Background <p>Fatigue is a prevalent and debilitating symptom for patients with incurable cancer. Cognitive behavioral therapy (CBT) can significantly reduce cancer-related fatigue in this patient group. However, implementation of CBT into clinical care is difficult as the intervention is time-intensive, costly, and requires face-to-face consultations with a specialized CBT therapist. Since nurses already support patient with symptom management, including fatigue, internet supported CBT delivered by nurses could be a promising alternative for patients with incurable cancer. The primary aim of this study is to determine the non-inferiority of nurse-led web-based CBT in its effect on cancer-related fatigue, compared to CBT provided by CBT therapists.</p> Methods <p>The study is a prospective, non-randomized study using historical cohorts as the benchmark for comparison. Severely fatigued patients with incurable cancer of a solid tumor receive a 12-week nurse-led web-based CBT intervention. Primary and secondary outcome measures are assessed at baseline, post-intervention (14 weeks), and follow-up (26 weeks). The primary outcome measure is fatigue severity assessed with the Checklist Individual Strength (CIS-subscale fatigue severity). Secondary outcomes include functional impairment, quality of life and fatigue assessed with EORTC-QLQ-C30, and health care costs. Primary and secondary outcomes of the TIRELESS study and the benchmark are compared to determine non-inferiority. Non-inferiority of fatigue reduction is concluded if the upper bound of the one-sided 95% CI does not exceed + 5 on the CIS, with higher scores indicating more severe fatigue. In addition, interviews are conducted to gain insight in nurses’ and patients’ experiences with the intervention. These data are analyzed applying a thematic analysis method.</p> <p>Recruitment has started in June 2024.</p> Discussion <p>Especially for this burdened patient group, integration of CBT for fatigue in routine medical care is essential. With the TIRELESS study, we aim to reduce patient burden, foster scalability and accessibility of CBT for fatigue, and increase patients’ self-management. If this approach is non-inferior to the original evidence-based (benchmark) intervention, this will enable implementation of cancer-related fatigue interventions for the growing group of patients with incurable cancer.</p> Trial registration <p>NCT06511518; date of registration: 23/02/2024.</p>