Background

Cancer-related fatigue (CRF) is still undertreated in most patients, as evidence for pharmacologicaltreatments is limited and conflicting. Also, the efficacy of the pharmacological agents relative to each other is stillunclear. Therefore, medications that may potentially contribute to improving CRF will be investigated in this head-toheadtrial. Our main objective is to compare the efficacy of methylphenidate vs. bupropion vs. ginseng vs. amantadinevs. placebo in patients with advanced cancer.

Methods

The 5-EPIFAT study is a 5-arm, randomized, multi-blind, placebo-controlled, multicenter trial that will usea parallel-group design with an equal allocation ratio comparing the efficacy and safety of four medications (Methylphenidatevs. Bupropion vs. Ginseng vs. Amantadine) versus placebo for management of CRF. We will recruit 255adult patients with advanced cancer who experience fatigue intensity ≥ 4 based on a 0–10 scale. The study periodincludes a 4-week intervention and a 4-week follow-up with repeated measurements over time. The primary outcomeis the cancer-related fatigue level over time, which will be measured by the functional assessment of chronic illnesstherapy-fatigue (FACIT-F) scale. To evaluate safety, the secondary outcome is the symptomatic adverse events, whichwill be assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for AdverseEvents in cancer clinical trials (PRO-CTCAE). Also, a subgroup analysis based on a decision tree-based machine learningalgorithm will be employed for the clinical prediction of different agents in homogeneous subgroups.

Discussion

The findings of the 5-EPIFAT trial could be helpful to guide clinical decision-making, personalization treatmentapproach, design of future trials, as well as the development of CRF management guidelines.

Trial registration IRCT.ir IRCT20150302021307N6. Registered on 13 May 2023.