PracticeUpdate Conference Series - ANZAN 2018

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AUSTRALIAN & NEW ZEALAND ASSOCIATION OF NEUROLOGISTS ANNUAL SCIENTIFIC MEETING 29 MAY–1 JUNE 2018 • DARWIN, AUSTRALIA

THE BEST OF ANZAN 2018 Recurrent Untreated Seizures Often Exhibit Subtler Semiology and More Likely to Exhibit Normal MRI and EEG Results Than New-Onset Seizures • Peginterferon ß-1a Improves Clinical and Radiological Outcomes of Patients Newly Diagnosed With RRMS • A Hyperdirect Pathway Generates Doorway Freezing in Parkinson’s Disease • Results of Three Studies on Timely Thrombolysis Point to Improved Stroke Care

The production and distribution of this publication is sponsored by Sanofi Genzyme.

DYSPHAGIA 1

MUSCLE PAIN 1

PROXIMAL MUSCLE WEAKNESS 1

RESPIRATORY INSUFFICIENCY 1

EXERCISE INTOLERANCE 3

FATIGUE 3

GAIT ABNORMALITIES 1

UNKNOWN CAUSE OF HYPERCKEMIA 2

FREQUENT FALLS 1

IT’S NOT IN YOUR PATIENT’S HEAD

SLEEP APNOEA 3

IT’S IN THEIR MUSCLES

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For more information on Pompe Disease, please visit: https://sanofigenzymeonline.com.au/pompe-disease References: 1. Kishnani PS, et al. Gen Med 2006; 8: 267–88. 2. Lukacs Z, et al. Neurology 2016; 87: 295–8. 3. Chan J, et al. Mol Genet Metab 2017; 120:163–72. 4. American Association of Neuromuscular & Electrodiagnostic Medicine. Muscle Nerve 2009; 40: 149–60. sanofi-aventis Australia pty ltd trading as Sanofi Genzyme ABN 31 008 558 807.Talavera Corporate Centre,Building D, 12–24 Talavera Road,Macquarie Park,NSW 2113.GZANZ.MYOZ.16.08.0142a.Date of Preparation March 2018.AM7338.

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Contents

ANZAN 2018 • 29 May–1 June 2018, Darwin, Northern Territory, Australia BY THE PRACTICEUPDATE EDITORIAL TEAM

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4 Recurrent Untreated Seizures Often Exhibit Subtler Semiology and More Likely to Exhibit Normal MRI and EEG Results Than New-Onset Seizures 6 Natalizumab Reduces Disease Activity More Than and Faster Than Fingolimod in Patients With Active RRMS 10 Ocrelizumab Reduces Progression of Disability Independent of Relapse Activity in Relapsing MS 12 Better Screening for Atrial Fibrillation Needed in Patients Who Present With TIA/Stroke 12 Peginterferon ß-1a Improves Clinical and Radiological Outcomes of Patients Newly Diagnosed With RRMS

14 Efficacy of Alemtuzumab for Active RRMS is Maintained for 7 Years, in the Absence of Continuous Treatment 16 Perampanel Demonstrates Sustained Long-Term Efficacy Against Secondarily Generalized Seizures and Safety in Idiopathic Generalized Epilepsy 18 A Hyperdirect Pathway Generates Doorway Freezing in Parkinson’s Disease 20 Results of Three Studies on Timely Thrombolysis Point to Improved Stroke Care 22 CTA Spot Sign Fails to Predict Expansion of Spontaneous Intracerebral Hemorrhage

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Recurrent Untreated Seizures Often Exhibit Subtler Semiology and More Likely to Exhibit Normal MRI and EEG Results Than New-Onset Seizures Recurrent untreated seizures have been found to often exhibit subtler semiology and are more likely to exhibit normal MRI and EEG results than new-onset seizures, finds a retrospective chart review.

E mma J. Foster, MBBS (Hons) and Sarah J. Holper, MBBS (Hons), of the Royal Melbourne Hospital in Victoria, explained that diagnosis of a first seizure may be delayed due to financial, geographical, or social barriers to healthcare ser- vices, or to misdiagnosis with other disorders, such as syncope or stroke. Patrick Kwan, FRACP, PhD, also of the Royal Melbourne Hospital, participated in the chart review as well. “Seizures are a common neurological presentation in both community and hospital settings,” Dr. Foster told Elsevier’s PracticeUpdate . “It is likely that new-onset or newly diagnosed seizures occur- ring in the community and during hospitalization for other illnesses have different etiologies and prognoses, and thus require different investigation and treatment approaches.” She continued, “Previous studies have tended to investigate these cohorts separately, but direct com- parison of patient characteristics between these studies is difficult because of varying study settings.” “Within the same hospital,” she said, “we compared the clinical presentation and management of new-onset and newly diagnosed seizures in two cohorts: (1) patients who experienced a new-onset or newly diagnosed seizure in the community and presented to the emergency department, and (2) those admitted for an unrelated illness who expe- rienced a new-onset or newly diagnosed seizure in the hospital ward.” Medical charts were reviewed and information extracted on patient demographics and clinical characteristics. Inclusion criteria were age ≥18

years and attendance at a tertiary-level hospital in Melbourne between 2008 and 2016 with dis- charge codes ICD-10 G40 epilepsy, G41 status epilepticus, or R56.9 unspecified convulsions. A total of 367 episodes were identified, of which 151 met inclusion criteria (n=115 new-onset seizures; n=36 recurrent, untreated seizures). A total of 216 cases were excluded (n=186 preexist- ing epilepsy; n=30 nonseizure events). The cohort with recurrent, untreated seizes experienced a median of 2 seizures prior to receiving medical attention. Most of these were focal impaired-awareness seizures (50.00%). Focal seizures were more com- mon index seizures in the cohort with recurrent, untreated seizures (36.11% vs 24.35%). Primary generalized seizures predominated in the cohort with new-onset seizures (62.61% vs 50.00%). Compared with the cohort with new-onset seizures, the cohort with recurrent, untreated seizures was more likely to have suffered unprovoked seizures (72.22% vs 55.65%), to carry identifiable remote risk factors (41.67% vs 26.09%), to be younger (69 vs 76 years of age), to exhibit normal MRI and EEG, to be discharged with antiepileptic drugs (86.11% vs 73.91%), and to be followed by a neurologist (72.22% vs 39.99%). Follow-up was more timely than in the cohort with new-onset seizures. In fact, 30.56% vs 11.31% saw a neurologist within 1 month of discharge. “Our study revealed,” Dr. Foster said, “an older cohort than previously reported (median age 74 years),

Dr. Emma J. Foster

Dr. Sarah J. Holper

Dr. Patrick Kwan

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seizure etiology and management strat- egies in this demographic. This retrospective chart review included patients age ≥18 with a hospital separa- tion coded as ICD-10 G40 (epilepsy), G41 (status epilepticus), or R56.9 (convulsions not otherwise specified) who presented from 2008–2016 at a large metropolitan private hospital. A total of 97 episodes of emergency department attendance for a first seizure and 54 episodes of hospital-onset sei- zures were identified. Median patient age was 70 years in the community-onset seizure cohort and 80.5 years in the cohort with hospital-onset seizures. Symptomatic seizure risk factors were identified in 26.8% of the community- onset seizure cohort and 63.0% of the cohort with hospital-onset seizures. These factors included exposure to known proconvulsant drugs in 38.89% of the cohort with hospital-onset seizures. Antiepileptic drugs were prescribed on discharge to 74.2%of the community-onset seizure cohort and 81.5% of the cohort with hospital-onset seizures. Far fewer patients received a scheduled review by a neurologist (58.8% of the community-onset seizure cohort and 35.2% of the cohort with hospital-onset seizures). Dr. Foster concluded that more older patients than usually reported was stud- ied, providing important insights into seizure etiology and management strat- egies in this demographic. “We found that patients with recurrent untreated seizures often exhibited subtler seizure semiology and were more likely to exhibit normal MRI and EEG results than those presenting immediately following new-onset seizures,” she said. “Clinicians should be mindful of these differences. Caution is needed when prescribing known proconvulsant drugs, especially tranexamic acid, and physicians should be mindful of their prescription of antiep- ileptic drugs on discharge.” Adequate follow-up with a neurologist is needed to monitor further seizure activ- ity, address risk factors for seizures, and assess any ongoing need for an antiep- ileptic drug. She added, “Future studies will review mortality and morbidity in cohorts with a first seizure, with a view toward identifying areas for improvement in assessment and management of a first seizure.”

with significantly more provoked seizures occurring in the hospital. Exposure to proconvulsant drugs, tranexamic acid in particular, was a major risk factor.” She continued, “We also noted variation from International League Against Epilepsy diagnostic criteria for epilepsy regarding the decision to prescribe antiepileptic therapy. This variation reflected the complex nature of seizures, epilepsy, and the importance of tailoring treatment to individual patients.” Drs. Foster and Holper concluded that patients with recurrent, untreated seizures often exhibit subtler semiology and are more likely to exhibit normal MRI and EEG results than those presenting immediately following new-onset seizures. The cohort with recurrent, untreated sei- zures tended to receive more inpatient investigations and antiepileptic drug pre- scriptions, and was offered more timely neurology follow-up than the cohort with new-onset seizures. “Results showed,” Dr. Foster stated, “that community-onset seizures were more likely to be unprovoked, and hospital- onset seizures, more likely to be provoked, mostly from exposure to proconvulsant drugs.” She added, “This pilot study provided val- uable information on the current paradigm of management of a first seizure. The

results have laid a foundation for more extensive studies into morbidity and mor- tality of patients with first seizures, as well as assessment and management of first seizures in the emergency department.” “We further analyzed patient and clinical characteristics of the cohort of patients with a first-ever seizure vs the cohort with recurrent untreated seizures,” Dr. Foster explained. Drs. Foster, Holper, and Kwan charac- terized first seizures in the emergency department vs the ward in elderly patients. Dr. Foster explained that seizures are common in hospitals, as either presenta- tions to emergency departments or as hospital-onset seizures. The latter occur in ward patients hospitalized for illnesses unrelated to seizures. Prompt identifi- cation of seizure etiology is important because identification affects prognosis and management choices. Acute symptomatic seizures due to acute disturbance of brain function are far less likely to recur than unprovoked seizures. Through timely investigation and spe- cialist review, individual risk of seizure recurrence is assessed. Such assessment then guides therapeu- tic decisions including antiepileptic drug choice. The present study included more older patients than usually reported. As such, it provided important insights into

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Natalizumab Reduces Disease Activity More Than and Faster Than Fingolimod in Patients With Active RRMS

Natalizumab has been found to reduce disease activity more than, and to a greater extent than fingolimod in patients with active relapsing-remitting multiple sclerosis (RRMS), reports the randomized head-to-head REVEAL trial. Other research presented on natalizumab included the outcomes of patients who remained on the drug vs those who switched off it, measures to reduce adverse events, and experience with home infusion. H elmut Butzkueven, MD, of Monash University in Box Hill, Victoria, explained that REVEAL was designed as a 1-year, multicenter, rand- (cumulative gadolinium-enhancing lesions over time).

As expected for a randomized study, patient characteristics and follow-up duration (median 39 weeks) were similar between groups. Natalizumab patients were less likely than those taking fingolimod to develop new gadolinium- enhancing lesions (for at least one lesion, cumulative probability 40.68% vs 57.99%; hazard ratio [HR] 1.678 [95% CI 0.865–3.255]; P = .1258; for at least two lesions, cumulative probability 11.54% vs 48.48%; HR 4.053 [95% CI 1.474–11.144]; P = .007). Consistently, natalizumab patients exhibited 63–72% fewer gadolinium-enhancing lesions than fingolimod patients, with between-group dif- ferences apparent within 4 weeks and reaching significance by 12 weeks (P = .030). The annualized relapse rate was 83% lower with natalizumab than with fingolimod (0.05 vs 0.29; P = .023). The cumulative probability of relapse was 1.85% with natalizumab vs 22.28% with fingolimod

omized, rater- and sponsor-blinded, prospective comparison of natalizumab vs fingolimod in patients with active RRMS. Though the study closed early for reasons unre- lated to safety or efficacy, the data permitted comparison of effects that occurred soon after treatment initiation. The analysis compared onset of efficacy with natalizumab vs fingolimod. Patients were randomized to open-label intrave- nous natalizumab 300 mg every 4 weeks (n=54) or oral fingolimod 0.5 mg once daily (n=54). MRI was scheduled every 4 weeks for the first 24 weeks and at weeks 36 and 52. Analyses included Kaplan-Meier and Cox regression, negative binomial regression (annualized relapse rate), the number of T1 gadolinium-enhancing lesions, and a negative binomial generalized estimating equation

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" …staying on natalizumab longer than 2 years yielded better clinical outcomes than switching to oral or injectable therapies. "

(HR 12.184 [95% CI 1.552–95.634]; P = .017). Adverse events were consistent with known safety profiles. Dr. Butzkueven concluded that the results sug- gested that natalizumab reduces disease activity more rapidly and to a greater extent than fingoli- mod in patients with active RRMS. Given the early study closure, available data did not permit primary endpoint evaluation. Interpretation of these results requires caution. Dr. Butzkueven and colleagues then set out to com- pare clinical outcomes of patients with RRMS who remained on natalizumab vs those who switched to oral or injectable therapies after 2 years in the Tysabri® Observational Program. Dr. Butzkueven explained that natalizumab is a high-efficacy therapy for RRMS, and data on post-natalizumab disease activity may be important. Dr. Butzkueven and colleagues compared outcomes in patients who switched to an oral or injectable therapy vs those in patients who remained on natalizumab. They analyzed post-natalizumab relapse predic- tors using data from the Tysabri® Observational Program, an ongoing 10-year observational study of patients with RRMS who were treated with natalizumab.

Data were analyzed for patients who stayed on natalizumab (≥3 years natalizumab and only natal- izumab during follow-up; n=2466; mean time on natalizumab 5.5 years). The comparison group switched to oral (n=660) or injectable (n=95) therapies for at least 1 year after ≥2 years on natalizumab (mean post-natalizumab follow-up duration 2.5 vs 2.4 years). Annualized relapse rates and risk of Expanded Disability Status Scale (EDSS) score worsening were evaluated. Disease activity predictors were compared using adjusted Cox models. Relapse risk was higher for oral switchers (HR 2.18; P < .001) or injectable switchers (HR 3.02; P < .001) than for patients who remained on natalizumab for over 2 years. Risk of EDSS score worsening was similar for oral (HR 1.19) and higher for injectable (HR 2.52; P < .001) switchers than for patients who stayed on natalizumab.

Continued on page 8

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Continued from page 7 Natalizumab Reduces Disease Activity More Than and Faster Than Fingolimod in Patients With Active RRMS

Annualized relapse rates decreased by 20.2% after 2 years in patients who stayed on natalizumab but increased from on-natalizumab rates by 17.8% in oral switchers (P < .001) and 108.1% in injectable switchers (P < .001). In oral switchers, shorter washout time was predic- tive of lower relapse risk (>12 vs ≤4 weeks; HR 2.03; P < .001), fewer prenatalizumab relapses (HR 1.24/ relapse in the prior year; P < .001), lower baseline EDSS score (>3.5 vs ≤3.5; HR 1.44; P = .007), and longer natalizumab duration (>3 vs ≤3 years; HR 0.76; P = .040). Dr. Butzkueven concluded that staying on natali- zumab longer than 2 years yielded better clinical outcomes than switching to oral or injectable ther- apies. Among those who discontinued natalizumab, switching to oral vs injectable therapy yielded better outcomes. Washout time, prenatalizumab relapses, EDSS score, and time on natalizumab were predictive of risk of disease activity in oral switchers. Lana Zhovtis Ryerson, MD, of New York University, and colleagues set out to evaluate extended interval dosing of natalizumab to reduce risk of progressive multifocal leukoencephalopathy (PML) vs standard interval dosing in the TOUCH® Prescribing Program. Dr. Zhovtis Ryerson explained that natalizumab, approved for 300 mg dosed intravenously every 4 weeks, is associated with risk of PML. Prior studies have been inconclusive regarding the impact of extended interval dosing on the risk of PML. The US Risk Evaluation and Mitigation Strategy program (TOUCH) offers the largest data source that can inform on risk of PML in patients receiving extended interval dosing. Dr. Zhovtis Ryerson and colleagues looked to determine whether natalizumab extended interval dosing is associated with reduced risk of PML vs standard interval dosing. The investigators finalized the statistical analysis plan while blinded to events related to PML. “My colleagues and I,” Dr. Zhovtis Ryerson told Elsevier’s PracticeUpdate , “have been working on evaluating extended interval dosing of natalizumab for many years, hoping that this approach can opti- mize this excellent drug in terms of reducing risk of progressive multifocal leukoencephalopathy while maintaining efficacy.” She continued, “Our team carried out a retrospec- tive review in 2016. Results suggested that the

efficacy of extended interval dosing of natalizumab may be maintained. Risk of progressive multifocal leukoencephalopathy, however, could not be esti- mated since it is such a rare event.” She noted, “Collaborating with Biogen to assess data in the TOUCH database gave us the best opportunity to determine whether risk of progres- sive multifocal leukoencephalopathy is reduced using this approach. The optimal extended interval dosing schedule is not known, and we wanted to avoid considering patients with poor compliance as receiving the extended interval dosing.” “We developed three vigorous definitions to capture patients who were utilizing the extended interval dosing schedule. We hoped to see a difference in even one of the definitions.” Average dosing intervals were ≥3 to <5 weeks for standard interval dosing and >5 to ≤12 weeks for extended interval dosing. The primary analysis assessed average dosing intervals during the last 18 months of infusion. The secondary analysis iden- tified any prolonged period of extended interval dosing at any during infusion. The tertiary analysis assessed average dosing intervals over the full infusion history. Only anti-John Cunningham virus antibody-positive patients with dosing intervals ≥3 to ≤12 weeks were included. Hazard ratios for PML were compared using adjusted Cox regression models and Kaplan-Meier estimates. The analyses included 13,132 patients who received standard interval dosing and 1988 who received extended interval dosing (primary), 15,424 patients who received standard interval dosing and 3331 who received extended interval dosing (second- ary), and 23,168 patients who received standard interval dosing and 815 who received extended interval dosing (tertiary). In primary analyses, average dosing interval was 30 days for standard and 37 days for extended interval dosing. Median exposure was 44 months for standard and 59 for extended interval dosing. Most patients who received extended interval dos- ing received >2 years of standard interval dosing prior to extended interval dosing. The hazard ratio for PML (95% CI) was 0.06 (0.01– 0.22; P < .001) for the primary and 0.12 (0.05–0.29; P < .001) for the secondary analysis (both favored extended interval dosing). No cases of PML were observed with extended interval dosing in tertiary analyses (Kaplan-Meier log-rank test P = .02).

Dr. Lana Zhovtis Ryerson

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" We were all very pleasantly surprised … to observe such a robust reduction in risk of progressive multifocal leukoencephalopathy across all three definitions. Since efficacy is not captured by the TOUCH database, the next step will be to evaluate the efficacy of extended interval dosing of natalizumab. "

Dr. Zhovtis Ryerson concluded that in patients with John Cunningham virus antibody-positive MS, natalizumab extended interval dosing was asso- ciated with a clinically and statistically significant reduction in risk of PML vs standard interval dosing. “We were all very pleasantly surprised,” Dr. Zhovtis Ryerson said, “to observe such a robust reduction in risk of progressive multifocal leukoencephalop- athy across all three definitions. Since efficacy is not captured by the TOUCH database, the next step will be to evaluate the efficacy of extended interval dosing of natalizumab.” Tim Schultz, PhD, of the University of Adelaide in South Australia, and colleagues set out to evaluate home infusion of natalizumab. He explained that for peoplewithMS, monthly infusions at specialist clinics are time-consuming, potentially costly, and restrictive. Conversely, increased demand for hospital services drives innovation, including home delivery of care. Dr. Schultz and colleagues developed a rigorous model of care for home infusions of natalizumab and evaluated it in a randomized crossover trial. The pilot study tested the feasibility and safety of home infusions and compared the acceptability and clinical effectiveness vs usual clinic-based care in a hospital outpatient clinic. Thirty-seven stable adult patients were recruited who had received at least 6 prior natalizumab infusions and were assessed as safe by their neurologist. They were randomized to home or clinic-based infusions. After 3 infusions, patients crossed over to the alternate treatment for another 3 infusions. Treatment adherence, patient safety outcomes, quality of life (Multiple Sclerosis Quality of Life Inventory), and patient satisfaction were assessed.

A total of 2 patients moved out of Adelaide and withdrew. No adverse events were reported with either home or clinic infusion. No difference was observed in the adherence rate (86/104, 82.7% at home) and (84/103, 81.6% at clinic) (X 2 = 0.0), nor in the number of infections during home care (n=8) vs the clinic (n=10) (X 2 = 0.04). No difference was observed in any of the nine subscales of the Multiple Sclerosis Quality of Life Inventory. Of the four subscales of the Treatment Satisfaction Questionnaire for Medication (effec- tiveness, side effects, convenience, global satisfaction); patients who had most recently received home care were significantly more satisfied with the convenience of their treatment (P = .0008). Dr. Schultz concluded that the results suggested that delivery of infusions of natalizumab at home was feasible, safe, and as effective as in the hos- pital. Patients reported home infusions to be more convenient than those in the clinic.

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Ocrelizumab Reduces Progression of Disability Independent of Relapse Activity in Relapsing MS

Ocrelizumab has been shown to reduce progression of disability in relapsing multiple sclerosis (MS) significantly vs interferon β -1a, more in patients at higher risk of secondary progressive disease, reports phase I/II OPERA trial.

L udwig Kappos, MD, of University Hospital Basel in Switzerland, explained that ocrelizumab showed superior efficacy vs interferon β-1a in the OPERA 1/2 trials in relapsing MS. Confirmed disability progression based on a com- posite of the Expanded Disability Status Scale (EDSS), timed 25-foot walk, and 9-hole peg test may characterize aspects of disability progression better than the EDSS alone. The composite has demonstrated improved sensitivity for assessing progression in secondary progressive MS. Patients with relapsing MS, including those with relapsing secondary progressive disease in OPERA 1/2, received IV ocrelizumab 600 mg (every 24 weeks) or subcutaneous interferon β-1a 44 μg (3 times weekly) for 96 weeks. Composite confirmed disability progression was defined as disability progression measured by the EDSS score (increase ≥1.0 or 0.5 if baseline >5.5) or ≥20% increase in timed 25-foot walk or ≥20% increase in the 9-hole peg test, confirmed after ≥12/≥24 weeks. Definition 1 of composite confirmed disability progression independent of relapse activity was reference EDSS score/timed 25-foot walk/nine- hole peg test was re-baselined at the first available assessment ≥30 days, after each relapse, without relapse between baseline and initial progression of disability, and within 30 days post initial progression

of disability and 30 days prior to confirmation of initial progression of disability. Definition 2 was a period of no relapse for 30 days post confirmation of initial progression of disability. Subgroup analysis included patients at potentially higher risk of secondary progressive MS based on baseline EDSS score ≥4.0 and pyramidal Kurtzke Functional Systems Score ≥2. In the pooled intent-to-treat cohort (n=1656), risk reduction (ocrelizumab vs interferon β-1a) for 12 to 24-week composite confirmed disability progres- sion was 34% (30.7% vs 21.5%; P < .001) and 31% (22.6% vs 16.1%; P = .002). Risk ratios for the 12–24-week composite con- firmed disability progression independent of relapse activity for definition 1 were 24% (25.4% vs 19.6%; P = .010) and 22% (19.2% vs 14.9%; P = .046). Risk ratios for the 12 to 24-week composite confirmed disability progression independent of relapse activity for definition 2 were 25% (25.4% vs 19.5%; P = .008) and 23% (19.2% vs 14.8%; P = .039). In the subgroup at higher risk of secondary pro- gressive MS, 12 to 24-week risk ratios for composite confirmed disability progression independent of relapse activity (definition 2) were 40% (31.2% vs 19.1%; P = .022) and 36% (26.9% vs 16.6%; P = .064). All composite confirmed disability progression independent of relapse activity components in the intent-to-treat and subgroups followed similar trends.

Dr. Edward J. Fox

PRACTICEUPDATE CONFERENCE SERIES • ANZAN 2018 10

The hand with lower baseline time was termed the better hand, and the hand with higher baseline time was termed the worse hand. Average dominant and nondominant hand times were combined and termed both hands. Analyses included time-to-confirmed progression in hand func- tion, defined as ≥15%, ≥20%, or ≥25% increase in 9-hole peg test time from baseline, confirmed at 12 and 24 weeks, and change in 9-hole peg test time from baseline to week 120. Compared with placebo, ocrelizumab reduced the time to 12- and 24-week confirmed progression of ≥15% increase in nine-hole peg test time by: ƒ ƒ 37% (HR 0.627; P = .001) and 39% (HR 0.607; P = .002), respectively, for both hands ƒ ƒ 30% (HR 0.699; P = .011) and 40% (HR 0.599; P < .001), respectively, for the better hand ƒ ƒ 29% (HR 0.705; P = .016) and 28% (HR 0.717; P = .040), respectively, for the worse hand Time to 12- and 24 week confirmed progression of ≥20% increase in nine-hole peg test time was reduced by: ƒ ƒ 44% (HR 0.561; P < .001) and 45% (HR 0.545; P < .001), respectively for both hands ƒ ƒ 28% (HR 0.723; P =.046) and 35% (HR 0.646; P = .014), respectively, for the better hand ƒ ƒ 37% (HR 0.632; P = .005) and 40% (HR 0.599; P = .004), respectively, for the worse hand Ocrelizumab also reduced the time to 12- and 24-week con- firmed progression of a ≥25% increase in nine-hole peg test time by: ƒ ƒ 48% (HR 0.520; P < .001) and 49% (HR 0.507; P < .001), respectively, for both hands ƒ ƒ 30% (HR 0.698; P = .048), and 39% (HR 0.613; P = .015), respectively, for the better hand ƒ ƒ 48% (HR 0.521; P < .001) and 42% (HR 0.578; P = .004), respectively, for the worse hand At week 120, the increase from baseline 9-hole peg test time for both hands and the worse hand was significantly smaller with ocrelizumab than with placebo (P < .001 and P = .041, respectively). For the better hand, the increase was smaller with ocrelizumab (difference not significant). Dr. Fox concluded that ocrelizumab treatment lowered the risk of progression of upper extremity disability as measured by 9-hole peg test time vs placebo in patients with primary progressive MS. “Our assessment of this data set,” he said, “was that a clear ben- efit could be seen with ocrelizumab treatment in maintaining upper extremity function. The reason for the multiple data points was that it was important to look at each arm independently, since multiple sclerosis is often asymmetric.” He continued, “Better and worse arms were identified and followed over the course of the trial, and multiple degrees of worsening were looked at independently to be more certain of the clinical significance of the findings.” He added, “We recommend that ocrelizumab and other agents be evaluated further with these endpoints in mind. Such assess- ments may yield important information about the prevention of disability caused by upper limb impairment.”

Dr. Kappos concluded that ocrelizumab was shown to reduce progression of disability significantly vs interferon β-1a in the OPERA intent-to-treat population of patients with relapsing MS, more in the subgroup at higher risk of secondary progressive disease. The results showed that considerable disability progression in relapsing MS occurs independently of protocol-defined relapses. Edward J. Fox, MD, PhD, of Central Texas Neurology Consultants in Round Rock, Texas, and colleagues set out to evaluate the effect of ocrelizumab on upper limb function in patients with primary progressive multiple sclerosis in the ORATORIO study (Encore). Dr. Fox told Elsevier’s PracticeUpdate , “The post hoc analysis of the ORATORIO trial is an important piece of information for clinicians and for patients with primary progressive multiple scle- rosis because it explores the effects of ocrelizumab on upper extremity function.” He continued, “The substantial relevance of losing arm and hand dexterity as a part of primary progressive multiple sclerosis is well accepted, but rarely has any data been presented on the impact of treatment on this symptom.” Dr. Fox explained that functional impairment of the upper limb is prevalent among patients with primary progressive MS. Such impairment alters quality of life. The nine-hole peg test is a validated quantitative assessment of upper limb function in multiple sclerosis. The test was administered at baseline and every 12 weeks until study end. The team compared average nine-hole peg test times from two trials of dominant and nondominant hands.

www.practiceupdate.com/c/68170

ANZAN 2018 • PRACTICEUPDATE CONFERENCE SERIES 11

Better Screening for Atrial Fibrillation Needed in PatientsWho PresentWithTIA/Stroke Anticoagulant use among patients who present with transient ischemic attack (TIA) or stroke remains inadequate. Improved screening for atrial fibrillation in patients presenting with TIA or stroke is needed, results of a retrospective chart review show. Z ainab Khan, MD, of Western Sydney University in Penrith, NSW, explained that atrial fibrillation raises risk of

Known atrial fibrillation occurred in 34 (82.9%) stroke admissions and 8 (100%) admissions for TIA. Therefore, atrial fibril- lation was diagnosed post stroke in 17.1% of participants. Prior to stroke and TIA, 61.9% of patients were receiving anticoagulants. Treatment prior to stroke or TIA consisted of 11 (26.2%) on direct oral anticoagulants, 15 (35.7%) on warfarin, 5 (11.9%) on antiplate- lets, and 11 (26.2%) with no antithrombotics. Subtherapeutic international normalized ratios (<2.0) on admission were found in 60% of participants receiving warfarin. Among the 11 untreated patients, one was noncompliant, one had experienced recent subarachnoid hemorrhage, and no explanation was found for the remaining 9 participants. Anticoagulation rates improved on discharge with 40 (81.6%) patients prescribed either direct oral anti- coagulants or warfarin.

Dr. Khan concluded that anticoagulation rates have improved since 2009 (61.9% vs 41%) in stroke/TIA admissions associated with atrial fibrillation. Use of anticoagulants in this population remains inadequate, however. Of patients on warfarin, 60% exhibited subtherapeutic international normalized ratios on admission. A need remains for improved screening for atrial fibrillation. Only a slight decrease in rates of new diagnosis of atrial fibrilla- tion was observed vs the 2009 audit (from 22% to 17.1%). Detection of atrial fibrillation in patients with cryptogenic stroke using an insert- able cardiac monitor was evaluated in terms of cost-effectiveness. Vincent Thijs, MD, of the Florey Institute of Neuroscience andMental Health, University of Melbourne, Victoria, explained that atrial fibrillation needs to be detected prior to Annualized relapse rate, time to first relapse, 24-week confirmed disability worsening, MRI endpoints, and safety were compared between the every-2- week group vs the delayed-treatment group. Over 2 years, the adjusted annualized relapse rate in newly diagnosed patients was 32.3% lower in the peginterferon ß-1a every-2-week group (n=231) than in the delayed-treatment group (n=229; P = .0352). Time to first relapse was longer in the every- 2-week group than in thedelayed-treatment group (P = .0101). The rate of 24-week con- firmed disability worseningwas numerically lower in the every-2-week than in the delayed-treatment group. At year 2, the number of new/newly enhancing T2 lesions was lower in the every-2-week than in the delayed- treatment group (P < .0001), though no difference in the number of gadolinium- enhancing lesions was observed.

potentially fatal or disabling ischemic stroke. Under 70% of eligible patients with atrial fibrillation have been noted to take oral anticoagulants. Dr. Khan and colleagues reviewed med- ical records of patients admitted with stroke/TIA associated with a known or new diagnosis of atrial fibrillation from 2016 to 2017. The data were compared with a similar audit conducted in 2009. Data collected included age, sex, history of atrial fibrillation, adequacy of anticoag- ulation (before and after admission), and vascular risk factors. A total of 49 patients (29 males, average age 76 years) were included. The incidence of atrial fibrillation was found to be 27.9% in stroke and 8.4% among TIA admissions.

Peginterferon ß-1a Improves Clinical and Radiological Outcomes of Patients Newly Diagnosed With RRMS

Consistent with results of the ADVANCE trial, newly diagnosed, treatment- naive patients with relapsing-remitting multiple sclerosis (RRMS) experienced significantly reduced disease activity when administered peginterferon ß-1a every 2 weeks vs patients whose treatment is delayed. T his was a finding of a post hoc sub- evaluation of peginterferon ß-1a in the pivotal phase III, randomized Dr. Newsome and colleagues set out to evaluate the effect of peginterferon ß-1a on clinical and radiological disease activ- ity in newly diagnosed, treatment-naive patients in ADVANCE.

ADVANCE trial. In addition, results of an interim analysis of a 5-year trial of the drug pointed to a tolerability profile consistent with that observed in the pivotal phase III trial were also reported. Scott Douglas Newsome, DO, of Johns Hopkins University School of Medicine in Baltimore, Maryland, explained that the pivotal phase III ADVANCE study evaluated the efficacy of subcutaneous peginterferon ß-1a 125 µg every 2 weeks in patients with RRMS. Approximately 45% of participants had been newly diagnosed and had received no prior disease-mod- ifying therapy.

ADVANCE was a 2-year, double-blind study. In year 1, patients were randomized to peginterferon ß-1a every 2 or 4 weeks or placebo. In year 2, patients who were receiving placebo were re-randomized to peginterferon ß-1a every 2 or 4 weeks (delayed-treatment group). The present analysis assessed the sub- group of patients diagnosed ≤1 year prior to enrollment who had received no prior disease-modifying therapy.

12 PRACTICEUPDATE CONFERENCE SERIES • ANZAN 2018

" …loop recorders provide good value for the money in the Australian context. They identify patients who need anticoagulation to prevent recurrent stroke. We hope clinicians adopt this strategy to help reduce the burden of stroke in Australia. "

initiating oral anticoagulation after crypto- genic stroke. Paroxysmal atrial fibrillation can be difficult to diagnose, however, with short-term cardiac monitoring. Dr. Thijs and colleagues set out todetermine whether long-term continuous monitoring with an insertable cardiac monitor is cost-ef- fective for preventing recurrent stroke in patients with cryptogenic stroke. Dr. Thijs told Elsevier’s PracticeUpdate , “Whether loop recorders provide good value for money when used to detect atrial fibrillation after unexplained ischemic stroke has been questioned. We therefore modeled the trajectory of patients after such a stroke and counted both costs and how much quality adjusted life years changed when such a device was used.” A lifetime Markov model was developed to simulate patient follow-up. Long-term continuous monitoring with an insertable cardiac monitor was compared with con- ventional monitoring. A linked evidence approach was used to estimate rates of recurrent stroke when atrial fibrillation detection led to initiation of oral anticoagulation, as detected using the insertable cardiac monitor during the lifetime of the device vs detection during usual care. The safety profile in newly diagnosed patients was similar to that of the overall patient population. Dr. Newsome concluded that, consistent with results of the ADVANCE trial, newly diagnosed, treatment-naive patients with RRMS experienced significantly reduced disease activity when administered pegin- terferon ß-1a every 2 weeks vs patients whose treatment was delayed. The results were consistent with those of the overall ADVANCE population and highlighted the benefits of initiating ther- apy early in the disease course of RRMS. Marco Salvetti, MD, of Sapienza University, S. Andrea Hospital in Rome, Italy, and col- leagues set out to delineate the baseline characteristics and safety profile of patients with RRMS in the first interim analysis of peginterferon ß-1a treatment in the phase IV Plegridy Observational Program. Dr. Salvetti explained that the 5-year, observational, phase IV Plegridy Observational Program study explores the long-term safety and effectiveness of peginterferon ß-1a 125 µg every 2

Diagnostic and patient management costs were modeled. Other model inputs were determined by literature review. Probabilistic sensitivity analysis was undertaken to explore the effect of parameter uncertainty according to the Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; prior Stroke, TIA, or thromboembolism (CHADS 2 ) score; and oral anticoagulation treatment effect. In the base-case analysis, the model pre- dicted an incremental cost-effectiveness ratio of $29,570 AUD per quality-adjusted life year. Among CHADS 2 subgroup anal- yses, the incremental cost-effectiveness ratio ranged from $26,342 AUD per quality-adjusted life year (CHADS 2 = 6) to $42,967 AUD per quality-adjusted life year (CHADS 2 = 2). weeks in patients with RRMS treated in real-world settings. He presented interim data from the Plegridy Observational Program study in terms of baseline characteristics, adverse events, and clinical effectiveness. The Plegridy Observational Program study is ongoing in >150 sites in 14 countries. Patients who initiated peginterferon ß-1a treatment either ≤31 days prior to enrol- ment (naive subgroup) or >31 days prior to enrolment (experienced subgroup) will be followed for ≤5 years. At the time of the analysis, 467 patients were included, 411 (88%) of whom were followed for ≥12 months. A total of 153 patients (33%) discontinued treatment, primarily due to adverse events (55%) or lack of efficacy (13%). At baseline, mean patient age was 44.9 years, 76% of patients were female, and mean EDSS score was 1.9. Of the 371 patients (79%) who had received prior dis- ease-modifying therapy, 217 (58%) hadbeen treated with intramuscular interferon ß-1a. More patients were naive than experi- enced (60% vs 40%). Adverse events

Probabilistic sensitivity analysis sug- gested that the probabilities of a strategy employing an insertable cardiac monitor being cost-effective were 53.4% and 78.7% at thresholds of $30,000 AUD (highly cost-effective) and $50,000 AUD per quality-adjusted life year (cost-effec- tive), respectively. Dr. Thijs concluded that long-term contin- uous monitoring with an insertable cardiac monitor is cost-effective in preventing recurrent stroke in patients following cryp- togenic stroke in the Australian context. “The results demonstrated,” he said, “that loop recorders provide good value for the money in the Australian context. They identify patients who need anticoagulation to prevent recurrent stroke. We hope cli- nicians adopt this strategy to help reduce the burden of stroke in Australia.” were more common in naive than in experienced patients (35% vs 20%), as were adverse events leading to treatment discontinuation (29% vs 15%). The most commonly reported adverse events leading to treatment discontinu- ation in both groups were injection-site erythema and influenza-like illness. Serious adverse events were reported in 5% of naive and 9% of experienced patients. A high proportion of patients in both groups were relapse-free (naive 84.4%; experienced 81.5%). Dr. Salvetti concluded that in this first interim analysis of the Plegridy Observational Program study, the safety profile was consistent with that observed in the phase III trial of peginterferon ß-1a. No new safety signals were observed. Naive patients were more likely than experienced patients to experience adverse events and to discontinue treat- ment due to injection-site reactions and flulike symptoms. Prophylactic strategies to mitigate these adverse events are needed. www.practiceupdate.com/c/68172

www.practiceupdate.com/c/68175

13 ANZAN 2018 • PRACTICEUPDATE CONFERENCE SERIES

Efficacy of Alemtuzumab for Active RRMS is Maintained for 7 Years, in the Absence of Continuous Treatment Alemtuzumab efficacy was maintained for 7 years in treatment- naive patients with active relapsing-remitting multiple sclerosis (RRMS), despite 59% receiving no additional treatment since the initial two courses. In all, 37% of patients also showed improvement of disability.

T his finding of TOPAZ, the 5-year extension following the 4-year extension of the 2-year Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, study I (CARE-MS I) trial, was reported at ANZAN 2018. Pamela A. McCombe, MD, of the University Of Queensland in Brisbane, QLD, explained that in CARE-MS I, alemtuzumab 12 mg daily (baseline, 5 days; 12 months later, 3 days) improved clinical/MRI outcomes vs subcutaneous interferon ß-1a over 2 years in patients with treatment-naive RRMS. Efficacy was durable in a 4-year extension (95% enrolled, 92% completed), wherein patients could receive as-needed alemtuzumab retreatment for relapse/MRI activity or other disease-modifying thera- pies per investigator’s discretion. Patients completing the extension could enroll in the 5-year TOPAZ study for further evaluation. Dr. McCombe and colleagues set out to examine efficacy and safety through year 7 in patients treated with alemtuzumab from CARE-MS I. In TOPAZ, patients can receive alemtuzumab retreat- ment (≥12 months apart) or other disease-modifying therapies (both per investigator discretion). MRI scans are performed annually. Assessments are annualized relapse rate; stable/ improved Expanded Disability Status Scale (EDSS) score from core study baseline; 6-month confirmed worsening of disability; 6-month confirmed improve- ment in disability; no evidence of disease activity; and adverse events. A total of 299 of 321 patients (93%) completed TOPAZ year 1 (year 7 after initiating alemtuzumab). Annualized relapse rate remained low (year 7: 0.13). A total of 60% were relapse-free in years 3–7.

The percentage of patients with stable or improved EDSS score remained high (year 7: 78%). Through year 7, 74% were free from 6-month con- firmed worsening of disability. In all, 37% achieved 6-month confirmed disability improvement, and the majority achieved no evidence of disease activity each year (year 7: 61%). Overall, 59% received no additional treatment (alemtuzumab or other disease-modifying therapy) after the initial two courses. Overall incidence of adverse events, infusion-asso- ciated reactions, and infections decreased over time. The incidence of thyroid adverse events peaked in year 3 (15%) and then declined. Dr. McCombe concluded that alemtuzumab effi- cacy was maintained for 7 years in treatment-naive patients with active RRMS, despite 59% receiving no additional treatment since the initial two courses. In all, 37% of patients also showed improvement in disability. The alemtuzumab safety profile remained consistent. The overall incidence of adverse events decreased over time. Alemtuzumab may provide a unique treatment approach for patients with relapsing-remitting multi- ple sclerosis. It offers durable efficacy in the absence of continuous treatment. Richard AL Macdonell, MD, of Austin Health and the Florey Institute of Neuroscience and Mental Health in Melbourne, Victoria, and colleagues set out to examine improvement in disability in each functional system in alemtuzumab-treated patients with active RMS in the CARE-MS II extension. Dr. Macdonell explained that in CARE-MS II, alemtu- zumab (12 mg daily, baseline: 5 days; 12 months later: 3 days) improved clinical/MRI outcomes significantly

PRACTICEUPDATE CONFERENCE SERIES • ANZAN 2018 14