Lahar Mehta

Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial

BACKGROUND In animal models of acute ischaemic stroke, blocking of the leukocyte-endothelium adhesion by antagonism of α4 integrin reduces infarct volumes and improves outcomes. We assessed the effect of one dose of natalizumab, an antibody against the leukocyte adhesion molecule α4 integrin, in patients with acute ischaemic stroke. METHODS In this double-blind, phase 2 study, patients with acute ischaemic stroke (aged 18-85 years) from 30 US and European clinical sites were randomly assigned (1:1) to 300 mg intravenous natalizumab or placebo with stratification by treatment window and baseline infarct size. Patients, investigators, and study staff were masked to treatment assignments. The primary endpoint was the change in infarct volume from baseline to day 5 and was assessed in the modified intention-to-treat population. Secondary endpoints were the change in infarct volume from baseline to day 30, and from 24 h to days 5 and 30; the National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at days 5 (or discharge), 30, and 90; and modified Rankin Scale (mRS) and Barthel Index (BI) at days 5 (or discharge), 30, and 90. This trial is registered with ClinicalTrials.gov, number NCT01955707. FINDINGS Between Dec 16, 2013, and April 9, 2015, 161 patients were randomly assigned to natalizumab (n=79) or placebo (n=82). Natalizumab did not reduce infarct volume growth from baseline to day 5 compared with placebo (median absolute growth 28 mL [range -8 to 303] vs 22 mL [-11 to 328]; relative growth ratio 1·09 [90% CI 0·91-1·30], p=0·78) or to day 30 (4 mL [-43 to 121] vs 4 mL [-28 to 180]; 1·05 [0·88-1·27], p=0·68), from 24 h to day 5 (8 mL [-30 to 177] vs 7 mL [-13 to 204]; 1·00 [0·89-1·12], p=0·49), and from 24 h to day 30 (-5 mL [-93 to 81] vs -5 mL [-48 to 48]; 0·98 [0·87-1·11], p=0·40). No difference was noted between the natalizumab and placebo groups in the NIHSS (score ≤1 or ≥8 point improvement) from baseline at 24 h, day 5 (or discharge), day 30 (27 [35%] vs 36 [44%]; odds ratio 0·69 [90% CI 0·39-1·21], p=0·86), and day 90 (36 [47%] vs 37 [46%]; 1·10 [0·63-1·93], p=0·39). More patients in the natalizumab group than in the placebo group had mRS scores of 0 or 1 at day 30 (13 [18%] vs seven [9%]; odds ratio 2·88 [90% CI 1·20-6·93], p=0·024) and day 90 (18 [25%] vs 16 [21%]; 1·48 [0·74-2·98], p=0·18); and BI (score ≥95) at day 90 (34 [44%] vs 26 [33%]; 1·91 [1·07-3·41], p=0·033) but not significantly at day 5 or day 30 (26 [34%] vs 26 [32%]; 1·13 [0·63-2·00], p=0·37). Natalizumab and placebo groups had similar incidences of adverse events (77 [99%] of 78 patients vs 81 [99%] of 82 patients), serious adverse events (36 [46%] vs 38 [46%]), and deaths (14 [18%] vs 13 [16%]). Two patients in the natalizumab group died because of adverse events assessed as related to treatment by the investigator (pneumonia, and septic shock and multiorgan failure). INTERPRETATION Natalizumab administered up to 9 h after stroke onset did not reduce infarct growth. Treatment-associated benefits on functional outcomes might warrant further investigation. FUNDING Biogen.

Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial

Background: Mobility impairment is a common disability in MS and negatively impacts patients’ lives. Objective: Evaluate the effect of prolonged-release (PR) fampridine (extended-release dalfampridine in the United States) on self-assessed walking disability, dynamic/static balance and safety in patients with MS. Methods: MOBILE was a randomised, double-blind, exploratory, placebo-controlled trial. Patients with progressive/relapsing-remitting MS and Expanded Disability Status Scale score of 4.0–7.0 were treated with PR-fampridine or placebo twice daily for 24 weeks. Efficacy endpoints included change from baseline in the 12-item MS Walking Scale (MSWS-12), Timed Up and Go (TUG) test and Berg Balance Scale (BBS). Results: 132 patients were randomised at 24 sites in six countries. PR-fampridine therapy resulted in greater median improvements from baseline in MSWS-12 score, TUG speed and BBS total score versus placebo over 24 weeks. A higher proportion of patients receiving PR-fampridine versus placebo experienced significant improvements at MSWS-12 improvement thresholds ⩾7 (p = 0.0275), ⩾8 (p = 0.0153) and ⩾9 points (p = 0.0088) and TUG speed thresholds ⩾10% (p = 0.0021) and ⩾15% (p = 0.0262). PR-fampridine was well tolerated. Conclusions: PR-fampridine therapy resulted in early and sustained improvements in broad measures of walking and balance over six months.

Disease-activity-free status in patients with relapsing–remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study

Background: Daclizumab high-yield process (DAC HYP) is a humanized anti-CD25 monoclonal antibody that inhibits high-affinity interleukin-2 receptor signaling. Objective: The objective of this paper is to assess the proportion of DAC HYP- versus placebo-treated patients who were free from disease activity. Methods: SELECT was a randomized, double-blind, multicenter study of DAC HYP 150 mg or 300 mg, or placebo, administered subcutaneously every four weeks for 52 weeks. In this post-hoc analysis of the SELECT trial, ‘disease-activity free’ was defined as completion through week 52 without relapses or confirmed three-month disability progression (clinical), with no new/newly enlarging T2-hyperintense lesions and no new gadolinium-enhancing lesions at the week 52 scan (radiological). Primary analyses were based on logistic regression controlling for baseline characteristics. Results: More DAC HYP-treated (39%, n = 156) versus placebo-treated patients (11%, n = 22) were disease-activity free (odds ratio (95% confidence interval), 6.18 (3.71–10.32); p < 0.0001). Furthermore, 77% and 48% of DAC HYP-treated patients were free from clinical or radiological disease activity, respectively, compared with 60% and 18% of placebo-treated patients. Conclusion: At one year, DAC HYP resulted in a meaningful increase in the proportion of relapsing–remitting MS patients who were disease-activity free versus placebo.

Immune Response to Seasonal Influenza Vaccine in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Long-term Daclizumab Beta

BACKGROUND For patients with relapsing-remitting multiple sclerosis (RRMS) undergoing continuous immunomodulatory therapy, understanding whether vaccinations can be performed safely and effectively is important. We tested the immune response to inactivated seasonal influenza vaccine during long-term daclizumab beta treatment. METHODS In this prospective, open-label, single-arm extension SELECTED study, an optional vaccine substudy was performed on patients with RRMS who had already received daclizumab beta for 1 to 2 years in previous studies. Patients were administered the seasonal vaccine as a single intramuscular dose containing three inactivated influenza virus strains: A/California/7/2009 (A/H1N1), A/Texas/50/2012 (A/H3N2), and B/Massachusetts/2/2012 (B). Endpoints included proportion of patients achieving seroprotection, proportion of patients who seroconverted, geometric mean titer ratio before and after vaccination, and adverse events reported during 28-day follow-up. RESULTS Ninety patients received the influenza vaccine (mean previous daclizumab beta exposure, 49.6 doses). Seroprotection (anti-hemagglutination immunoglobulin G titer ≥40) was detected in 92% (95% confidence interval [CI], 85%-97%) of patients for A/H1N1, 91% (83%-96%) for A/H3N2, and 67% (56%-76%) for B. The proportion of patients who seroconverted was 69% (95% CI, 58%-78%) for A/H1N1, 69% (58%-78%) for A/H3N2, and 44% (34%-55%) for B. The anti-hemagglutination immunoglobulin geometric mean titer ratio was 7.7 for A/H1N1, 9.0 for A/H3N2, and 4.3 for B. There were no significant adverse events considered related to vaccination during 28-day follow-up. CONCLUSIONS Patients with RRMS receiving long-term daclizumab beta treatment mounted an immune response to the seasonal influenza vaccine at levels considered to confer protection. No major or new safety issues were identified.

Identifying an important change estimate for the Multiple Sclerosis Walking Scale-12 (MSWS-12v1) for interpreting clinical trial results

Background The 12-question Multiple Sclerosis Walking Scale (MSWS-12v1) is a widely-used patient-reported outcome (PRO) measure of walking ability in multiple sclerosis (MS). Objective To estimate the magnitude of an important change in MSWS-12v1 scores for the interpretation of meaningful subject-level improvements across a 6-month trial of MS patients with walking disability. Methods MOBILE was a 6-month exploratory study assessing fampridine’s effect on walking ability in 132 people with MS. Three PRO measures assessed walking ability: MSWS-12v1, EuroQol 5-Dimension-5 Level (EQ-5D-5L) mobility question, and a patient global impression of change (PGIC) in overall walking ability. Pre-specified anchor- and distribution-based analyses estimated the MSWS-12v1 change scores representing an important change for participants. Results were triangulated to propose a single best value indicating meaningful improvement. Results Using baseline to week 2 through week 24 change scores, anchor-based analyses demonstrated mean and median improvements of 5.2–6.6 (PGIC) and 9.7–13.4 (EQ-5D-5L mobility) points on the MSWS-12v1, indicating meaningful improvements. The distribution-based estimate was 6.8 points. Triangulation across the results suggested an 8-point reduction in MSWS-12v1 score represents an important subject-level change in these participants. Conclusion In similar MS clinical trials, an 8-point improvement on the MSWS-12v1 is a reasonable estimate of meaningful improvement in walking ability.

Prolonged-release fampridine treatment improved subject-reported impact of multiple sclerosis: Item-level analysis of the MSIS-29

Prolonged-release (PR) fampridine is approved to treat walking impairment in persons with multiple sclerosis (MS); however, treatment benefits may extend beyond walking. MOBILE was a phase 2, 24-week, double-blind, placebo-controlled exploratory study to assess the impact of 10mg PR-fampridine twice daily versus placebo on several subject-assessed measures. This analysis evaluated the physical and psychological health outcomes of subjects with progressing or relapsing MS from individual items of the Multiple Sclerosis Impact Scale (MSIS-29). PR-fampridine treatment (n=68) resulted in greater improvements from baseline in the MSIS-29 physical (PHYS) and psychological (PSYCH) impact subscales, with differences of 89% and 148% in mean score reduction from baseline (n=64) at week 24 versus placebo, respectively. MSIS-29 item analysis showed that a higher percentage of PR-fampridine subjects had mean improvements in 16/20 PHYS and 6/9 PSYCH items versus placebo after 24weeks. Post hoc analysis of the 12-item Multiple Sclerosis Walking Scale (MSWS-12) improver population (≥8-point mean improvement) demonstrated differences in mean reductions from baseline of 97% and 111% in PR-fampridine MSIS-29 PHYS and PSYCH subscales versus the overall placebo group over 24weeks. A higher percentage of MSWS-12 improvers treated with PR-fampridine showed mean improvements in 20/20 PHYS and 8/9 PSYCH items versus placebo at 24weeks. In conclusion, PR-fampridine resulted in physical and psychological benefits versus placebo, sustained over 24weeks.