Norm-based comparison of the quality-of-life impact of ravulizumab and eculizumab in paroxysmal nocturnal hemoglobinuria

Abstract

Aims: Paroxysmal 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.

Methods: Multivariate 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.

Results: Across 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).

Conclusions: This 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.

Keywords: Clinical trial; EORTC; Eculizumab; Norms; Paroxysmal nocturnal hemoglobinuria; Patient-reported outcome; Quality of life; Ravulizumab; Response shift.

Conflict of interest statement

Dr. Schwartz and Mr. Stark are employees of DeltaQuest Foundation, which received research funding for the work reported herein. Dr. Nolte declares no potential conflicts of interest and reports no disclosures. Mr. Myren is an employee of Alexion Pharmaceuticals which developed the drugs being evaluated.

© 2021. The Author(s).

Figures

Fig. 1

Heat maps. Heat maps illustrate group differences for ravulizumab (a) and eculizumab (b) using Cohen’s d effect size computed from aggregated means and standard deviations by age and gender groupings. Conditional formatting illustrates effect-size magnitude with a more saturated color reflecting larger effect size. Since all of the differences were in the direction of PNH group scoring better than the general population (i.e., higher on function/global QOL scales, lower on symptom scales/items), only one color is used for the conditional formatting. Figure a includes people with PNH on ravulizumab after 26 weeks either during the randomized period or during the extension-trial period. This meant assessment at 52 weeks for patients who had eculizumab for 26 weeks and then had ravulizumab for 26 weeks. Includes Trial 301 (N = 242) and 302 (N = 185). Figure b includes people with PNH who had been on eculizumab for 26 weeks. All these patients' assessments were made during the randomized period. Includes Trial 301 (N = 118) and 302 (N = 95)

Fig. 1

Heat maps. Heat maps illustrate group differences for ravulizumab (a) and eculizumab (b) using Cohen’s d effect size computed from aggregated means and standard deviations by age and gender groupings. Conditional formatting illustrates effect-size magnitude with a more saturated color reflecting larger effect size. Since all of the differences were in the direction of PNH group scoring better than the general population (i.e., higher on function/global QOL scales, lower on symptom scales/items), only one color is used for the conditional formatting. Figure a includes people with PNH on ravulizumab after 26 weeks either during the randomized period or during the extension-trial period. This meant assessment at 52 weeks for patients who had eculizumab for 26 weeks and then had ravulizumab for 26 weeks. Includes Trial 301 (N = 242) and 302 (N = 185). Figure b includes people with PNH who had been on eculizumab for 26 weeks. All these patients' assessments were made during the randomized period. Includes Trial 301 (N = 118) and 302 (N = 95)