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Highlights: Patients who switched from Ecu to Peg, reported improvements in fatigue, with greater improvements for those whose hemoglobin normalized We demonstrate treatment-related reductions in fatigue by highlighting the items most responsive to clinically important changes in a patient-reported outcome measure Background. A common symptom of paroxysmal nocturnal hemoglobinuria (PNH) is fatigue, which in some patients can be severe. Eculizumab (Ecu) has proven efficacy in controlling intravascular hemolysis, but commonly results in persistent anemia and fatigue. Pegcetacoplan's (Peg) efficacy was documented in the PEGASUS phase III clinical trial, showing improved hemoglobin (Hb) and patient-reported fatigue. This post-hoc analysis sought to describe this fatigue improvement related to Hb normalization using the Functional Assessment of Chronic Illness Therapy—Fatigue subscale (FACIT-F)'s individual questions to speak more directly to patients' experience and clinicians' day-to-day practice. Methods. The PEGASUS trial compared Peg with Ecu in patients who remained anemic on Ecu over 16 weeks (n = 41 and 39, for Peg and Ecu, respectively), after which all patients received Peg open label for 32 weeks ("Peg" vs. "Ecu-to-Peg" at Week 48). Hb normalization was defined as ≥12–16 g/dL for females and ≥13.6–18 g/dL for males. The FACIT-F assessed fatigue. Using the complete-case data set, Cohen's d summarized the effect sizes of the mean FACIT-F item change for both study arms from the baseline to week 16 (n = 36 and 37, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 30 and 29, for Peg and Ecu-to-Peg, respectively), and for Hb-normalized patients in each study arm from the baseline to week 16 (n = 14 and 0, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 10 and 12, for Peg and Ecu-to-Peg, respectively). Results. The FACIT-F scores for both arms were worse at the baseline compared to later in the trial. Peg patients reported improvements on all fatigue items at Week 16, but Ecu patients reported improvement in only one item. At Week 48, the improvement in fatigue was maintained in Peg patients, and Ecu-to-Peg patients' fatigue improved on all FACIT-F items. Hb normalization was achieved in 14 Peg patients but no Ecu patients at Week 16, and in 10 Peg and 12 Ecu-to-Peg patients, respectively, at week 48. The FACIT-F single items showing the largest change overall, and particularly in Hb-normalized patients across the study arms, were related to symptoms and social limitations. Conclusions. Peg patients reported lasting improvements in fatigue. Patients who were anemic on Ecu reported sustained improvements in fatigue with Peg treatment. Patients who had Hb normalization generally had large, clinically important improvements in fatigue items. [ABSTRACT FROM AUTHOR]