Eculizumab improves fatigue in refractory generalized myasthenia gravis

Purpose To evaluate the effect of eculizumab on perceived fatigue in patients with anti-acetylcholine receptor antibody-positive, refractory, generalized myasthenia gravis (MG) using the Quality of Life in Neurological Disorders (Neuro-QOL) Fatigue subscale, and to evaluate correlations between improvements in Neuro-QOL Fatigue and other clinical endpoints. Methods Neuro-QOL Fatigue, MG Activities of Daily Living (MG-ADL), Quantitative MG (QMG), and the 15-item MG Quality of Life (MG-QOL15) scales were administered during the phase 3, randomized, placebo-controlled REGAIN study (eculizumab, n = 62; placebo, n = 63) and subsequent open-label extension (OLE). Data were analyzed using repeated-measures models. Correlations between changes in Neuro-QOL Fatigue and in MG-ADL, QMG, and MG-QOL15 scores were determined at REGAIN week 26. Results At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderate, and weak, respectively, for placebo-treated patients. Conclusions Compared with placebo, eculizumab was associated with improvements in perceived fatigue that strongly correlated with improvements in MG-specific outcome measures. Trial ID Registration: NCT01997229, NCT02301624. Electronic supplementary material The online version of this article (10.1007/s11136-019-02148-2) contains supplementary material, which is available to authorized users.

Perceived fatigue (a feeling of tiredness, lack of energy, and difficulty concentrating; referred to as fatigue hereafter) is also an important clinical issue for these patients and may be distinct from muscle weakness and fatigability [3][4][5][6][7].
Validated MG-specific assessments used to measure disease severity and response to intervention include the patient-reported MG Activities of Daily Living (MG-ADL) and 15-item MG Quality of Life (MG-QOL15) scales, and the physician-completed Quantitative MG (QMG) assessment of muscle strength [8][9][10]. None of these evaluate the impact of fatigue in gMG. The Quality of Life in Neurological Disorders (Neuro-QOL) assessment is designed to measure health-related quality of life across 13 subscales in patients with neurological conditions [11]. Neuro-QOL has been validated in a range of disorders, including multiple sclerosis, Parkinson's disease, and epilepsy, but not in MG [12][13][14]. The Neuro-QOL Fatigue subscale comprises a 19-item, patient self-assessment of fatigue that encompasses 'sensations ranging from tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that decrease one's capacity for physical, functional, social, and mental activities' [15]. A short form Neuro-QOL Fatigue subscale is also available; this was recently validated in patients with MG [7].
Eculizumab is a humanized monoclonal antibody that binds to complement protein C5, inhibiting the activation of the terminal complement component proteins that are believed to mediate damage at the neuromuscular junction in AChR+ gMG [2,16]. In the phase 3 REGAIN study, eculizumab demonstrated clinically meaningful improvements in patients with AChR+ refractory gMG, evaluated using MG-ADL, QMG, and MG-QOL15 assessments (NCT01997229) [17].
The current analysis investigated the effect of eculizumab versus placebo on fatigue in patients with AChR+ refractory gMG, and assessed the relationship between fatigue and MG-specific measures. We used the Neuro-QOL Fatigue subscale to evaluate changes in patients' self-reported assessment of fatigue during REGAIN and its open-label extension study (NCT02301624; interim analysis, 31 December 2017) [18]. We also measured the correlation between outcomes measured using the Neuro-QOL Fatigue subscale and the MG-ADL, QMG, and MG-QOL15 scales in REGAIN.
The Neuro-QOL Fatigue subscale was used to assess fatigue, and the MG-ADL, QMG, and MG-QOL15 scales were used to measure MG-specific activities of daily living, muscle strength, and quality of life, respectively. In REGAIN, all assessments were performed at baseline (day 1), every 4 weeks to week 20, and at week 26. MG-ADL and QMG assessments were also conducted at weeks 1, 2, and 3. Details of scoring for MG-ADL, QMG, and MG-QOL15 during REGAIN have been reported previously; briefly, for each measure, a reduction from baseline total score indicates improvement [17]. The response scale for Neuro-QOL Fatigue items was: 1 = never; 2 = rarely; 3 = sometimes; 4 = often; and 5 = always. The range of potential total scores was 19-95. Higher Neuro-QOL Fatigue subscale total scores indicate greater fatigue; a reduction from baseline total score indicates improvement [15].
Patients who completed REGAIN could enroll into the extension study [18]. Following a 4-week blinded induction phase, all patients received open-label eculizumab (1200 mg) at week 4 and every 2 weeks thereafter. Assessments occurred as in REGAIN to week 26, then at week 40, week 52, and every 6 months [18].

Statistical analysis
A repeated-measures model was used to test whether changes in Neuro-QOL Fatigue total scores from baseline to REGAIN week 26 for eculizumab and placebo were equal ( Fig. 1). Model-estimated changes from REGAIN baseline data were reported up to open-label study week 52 (interim analysis, 31 December 2017) (Fig. 1). To evaluate the treatment effect on Neuro-QOL Fatigue subscale individual items at REGAIN week 26, a repeated-measures proportional odds model was implemented using the GEEORD SAS Macro (Table 2) [19]. Missing scores were not imputed in either model.
Pearson correlation coefficients (r) were calculated for the treatment arms using observed changes from baseline to REGAIN week 26 for Neuro-QOL Fatigue total scores versus observed changes for MG-ADL, QMG, and MG-QOL15 total scores (Fig. 2). The strength of association for absolute values of r was classified as follows: very weak, 0-0.19; weak, 0.2-0.39; moderate, 0.40-0.59; strong, 0.6-0.79; and very strong, 0.8-1 [20]. Within each treatment arm, the null hypothesis was r = 0.4 (the lower limit for moderate correlations). For all evaluations, statistical significance was established using a two-sided p value of less than 0.05, without any multiplicity adjustment.

Results
Baseline demographics and characteristics were similar between treatment groups, with the exception of a higher proportion of Asian patients in the placebo group (Table 1). All patients were assessed using the Neuro-QOL Fatigue subscale (Table 1); mean (standard deviation) baseline total score was 64.1 (14.1) for the eculizumab group and 61.8 (15.9) for the placebo group.
Eculizumab was associated with greater improvements in fatigue than placebo. At REGAIN week 26, patients receiving eculizumab had a model-estimated mean change from baseline Neuro-QOL Fatigue total score of − 16  placebo-treated patients selected lower scoring responses (i.e., more selected 'never' or 'rarely,' and fewer selected 'often' or 'always') ( Table 2). This was statistically significant for 15 of 19 items (range of common odds ratios with p < 0.05: 1.8-2.9; Table 2), indicating that eculizumab treatment was associated with milder fatigue than placebo. For the eculizumab group, there were significant correlations (i.e., different from r = 0.4) for changes in total score from baseline to REGAIN week 26 between Neuro-QOL Fatigue and MG-QOL15 (r = 0.74), MG-ADL (r = 0.70), and QMG (r = 0.64) (Fig. 2). For the placebo-treated group, a strong correlation for change from baseline to REGAIN week 26 was observed between Neuro-QOL Fatigue and MG-QOL15 (r = 0.65); conversely, correlations between Neuro-QOL Fatigue and QMG and MG-ADL were not significantly different from r = 0.4 (r = 0.45 [moderate] and r = 0.35 [weak]) (Fig. 2).

Discussion
This was the first use of the extended Neuro-QOL Fatigue subscale in patients with AChR+ refractory gMG. In REGAIN, levels of fatigue at baseline were generally   consistent with previously published reports for MG; however, in these previous studies, fatigue was assessed using a variety of measures, and patients were not explicitly refractory to treatment [6,7,21]. At REGAIN week 26, eculizumab-treated patients were approximately twice as likely to report improved scores for the 15 of 19 subscale items where significant differences were observed, compared with placebo (range for odds ratios: 1.8-2.9; Table 2).
Patients who received eculizumab for the first time during the open-label study had similar improvements in fatigue to those seen with eculizumab during REGAIN. These were sustained through to week 52 of the open-label study and were consistent with previously reported improvements in MG-validated measures of disease burden (QMG, MG-ADL, and MG-QOL15) [17,22]. The consistently strong, positive correlations between changes in Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG observed in eculizumabtreated patients suggest that the effect of eculizumab on fatigue is a valid clinical outcome in this patient population. The greater variability in observed correlations in placebotreated patients may reflect the degree of similarity between the items assessed by the Neuro-QOL Fatigue subscale and those assessed by the MG-QOL15 (most similar, strong correlation), the MG-ADL (some similarities, moderate correlation), and the QMG (least similar, weak correlation).
Our findings suggest that the Neuro-QOL Fatigue subscale may be used to assess the clinical impact of perceived fatigue and the effect of therapeutic interventions in patients with AChR+ refractory gMG. Use of this scale demonstrated that eculizumab provided sustained, clinically meaningful improvements in fatigue. Our results contribute to the consistency and totality of the data demonstrating that eculizumab lowers the clinical burden in patients with AChR+ refractory gMG. stitutes of Health (including the National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases); research support from the Muscular Dystrophy Association; honoraria from Alexion Pharmaceuticals, Argenx BVBA and Ra Pharmaceuticals; and non-financial support from Alexion Pharmaceuticals, Argenx BVBA, Ra Pharmaceuticals and Toleranzia AB, outside of the submitted work.
Research involving human participants This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and are consistent with International Council for Harmonisation (ICH) harmonised tripartite guideline E6(R1): Good Clinical Practice (ICH E6[R1]) and applicable regulatory requirements.
Informed consent Written informed consent was obtained from all participants.