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Abstract
AimsParoxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening intravascular hematologic disorder with significant morbidity and premature mortality. Clinical trials (NCT02946463 and NCT03056040) comparing ravulizumab with eculizumab for PNH have supported the non-inferiority of the former and similar safety and tolerability. This secondary analysis compared PNH trial participants after 26 weeks on either treatment (n = 438) to a general-population sample (GenPop) (n = 15,386) and investigated response-shift effects.MethodsMultivariate analysis of covariance (MANCOVA) investigated function and symptom scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 of people with PNH as compared to GenPop, after covariate adjustment. Risk-factor groups were created based on clinical indicators known to be associated with worse PNH outcomes, and separate MANCOVAs were computed for lower- and higher-risk-factor groups. Differential item functioning (DIF) analyses examined whether item response varied systematically (1) by treatment, (2) compared to GenPop, and (3) over time, the latter two suggesting and reflecting response-shift effects, respectively. DIF analyses examined 24 items from scales with at least two items. Recalibration response shift was operationalized as uniform DIF over time, reflecting the idea that, for a given group, the difficulty of endorsing an item changes over time, after adjusting for the total subscale score. Reprioritization response shift was operationalized as non-uniform DIF over time, i.e., the relative difficulty of endorsing an item over time changes across the total domain score.ResultsAcross PNH risk-factor levels, people who had been on either treatment for 26 weeks reported better-than-expected functioning and lower symptom burden compared to GenPop. Ravulizumab generally showed larger effect sizes. Results were similar for lower and higher PNH risk factors, with slightly stronger effects in the former. DIF analyses revealed no treatment DIF, but did uncover group DIF (9 items with uniform DIF, and 11 with non-uniform) and DIF over time (7 items with uniform DIF, and 3 with non-uniform).ConclusionsThis study revealed that people with PNH on ravulizumab or eculizumab for 26 weeks reported QOL levels better than those of the general population. Significant effects of DIF by group and DIF over time support recalibration and reprioritization response-shift effects. These findings suggest that the treatments enabled adaptive changes.
Highlights
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder with significant morbidity and premature mortality [1]
Trial (ALXN1210-PNH-301) [22] was implemented in people with PNH naïve to complement inhibitors [22]; Trial (ALXN1210-PNH-302) [21], in people with PNH who were stable on eculizumab for at least 6 months and of which half were randomized to switch to ravulizumab [21]
Trial (ALXN1210-PNH-301) was implemented in people with PNH not previously treated with complement inhibitors [22]; Trial (ALXN1210PNH-302), in people with PNH who were stable on eculizumab for at least 6 months and of whom half were randomized to switch to ravulizumab [21]
Summary
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder with significant morbidity and premature mortality [1]. PNH is characterized by dysregulation of the terminal complement pathway, leading to intravascular hemolysis and thrombosis. Such patients generally have a poor quality of life (QOL) [8]. Onset can occur at any age, PNH has a worldwide mean age of diagnosis of 39.3 years (SD = 18.6) [2, 3, 14,15,16]. Some patients have sudden onset and rapid progression to death, whereas others have long-term chronic illness but few life-threatening complications [3]
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