The HYPE study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board (22-505). All participants provide informed consent in week 0 (Table 1) electronically or in person. Electronic consent allows participant enrollment using a distance-based approach that reduces patient burden by limiting the number of visits they are asked to make to DFCI. REDCap (Vanderbilt University) is used for storing all participant data. REDCap is a free, secure, Health Insurance Portability and Accountability Act (HIPAA) compliant web-based application. Participants are provided with equipment to perform the HIIT exercise intervention, which they keep after completing the study in lieu of compensation. The study sponsor or funders are not involved in the trial design, conduct, analysis, or reporting of the trial.

The study is a single-center, 2-arm pilot randomized controlled trial conducted at the Dana-Farber Cancer Institute (DFCI; Boston, Massachusetts). A total of 30 young adult survivors of pediatric brain tumors who completed tumor-directed therapy at least 2-years prior (aged 18‐45 years) and young adult patients diagnosed with IDH mutant gliomas who completed their most recent treatment (surgery, radiation, and chemotherapy) at least 1-year prior (aged 18‐45 years) will be recruited and randomly assigned to either a 16-week home-based cycling HIIT exercise intervention (exercise group; n=20) or a 16-week attention stretching control period (control group; n=10). Outcomes are measured at baseline (week 1), postintervention (week 18), and follow-up (week 34; exercise group only) (Figure 1). Participants assigned to the exercise group complete 16-weeks of HIIT exercise intervention and a 16-week self-directed exercise follow-up period. The control group performs a home-based program of the same stretches used in the exercise group. As flexibility exercises are low-intensity, low-impact, and low-volume, minimal caloric expenditure is expected to be incurred.

Participants must meet all criteria to be eligible. Inclusion and exclusion criteria are provided in Textbox 1. Trained study staff confirm eligibility criteria and complete the protocol-specific eligibility checklist.

Various recruitment strategies are used to identify potential participants at DFCI, including direct referral from neuro-oncologists, screening neuro-oncology clinic lists, and advertisements in patient waiting areas. Additionally, recruitment takes place outside the clinical setting via appropriate social media platforms specifically for young adult survivors of pediatric brain tumors or young adults with IDH-mutant gliomas, patient email lists, and research study advertisement websites. All interested patients and survivors complete a phone- or Zoom video call (Zoom Communications)-based screening to determine eligibility. Those who are eligible and agree to participate are asked to provide written or electronic informed consent. The use of electronic consent allows for consent to be obtained remotely. This distance-based approach can reduce participant burden and distress associated with hospital visits and reduce their number of visits to DFCI.

After baseline testing, participants are randomly assigned to either the exercise or control group in an allocation ratio of 2:1 using a permuted blocked design with varying block size (with investigators blinded to block size). We use a 2:1 allocation ratio instead of 1:1 because it provides a more precise estimate for the feasibility of the exercise intervention. The study biostatistician prepared the randomization list prior to study start-up, after which a research staff member uploaded the list to REDCap. After participants have provided informed consent, study eligibility is determined, and baseline assessments are completed, a study staff member accesses REDCap to provide the randomization allocation. Given the nature of the intervention, study staff were not blinded after randomization.

Testing is completed at baseline (week 1), postintervention (week 18), and follow-up (week 34). Study staff members trained in exercise oncology and administration of neuropsychological assessments supervise and lead all testing, unless otherwise specified below (Table 1).

Participants additionally undergo dietary and physical activity assessments. An automated, self-administered 24-hour dietary assessment tool is used to assess recent dietary patterns for 2 weekdays and 1 weekend day (nonconsecutive where possible) [68]. To measure 7-day physical activity, participants are provided with a hip-worn accelerometer (ActiGraph, Pensacola, FL) to wear for 7 days at baseline, postintervention, and follow-up (exercise group only) testing visits and are instructed to wear the water-resistant accelerometer except when sleeping, swimming, or bathing. The device records activity data and is electronically transferred to a computer via USB cable at the time of completion.

Individuals are asked about adverse events at each supervised visit and are provided with a phone number to report potential intervention-related adverse events to study staff. All adverse events are reported, and these are evaluated for the likelihood that they occurred as a result of the intervention (very likely to be related, likely to be related, possibly related, or unlikely to be related). Adverse events are reported to the principal investigator and project manager as soon as study staff learns of their occurrence, as well as to the treating neuro-oncologist if deemed necessary, such as in the event of a seizure or acute worsening of neurologic function; this includes events that occur after the initiation of the study intervention, during the intervention, and within 30 days of intervention completion. Additionally, participants are instructed to report any serious poststudy events that might reasonably be related to participation in this study. Serious adverse events must be reported within 24 hours of learning of the event. The principal investigator reports adverse events that are severe, life-threatening or disabling, and fatal, and are possibly, probably, or definitely related to the intervention to the institutional review board. All other adverse events are logged and documented.

All adverse events, both serious and nonserious, and deaths that are encountered from initiation of the study intervention through 30 days of intervention completion are followed to their resolution, or until the participating investigator assesses the participant to be stable, or determines the event to be irreversible, or the participant is lost to follow-up. The presence and resolution (if applicable) of adverse events is documented and recorded in the participant’s regulatory folder.

The study team will collect, manage, and perform quality checks on the data for this study (eg, verification of REDCap data entries). All data is monitored for timeliness of submission, completeness, and adherence to protocol requirements. Monitoring begins at the time of participant registration and continues during protocol performance and completion. Potential audits or inspections may be conducted by representatives designated by the principal investigator or Dana-Farber/Harvard Cancer Center. REDCap is used for storing participant outcome data, and the study database is password-protected and stored on a secure network.

We designed the study to have a total of 25 complete cases for the analyses. Considering a possible dropout rate of 15%, the total accrual goal is 30 participants. This sample size was determined based on recommendations of sample sizes between 24 and 50 for pilot studies assessing the feasibility of exercise interventions and estimating effect sizes for designing future studies [69-71]. The primary endpoint of this study is the feasibility of the HIIT exercise intervention. With the 2:1 allocation, 20 participants are allocated to the exercise group. We are able to observe an 80% (16/20) or higher proportion of minutes of intended prescribed exercise completed with a probability of 80%. The study will be able to detect an intervention effect between groups with 80% power, at a 0.05 2-sided α level, when the effect size (Cohen d) is 1.25 or higher. Given the exploratory nature of the study, no adjustment for multiple comparisons will be applied.

To assess feasibility endpoints, the analysis will include all participants who are assigned to the exercise intervention, including those who never start the exercise intervention. The primary analysis population includes all eligible participants who complete the baseline (week 1) and postintervention (week 18) assessments. The secondary analysis population includes eligible participants who complete all assessments up to Week 34. The primary analysis will potentially include missing values due to population dropout, and the all available case analysis method will be used. Multiple imputations will be used for sensitivity analyses. Analyses stratified by subpopulation will also be conducted.

To test hypotheses related to the feasibility of a 16-week virtually supervised HIIT exercise intervention for young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas (primary objective), the proportion of participants who attend 70% of the total prescribed number of exercise sessions and complete 70% of the total prescribed minutes per exercise session will be calculated; a corresponding 0.95 exact CI will also be calculated. To test hypotheses related to the intervention effects on change in cognitive-, physical-, HRQOL-, and psychosocial health–related outcomes from baseline to week 18 (secondary objective), within- and between-group comparisons will be performed on the primary analysis population. Paired tests will be used to assess within-group differences, and 2-sample t tests will be used to assess differences between groups for each outcome; mean difference scores and a corresponding 0.95 CI will be calculated and normalizing transformations will be applied as needed. Analysis of covariance (ANCOVA) will also be used to assess mean differences in each outcome while adjusting for participant baseline characteristics and clinical covariates. Chi-square tests will be used for between-group comparison of binary outcomes (eg, occurrence of adverse events). The magnitude of the intervention effect on binary outcomes will be summarized by odds ratio and corresponding 0.95 CI. For each analysis, a 2-sided P value ≤.05 will be considered statistically significant. Because this is a pilot study, we will not perform corrections for multiple comparisons. To test hypotheses related to the sustainable effects of the intervention and associations between outcome measures (tertiary objective), the difference between scores at follow-up (week 34) and postintervention (week 18) will be assessed in the secondary analysis population. Mean and median difference scores and corresponding 0.95 CIs will be calculated, and paired t tests will be performed. Wilcoxon signed-rank tests will be used if model assumptions are violated. Linear mixed-effects models will be applied to each outcome’s longitudinal data (week 1, 18, and 34) to explore trends over time and the association between outcome and baseline characteristics. Associations between outcome measures will be assessed using Pearson correlation, or Spearman rank correlation if model assumptions are violated. Additional statistics related to future trial planning will include screening rate, enrollment, eligibility rate, retention rate, and occurrence of adverse events.

For the exploratory health equity aim, participant characteristics will be described by self-reported race, ethnicity, and household material hardship exposure as compared to US epidemiologic data to evaluate participant representativeness. Associations will be explored between self-reported social determinants of health, using household material hardship as the primary exposure, and study endpoints, including (1) feasibility measures, (2) baseline and end-intervention cognitive status, and HRQOL.

The HYPE study advances exercise oncology by evaluating the feasibility of HIIT in 2 understudied populations and providing preliminary insights into its impact on cancer-related sequelae and exercise sustainability. It is hypothesized that ≥80% of young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas assigned to the exercise group will attend ≥70% of prescribed HIIT exercise sessions and complete ≥70% of prescribed minutes per exercise session. HIIT will also improve cognitive, physical, HRQOL, and psychosocial health outcomes relative to the control group and baseline. Additionally, it is hypothesized that the removal of exercise supervision after the intervention period will attenuate intervention effects at follow-up and that poverty exposure will moderate this effect.

The safety, tolerability, and efficiency of HIIT position it as a feasible intervention in young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas. However, despite these advantages and the increased use of aerobic exercise to improve cancer-related outcomes, most exercise oncology interventions to date have used moderate-intensity continuous training [72]. HIIT may offer a particularly time-efficient alternative, as lower exercise volumes are needed to achieve greater improvements in cardiovascular and physical fitness outcomes, including VO₂max [73]. This efficiency is especially important given the physical activity barriers faced by young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas. Further, HIIT may also elicit neurophysiological benefits relevant to cognition. Compared to moderate-intensity continuous training, HIIT elicits greater oxygen use [74] and cerebral oxygenation [75], which may contribute to stronger cognitive effects. Consistent with this possibility, HIIT has been shown to promote greater cognitive improvements in healthy young adults [76] and survivors of cancer [77], and higher aerobic exercise intensity has been associated with structural brain changes that support efficient cognitive processing [78]. Finally, HIIT is often perceived as more enjoyable than continuous exercise [79], which may further support physical activity engagement and feasibility of the HYPE study [80-82].

While the effects of HIIT on cognition in young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas are currently unknown, HYPE aims to fill this knowledge gap. Executive function, memory, and processing speed are sensitive to the benefits of chronic aerobic HIIT (>8 weeks) in healthy adults [41], and to aerobic exercise more broadly in both survivors of pediatric brain tumors [27,28] and adults with grade 2/3 gliomas [31]. Mechanistically, exercise-related improvements likely reflect neurobiological effects in brain networks that support these cognitive domains [27-29,83-85]. Given the vulnerability of survivors of pediatric brain tumors to tumor- and treatment-related brain disruption (eg, tumor location, age at diagnosis, cranial radiation, and chemotherapy) [12,86] and similar therapy-related cognitive risks in young adults with IDH-mutant gliomas (eg, tumor progression, radiation, and chemotherapy) [9,87,88], it is plausible that HIIT will produce measurable cognitive improvements in both populations. Future research should investigate the neurobiological mechanisms that may drive HIIT-cognitive improvement in these populations as well.

HYPE is also the first study to investigate the effects of HIIT on cardiorespiratory fitness in survivors of pediatric brain tumors and patients with IDH-mutant gliomas. Like cognitive impairment, reduced cardiorespiratory fitness is often due to tumor- and treatment-related effects, such as endocrine and cardiovascular conditions [89,90]; in young adult survivors of pediatric brain tumors, levels can resemble those of adults 60 years and older [14], and lower cardiovascular fitness in patients with IDH-mutant gliomas is associated with fatigue that interferes with daily functioning [16]. Evidence from adult patients and survivors with cancer shows that HIIT safely improves cardiorespiratory fitness [42,43], and aerobic exercise yields similar benefits in survivors of pediatric brain tumors [91] and young adults with stable grade 2/3 gliomas [92]. Benefits of aerobic exercise also extend beyond fitness, including improved physical functioning [93], higher self-reported physical activity, and lower BMI [82]. Accordingly, we expect HIIT to improve physical fitness and functioning, and related outcomes in young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas. Additionally, given their high symptom burden [15,16], routine assessment of cardiorespiratory fitness is important. The HYPE study is also the first to assess patients’ and survivors’ cardiorespiratory fitness over a 32-week period (16-week intervention plus 16-week follow-up).

Psychosocial health is a key component of HRQOL that may also improve with HIIT. Survivors of pediatric brain tumors report the poorest HRQOL among survivors of pediatric cancer [94], with 60% not achieving complete independence in adulthood—a limitation that is in part driven by reduced aerobic capacity and adaptive physical functioning [95]. Cognitive impairment is also associated with poor social adjustment [96-98] and mediates social outcomes [96] in these survivors. Young adults with IDH-mutant gliomas similarly report unmet psychosocial needs [10]. Aerobic exercise improves psychosocial health in adults with grade 2/3 gliomas [31] and vigorous exercise promotes similar improvement in adult survivors of childhood cancer [44]. By reducing anxiety, depression, and stress [99], HIIT may help counteract emotional effects related to cancer management and survivorship [45-48].

Equity considerations are integral to the HYPE study. Poverty and adverse social determinants of health negatively affect cognitive [100,101] and physical [102] outcomes and represent modifiable risk factors for late effects of brain tumors and treatment. Given the risk of cognitive and physical sequelae in young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas, and the benefits of exercise, an equity-centered study design (eg, remote consent, provision of exercise equipment, language accessibility), and collection of self-reported sociodemographic and social determinants of health data are necessary to assess the generalizability and sustainability of the HIIT intervention.

The strengths of this study include a 2-arm randomized controlled design, access to a large patient population, and the comprehensive measures used to determine feasibility of the HIIT intervention, its preliminary efficacy to improve cognitive, physical, HRQOL, and psychosocial health, and exercise sustainability. Limitations of the study also merit consideration. First, as a single-center study that operates within the context of a comprehensive cancer treatment and research institution, there is the potential for recruitment bias. We have attempted to mitigate this bias through recruiting via social media platforms for young adult survivors of pediatric brain tumors and patients with IDH-mutant gliomas, and research study advertisement websites, rather than solely in clinical settings. Of note, study recruitment is slow due to the rarity of the disease and time commitment. Accrual will be monitored and the need for future multisite trials will be assessed. Additionally, participants may already have an established interest in sports or other physical activities, which could influence their baseline fitness level. To address this, physical activity at baseline is captured by an accelerometer over a 7-day period and the health questionnaire, allowing analyses to account for baseline fitness. In light of the study’s feasibility aims, the control group was also not matched for attention exposure to that of the exercise group. Future efficacy trials should use equivalent attention exposures between groups. Finally, given follow-up testing is limited to participants in the exercise group, sustainability analyses will exclusively assess within-group change. While the study cannot establish comparative sustainability with the control group, evaluating sustainability of no-exercise is outside of its scope.

In summary, the HYPE study will evaluate the feasibility of virtually supervised HIIT, generate preliminary evidence on its efficacy to improve cancer-related sequelae, and explore exercise sustainability in young adult survivors of pediatric brain tumors and young adults with IDH-mutant gliomas. The findings of this pilot feasibility randomized controlled trial will inform the design of a larger efficacy trial.