Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.

BACKGROUND: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR. METHODS: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients. RESULTS: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups. CONCLUSIONS: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/study/NCT03127514.

Eptinezumab treatment initiated during a migraine attack is associated with meaningful improvement in patient-reported outcome measures: secondary results from the randomized controlled RELIEF study.

BACKGROUND: Demonstrating therapeutic value from the patient perspective is important in patient-centered migraine management. The objective of this study was to investigate the impact of eptinezumab, a preventive migraine treatment, on patient-reported headache impact, acute medication optimization, and perception of disease change when initiated during a migraine attack. METHODS: RELIEF was a randomized, double-blind, placebo-controlled trial conducted between 2019 and 2020 in adults with ≥1-year history of migraine and 4-15 migraine days per month in the 3 months prior to screening. Patients were randomized (1:1) to a 30-min infusion of eptinezumab 100 mg or placebo within 1-6 h of a qualifying migraine attack onset. The 6-item Headache Impact Test (HIT-6) and 6-item Migraine Treatment Optimization Questionnaire (mTOQ-6) were administered at baseline and week 4, and the Patient Global Impression of Change (PGIC) at week 4. A post hoc analysis of these measures was conducted in patients who reported headache pain freedom at 2 h after infusion start. RESULTS: Of 480 patients enrolled and treated, 476 completed the study and are included in this analysis. Mean baseline HIT-6 total scores indicated severe headache impact (eptinezumab, 65.1; placebo, 64.8). At week 4, the eptinezumab-treated group demonstrated clinically meaningful improvement in HIT-6 total score compared with placebo (mean change from baseline: eptinezumab, - 8.7; placebo, - 4.5; mean [95% CI] difference from placebo: - 4.2 [- 5.75, - 2.63], P < .0001), with greater reductions in each item score vs placebo (P < .001 all comparisons). Change in HIT-6 total score in the subgroup with 2-h headache pain freedom was - 13.8 for the eptinezumab group compared with - 4.9 for the placebo group. mTOQ-6 total score mean change from baseline favored eptinezumab (change, 2.1) compared with placebo (1.2; mean [95% CI] difference: 0.9 [0.3, 1.5], P < .01). More eptinezumab-treated patients rated PGIC as much or very much improved than placebo patients (59.3% vs 25.9%). CONCLUSIONS: When administered during a migraine attack, eptinezumab significantly improved patient-reported outcomes after 4 weeks compared with placebo, with particularly pronounced effects in patients reporting headache pain freedom at 2 h after infusion start. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 . November 5, 2019.

Long-term safety and tolerability of eptinezumab in patients with chronic migraine: a 2-year, open-label, phase 3 trial.

BACKGROUND: Eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody recently approved in the United States for preventive treatment of migraine in adults, was found to be well tolerated in double-blind, placebo-controlled studies in patients with episodic and chronic migraine. The objective of the PREVAIL study was to evaluate the long-term safety, immunogenicity, and impact on patient-reported outcomes of repeat doses of eptinezumab in patients with chronic migraine. METHODS: PREVAIL was an open-label, phase 3 trial comprising a 48-week treatment phase followed by a second 48-week treatment phase. Adults with chronic migraine received eptinezumab 300 mg by 30-min intravenous administration every 12 weeks for up to 8 doses. Patients were followed for 20 weeks after the final infusion (end-of-study visit at week 104). RESULTS: Overall, 128 adults (mean age, 41.5 years) with chronic migraine were included. During the 2 years, the most frequently reported treatment-emergent adverse events were nasopharyngitis (14.1%), upper respiratory tract infection (7.8%), sinusitis (7.8%), influenza (6.3%), bronchitis (5.5%), and migraine (5.5%). The rate of study-drug discontinuation due to adverse events was 6.3%, which included 3 patients with infusion-related hypersensitivity. The incidence of anti-eptinezumab antibodies peaked at week 24 and declined despite continued dosing, to nondetectable levels at week 104. Improvements in patient-reported outcomes were observed at first assessment (week 4) and generally sustained through week 104. CONCLUSION: In adults with chronic migraine, eptinezumab 300 mg demonstrated a favorable safety profile, limited long-term immunogenicity, early and sustained reductions in migraine-related burden, and improvements in health-related quality of life over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02985398 ).

Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: Subgroup analysis of PROMISE-2.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH). BACKGROUND: Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. METHODS: PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled, phase 3 study that comprised a screening visit, a 28-day pretreatment period, and a 32-week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1-12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1-24. RESULTS: There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg (n = 139), 300 mg (n = 147), or placebo (n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1-12, eptinezumab-treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = -8.4, difference from placebo [95% confidence interval (CI)] = -3.0 [-4.56, -1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = -8.6, difference from placebo [95% CI] = -3.2 [-4.66, -1.78], p < 0.0001 vs. placebo; placebo, -5.4). Compared with placebo, more eptinezumab-treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1-12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24-week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo-treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication-overuse thresholds. CONCLUSIONS: In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

Preventive migraine treatment with eptinezumab reduced acute headache medication and headache frequency to below diagnostic thresholds in patients with chronic migraine and medication-overuse headache.

OBJECTIVE: This post hoc analysis in patients medically diagnosed with chronic migraine (CM) and medication-overuse headache (MOH) evaluated reductions in the use of acute headache medication (AHM) and sustained changes in the diagnostic status of CM and MOH following eptinezumab treatment in the PROMISE-2 study. BACKGROUND: Eptinezumab, a monoclonal antibody that inhibits calcitonin gene-related peptide, is approved in the United States for the preventive treatment of migraine. A previous analysis showed that eptinezumab reduced monthly migraine days and was well tolerated in the subgroup of PROMISE-2 patients diagnosed with both CM and MOH. METHODS: The phase 3, double-blind, placebo-controlled PROMISE-2 study (NCT02974153) randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo (administered intravenously every 12 weeks for up to two doses). MOH was prospectively diagnosed at screening by trained physicians based on 3 months of medication history and International Classification of Headache Disorders-3ß criteria. This post hoc analysis evaluated changes in total and class-specific days of AHM usage, the percentage of patients using AHM at or above MOH diagnostic thresholds, and the percentage of patients experiencing monthly headache and migraine day frequency below diagnostic thresholds for MOH and/or CM. RESULTS: In PROMISE-2, 431/1072 (40.2%) patients with CM were diagnosed with MOH (eptinezumab 100 mg, n = 139; 300 mg, n = 147; placebo, n = 145) and were included in this analysis. Total monthly AHM use decreased from 20.6 days/month at baseline to 10.6 days/month over 24 weeks of treatment (49% decrease) with eptinezumab 100 mg, from 20.7 to 10.5 days/month (49% decrease) with eptinezumab 300 mg, and from 19.8 to 14.0 days/month (29% decrease) with placebo. Numerically greater decreases from baseline with eptinezumab were also observed for individual drug classes. In each study month, the percentages of patients who were below MOH thresholds were numerically higher for both eptinezumab doses compared with placebo, as were the percentages of patients experiencing headache and migraine frequency below CM thresholds. Of patients with available data across the entire treatment period, 29.0% (58/200) of patients treated with eptinezumab stopped meeting and remained below diagnostic thresholds for both CM and MOH during Weeks 1-24, as well as 6.3% (6/96) of patients who received placebo. CONCLUSIONS: Across 24 weeks of treatment, eptinezumab reduced AHM use in patients diagnosed with CM and MOH. More than one-fourth (29%) of patients treated with eptinezumab did not meet the diagnostic thresholds for either CM or MOH for the entire treatment period.

Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial.

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion. Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack. Design, Setting, and Participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack. Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine. Main Outcomes and Measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours. Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred. Conclusions and Relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established. Trial Registration: ClinicalTrials.gov Identifier: NCT04152083.

Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials.

BACKGROUND: The humanized anti-CGRP monoclonal antibody eptinezumab has been evaluated in five large-scale clinical trials conducted in patients with migraine. This integrated analysis was conducted to evaluate the comprehensive safety and tolerability of eptinezumab in patients with migraine across these studies. METHODS: Data were pooled from four randomized, double-blind, placebo-controlled studies and the first year of one open-label study. RESULTS: The pooled population comprised 2867 adults with migraine: eptinezumab, n = 2076 (4797 infusions); placebo, n = 791 (1675 infusions). A total of 1137/2076 (54.8%) patients who received eptinezumab and 414/791 (52.3%) patients who received placebo experienced ≥1 treatment-emergent adverse event (TEAE); rates were similar across eptinezumab dose groups (10-1000 mg). For most patients with TEAEs, the events were mild or moderate in severity and considered unrelated to study drug by the investigators. Thirty infusion-site AEs occurred in 27/2076 (1.3%) patients who received eptinezumab and 7 in 7/791 (0.9%) patients who received placebo. Infusion-site AEs led to infusion interruption in 19/2076 (0.9%) and 5/791 (0.6%) patients in the eptinezumab and placebo groups, respectively. Nasopharyngitis occurred in ≥2% of patients in the eptinezumab 300-mg group and with an incidence of at least 2 percentage points greater than in the placebo group; however, in most patients (eptinezumab, 139/140; placebo 40/41), its occurrence was considered not related to study treatment. Adverse events coded to hypersensitivity occurred for 23/2076 (1.1%) patients treated with eptinezumab and no patients in the placebo group. If additional TEAE terms that could indicate hypersensitivity are considered (e.g., urticaria, flushing/hot flush, rash, and pruritus), hypersensitivity reactions in the two pivotal placebo-controlled phase 3 studies occurred in ≥2% of patients in the eptinezumab 100-mg and 300-mg groups, and the incidence was at least 2 percentage points greater in either of these groups than in the placebo group. Most hypersensitivity reactions were not serious and resolved with standard medical treatment or observation without treatment, usually within 1 day. CONCLUSIONS: In adults with migraine, the intravenous administration of eptinezumab every 12 weeks demonstrated a favorable safety and tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov (Identifiers: NCT01772524 , NCT02275117 , NCT02559895 , NCT02974153 , NCT02985398 ).

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.

Impact of Baseline Characteristics on the Efficacy and Safety of Eptinezumab in Patients With Migraine: Subgroup Analyses of PROMISE-1 and PROMISE-2.

PURPOSE: In the PROMISE-1 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1) and PROMISE-2 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2) clinical trials, eptinezumab 100 mg and 300 mg met the primary efficacy end point, significantly reducing mean monthly migraine days across weeks 1 to 12. Clinical efficacy was also shown across key secondary end points. However, to determine if clinical efficacy varies across subgroups, it is necessary to determine efficacy in patients with different sociodemographic features and headache characteristics. These post hoc analyses of patients in PROMISE-1 and PROMISE-2 evaluated the impact of intrinsic factors on the efficacy and safety of eptinezumab in subgroups defined according to baseline demographic and migraine disease characteristics. METHODS: PROMISE-1 and PROMISE-2 were Phase III, parallel-group, double-blind, randomized, placebo-controlled trials of repeat quarterly intravenous infusions of eptinezumab or placebo in adults with episodic (PROMISE-1) or chronic (PROMISE-2) migraine. FINDINGS: Demographic and baseline characteristics were similar across treatment groups in both the PROMISE-1 and the PROMISE-2 studies. Analyses did not show a clear pattern of baseline demographic characteristics driving treatment effects except for the obesity subgroups. For the ≥50% migraine responder rate in the obese class I (body mass index 30.0-35.0 kg/m2) subgroup, although separation from placebo was not as large (<10% separation compared with ≥10% separation across most baseline demographic factors), both doses showed improved ≥50% migraine responder rate compared with placebo, with slightly better results in patients receiving eptinezumab 300 mg. IMPLICATIONS: Eptinezumab treatment showed consistent clinically relevant reductions from baseline in mean monthly migraine days compared with placebo based on ≥50% migraine responder rate across clinically important intrinsic subgroups of adults with episodic or chronic migraine. CLINICALTRIALS: gov identifiers: NCT02559895 (PROMISE-1) and NCT02974153 (PROMISE-2).

A randomized trial of memantine as treatment for spasticity in multiple sclerosis.

We report the results of a single center randomized, double-blind, placebo-controlled, parallel group trial of memantine in adults with multiple sclerosis and spasticity conducted over 12 weeks. Eligible MS patients had to have an Ashworth spasticity rating of 2 or higher in at least one lower extremity muscle group. Subjects were randomized to receive either placebo or memantine 10 mg twice a day. The primary outcome measure for efficacy was the change in Ashworth Spasticity Scale Score. Although well tolerated, memantine treatment did not demonstrate efficacy in treatment of spasticity in this 12-week small exploratory study.

Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension.

OBJECTIVE: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis. METHODS: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-ß-1a (44 µg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed. RESULTS: Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-ß-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-ß-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-ß-1a (-1.87% vs -2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment. CONCLUSION: Compared with patients switching from IFN-ß-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-ß-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE. CLINICAL TRIAL IDENTIFIERS: NCT01247324/NCT01412333.

Polyunsaturated fatty acids and their potential therapeutic role in multiple sclerosis.

Considerable interest has been shown in the potential anti-inflammatory effects of polyunsaturated fatty acids (PUFAs) in multiple sclerosis (MS) and other autoimmune inflammatory disorders. Studies suggest a modest association between consumption of low levels of unsaturated fat and an increased incidence of MS. Moreover, in vitro and in vivo studies have demonstrated that omega-3 and omega-6 PUFA supplementation can reduce immune-cell activation via a number of complex pathways. Noncontrolled and controlled clinical trials of PUFA supplementation in patients with MS have, however, provided mixed results. These studies had important limitations in design and selection of outcome measures, and these factors might partially explain the inconsistent results. We propose that the potential role of PUFAs as disease-modifying, anti-inflammatory treatments for MS should be revisited in proof-of-concept trials that use accepted MRI outcome measures.

Immune Response to Seasonal Influenza Vaccine in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Long-term Daclizumab Beta: A Prospective, Open-Label, Single-Arm Study.

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.

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 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.

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.

Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis.

Patients with highly active relapsing-remitting multiple sclerosis (RRMS) are at greater risk for disease progression and may respond differently to MS therapeutics than those with less active disease. The current post hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in patients with highly active RRMS in the SELECT study. Highly active RRMS was defined as patients with ≥2 relapses in the year before randomization and ≥1 gadolinium-enhancing (Gd(+)) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis. Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS patients. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p < 0.0001) groups vs. placebo, respectively (interaction p = 0.82). DAC HYP reduced new/newly-enlarging T2 lesions (highly active RRMS 76 % reduction, p < 0.0001; less active RRMS 73 % reduction, p < 0.0001; interaction p = 0.18), the risk of having more Gd(+) lesions (highly active RRMS 89 % reduction, p < 0.0001; less active RRMS 86 % reduction, p < 0.0001; interaction p = 0.46), and sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo. DAC HYP efficacy was similar across the spectrum of MS disease activity as assessed prior to treatment initiation.

The syndrome of delayed post-hypoxic leukoencephalopathy.

Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome characterized by acute onset of neuropsychiatric symptoms days to weeks following apparent recovery from coma after a period of prolonged cerebral hypo-oxygenation. It is diagnosed, after excluding other potential causes of delirium, with a clinical history of carbon monoxide poisoning, narcotic overdose, myocardial infarction, or another global cerebral hypoxic event. The diagnosis can be supported by neuroimaging evidence of diffuse hemispheric demyelination sparing cerebellar and brainstem tracts, or by an elevated cerebrospinal fluid myelin basic protein. Standard or hyperbaric oxygen following CO poisoning may reduce the likelihood of DPHL or other neurologic sequelae. Bed rest and avoidance of stressful procedures for the first 10 days following any prolonged hypoxic event may also lower the risk. Gradual recovery over a 3 to 12 month period is common, but impaired attention or executive function, parkinsonism, or corticospinal tract signs can persist. Stimulants, amantadine or levodopa may be considered for lasting cognitive or parkinsonian symptoms. Anticipation and recognition of DPHL should lead to earlier and more appropriate utilization of health care services.