Study design

REGAIN was a 26-week, phase 3, randomized, double-blind, placebo-controlled study evaluating eculizumab efficacy and safety [17]. Briefly, patients were randomized 1:1 to receive eculizumab (n = 62; induction: 900 mg for 4 weeks; maintenance: 1200 mg at week 4 and then every 2 weeks until week 26) or placebo (n = 63) [17]. The primary endpoint was the change in MG-ADL total score with eculizumab versus placebo.

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.

Fig. 1 Change in Neuro-QOL Fatigue subscale total score from REGAIN baseline to week 52 of the open-label study using a repeated-measures model.aaA repeated-measures model using the restricted maximum likelihood for the changes from baseline was used to compare the two treatment groups at each assessment visit and over time. The model included the following terms: treatment, visit, treatment by visit interaction, pooled Myasthenia Gravis Foundation of America (MGFA) randomization stratification variable (based on their MGFA classification at screening, patients were assigned to one of two categories: IIa/IIIa/IVa [a, symptoms predominantly affecting limb or axial muscles, or both] or IIb/IIIb/IVb [b, symptoms predominantly affecting oropharyngeal or respiratory muscles, or both]), and Neuro-QOL Fatigue total score at baseline. bNumber of patients who completed the assessment at each time point. Some patients did not complete all items of the questionnaire at every timepoint. When this occurred, total scores could not be computed at that time point. Missing scores were not imputed. BL baseline, CI confidence interval, Neuro-QOL Fatigue Quality of Life in Neurological Disorders Fatigue subscale, REGAIN Eculizumab for REfractory GenerAlIzed MyastheNia Gravis Full size image

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.