptom monitoring purposes in clinical care [36] powered with self-management features specifically designed for this trial, that are delivered according to the study arm.

### 3.4.1. Intervention development process

The development process of the digitally delivered fatigue self-management program followed the Medical Research Council framework for co-designing and developing complex interventions including its phasic approach of development, feasibility/piloting, evaluation, and implementation [37,38]. A 4-step iterative process was established, including: i) preliminary needs assessment and acceptability of digital health interventions with patients and providers through qualitative interviews [39–41]; ii) identification of validated digitally-delivered self-management programs through formal literature review [42,43]; iii) prototype design, testing and improvement with a patient representatives [44]; iv) refinement and formal efficacy evaluation in the STEPPING STONE clinical trial.

### 3.4.2. Resilience® mobile app (arms 1, 2, and 3)

Patients will have access to educational content in the format of articles, videos, or podcasts addressing treatment-related symptoms, concerns, and validated supportive care resources. The educational content displayed is personalized according to tumor type/site, treatment received (chemotherapy, radiotherapy, endocrine therapy, immunotherapy or targeted therapies), phase (active vs. surveillance), and symptoms reported by the patients in the app.

### 3.4.3. Resilience® fatigue self-management program (arms 2 and 3)

In addition to the standard educational mobile app, patients in arms 2 and 3 will have access to a self-guided fatigue self-management program, which consists of a 7-week cognitive behavioral therapy program focused on key techniques to support behavioral change and self-efficacy. The content is delivered in various formats including videos, articles, podcasts, and patient testimonials. The program also prompts and provides online resources for patients to perform practical self-

management exercises, fatigue self-monitoring (diary technique), and beneficial supportive care interventions such as mindfulness meditation, guided relaxation exercises, and adaptive physical activity. Participants are presented with an onboarding module, including a welcome program page outlining the purpose of the self-management program and guiding them through weekly sessions and tasks. The content is delivered progressively according to completion status of the weekly tasks. Motivational messages and engagement reminders are periodically programmed through push notifications that may be silenced if the patient wishes. A support booklet is also sent to the patients to motivate engagement (Supplementary Material – Fatigue Self-Management Program Booklet). The outline of the program is described in Table 2 and depicted in Fig. 3.

### 3.4.4. Professional guidance support (arm 3)

In addition to the educational mobile app and the self-management program, patients randomized to arm 3 will benefit from weekly 45-min videoconference calls (7 sessions) with a licensed mental health professional (clinical psychologist) to review the objectives of the week, reinforce cognitive behavioral therapy techniques and troubleshoot problems.

### 3.4.5. Standardization of the intervention

The digital self-management program will be automatically delivered, which ensures standardization. Licensed mental health professionals (clinical psychologists) performing the guidance in arm 3 have received a 12 h training on cognitive behavioral therapy techniques, the fatigue self-management program and the clinical trial protocol. Weekly calls will follow a standard operating procedure to ensure intervention homogeneity (Supplementary Material – “Structured Guidance for mental health professionals’ calls”).

## 3.5. Study assessments

### 3.5.1. Patient-reported outcomes and clinical data

Instruments and timepoints for each study outcome are shown in Table 2. The study's primary endpoint is the EORTC QLQ-C30 fatigue subscale score, consisting of three items assessing the burden of CRF [45]. Secondary endpoints will be evaluated using the following tools: [1] Self-efficacy: Patient-Reported Outcomes Measurement Information System for Self-Efficacy (PROMIS-SE); [2] Overall Quality of life:

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLC-C30) – excluding the fatigue subscale score which is the primary endpoint of the study; [3] Physical, cognitive, and emotional fatigue: EORTC.

QLQ-FA 12 [46–48]. Electronic-Health literacy: the eHealth Literacy (eHLQ) [49] and Health literacy (HLQ) [50] questionnaires will be collected at baseline and studied as mediators metrics of effectiveness. In addition, detailed sociodemographic data will be collected at baseline through a self-reported questionnaire.

The impact on the usage of health resources and facilities will be measured using an ad hoc self-reported questionnaire assessing the number of emergency visits, hospitalizations, general practitioner visits, mental health professional visits, and use of complementary approaches, within the last three months.

### 3.5.2. Implementation assessment

Implementation of the intervention (Resilience® Mobile app) and the digitalized clinical trial procedures (WeShare) will be assessed according to the RE-AIM framework, through the following aspects: reach, effectiveness, adoption, implementation, and maintenance [30,51]. Acceptability and recruitment will be assessed through number of patients referred or self-referred, sources of referral to the study, number of patients consenting to participate, reasons for non-participation, duration of the recruitment period, reasons for participation, reach of individuals with low level of health literacy or low level of education.
<table><caption>**Table 2**
Study outcomes, instruments, and timeline.</caption><thead><tr><th colspan="2">Outcomes and instruments</th><th colspan="4">Time points</th></tr><tr><th>Outcomes</th><th>Instruments</th><th>T0</th><th>T1</th><th>T2</th><th>T3</th></tr></thead><tbody><tr><td>Primary outcome</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Burden of fatigue</td><td>EORTC QLQ C30 Fatigue Subscale (3 items assessing the burden of cancer related fatigue)</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Secondary outcomes</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Self-efficacy</td><td>PROMIS-SE's 4-item short form is a 4-item questionnaire measuring five behavioral domains (daily activities, emotions, medications and treatments, social interactions, and symptoms) to provide patient multidimensional categorical outcomes (high, transition, or low self-efficacy).</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>EORTC QLQ FA 12</td><td>12 items evaluating different dimensions of cancer related fatigue: physical, emotional and cognitive</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Quality of life</td><td>EORTC Quality of Life of Cancer Patients Questionnaires (EORTC QLQ-C30) assessing functional health, symptom burden and health-related quality of life of patients with localizedto-advanced cancer. The EORTC QLQ-C30 includes 15 scales: five functional scales assessing physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning, nine multi and single-item scales assessing fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties and a global health status/QoL scale.</td><td>X</td><td>X</td><td>X</td><td>X</td></tr><tr><td>eHealth literacy</td><td>eHealth literacy Questionnaire (eHLQ)</td><td>X</td><td></td><td></td><td></td></tr><tr><td>Health literacy</td><td>The following subscales of the HLQ (HLQ Osborne 2013) questionnaire will be used to understand baseline health literacy aspects as mediators of program efficacy and adoption: scale 2: Having sufficient information to manage my health, scale 3: Actively managing my health and scale 9: Understand health information enough to know what to do</td><td>X</td><td></td><td></td><td></td></tr><tr><td>Use of health resources</td><td>Ad-hoc questionnaire, assessing the number of emergency visits, hospitalizations, general practitioner visits, mental health professional visits, and use of complementary approaches, within the last 3 months</td><td>X</td><td></td><td>X</td><td>X</td></tr><tr><td>Qualitative interviews</td><td>Qualitative interviews with at least 12 patients in each aid modality</td><td></td><td></td><td>X</td><td></td></tr><tr><td>Focus Groups</td><td>Focus groups with healthcare providers, technology providers and research team</td><td></td><td></td><td></td><td>X</td></tr></tbody></table>

T0, before the first stage of randomization (baseline); T1, at the end of the intervention (postimmediate); T2, 3 months after the end of the intervention (short term follow-up); T3, 6 months after the end of the intervention.

Effectiveness will be assessed as per primary endpoint. Adherence will be assessed via participants' usage data of the three digital aid modalities (frequency, duration, and evolution of connections to the digital aid modality, type and proportion of components effectively consulted, completion of the tasks in the digital self-management program) – for each type of intervention. Retention will be assessed through attrition rate (after randomization until the end of the intervention and during the follow-up), reasons for dropout and response rates to study questionnaires.

Acceptability will be measured using the System Usability Scale (SUS), a 10-item questionnaire evaluating individual acceptability, satisfaction and experience using a web service [52]. Adaptation will be evaluated through modifications of the digital aid modalities and in the study protocol. Resources will be assessed through human, material and financial resources used to deliver the three digital aid modalities and implement the trial procedures via the web platform.

### 3.5.3. Qualitative assessment

Qualitative analysis will be performed by a qualitative researcher to deepen understanding of some of the study questions. At three months after the end of the intervention (T2), at least 12 participants from each arm will be systematically contacted to participate in in-depth interviews. New study participants will be interviewed until the threshold for saturation in qualitative research is reached, meaning that no extra relevant information is expected to be obtained from additional interviews [53]. To ensure diversity, particular attention will be paid to the following individual characteristics of interview participants: age, level of education, treatment phase, level of fatigue, adherence or non-adherence to the intervention, and preferences regarding the format of the intervention. Interviews will be performed by phone by a qualitative researcher, following an interview guide, and will last about 30 to 45 min.

At the end of the study, focus groups [54] will be held with all stakeholders involved in the implementation of the study (oncologists and healthcare professionals in the recruiting centers, technical and product team of the Resilience® mobile app, technical and product team of the WeShare digital platform, licensed mental health professionals delivering the intervention in arm 3). Each group will be made up of at least 6 to 8 stakeholders and will last approximately 90 min. Focus

groups will be conducted by the qualitative researcher and will focus on barriers and facilitators, as well as their experience of implementing i) the digital intervention to mitigate cancer-related fatigue and ii) the digital platform for clinical trial procedures. All interviews and group discussions will be fully recorded and transcribed prior to thematic content analysis. All personal identifiers will be removed.

## 3.6. Statistical considerations

### 3.6.1. Determination of sample size

Sample size calculation is based on a primary endpoint benefit measured in the fatigue subscale of the QLQ-C30 questionnaire, a scale scored from 1 to 100. Assuming a clinically meaningful absolute 6-point difference in the fatigue score between the intervention arms (arms 2 and 3) and the control arm (educational material alone – arm 1) at 3-month follow-up compared to baseline, 99 patients should be included in each arm to achieve 80 % power to identify the prespecified 6 % absolute difference with 5 % probability of type 1 error (Wilcoxon-Mann-Whitney test, two-sided p-value; calculation performed with East 6.5 software) [55]. Sample size was planned accounting for an maximum expected 25 % drop-out rate to include 124 patients per intervention arm, reaching 372 patients in total.

## 3.7. Statistical analysis

Intention-to-treat analysis of the primary efficacy endpoint (difference in the fatigue subscale score from baseline to three months after the end of the intervention) will undergo hierarchy testing to maintain the overall two-sided type-I error rate to 0.05 or less, in the following order [1]: arms 3 and 1 [2]; arms 2 and 1 [3]; arms 3 and 2. The formal statistical comparison between the study arms will be stopped after the first non-significant test according to this prespecified order.

To clarify the impact of each type of intervention in retention and adherence, a chi squared test will be used to compare attrition rates and response rates to questionnaires across the study arms. One-way analysis of variance will be applied to identify differences in levels of adherence. Mixed models for repeated measures will be used to ensure appropriate management of longitudinal observations. For mixed modeling, additional analyses will address the management of missing questionnaire
<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Screenshots of the fatigue self-management program in the resilience mobile app.</figcaption></figure>

data using methods such as pattern mixture models, which are suitable for handling data that are not missing at random [56]. In addition, dedicated methods, such as full information maximum likelihood or multiple-imputation based methods, will be chosen based on data characteristics [57,58]. Possible demographic and clinical differences at baseline between participants who have completed the study and those who have withdrawn before completing the intervention will be contrasted in sensitivity analyses.

### 3.7.1. Qualitative analysis

A thematic content analysis will be conducted on the interview transcripts of both participants and stakeholders by the qualitative researcher and by an independent coder. This process will involve [1]: identifying main themes using NVivo software by repeatedly reading the transcripts [2]; creating a common codebook [3]; performing two independent coding of the data; and [4] comparing and discussing coding discrepancies with the input of an external third coder [59]. Inter-rate reliability will be assessed, and descriptive analyses will be performed to summarize data. Quantitative and qualitative data will be triangulated to provide a comprehensive view of the study implementation, the specificities of each aid modality, and their theoretical frameworks as well as barriers and facilitators of implementing the study intervention and the digital platform for trial procedures. A synthesis will be first performed by the qualitative researcher and the study statistician and then discussed with the rest of the research team.

### 3.8. Equity, inclusion, and diversity considerations

The study PIs will follow the guidance of inclusion and diversity provided by the WeShare platform to reduce unconscious bias of physicians including patients in the study and stimulate the implementation of equity strategies to ensure the recruitment of a representative population. Since digital technologies may be harder to navigate for vulnerable patients [60,61], digital navigation support will be available as needed during the trial. In addition, sociodemographic characteristics of patients included in the trial will be followed in real-time to trigger action planning with recruiting centers in case disparities in recruitment are detected.

#### 3.8.1. Ethics considerations

The protocol was approved by the national review board in March 2024 (IRB approval: 2023-A02082-43).

### 3.9. Dissemination

The trial will be reported in accordance with CONSORT 2025 guidelines. The study protocol and the study findings will be

disseminated through academic peer-reviewed publications as well as through presentations in appropriate scientific congresses. Study findings will also be communicated in a simplified format to interested participants and through patient advocacy groups.

## 4. Conclusion

STEPPING-STONe is a randomized controlled trial addressing two important questions: one clinical, one methodological. On the clinical side, this study will investigate the efficacy of a stepwise educational self-management support strategy using a mobile app (Resilience®) to empower patients suffering from moderate to severe cancer-related fatigue to better manage their own symptoms. Whilst, on the methodological side, STEPPING-STONe brings an important innovation as it is a digitally enabled, fully electronically conducted clinical trial, from patient accrual and consent to follow-up and outcome collection.

Different self-administered internet-based interventions to ameliorate post-treatment CRF have already been developed. CHANGE and REFRESH are based on cognitive-behavioral therapy; while RESTORE, UNTIRE and Health Navigation are based on mixed approaches using cognitive-behavioral therapy, social cognitive theory and other strategies [42,43,62–66]. While CHANGE, UNTIRE and Health Navigation have proved to be effective in reducing CRF in randomized controlled trials, RESTORE has been shown to be feasible and acceptable in a multi-center proof-of-concept randomized study [42,62,64,65]. Data have not yet been published for the REFRESH trial.

Despite the promising results of these preliminary data, there are still some important knowledge gaps which hamper the external validity of these trials and prevent their wide incorporation in clinical practice. First, most of these tools have been tested in patients with no active cancer, mainly breast or colorectal cancers in remission. Second, in some of the trials, recruitment was performed exclusively in English-speaking countries using a decentralized process via Facebook, which resulted in a trial population composed of more than 90 % female, middle-aged Facebook users [66]. This methodological caveat ended up selecting a population of users that does not represent most cases in an oncological clinical practice. Third, there was no official link to medical records, thereby generating data with no confirmation of disease type and status. In addition, implementation challenges and barriers in these trials were not investigated or addressed in a detailed way, potentially compromising the scalability of these interventions in real-world settings.

On the other hand, the STEPPING-STONe trial will implement a pragmatic decentralized randomized design recruiting a broad spectrum of patients (including all cancer types and stages). While aiming for a widely representative sample, safety and the robustness of the methodology were key considerations in the investigators’ decision of not to promote and allow recruitment through social media. The trial will be
conducted only in cancer centers to ensure implementation in a care pathway and facilitate an official link with medical records.

One important limitation that CRF research still faces is the lack of hybrid evaluation of both effectiveness and implementation [29,67]. Considering this, we have opted for a mixed methodology approach. For effectiveness analyses, we will include quantitative data (such as numerical measurements data and statistics) and qualitative analyses to capture the nuanced and personal aspects of how fatigue may impact individuals' personal lives. For the implementation analyses, quantitative implementation metrics will be complemented by qualitative methods to study in detail the implementation process of research interventions and clinical trial execution. The research protocol presented here includes a pre-specified qualitative analysis based on structured individual interviews and focus groups to evaluate the implementation experience of different stakeholders involved in the trials: patients, providers, hospital staff, research teams and technology providers. Special interest will be placed in understanding reasons for non-adherence and acceptability of the protocol as well as cultural barriers and health-system facilitators for the implementation of the digital self-management tool and digitally enabled trial procedures.

STEPPING-STONE is a digitally enabled trial investigating the distinct potential benefits of three digital aid modalities for CRF to empower patients to better deal with this symptom.

In addition, several other benefits are expected from this investigation [1]: an evaluation of implementation, which will provide healthcare systems with guidance for real-world uptake [2], proof of concept for a new generation of pragmatic trials that leverage technology to advance medical research yielding high quality evidence at lower costs and with broader reach, and [3] the inclusion of a representative sample of patients. We expect that this trial will pave the way towards a more effective, personalized and participatory health care which positively impacts people's lives.

## Funding sources

This study is supported by the National Cancer Institute (INCA) - Grant number: SEQL21-009 and complementary philanthropic funding from InfoPRO digital. WeShare (ANR-21-ESRE-0017) is supported by the French State, managed by the Agence Nationale de la Recherche under the the Investissements Program integrated into France 2030, with reference number "ANR-21-ESRE-0017".

## CRediT authorship contribution statement

**Maria Alice Franzoi:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. **Arnaud Pages:** Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Conceptualization. **Cecile Charles:** Writing – review & editing, Writing – original draft, Methodology, Funding acquisition, Conceptualization. **Marcio Debiasi:** Writing – review & editing, Writing – original draft, Investigation. **Emma Gillanders:** Writing – review & editing, Writing – original draft, Software, Project administration, Methodology. **Arlindo Ferreira:** Writing – review & editing, Writing – original draft, Software. **Fanny Jacques:** Writing – review & editing, Writing – original draft, Software, Methodology, Conceptualization. **Sibille Everhard:** Writing – review & editing, Writing – original draft, Software, Methodology. **Guillaume GaryBobo:** Writing – review & editing, Writing – original draft, Software. **Cesarine Sambou:** Writing – review & editing, Writing – original draft, Methodology, Funding acquisition, Conceptualization. **François Alla:** Writing – review & editing, Writing – original draft, Methodology, Funding acquisition, Conceptualization. **Amandine Quivy:** Writing – review & editing, Writing – original draft, Project administration, Investigation. **Sophie Morin:** Writing – review & editing, Writing – original draft, Project administration, Investigation. **Ines

**Vaz-Luis:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

**Maria Alice Franzoi:** Research funding: Gilead (Institution); Resilience (Institution); Speaker honoriaria: Novartis (Institution).

Arnaud Pages: none.

Cecile Charles: none.

**Marcio Debiasi:** Speaker/Consultancy fee: Lilly, Novartis, Astra Zeneca, Daiichi-Sankyo. Support for attending medical conferences: Roche, Gillead, Lilly, Astra Zeneca, Daiichi-Sankyo. Institutional research grant: MSD.

Aude Barbier: none.

Arlindo Ferreira: Employment/Personal salary: Resilience.

Fanny Jacques: Employment/Personal salary: Resilience.

Charles Ferté: Employment/Personal salary: Resilience.

Sibille Everhard: none.

Guillaume Gary-Bobo: none.

Cesarine Sambou: none.

François Alla: none.

Amandine Quivy: none.

Sophie Morin: none.

**Ines Vaz-Luis:** Honoraria: AstraZeneca (Inst), Amgen (Inst), Pfizer (Inst), Novartis (Inst), Sandoz. Research Funding: Resilience Care (Inst)

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.cct.2025.107993.

## Data availability

Data will be made available on request.

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