Correction to: Improvements in Cognitive Processing Speed, Disability, and Patient‑Reported Outcomes in Patients with Early Relapsing‑Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4‑year, Real‑World, Open‑Label Study

3.1 Patient Enrollment and Baseline Characteristics

The STRIVE ITT population, defined as all enrolled patients who completed informed consent and received one or more doses of natalizumab, consisted of 222 patients. Of the 155 patients in the ITT population who completed the study, 105 were treated with natalizumab over the entire 4 years of STRIVE (i.e., the 4-year natalizumab completers) [6]. The main reason for natalizumab discontinuation was seroconversion to anti-JC virus antibody-positive status/elevated index/progressive multifocal leukoencephalopathy risk (n = 27). Reported lack of efficacy was listed as a reason for discontinuation of natalizumab in only eight patients [6].

At baseline, patients in the ITT population (N = 222) had a median (range) of 1 (0–12) relapses in the prior year, 0 (0–71) Gd+ lesions, and a median (range) EDSS score of 2.0 (0–6.5) [6]. The mean (SD) SDMT score at baseline was 52.0 (14.0) (Table 1). The mean (SD) MSIS-29 physical and psychological score at screening was 42.2 (19.0) and 22.0 (9.3), respectively, in the ITT population (Table 1). Most patients (69.7%) were employed, reporting an average (SD) of 5.4 (12.7) hours missed from work per week because of MS and a median (range) score of 2 (0–10) on work productivity affected by MS at screening. The median (range) score on regular activities affected by MS for ITT patients regardless of employment status at screening was 3 (0–10) (Table 1).

Table 1 SDMT and PRO scores at baseline/screening in the STRIVE ITT population and 4-year natalizumab completers

Baseline characteristics of the 4-year natalizumab completers (n = 105) were similar to those of the ITT population. Patients had a median (range) of 1 (0–4) relapses in the prior year, 0 (0–71) Gd+ lesions, and a median (range) EDSS score of 2.0 (0–4.0) [6]. The mean (SD) SDMT score at baseline was 51.3 (14.5) (Table 1).

The mean (SD) MSIS-29 physical and psychological score at screening was 40.0 (18.1) and 20.7 (9.0), respectively, in the 4-year natalizumab completer population (Table 1). Most patients (72.8%) were employed, reporting an average (SD) of 4.3 (10.7) hours missed from work per week because of MS and a median (range) score of 1 (0–9) on work productivity affected by MS at screening. The median (range) score on regular activities affected by MS for 4-year completers regardless of employment status at screening was 3 (0–10) (Table 1).

3.2 Clinical Outcomes3.2.1 Cognitive Processing Speed

In the ITT population, the percentage of patients with a clinically meaningful improvement in their SDMT score from baseline (i.e., SDMT score change ≥ 4) ranged from 41.9% (80 of 191) to 54.0% (94 of 174) across the four annual assessments (Table 2). Similar results were observed in the 4-year natalizumab completers, with the percentage of patients experiencing a clinically meaningful improvement in their SDMT score from baseline ranging from 44.8% (47 of 105) to 63.8% (67 of 105) across the four annual assessments (Table 2). Of the 4-year natalizumab completers who experienced a clinically meaningful improvement in year 1 (44.8%; n = 47), 83.0% (39 of 47) maintained that improvement at year 4 (see Table 2).

Table 2 Change in SDMT scores in the ITT population and 4-year natalizumab completers

Exploratory analyses were conducted to determine whether the change in the SDMT score varied depending on the patients’ SDMT scores at baseline. Patients were categorized into three subgroups based on the baseline SDMT score quartiles (i.e., those with baseline SDMT scores either below the lowest quartile (< 25%), within the interquartile range (≥ 25% to < 75%), or above or equal to the highest quartile (≥ 75%)]. In the ITT population, a higher proportion of patients with baseline SDMT scores below the lowest quartile (< 25%) experienced clinically meaningful improvement in their SDMT scores than the other two quartile subgroups (i.e., ≥ 25% to < 75% and ≥ 75%) over the course of the study (Table 3). The differences were most evident between the lowest (< 25%) and highest (≥ 75%) quartile subgroups at years 1 (i.e., 56.1% (23 of 41) vs. 27.3% (15 of 55)) and 2 (i.e., 66.7% (22 of 33) vs. 34.9% (15 of 43)) (Table 3). Consistent results were found in the 4-year natalizumab completers.

Table 3 Change in SDMT scores in quartile subgroups of the ITT population and 4-year natalizumab completers3.2.2 CDI

The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥ 2 (N = 133) was 43.9% (Fig. 1). Of the ITT patients with a baseline EDSS score ≥ 2, 32.3% (43 of 133) patients experienced 24-week CDI at some point during the study. Baseline demographics, disease characteristics, and PROs of these two patient groups (i.e., ITT patients with baseline EDSS score ≥ 2.0 and those who achieved CDI during the study) were generally similar (Table 4). Of the patients who achieved CDI, 62.8% (27 of 43) exhibited a reduction in EDSS score ≥ 1.5, and 44.2% (19 of 43) exhibited a reduction ≥ 2.0. Most of the patients who experienced CDI (79.1%; 34 of 43) maintained the improvement for the remainder of the 4-year study period.

Fig. 1figure 1

Cumulative probability for time to confirmed disability improvement (CDI) over 4 years in the intent-to-treat population. Time point shown is for onset of Expanded Disability Status Scale score decrease, which was confirmed 24 weeks later. Dashed lines show the 95% confidence interval

Table 4 Baseline characteristics of ITT patients with baseline EDSS score ≥ 2.0 and those with baseline EDSS score ≥ 2.0 who experienced CDI3.3 PROs3.3.1 QoL: MSIS-29

Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, which signify better QoL, were observed over all 4 years of the study in the ITT population with similar results seen in the 4-year natalizumab completers (Table 5). For example, at year 4, the mean change from screening in the MSIS-29 physical and psychological scores (95% CI; P value) in the ITT population was − 4.7 (−6.9, − 2.4; < 0.0001) and − 2.6 (−3.8, − 1.4; < 0.0001), respectively. Similarly, in the 4-year natalizumab completers the mean change from screening in the MSIS-29 physical and psychological scores (95% CI; P value) at year 4 was − 4.5 (− 7.2, − 1.7; 0.0003) and −2.3 (− 3.8, − 0.7; 0.0125), respectively.

Table 5 Change in MSIS-29 scores in the ITT population and 4-year natalizumab completers

At 4 years, most patients in the ITT population were stable or exhibited improvement on both the physical (88.5%, 154 of 174) and psychological (91.3%, 157 of 172) components of the MSIS-29 relative to screening, with similar results seen among the 4-year natalizumab completers (Fig. 2).

Fig. 2figure 2

Proportion of patients experiencing worsening, stability, or improvement in Multiple Sclerosis Impact Scale (MSIS-29) scores at year 4 compared with baseline in the intent-to-treat (ITT) and 4-year completer populations

3.3.2 Capacity for work: WPAI

There were no statistically significant differences in the percent change of patients who were employed at each annual assessment compared to screening in either the ITT or the 4-year natalizumab completer populations (Table 6). Of the patients who were employed at screening and subsequently completed all four annual assessments, 74.2% (72 of 97) and 76.9% (50 of 65) maintained their employment throughout the study in the ITT and 4-year natalizumab completer cohorts, respectively.

Table 6 Mean change from screening in WPAI results in the ITT population and 4-year natalizumab completers

In the ITT population, irrespective of employment status, a statistically significant decrease in the impact of MS on regular activities was observed over all 4 years of the study (year 1: – 0.4, P = 0.0321; year 2: – 0.6, P = 0.0070; year 3: – 0.9, P = 0.0004; year 4: – 0.9, P < 0.0001) compared with the impact at screening (Table 6). For those employed ITT patients, there was also a statistically significant decrease in the impact of MS on work productivity in years 3 (– 0.6, P = 0.0337) and 4 (– 0.5, P = 0.0172) compared with the impact at screening (Table 6). The number of hours missed per week due to MS was also significantly reduced in years 2 (– 2.8, P = 0.0153) and 4 (– 2.5, P = 0.0260) compared with screening (Table 6). These changes all indicate improvements on these WPAI measures.

Although similar results were observed in the 4-year natalizumab completers, statistically significant decreases compared with screening were observed only with respect to the impact of MS on regular activities in years 3 (–0.9, P = 0.0054) and 4 (–1.0, P = 0.0017; Table 6).

3.4 Exploratory Analyses3.4.1 PROs and NEDA Status in Patients with Clinically Meaningful Improvement in Their SDMT Score at 4 Years (ITT Population)

An exploratory analysis using the STRIVE ITT population was conducted to determine how patients with clinically meaningful improvement in their SDMT score at year 4 did on other outcome measures (i.e., PROs and NEDA) at that timepoint. Most patients who experienced a clinically meaningful improvement in their SDMT score (i.e., ≥ 4) at year 4 also exhibited stability or improvement on their MSIS-29 physical (92.4%, 85 of 92) and psychological (92.3%, 84 of 91) categories (Fig. 3). For those patients who were employed at that time and completed the WPAI questionnaire, most (90.8%, 49 of 54) were stable or had improvements with respect to the number of work hours missed/week due to MS (Fig. 3). Irrespective of employment status, 56.7% (51 of 90) of patients who experienced clinically meaningful improvement on their SDMT score from baseline at year 4 also exhibited an improvement on their ability to do regular activities affected by MS (Fig. 3).

Fig. 3figure 3

Proportion of patients with clinically meaningful improvements on their SDMT (Symbol Digit Modalities Test) score (≥ 4) who exhibited worsening, stability, or improvement on patient-reported outcomes at year 4. MSIS-29 is categorical change in physical and psychological scores. For WPAI, hours of work missed/week and impact on regular activities are due to multiple sclerosis (MS) (impact on regular activities assessed in all patients regardless of employment status). MSIS-29 Multiple Sclerosis Impact Scale, WPAI Work Productivity and Activity Impairment Questionnaire

The majority of patients who experienced clinically meaningful improvement in their SDMT score at year 4 also achieved NEDA (70.1%, 54 of 77), Clinical NEDA (89.3%, 75 of 84), and MRI NEDA (81.8%, 63 of 77) (Fig. 4).

Fig. 4figure 4

Proportion of patients with clinically meaningful improvements on their SDMT score (≥ 4) who achieved NEDA, Clinical NEDA, or MRI NEDA at year 4. NEDA was defined as no relapses or 24-week CDW, no Gd+ lesions, and no new or newly enlarging T2 lesions (CDW was defined as a ≥ 1.5-point increase from a baseline EDSS score of 0.0, a ≥ 1.0-point increase from a baseline EDSS score of 1.0 to < 6.0, or a ≥ 0.5-point increase from a baseline score ≥ 6.0, confirmed 24 weeks later). Clinical NEDA was defined as no relapses or 24-week CDW. MRI NEDA was defined as no Gd+ lesions and no new or newly enlarging T2 lesions. CDW confirmed disability worsening; EDSS Expanded Disability Status Scale; Gd+ gadolinium-enhancing; MRI magnetic resonance imaging; NEDA No Evidence of Disease Activity

3.4.2 PROs and NEDA Status in Patients Who Experienced CDI (ITT Population with Baseline EDSS Score ≥ 2)

An exploratory analysis using the STRIVE ITT population was conducted to determine how patients with CDI did on other outcome measures (i.e., PROs and NEDA) at year 4. Most patients who experienced CDI also exhibited stability or improvement on their MSIS-29 physical (97.3%, 36 of 37) and psychological (94.6%, 35 of 37) categories at year 4 (Fig. 5). For those patients who were employed at that time and completed the WPAI questionnaire, all (100%, 23 of 23) were stable or had improvements with respect to the number of work hours missed/week due to MS (Fig. 5). Irrespective of employment status, 61.1% (22 of 36) of patients who experienced CDI also exhibited an improvement on their ability to perform regular activities impacted by MS at year 4 (Fig. 5).

Fig. 5figure 5

Proportion of ITT patients with confirmed disability improvement who exhibited worsening, stability, or improvement on patient-reported outcomes at year 4. MSIS-29 is categorical change in physical and psychological scores. For WPAI, hours of work missed/week and impact on regular activities are due to MS (impact on regular activities assessed in all patients regardless of employment status). ITT Intent-to-treat; MSIS-29 Multiple Sclerosis Impact Scale; WPAI Work Productivity and Activity Impairment Questionnaire

The majority of patients who experienced CDI also achieved NEDA (67.7%, 23 of 34), Clinical NEDA (88.9%, 32 of 36) and MRI NEDA (79.4%, 27 of 34) at year 4 (Fig. 6).

Fig. 6figure 6

Proportions of ITT patients with confirmed disability improvement who achieved NEDA, Clinical NEDA, or MRI NEDA at year 4. NEDA was defined as no relapses or 24-week CDW, no Gd+ lesions, and no new or newly enlarging T2 lesions (CDW was defined as a ≥ 1.5-point increase from a baseline EDSS score of 0.0, a ≥ 1.0-point increase from a baseline EDSS score of 1.0 to < 6.0, or a ≥ 0.5-point increase from a baseline score ≥ 6.0, confirmed 24 weeks later). Clinical NEDA was defined as no relapses or 24-week CDW. MRI NEDA was defined as no Gd+ lesions and no new or newly enlarging T2 lesions. CDW confirmed disability worsening; EDSS Expanded Disability Status Scale; Gd+ gadolinium-enhancing; ITT Intent-to-treat; MRI magnetic resonance imaging; NEDA No Evidence of Disease Activity

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