REBIFLECT was performed at 134 study centers; 746 patients were enrolled; 15 patients were excluded from the analysis because of missing adherence data. The analysis population thus included 731 patients who were predominantly female (73.9%), at a median age of 43 years. One hundred eighty-five patients (24.8%) discontinued the study prematurely, the most frequent reason being change of treatment strategy (n = 97).
Most participating patients (87.3%) suffered from relapsing–remitting MS (RRMS); 8.2% had CIS (Table 1). The mean EDSS score at baseline was 2.1. Prior treatment with other disease-modifying drugs was reported for 119 patients (16.3%). Glatiramer acetate was the most common prior drug (n = 36). Interferon beta1a sc had been administered for > 6 months in 82.6% of patients.
Table 1 Patient disposition and characteristics The median number of reflection talks per patient was 3 during both the first and second year of study (Table 2). Over the full study period (month 1–24) the median number of talks per patient was 4 (range 0–9). Readout data recorded by RebiSmart were available for > 86% of the patients at all time points.
Table 2 Reflection and adherence results Treatment Adherence
Mean quantitative treatment adherence during the first 12 months, based on the RebiSmart® readout data of 642 patients, was 98.8% (median: 100.2%). Quantitative adherence of 85% through 105% was documented in 88.5% of 642 patients (n = 568). Adherence rates < 85% were reported in 9.3% (n = 60). Adherence rates > 105% were seen in 14 patients (2.2%).
During the second 12-month period, mean quantitative treatment adherence was 96.8% (median: 100.2%, n = 482). Quantitative adherence of 85% through 105% was documented in 86.5% of patients. Adherence rates < 85% were seen in 9.8%; 3.7% had an adherence rate > 105%.
Mean quantitative treatment adherence over the full study period (month 1–24) was 97.9 ± 30.2% (SD) (median: 99.9%, n = 644), with 87.4% patients showing quantitative adherence of 85% through 105%, 10.7% had an adherence of < 85%, and 1.9% were over-adherent with > 105% of prescribed doses.
Comparison of quantitative treatment adherence between the first and second year in patients with RebiSmart® injection data available for the complete duration of 24 months (n = 251) showed a mean difference of 1.8% (p = 0.0025). Mean adherence rates were high during both periods (first year: 98.9%; second year: 97.1%) and with an identical median of 100.2% in both years.
Significant differences (p = 0.025) in quantitative adherence were observed between men and women in the second year: 96.4% in females vs. 98.1% in males and a somewhat higher proportion of men vs. women with an adherence of 85% through 105% (90.4% vs. 85.2%).
Median values of quantitative adherence were highly similar between genders (100.4% vs. 100.2%). During the full 2-year observation period, the differences between men and women were not significant, with identical proportions of patients being in the 85–105% adherence category (87.4% each).
Statistically significant differences (p ≤ 0.005) were seen between the dropout vs. persistent subgroups during all three periods, with considerably lower mean adherence rates in the dropout subgroup compared to the persistent subgroup: 74.1% vs. 99.3% during the first year, 79.7% vs. 97.7%) during the second year, and 82.2% vs. 99.0% during the full study period. Thus, in all three observation periods the share of patients with 85–105% adherence was considerably lower among the dropouts than in the persistent subgroup (< 58% vs. > 88% of patients).
No statistically significant differences between the subgroups defined by disease duration or prior MS treatment were seen in any of the observation periods. Mean quantitative adherence during the second year among the subgroups defined by pre-baseline relapse frequency was numerically lowest in the subgroup with > 1 relapse.
Adherence frequency categories could not be compared between dose groups because of the high percentage (33.7%) of patients with missing quantitative adherence rates in the 22-μg subgroup.
Mean qualitative adherence was approximately 82% in all three study periods, with medians of 90.4% through 90.6%. Approximately 70% of the patients with adherence data available in the respective periods had a qualitative treatment adherence of 80–100%. Low qualitative adherence (< 50%) to the prescribed regimen was observed in < 10% of the patients in each period.
Quantitative and qualitative adherence exhibited moderate but significant positive correlation in both the first and second year of study (Spearman rank coefficients: 0.48 and 0.44; p < 0.001). No correlations were observed between quantitative adherence and the following parameters: duration of prior interferon beta-1a sc treatment, change of EDSS from baseline, and EQ-5D-3L (total score and VAS).
Physician-assessed treatment adherence was “high” in > 80% of patients at all times. The median total Morisky Scale score was 4 at all times, indicating very strong patient-reported adherence. Patient adherence self-assessed by VAS was very strong as well, with mean VAS scores > 90 (median ≥ 98; on a scale of 0–100) at baseline and all follow-up times. Any changes from baseline were not statistically significant. Spearman rank correlation analysis revealed no or very weak positive correlations between changes from baseline in quantitative adherence vs. self-assessed adherence at months 12 and 24.
Mean quality of life (EQ-5D-3L total score) was high at baseline (mean: 0.79 of 1.00) and did not change substantially during the study. Similar results were seen with the EQ-5D-3L VAS score (data not shown).
The proportion of patients with MS-related visits to the neurologist in addition to the regular follow-up visits was 19.4% (142/731) during the year before baseline, 16.8% (33/488) in the first year, and 5.9% (22/375) in the second year of the study.
Quantitative treatment adherence in the first year, second year, and full observation period was compared with the Wilcoxon rank sum test or Kruskal-Wallis test in subgroups defined by age, subcutaneous interferon beta-1 dose, use of the Rebif starter pack, and the number of reflection talks.
Statistically significant differences (p = 0.039) were observed between patients who did or did not use the starter pack in the second year, with slightly lower mean adherence rates in patients who did not use the starter pack (97.6% vs. 95.3%) and a slightly higher share of patients in the 85% through 105% adherence category in the subgroup with the starter pack (87.1% of patients) vs. without (85.3% of patients). The median values between both groups were similar (100.4% vs. 100.1%).
The differences between the subgroups by number of reflection talks (0 through 5 and > 5 talks) were statistically significant (p = 0.020) for the entire study period. No trend toward higher quantitative adherence rates in patients with a larger number of reflection talks was seen. During the full trial period, mean quantitative adherence was strongest in the subgroup with 1 reflection talk (116.3%; including outliers) followed by the subgroup with > 5 reflection talks (97.9%) and weakest in the subgroup with 2 reflection talks (90.7%).
In line with this finding, the share of patients with 85% through 105% adherence was largest in the subgroup with > 5 talks (93.8%), which was also the largest subgroup, and smallest in the subgroup with 2 reflection talks (72.8%). There were no statistically significant differences in any of the three periods between the subgroups defined by age or subcutaneous interferon beta-1a dose.
Safety Findings
A total of 132 patients (18.1% of 731 patients) experienced 263 adverse events (AEs) during the study period. Thirty AEs in 20 patients (2.7%) were reported as serious: 5 of these events in 4 patients (0.5%) were considered medically significant. The pattern and frequencies of reported adverse events were consistent with the established safety profile of interferon beta-1a sc and primarily involved injection site reactions (5.5%), influenza-like illness (3.3%), injection site erythema (2.3%), and injection site pain (1.5%).