Safety, Patient-Reported Well-Being, and Physician-Reported Assessment of Walking Ability in Patients with Multiple Sclerosis for Prolonged-Release Fampridine Treatment in Routine Clinical Practice: Results of the LIBERATE Study

Giovanni Castelnovo, Oliver Gerlach, Mark S Freedman, Arnfin Bergmann, Vladimiro Sinay, Tamara Castillo-Triviño, George Kong, Thijs Koster, Heather Williams, Arie R Gafson, Joep Killestein, Giovanni Castelnovo, Oliver Gerlach, Mark S Freedman, Arnfin Bergmann, Vladimiro Sinay, Tamara Castillo-Triviño, George Kong, Thijs Koster, Heather Williams, Arie R Gafson, Joep Killestein

Abstract

Background: Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world.

Objectives: The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM.

Methods: Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed.

Results: Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21-85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p < 0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: - 9.99 vs. - 0.34 points; p < 0.001). Results were similar for MSIS-29 psychological impact.

Conclusion: No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported.

Trial registration: ClinicalTrials.gov: NCT01480063.

Conflict of interest statement

Giovanni Castelnovo has received research/educational grants from Allergan, Biogen, Merz, and Novartis, and speaking/consulting fees from Allergan, Biogen, Ipsen, Merck, Merz, Novartis, and Sanofi-Genzyme. Mark S. Freedman has received research/educational grants from EMD (Canada), Roche, and Sanofi-Genzyme (Canada); consulting fees from Actelion (Janssen/J&J), Alexion, Biogen, Celgene (BMS), EMD, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva Canada Innovation; advisory board/board of directors/similar group for Actelion (Janssen/J&J), Alexion, Atara Biotherapeutics, Bayer, Biogen, Celgene (BMS), Clene Nanomedicine, GRI Bio, Magenta Therapeutics, Merck Serono, MedDay, Novartis, Roche, Sanofi-Genzyme, and Teva Canada Innovation; and speaker bureaus for EMD Serono and Sanofi-Genzyme. Vladimiro Sinay has received reimbursement for developing educational presentations, educational/research grants, and consultation fees/travel stipends from Bayer, Biogen, Biosidus, Gador, Genzyme, Merck, Novartis, Raffo/Asofarma, and Roche. Tamara Castillo-Triviño has received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Joep Killestein has received speaking/consulting fees from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. George Kong, Thijs Koster, Heather Williams and Arie R. Gafson are employees of, and hold stock/stock options in, Biogen. Oliver Gerlach and Arnfin Bergmann have no disclosures to declare.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient disposition. Data cut-off date: 21 June 2019. Percentages are calculated using the total number of patients (N) as the denominator. aSafety population: patients who enrolled in the study and received ≥ 1 dose of PR-FAM. CGI-I Clinical Global Impression of Improvement, MSIS-29 Multiple Sclerosis Impact Scale-29, PR-FAM prolonged-release fampridine
Fig. 2
Fig. 2
Patients on-treatment with PR-FAM showed improved walking ability compared with patients off-treatment. Data cut-off date: 21 June 2019. P value is presented to test the difference in proportion of patients with an improvement between the on-treatment and off-treatment groups using the Chi-square test. Nominal p value is presented. Percentages are calculated using the total number of patients with non-missing values as the denominator. PR-FAM prolonged-release fampridine
Fig. 3
Fig. 3
MSIS-29 PHYS and MSIS-29 PSYCH scores improved in patients treated with PR-FAM compared with patients off-treatment: a MSIS-29 PHYS; b MSIS-29 PSYCH. Data cut-off date: 21 June 2019. P-values are presented to test the difference in change from baseline between on-treatment and off-treatment groups using an analysis of covariance model with baseline value as covariate and a fixed term for treatment status at 12 months. MSIS-29 Multiple Sclerosis Impact Scale, PHYS physical impact subscale, PSYCH psychological impact subscale, PR-FAM prolonged-release fampridine

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