RESET in ALL part 1A was a single-arm, 12-week feasibility trial in which all participants received the intervention to optimize evaluation of intervention feasibility and acceptability. Target enrollment was 20 participants. The trial is registered at ClinicalTrials.gov (NCT06182163), and the registration record includes all items from the World Health Organization Trial Registration Data Set. The study schema for the part 1A trial is shown in Figure 2.

The primary aims of the RESET in ALL part 1A trial were to establish the feasibility and acceptability of a multicomponent mHealth intervention among eAYA (12‐21 y) patients with ALL receiving maintenance therapy at Children’s Hospital Los Angeles (CHLA). A secondary aim was to evaluate the effects of the intervention on objectively measured SB, assessed via accelerometer-measured sedentary time and time accrued in uninterrupted sedentary bouts ≥1 hour (min/d), as well as self-reported sitting time (min/d). Exploratory aims were to assess intervention effects on the following: (1) clinical and lab biomarkers of cardiometabolic health; (2) health-related quality of life (HRQoL); and (3) associations between psychosocial and environmental factors and change in SB metrics from preintervention to postintervention.

This study was conducted at CHLA in Los Angeles, CA, which serves a large, sociodemographically diverse patient population. Based on institutional experience, 1 to 3 eAYA patients with ALL per month were expected to meet eligibility criteria and enroll in the study. We expected our study population to be approximately 65% White Hispanic, 17% White non-Hispanic, 4% Asian, 5% Black, and 9% Pacific Islander, Native American, or Other. In addition, about two-thirds of CHLA oncology patients fall within the lowest 40% of socioeconomic status, and approximately 70% are covered by Medicaid (Medi-Cal/California Children’s Services).

Eligibility criteria are listed in Textbox 1. The age range of 12‐21 years was chosen as this group was developmentally appropriate to engage with the intervention and to participate together in an online peer support group based on shared life experiences (school, early jobs, etc). Patients with B-cell lymphoblastic lymphoma (B-LLy) or T-cell lymphoblastic lymphoma (T-LLy) and mixed phenotype acute leukemia (MPAL) were also eligible due to treatment similarities with ALL [39,40]. Patients were enrolled after completing at least 1 month of maintenance therapy (cycle 1 day 29) to allow for resolution of potential adverse effects from upfront intensive therapy; in addition, participants were required to have 1 cycle (3 mo) of therapy remaining to ensure that all participants were receiving active therapy at the time of study. Participants were eligible if they self-reported at least 4 hours per day of leisure-time SB, given this is the lower threshold of time spent in SB reported in studies among healthy children and adolescents [31,41].

Due to limited resources, the intervention could only be offered in English; thus, participants needed to be able to speak and read English, which aligns with the language fluency of nearly all CHLA patients from school age onward. Parents or guardians of participants under 18 years of age did not need to be English-speaking, as consent and surveys can be performed in the parent’s preferred language with the assistance of a certified medical interpreter. Exclusion criteria were related to medical or cognitive conditions that would affect a participant’s ability to fully engage in the intervention.

Participants were recruited through the oncology clinics of CHLA’s Cancer and Blood Disease Institute (CBDI). Clinic schedules were screened by the study principal investigator (PI; Ivory), and providers for potentially eligible participants were contacted for approval to approach the patient in the clinic. If approved, study staff approached the patient during their next clinic visit to assess interest and confirm eligibility. IRB-approved recruitment flyers were also disseminated in the oncology clinics for patient or parent viewing, and oncology providers were informed of trial eligibility criteria and objectives to promote patient referrals.

This protocol was developed in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2022 guidelines (Checklist 1) [42], and study results will be reported according to the CONSORT (Consolidated Standard of Reporting Trials) 2010 extension for pilot and feasibility trials [43]. All study procedures were reviewed and approved by the CHLA Institutional Review Board (IRB No. CHLA-23‐00346), and annual continuing reviews are ongoing during the data analysis phase. All protocol modifications were submitted for IRB review, and when relevant, study changes were communicated to participants in-person at study visits or via phone. Protocol versions 1‐6 were comprised of editorial changes during the initial IRB submission. Protocol versions 7‐11 comprised the following amendments to the approved protocol: (version 7) changed eligibility criteria to include participants with diabetes and/or autoimmune or rheumatologic disorders, defined which leukemia diagnoses were eligible for the study, and added clarification on timing of eligibility for patients treated with nelarabine; (version 8) changed the app platform for the peer support group to enhance participant privacy; (version 9) increased the upper age limit from 18 to 21 years to increase the number of eligible participants, changed consent procedures to include over the phone or Microsoft Teams, and added a parent exit interview survey; (version 10) reduced total number of participants from 30 to 24 to meet our study timeline requirements and changed eligibility criteria to allow participants to enroll in the study earlier on during treatment; and (version 11) updated the funding and study PI surname. Multimedia Appendix 1 provides details on changes between protocol versions and corresponding updates to the study record on ClinicalTrials.gov.

Informed consent was obtained from all individual participants ≥18 years old or from a parent or legal guardian for adolescents <18 years old by the study PI. Assent was also obtained from all participants less than 18 years old. In the case of parents or guardians who were not English-speaking, an approved short form in their preferred language was provided with the English consent form, and the informed consent process was conducted with a certified medical interpreter. Health Insurance Portability and Accountability Act (HIPAA) authorization was obtained from the parent or legal guardian (in their preferred language) or adult participant at the time of informed consent, given the plan for abstraction of oncologic history from the electronic medical record (EMR). Participants received a US $50 Amazon gift card as compensation for completing the study.

Given that this was a single-center feasibility trial with minimal anticipated risks, a formal Data Safety Monitoring Board was not established. Oversight and auditing functions were performed by the PI, including regular review of study data, evaluation of protocol adherence, and safety assessments as needed. No study-related adverse events occurred.

Participants continued to receive all usual medical and supportive care during the study, including physical and occupational therapy. However, they were asked not to enroll in other structured PA or SB interventions during the study period to minimize contamination of secondary and exploratory outcomes.

Participants were able to withdraw from the study at any time upon request or at the discretion of the study PI or treating oncologist if continued participation was deemed inappropriate (eg, due to disease relapse, change in medical status, hospitalization, or treatment complications). Participants who discontinued the intervention prematurely were invited to complete a study exit visit, including final outcome assessments, whenever possible. Participants received gift card compensation scaled to their duration of participation (ie, US $15 for ≤1 mo or US $30 for 1‐3 mo).

SB was objectively measured at baseline and postintervention using the ActivPAL micro4 triaxial accelerometer (PAL Technologies Ltd). The device yields valid estimates of sedentary time, postural changes, and light-to-moderate PA in 60-s epochs and has been validated for SB assessment in adolescents [63,64]. Participants wore the device mounted on the right thigh continuously for 7 days directly following the baseline visit and during weeks 11 or 12 (before or directly after the final study visit). At both time points, data were downloaded and screened for completeness using the PAL Software Suite (PAL Technologies Ltd). When possible, participants were asked to rewear the accelerometer if it was not worn for ≥4 days with ≥10 waking hours per day. Data was processed using the PAL Software Suite; measures of primary interest for this study included total sedentary time (min/d), sitting time (min/d), time accrued in uninterrupted sedentary periods >1 hour (min/d), and steps per day. To complement device-based measures, participants also self-reported daily sitting time using the validated International Physical Activity Questionnaire (IPAQ) long-form [51].

Throughout the 10-week intervention, SB and PA were assessed via the Fitbit tracker and monitored using the Fitabase analytics system (Small Steps Labs LLC), a secure online platform that aggregates Fitbit data for research use. Fitabase was used to synthesize and manage data on tracker wear time, heart rate, steps/day, and hours/day with <250 steps. Fitbit wear time was determined by the presence of heart rate data, which was measured continuously by the tracker and recorded in Fitabase.

Participants and their parents or guardians self-reported demographic information, including race, ethnicity, zip code of primary residence, number of parents in the household, and maternal education level. Clinical and treatment characteristics were abstracted from the electronic medical record and entered into the study database by the study PI and a research assistant. Extracted variables included age at enrollment, sex assigned at birth, leukemia type, date and age at diagnosis, type and estimated cumulative dose of steroids (mg/m²), cumulative vincristine dose (mg/m²), relevant therapy-related adverse effects (eg, steroid-induced hyperglycemia, myopathy, and neuropathy), chronic health conditions (eg, diabetes mellitus, dyslipidemia, and chronic heart disease), and total days of hospitalization.

As an optional procedure, residual blood samples from clinical and study laboratory draws at each study visit (ie, baseline, week 8, and week 12) were stored for future research examining biomarkers (eg, cardiometabolic, cancer-specific, etc) associated with SB in patients with ALL. Participation in this procedure was opt-in and required separate consent or assent as part of the initial informed consent process. Specimens were labeled with the participant’s study ID and stored in a secure, access-controlled laboratory freezer. All specimens were managed directly by the study PI in accordance with institutional biorepository policies.

After completion of primary analysis, results from the part 1A trial were used directly in part 1B, optimization of the RESET in ALL intervention (Figure 1) to enhance efficacy in subsequent trials. Table 1 provides a summary of how part 1A trial outcomes informed intervention optimization in part 1B. Specifically, acceptability of the intervention overall and each individual intervention component (ie, the Fitbit tracker with prompts to move, coaching sessions, and app-based peer support group) determined if modifications were needed to optimize participant satisfaction and engagement. Themes from the study exit surveys and interviews specifically were emphasized. The acceptability of the overall intervention was evaluated for the usefulness of integrating three components, mHealth monitoring and communication, and flexible, individually determined activities to interrupt SBs. Additionally, the need for more integration of parents or a designated support person into the intervention was assessed.

Participant feedback informed refinement of the wearable technology, health coaching, and peer support components, as well as the addition of new intervention features to improve feasibility, relevance, and participant engagement. A board-certified pediatric psychologist with expertise in eAYA oncology guided intervention refinement to enhance participant engagement, psychosocial acceptability, and cultural relevance, as appropriate. The resulting optimized intervention, incorporating these participant-informed refinements and evidence from the published literature, will be described in detail in the protocol for the subsequent RESET in ALL part 2 randomized pilot trial. Finally, psychosocial and environmental survey data, together with demographic and medical history data, will be integrated in a future secondary analysis to identify contextual and individual-level factors that may inform targeted and individualized approaches to reducing SB in this patient population.

Feasibility and acceptability served as the primary determinants of the appropriateness of progression to the part 2 RCT. We determined that the intervention would be deemed definitively feasible if a retention rate of ≥70% was met and definitively acceptable if ≥60% of participants reported on the study exit survey that participation in the study helped them reduce their sedentary time. In addition, a reduction of approximately 30 minutes/day in sedentary time is considered clinically meaningful based on prior evidence and will serve as a secondary benchmark for evaluating intervention promise and informing progression to part 2. Decisions regarding progression will also consider intervention adherence and findings from secondary and exploratory outcomes.

This protocol describes a multicomponent mHealth trial designed to evaluate preliminary feasibility and acceptability and optimize an intervention to reduce SB in eAYA patients undergoing cancer treatment. We hypothesized that participants would find the intervention feasible and acceptable and would show a signal toward reducing SB metrics over 12 weeks. The sequential study design allows for iterative refinements: part 1A was a 12-week, single-arm feasibility study evaluating a multicomponent mHealth intervention that combined a Fitbit tracker with inactivity-triggered prompts, individualized coaching, and an app-based peer support group. Data from the part 1A trial directly informed intervention optimization in part 1B, particularly acceptability measures and participant feedback. Together, parts 1A and 1B have produced a data-driven, participant-informed intervention for evaluation in part 2, a successor pilot RCT that is currently in development. The findings from these pilot trials are expected to support a larger, multisite RCT of the intervention compared to usual care.

The RESET in ALL trial addresses 2 critical research gaps in behavioral interventions for eAYAs with cancer: lack of a specific focus on SB and beginning behavior change during therapy. The RESET in the ALL trial employs a 2-part design to address these research gaps. We chose to focus on SB because it comprises a large proportion of the day, is highly prevalent among eAYAs with cancer early in treatment, and often persists into survivorship, contributing to cardiometabolic complications, chronic disease, and premature mortality [2,3,15,22]. By intervening during therapy and integrating intervention activities during regularly scheduled clinic appointments, our approach supports a scalable, clinically integrated program that may improve health outcomes.

In ALL, the most common malignancy in this age group, excessive SB may exacerbate treatment-related toxicities and lead to poorer outcomes [6,18-20]. Additionally, prior intervention studies in pediatric oncology have largely targeted MVPA, an independent health behavior only weakly correlated with SB [13,14], and PA-focused studies in CCS have not consistently reduced SB [37,65]. In contrast, evidence from healthy youth suggests that interrupting sitting or reallocating even 30 minutes/day of SB to light activity can improve metabolic and psychosocial outcomes [23,25-27], supporting SB as a more feasible and potentially impactful intervention target during ALL therapy. The maintenance phase, during which acute toxicities typically subside, offers an ideal window for introducing such strategies.

To our knowledge, RESET in ALL is the first on-therapy, SB-focused intervention for eAYAs with ALL. Thus, there are no direct comparisons of our expected findings with prior trials. However, the two-part design, including an innovative app-based peer support group, offers a novel, stepwise approach to developing and optimizing mHealth interventions in pediatric and AYA oncology. Given the high survival rates for eAYAs, intervening early with scalable, clinically integrated interventions is an attractive strategy for improving health outcomes in the decades of anticipated life after cancer.

The protocol has several strengths, including the novel focus on SB, intervening during therapy as part of routine care to minimize participant burden, the inclusion of an app-based peer support group, and a diverse study population. There are also limitations that should be noted. Due to the pilot nature of this trial, we had a small sample size, which precludes drawing definitive conclusions about the efficacy of the intervention. There was also no control group to compare intervention effects against, and we only recruited from a single site.

Findings from part 1A of the trial were used to optimize part 1B of the trial. Both part 1A and part 1B will inform part 2 of the trial. If the subsequent pilot trials show promising results, a fully powered, multisite RCT will be conducted to confirm the efficacy of RESET to reduce SB across diverse eAYA clinical populations undergoing treatment. This definitive trial will compare RESET to usual care and will incorporate a longer follow-up period to understand the sustainability of effects.

This protocol describes the first multicomponent mHealth intervention to reduce SB metrics in eAYAs undergoing cancer treatment. Using a sequential design, whereby prior trials inform the optimization of subsequent trials, we aim to develop and refine a scalable, clinically integrated approach to behavior change during treatment that enhances health outcomes in eAYA populations.