The most common and distressing long-term side effect of cancer and its treatment is cancer-related fatigue (CRF) [1-3]. CRF can be defined as “a distressing and persistent subjective sense of physical, emotional, and cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with daily functioning and is not relieved by sleep or rest” [3,4]. A third of the patients with cancer suffer from fatigue on a daily basis [5,6], which can persist for up to 10 years after diagnosis [4] with a considerable impact on their lives [2]. Besides the personal impact of CRF, the economic impact of CRF is substantial. A recent European health economics study has indicated that over 75% of patients with cancer who were employed changed their employment status, and 28% stopped working. A US study reported that 30% of patients reduced their work hours, with an overall average of 4 days per month per patient [5].

Most patients with cancer (74%) and oncologists (80%) perceive fatigue as a symptom impossible to manage or to treat successfully [7]. Oncology practice lacks an adequate approach to address the consequences of CRF. Usually, physicians inform patients with cancer about the risks of cancer treatment, including the possibility of becoming fatigued [8]. However, patients assume that treatment for CRF is not available or not effective, which often discourages patients from asking for help. Also, when physicians make recommendations to assist patients in addressing CRF, these recommendations tend to be nonspecific as 40% of physicians recommended doing nothing, followed closely by prescribing rest (37%). About 9% of the physicians in this situation used prescription drugs, which regularly have severe adverse effects [8]. The inadequate provision of care is not solely due to the lack of education about fatigue treatment, but also due to the complex origin and underlying mechanisms of fatigue. The etiology of CRF is multidimensional, involving physiological, biochemical, and psychological systems [9].

When it comes to the psychosocial treatment of CRF, therapist-guided face-to-face interventions have shown to be effective [10]. Such therapies include energy conservation, activity management, optimizing restful sleep, mindfulness-based stress reduction (MBSR) techniques, psychosocial support, and cognitive behavioral therapy (CBT) [4,11,12]. However, face-to-face treatment approaches are limited in reach and resource-intensive, as 1 therapist can only treat 1 patient or patient-group at a time. Therapist-guided electronic health (eHealth) interventions in which health care is delivered over the internet via technologies are offering a more flexible and low-threshold approach [13]. Another advantage of eHealth is that due to Web-delivery, also patients with little time and energy can take part in the treatment [14,15]. One example of a therapist-guided eHealth intervention to reduce fatigue in cancer survivors is the More fit after Cancer (Fitter na Kanker in Dutch) intervention in which patients received Web-based mindfulness-based cognitive therapy via a psychologist. This intervention showed strong evidence in reducing fatigue in survivors of cancer [13]. Although eHealth interventions involving therapist-guidance can be offered effectively over the internet reaching many patients worldwide, these interventions are still limited by the availability of specialized psychologists.

One way to reach many patients worldwide is to make use of self-management interventions delivered via the mobile phone (mobile health [mHealth], which is a subbranch of eHealth) in the form of an app. Advantages of mHealth apps concern the reach (ie, apps are widely and easily accessible by many patients), the low threshold intensity to engage in apps as compared with face-to-face treatment, and the low resource-intensity of the care provided (ie, it does not require input from a therapist as it can function as a self-management tool) [16]. As mHealth permits treatment of participants worldwide without having contact with health care professionals, online recruitment might be an effective way to reach out to a large number of potential mHealth users within a short time [17].

Inspired by the academic research and clinical practice from the Helen Dowling Institute (HDI) for psycho-oncology including the aforementioned More fit after Cancer trial, the start-up Tired of Cancer BV (Utrecht, The Netherlands) developed the so-called Untire app, with the goal to deliver an effective self-management tool to improve CRF and quality of life (QoL) of patients and survivors of cancer who feel fatigued. The Untire app is built for smartphones and tablets for both mobile operating systems iPhone (Apple Inc) and Android (Google). The intervention is based on the aforementioned successful elements of face-to-face therapy for CRF, that is, energy conservation, activity management, optimizing restful sleep, MBSR, psychosocial support, CBT, and physical activity exercises [9] and in line with the guidelines of the National Comprehensive Cancer Network [18]. The app aims to create awareness by providing psychoeducation, to give insight into one’s energy levels, thoughts and behaviors about fatigue, and to help users to challenge unhelpful thoughts (eg, catastrophizing thoughts) and behaviors (eg, increase physical activity) by means of exercises. It is hypothesized that creating awareness and adjusting unhelpful thoughts and behaviors will lead to improvements in CRF and QoL. The current international study aims to examine whether the use of the Untire app has the potential to reduce CRF and improve QoL in patients and survivors of cancer. Until 2017, as far as we know, no mHealth interventions were developed to decrease CRF in patients with cancer and survivors [4,19].

The primary aim of this waiting list randomized controlled trial (RCT) is to assess the effectiveness of the Untire app in reducing fatigue in patients and survivors of cancer after 12 weeks of app access as compared with patients in a waiting list control group.

Secondary aims are to assess the effectiveness of the Untire app in improving QoL in patients and survivors of cancer after 12 weeks of app access as compared with patients in a waiting list control group; to examine the reach and costs of online recruitment, study drop-out, and uptake and usage of the Untire app; and to determine which factors moderate (ie, age, gender, and country) and mediate (ie, mindfulness, physical activity, depression, sleep, pain interference, and fatigue catastrophizing) the hypothesized effect of the intervention.

The Untire app study has been approved by the Medical Ethical Committee of the University Medical Center Groningen (UMCG), the Netherlands. Hereafter, the study received either ethical approval or a waiver from authorized institutions in the 4 English-speaking countries targeted (ie, Australia, Canada, the United Kingdom, and the United States; see Multimedia Appendix 1 for a detailed overview of ethical review and approval by country). The trial has been registered on 29/11/2019 on the Netherlands Trial Registry (NL6642).

The Untire app study is a large-scale international waiting list RCT aimed to examine the effectiveness of the Untire app in improving CRF and QoL in patients and survivors of cancer. The Untire self-management app was launched worldwide from March 2018, where study enrollment took place until October 2018. Also, after the recruitment period, the app remained available. Participants randomly allocated to the intervention group received the Untire app at the start of the trial (Figure 1). After 12 weeks, also the control participants received the intervention (ie, 1 year of free app access). During the waiting time, control participants were allowed to seek or accept other treatments for their fatigue. The eligibility check and all other assessments, including demographics of participants, were carried out by using Questback’s Web-based questionnaire system EFS-survey.

The Untire app study targeted patients and survivors of cancer of 18 years or older, who experienced persistent fatigue at moderate or severe levels (ie, an average composite score of >3 on items 1, 2, and 3 of the Fatigue Symptom Inventory (FSI) [20,21]) and owned a smartphone, tablet, or iPad. Exclusion criteria were a diagnosis of and receiving treatment for a severe mental disorder (ie, major depression, psychotic disorder, anxiety disorder, or addiction) as these persons may need more intensive treatment than offered by the app. Also excluded were persons having a diagnosis of chronic fatigue syndrome, myalgic encephalomyelitis, or fibromyalgia as the app focusses on improving physical activity, which is not recommended and could potentially be harmful to these patients [22].

We approached potential participants over the internet via social media advertisement campaigns (Facebook and Instagram). Multiple advertisement campaigns were created to promote the link to the study page. Both female and male patients and survivors of cancer of all age groups >18 years, and who have shown interest in topics related to cancer, fatigue, and cancer survivorship were targeted in the first advertising campaigns. On the basis of participant characteristics of those who showed interest (ie, clicked on the advertisement link), comparable participants (ie, look-alike audiences) were approached in subsequent advertisement campaigns.

Interested persons were directed to the landing page of the Web-based survey tool (ie, Questback) that was used for data collection. Participants were screened for eligibility, and if eligible, they received an information letter and gave digitally informed consent. Hereafter, participants completed a baseline questionnaire, after which they were randomized into the intervention or control group. Next, participants received an email with the information letter (see Multimedia Appendix 2) and their digital signed consent (see Multimedia Appendix 3). Intervention participants received a second email with a unique access code that could be used to activate the Untire app after downloading it from the app store, enabling free usage. Subsequently, participants received email invitations and reminders at 4, 8, 12, and 24 weeks to fill in the questionnaires. Once control participants completed the 12-weeks survey, they also received an email with a unique access code that could be used to activate the app after downloading it from the app store, enabling free usage. The 24-weeks follow-up assessment was used to assess maintenance of the expected decline in fatigue in the experimental group. Assessments did not last longer than 15 min.

Participants in the intervention group were instructed to work through the app at their own pace and could freely choose modules to work on. Although daily use of the Untire self-management app was recommended, participants were instructed to use the app at least once a week. Users who had not been active for 5 days were sent a reminder. Users who opened the app at least seven times within 10 days received a rating pop-up (ie, to assess satisfaction and ask for feedback).

After opening the Untire app for the first time, participants received a short introduction on how to use the app. Participants were informed that every time they revisit the app (ie, reopen the app), a (new) daily program will be presented. The daily program consists of the 4 following core components: (1) My themes, (2) My exercises, (3) Tip of the day, and (4) My physical activity (Figure 2). Participants also received information about the weekly assessments of their fatigue and related components, the so-called Quick scan. The Vase of Energy is an integral part of the Quick scan. Participants were also invited to think about informing a friend or family member, a so-called buddy, to help or motivate them to work with the app. All the modules are explained below in detail (also see Table 1 and Figure 2).

Data in this study have been collected by means of Web-based questionnaires and in-app log data. Table 2 presents a complete overview of the variables assessed by the Web-based questionnaires at each measurement wave for the intervention and control participants, respectively. Variables were assessed by either using validated questionnaires, using a selection of items of a validated questionnaire, or by items specifically created for this trial. We realize it may be a burden for patients with CRF to fill out all these assessments. To enhance patients’ commitment to the study and to reduce attrition, we carefully selected a limited number of questionnaires and items to include.

Sample size calculations for the primary outcome of fatigue showed that we needed to include 164 participants with complete 12-weeks measures in the intervention and the control group (total N=328) to detect a between-group difference in change from baseline to 12 weeks with a minimal effect size of η²=0.10 (alpha=.05, 1−beta=.95). The sample size was calculated using the simplest between/within-group comparison (F tests—repeated measures analysis of variance [with within-between interaction]) in G*Power 3.1. With the inclusion of 820 participants (410 intervention participants; 410 control participants) and an estimated drop-out of (492/820) 60.0%, 164 participants are expected to remain in the intervention and 164 in the control group at the 12-week primary outcome measurement. The total baseline completer sample size of N=820 can be taken as a conservative upper bound as the final analyzes will be carried out using GLMM. GLMM takes more information into account and, thus, requires a smaller sample size given the same power.

This protocol describes an RCT to assess the effectiveness of the Untire app in reducing fatigue in patients and survivors of cancer after 12 weeks of app use as compared with a waiting list control group. Substudies nested within this trial include questions concerning the reach and costs of online recruitment and uptake and usage of the Untire app. There are advantages of stand-alone mHealth apps assumed, such as the immediate access to the app, the low thresholds to seek support via an app, and lower costs in supporting patients as compared with therapist-guided treatments.

The Untire app is based on a face-to-face therapy protocol, which was developed by the HDI in the Netherlands [25]. Although successful therapeutic elements have been used continuously over the years (eg, psychoeducation, CBT, physical activity, and mindfulness) [40], new ways of treatment delivery are increasingly being explored. For example, face-to-face treatment protocols have been effectively adapted to fit therapist-guided internet therapy [13]. More recently, the ingredients of the More fit after Cancer protocol were used to develop an adapted version in the form of a stand-alone app. The key therapeutic ingredients remained, but no supervision of a therapist is available. Apart from this shift to self-management, the app offers flexibility as the patients are allowed to choose from the entire library of education and exercises instead of following a structured week-by-week program. Although the app includes proven successful therapeutic elements, it is important to test its effectiveness as the delivery mode differs from previously tested interventions. If we do find the app to be effective, it can easily be offered worldwide to patients with cancer and survivors experiencing fatigue.

The findings will not only show whether or not the app is effective in reducing fatigue and improving QoL but will also provide more insight into the underlying mechanisms. Several routes may lead to a reduction in fatigue. For example, participants may gain vitality through improvements in the quality of their sleep, increases in physical exercise, and better management of their physical activities (eg, balancing activities throughout the day) [13]. Participants may also improve because they learn to better manage their unhelpful or catastrophizing thoughts about their fatigue, possibly through mindfulness [13]. Previous diary research has shown that such catastrophizing thoughts are associated with increases in negative affect and fatigue during the day [41]. This study will demonstrate whether improvements in these factors mediate hypothesized improvements in fatigue. Patients with specific problems concerning sleep or physical activity, or with respect to unhelpful and catastrophizing thoughts may benefit specifically from improvements in the respective areas.

The design of the study has both strengths and limitations. Strengths are its international focus and large scale, which will not only provide insight into the effectiveness of the app but also valuable information on the costs of online recruitment across different countries, the reach of patients who are interested in mHealth as a form of treatment for fatigue, and the uptake of the app. Costs of online recruitment might be hard to predict, as Facebook advertising campaigns cannot be targeted to patients with cancer directly. Patients with cancer can only be targeted indirectly based on shared interests in the field of cancer (eg, diagnosis, impact, and treatment of cancer). Furthermore, on the basis of the number of patients to be included, we hope to be able to conduct moderator analyses to determine whether the hypothesized intervention effect varies among different groups of participants (eg, patients with cancer versus survivors of cancer) and the context in terms of country where the intervention is delivered. The study contains a self-report eligibility check to include only patients with moderate and severe levels of fatigue, as these patients are hypothesized to benefit from the intervention. A drawback of our online recruitment procedure is the lack of access to hospital records, meaning that we cannot validate medical information (eg, type, duration, and treatment of cancer). Another study limitation is that remotely conducted automated mHealth studies regularly show large attrition rates [42]. Although high drop-out rates and sparing app use may be a natural characteristic, as the choice to discontinue usage is uncomplicated easy owing to the impersonal nature of the Web-based study and app assessments. We hope to counteract this mechanism by sending personal reminder emails to reinvite participants to complete the respective study assessments. Finally, the waiting list RCT will help to demonstrate causality (ie, can patients benefit from treatment versus no-treatment) and control for potential spontaneous improvements during the study period, but we cannot disentangle the effects of therapeutic elements and common factors (eg, attention). A drawback of using waiting list control designs might be that it artificially inflates intervention effect estimates as control participants could be influenced by design to literally wait-to-change and, thus, do not improve [43]. Using an active control condition could overcome this shortcoming but was not possible as an equivalent Web-based intervention was not available, and a comparison with therapist-guided treatment was not feasible owing to the international and large-scale character of the study.

This large-scale international RCT examines the effectiveness of the Untire app aimed at improving fatigue and QoL in patients and survivors of cancer. To provide more insight into the process of change, the study also tests the influence of several potential mediators such as physical activity, catastrophizing, and mindfulness. Moderator analyses will further our understanding of who benefits more depending on, for example, age, gender, and disease status. These findings will further improve the theoretical notions of fatigue in relation to other variables involved in facilitating or moderating change. In terms of practical implications, the findings will enable us to further improve the Untire app and similar interventions, for example, by giving more or less weight to specific therapeutic elements.