Articles
`
`Alemtuzumab versus interferon beta 1a as fi rst-line
`treatment for patients with relapsing-remitting multiple
`sclerosis: a randomised controlled phase 3 trial
`
`Jeff rey A Cohen*, Alasdair J Coles*, Douglas L Arnold, Christian Confavreux, Edward J Fox, Hans-Peter Hartung, Eva Havrdova, Krzysztof W Selmaj,
`Howard L Weiner, Elizabeth Fisher, Vesna V Brinar, Gavin Giovannoni, Miroslav Stojanovic, Bella I Ertik, Stephen L Lake, David H Margolin,
`Michael A Panzara, D Alastair S Compston, for the CARE-MS I investigators†
`
`Summary
`Background The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously
`untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess effi cacy and safety of fi rst-line
`alemtuzumab compared with interferon beta 1a in a phase 3 trial.
`
`Methods In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18–50 years with
`previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio
`by an interactive voice response system, stratifi ed by site, to receive intravenous alemtuzumab 12 mg per day or
`subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was
`given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse
`rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study
`drug. This study is registered with ClinicalTrials.gov, number NCT00530348.
`
`Findings 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated
`alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed
`(122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32–0·63];
`p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of
`patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab
`group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared
`with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40–1·23]; p=0·22). 338 (90%) of patients in the
`alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections,
`predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%)
`patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly
`cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the
`alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and
`three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the
`alemtuzumab group developed thyroid papillary carcinoma.
`
`Interpretation Alemtuzumab’s consistent safety profi le and benefi t in terms of reductions of relapse support its use
`for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefi t in terms of disability
`endpoints noted in previous trials was not observed here.
`
`Funding Genzyme (Sanofi ) and Bayer Schering Pharma.
`
`Introduction
`Alemtuzumab, a humanised anti-CD52 monoclonal anti-
`body used for treatment of multiple sclerosis, works via
`depletion and subsequent repopulation of circu lating
`T lymphocytes and B lymphocytes. This action leads to
`changes in the number, proportions, and functions of
`some lymphocyte subsets.1–3 Alemtuzumab has been
`shown to decrease the rate of relapses, disability
`accumulation, and MRI lesion activity.4–7 Superiority for
`alemtuzumab compared with interferon beta 1a, which
`was noted in a phase 2 trial,7 was maintained in an open-
`label follow-up study through 5 years.8 In the Comparison
`of Alemtuzumab and Rebif Effi cacy in Multiple Sclerosis
`
`(CARE-MS I) trial, we aimed to assess the eff ect of
`alemtuzumab compared with interferon beta 1a in a
`phase 3 trial of previously untreated patients with early,
`active relapsing-remitting multiple sclerosis.
`
`Methods
`Study design and patients
`In this randomised, rater-masked, phase 3 trial, we
`enrolled patients from 101 academic medical centres and
`clinical practices in 16 countries between Sept 7, 2007, and
`April 17, 2009. Eligible patients were aged 18–50 years and
`had relapsing-remitting multiple sclerosis fulfi lling the
`2005 McDonald criteria,9 a disease duration of up to
`
`www.thelancet.com Vol 380 November 24, 2012
`
`Lancet 2012; 380: 1819–28
`Published Online
`November 1, 2012
`http://dx.doi.org/10.1016/
`S0140-6736(12)61769-3
`See Editorial page 1792
`See Comment page 1795
`See Articles page 1829
`*Contributed equally
`†Members listed in appendix
`Mellen Center
`(Prof J A Cohen MD) and
`Department of Biomedical
`Engineering (E Fisher PhD),
`Cleveland Clinic, Cleveland,
`OH, USA; Department of
`Clinical Neurosciences,
`University of Cambridge,
`Cambridge, UK (A J Coles PhD,
`Prof D A S Compston FRCP);
`NeuroRx Research and
`Department of Neurology and
`Neurosurgery, Montreal
`Neurological Institute, McGill
`University, Montreal, Quebec,
`Canada (Prof D L Arnold MD);
`Service de Neurologie A,
`Hospices Civils de Lyon,
`Université Claude Bernard
`Lyon 1, Lyon, France
`(Prof C Confavreux MD); MS
`Clinic of Central Texas, Central
`Texas Neurology Consultants,
`Round Rock, TX, USA
`(E J Fox MD); Heinrich-Heine
`University, Department of
`Neurology, Düsseldorf,
`Germany
`(Prof H-P Hartung FRCP);
`Department of Neurology,
`First School of Medicine,
`Charles University, Prague,
`Czech Republic
`(Prof E Havrdova MD);
`Department of Neurology,
`Medical University of Lodz,
`Lodz, Poland
`(Prof K W Selmaj MD); Brigham
`and Women’s Hospital Center
`for Neurologic Diseases,
`Boston, MA, USA
`(Prof H L Weiner MD); Zagreb
`Medical School and University
`Hospital Center, Zagreb,
`Croatia (V V Brinar MD); Queen
`
`1819
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`

`
`Articles
`
`Mary University of London,
`Blizard Institute and
`The London School of Medicine
`and Dentistry, London, UK
`(Prof G Giovannoni PhD); Clinical
`Centre Kragujevac, Clinic of
`Neurology, Kragujevac, Serbia
`(M Stojanovic MD); and
`Genzyme, Cambridge, MA, USA
`(B I Ertik MD, S L Lake ScD,
`D H Margolin MD,
`M A Panzara MD)
`Correspondence to:
`Prof Jeff rey A Cohen, Mellen
`Center U-10, Neurological
`Institute, Cleveland Clinic,
`9500 Euclid Avenue, Cleveland,
`OH 44195, USA
`cohenj@ccf.org
`
`5 years, at least two relapses in the previous 2 years and at
`least one in the previous year, expanded disability status
`scale (EDSS)10 scores of 3·0 or lower, and cranial
`abnormalities on MRI attributable to multiple sclerosis.
`Key exclusion criteria included progressive disease course,
`previous multiple sclerosis disease therapy (apart from
`corticosteroids), previous immuno sup pressive, investi-
`gational, or monoclonal antibody therapy, and clinically
`signifi cant auto immunity other than multiple sclerosis.
`An independent data monitoring committee reviewed
`study conduct and all safety data. The study was done
`in accordance with the International Conference on
`Harmonisation Guidelines for Good Clinical Practice11
`and the principles of the Declaration of Helsinki.12 Local
`ethics committees approved the protocol. All patients
`provided written informed consent.
`
`Randomisation and masking
`We randomly allocated patients using an interactive voice
`response system in a 2:1 ratio to receive alemtuzumab
`(12 mg per day), infused intravenously on 5 days at
`
`733 patients screened
`
`152 excluded
`
`581 randomly allocated
`
`195 randomly allocated interferon beta 1a
`
`386 randomly allocated alemtuzumab 12 mg
`
`8 did not receive drug
` 7 withdrew consent
` 1 unknown
`
`10 did not receive drug
`
`1 adverse reaction
` 8 withdrew consent
`
`1 unknown
`
`187 received interferon beta 1a
`
`376 received alemtuzumab 12 mg
`
`14 discontinued the study
` after receiving study drug
`5 adverse event
`2 lack of efficacy
`1 physician decision
`1 pregnancy
`5 withdrew consent
`
`
`
`
`
`
`
`9 discontinued study drug
` but continued in the study
` 5 adverse event
` 1 lack of efficacy
` 1 non-compliance with
`
` study drug
` 2 physician decision
`
`9 discontinued the study
` after receiving study drug
` 2 physician decision
` 4 withdrew consent
` 1 lost to follow-up
` 1 death
` 1 unknown
`
`5 discontinued study drug
` but continued in the study
` 4 adverse event
` 1 lack of efficacy
`
`164 completed the study on assigned treatment
`
`362 completed the study on assigned treatment
`
`Figure 1: Trial profi le
`
`1820
`
`baseline and 3 days at 12 months, or interferon beta 1a
`(44 μg) given subcutaneously three-times per week after
`dose titration. Randomisation was stratifi ed by site.
`Because both study drugs have adverse eff ects that
`precluded masking of patients and treating clinicians to
`treatment assignment, and because subcutaneous inter-
`feron beta 1a was available only in proprietary prefi lled
`syringes that could not eff ectively be duplicated for
`placebo, we secured clinical data integrity by stringent
`clinical and MRI rater masking, and adjudication of
`relapses by a committee comprising six independent and
`masked neurologists. Raters com pleted a questionnaire
`assessing quality of the masking at each EDSS assess-
`ment. In the absence of a masked rater, unmasked raters
`could submit EDSS assess ments.
`
`Procedures
`Patients in both groups received 1 g per day of intra-
`venous methylprednisolone on 3 consecutive days at
`baseline and at month 12. Concomitant treatment with
`an antipyretic or antihistamine was permitted at the
`treating neurologist’s discretion. After a protocol amend-
`ment in January, 2009, alemtuzumab patients received
`oral aciclovir 200 mg twice daily during alemtuzumab
`infusion and for 28 days thereafter as prophylaxis against
`herpes infection.
`Raters who were masked to treatment group assign-
`ment assessed EDSS every 3 months and when a relapse
`was suspected. A masked rater tested multiple sclerosis
`functional composite (MSFC)13 three times before
`baseline to reduce practice eff ects14 then every 6 months.
`Standardised annual cranial MRI scans were analysed by
`imaging specialists from NeuroRx (Montreal, Canada;
`lesion analyses) and the Cleveland Clinic MS MRI
`Analysis Center (OH, USA; normalised brain volume),
`who were masked to treatment-group assign ment.
`We assessed benefi t in terms of the coprimary end-
`points of relapse rate and time to 6 month sustained
`accumulation of disability. We defi ned relapse as new or
`worsening neurological symptoms attributable to mul-
`tiple sclerosis, lasting at least 48 h, without pyrexia, after
`at least 30 days of clinical stability, with an objective
`change on neurological examination assessed by a
`masked rater. The relapse adjudication panel decided the
`status of suspected relapses on the basis of the protocol
`defi nition and their masked review of all data collected by
`the site, including whether there was an objective change
`corresponding to current relapse symptoms (one point
`on two functional system scales or two points on one
`functional system scale or increase in EDSS score).
`Sustained accumulation of disability was defi ned as an
`increase from baseline of at least one EDSS point (or
`≥1·5 points if baseline EDSS score was 0) confi rmed
`over 6 months. Secondary endpoints, measured over
`24 months, included the proportion of relapse-free
`patients, change
`in EDSS, percentage change
`in
`T2-hyperintense lesion volume, and change in MSFC.
`
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`
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`

`
`Articles
`
`and non-European Union Europe. We estimated yearly
`relapse rate with a negative binomial regression model23
`with geographical region included as a covariate. We
`estimated the proportion of patients with sustained
`accumulation of disability with the Kaplan-Meier method.
`We controlled secondary endpoints
`for multiple
`comparisons by testing sequentially the proportion of
`relapse-free patients, EDSS change, T2-hyperintense
`lesion volume change, and MSFC change. If any p value
`exceeded 0·05, formal sequential testing stopped; how-
`ever, all p values and 95% CIs are reported for descriptive
`purposes. We analysed the proportion of patients who
`were relapse-free with a proportional hazards model. We
`analysed changes from baseline in EDSS and MSFC at
`specifi c timepoints with a mixed model for repeated
`
`Interferon beta 1a
`(n=187)
`
`Alemtuzumab
`(n=376)
`
`33·2 (8·5)
`122 (65%)
`180 (96%)
`
`2·0 (1·3)
`1·5 (0·2–5·0)
`
`9 (5%)
`60 (32%)
`50 (27%)
`65 (35%)
`3 (2%)
`2·0 (0·8)
`2·0 (0–3·5)
`
`Age, years
`Sex, female
`Race, white
`Time from onset of symptoms to randomisation, years
`Mean
`Median
`EDSS score subgroup
`0
`1–1·5
`2·0
`2·5–3·0
`3·5–4·0*
`Mean
`Median
`Relapses in previous year
`4 (2%)
`0†
`66 (35%)
`1
`94 (50%)
`2
`23 (12%)
`≥3
`1·8 (0·8)
`Mean
`2·0 (0–5)
`Median (range)
`Number of gadolinium-enhancing lesions (T1-weighted images)
`Mean
`2·2 (4·9)
`Median (range)
`1·0 (0–36)
`Patients with baseline lesions
`94/183 (51%)
`T2-hyperintense lesion volume, cm³
`Mean
`Median
`Brain parenchymal fraction
`Mean
`Median
`
`7·3 (9·9)
`3·8 (0·1–55·5)
`
`0·818 (0·021)
`0·818 (0·763–0·865)
`
`33·0 (8·0)
`243 (65%)
`352 (94%)
`
`2·1 (1·4)
`1·7 (0·1–5·2)
`
`15 (4%)
`126 (34%)
`87 (23%)
`140 (37%)
`8 (2%)
`2·0 (0·8)
`2·0 (0–4·0)
`
`6 (2%)
`145 (39%)
`169 (45%)
`56 (15%)
`1·8 (0·8)
`2·0 (0–5)
`
`2·3 (5·1)
`0·0 (0–32)
`171/371 (46%)
`
`7·4 (9·0)
`4·2 (0·0–49·0)
`
`0·821 (0·022)
`0·821 (0·686–0·878)
`
`We defi ned freedom from clinical disease activity as
`absence both of relapses and sustained accumulation of
`disability. We defi ned freedom from MRI disease activity
`as absence both of gadolinium-enhancing lesions and
`new or enlarging T2-hyperintense lesions.
`To assess safety, we undertook monthly questionnaire
`follow-up of patients, and did complete blood counts,
`serum creatinine, urinalysis, and microscopy monthly
`(every three months in patients in the interferon beta 1a
`group), and thyroid function tests every 3 months.
`Patients and investigators were given instructional
`materials that described the signs and symptoms of
`poten tial alemtuzumab complications (particularly thy-
`roid dysfunction, immune thrombocytopenia, and anti-
`glomerular basement disease) and guided appro priate
`follow-up for suspected cases. We defi ned reactions
`associated with the infusion as any adverse event
`beginning during or within 24 h after alemtuzumab
`infusion. Circulating lymphocyte subsets were assessed
`every 3 months in all patients and 1 month after
`alemtuzumab administration. We screened for anti-
`alemtuzumab antibodies with a bridging ELISA (Meso
`Scale Discovery, Gaithersburg, MD, USA) before and at
`1 month, 3 months, and 12 months after each dosing. We
`confi rmed positive tests by use of competitive binding
`assays and inhibition of alemtuzumab binding to CD52-
`expressing CHO cells in a fl ow cytometric assay. We
`measured interferon beta 1a-neutralising antibodies at
`baseline and at 24 months with a cytopathic eff ect
`inhibition assay (BioMonitor, Copenhagen, Denmark).15
`
`Statistical analysis
`On the basis of previous trials16–19 and the phase 2 study,7
`we expected at least 20% of patients in the interferon beta
`1a group to meet the disability endpoint by 24 months.
`Therefore, 525 patients randomly allocated 2:1 to alemtu-
`zumab and interferon beta 1a were expected to provide at
`least 95% power to detect a 60% alemtuzumab treatment
`eff ect on time to sustained accumulation of disability
`with a two-sided signifi cance level of 5% and assuming a
`10% discontinuation rate. This sample size was also
`expected to provide at least 95% power to detect a 60%
`treatment eff ect on relapse rate, assuming 40% of
`patients in the interferon beta 1a group relapsed within
`24 months. Eligible patients in screening when recruit-
`ment closed were allowed to enrol in the study.
`We included all patients who received at least one
`dose of study drug in the effi cacy and safety analyses
`according to treatment assignment. We adjusted the
`primary effi cacy analysis for multiple comparisons with
`the Hochberg procedure.20 We assessed treatment eff ects
`on relapse rate with a proportional means model21 and on
`sustained accumulation of disability with a pro portional
`hazards model,22 both with robust variance estimation
`and treatment group and geographical region included as
`covariates. We categorised geographical regions as USA,
`Canada, and, Australia; Latin America; European Union;
`
`Data are mean (SD), n (%), n/n assessed (%), or median (range). Baseline characteristics did not diff er signifi cantly
`between groups. Patients were enrolled in the study based on data collected at the screening visit, which occurred
`before the baseline visit. *Patients with EDSS scores higher than 3·0 at the baseline visit had an EDSS of 3·0 or less at
`the screening visit. †Nine patients had a relapse during the year before the screening visit but the relapse was more
`than 1 year ago by the baseline visit, and one patient had their last relapse 18 months before screening.
`
`Table 1: Baseline characteristics
`
`www.thelancet.com Vol 380 November 24, 2012
`
`1821
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`

`
`Articles
`
`See Online for appendix
`
`measures. We made treatment comparisons of all available
`3 month assessments with the Wei-Lachin non-parametric
`test for repeated measures.24,25 We analysed changes in T2-
`hyperintense lesion volume and brain volume with a
`ranked ANCOVA model. We analysed proportions of
`patients with new or enlarging T2-hyperintense lesions or
`gadolinium-enhancing lesions, and those who were free
`from disease activity, with logistic regression. The appendix
`contains additional details about the statistical methods.
`This study is registered with ClinicalTrials.gov, number
`NCT00530348.
`
`Role of the funding source
`The study sponsor (Genzyme) was involved in the
`design and undertaking of the trial, data analysis and
`inter pretation, writing of the manuscript, and the
`decision to submit the manuscript for publication.
`
`Interferon beta 1a (n=187)
`
`Alemtuzumab (n=376)
`
`p value
`
`75 (40%)
`122
`··
`··
`0·39 (0·29 to 0·53)
`58·7% (51·1 to 65·5)
`
`0·07 (0·45)
`
`–6·5% (–20·7 to 2·5)
`
`Relapse
`Patients with any event
`Total number of events
`Rate ratio (95% CI)
`Risk reduction
`Yearly rate (95% CI)
`Relapse-free patients, % (95% CI)*
`Disability
`Sustained accumulation confi rmed over 6 months
`Patients
`20 (11%)
`Percentage of patients (95% CI)*
`11·12% (7·32 to 16·71)
`Hazard ratio (95% CI)
`··
`Risk reduction
`··
`Change in EDSS score from baseline
`–0·14 (–0·29 to 0·01)
`Mean change (95% CI)
`Change in MSFC score from baseline†
`Mean change
`MRI
`Median change in volume of
`T2-hyperintense lesions
`Patients with new or enlarging
`T2-hyperintense lesions§
`Patients with gadolinium-
`enhancing lesions at 24 months§
`Median change in brain
`parenchymal fraction§
`Disease-free survival
`Patients clinically disease-free§
`Odds ratio (95% CI)
`Patients MRI and clinically
`disease-free§
`Odds ratio (95% CI)
`
`99/172 (58%)
`
`34/178 (19%)
`
`–1·488% (–2·355 to –0·567)
`
`104 (56%)
`··
`46/172 (27%)
`
`··
`
`82 (22%)
`119
`0·45 (0·32 to 0·63)
`54·9%
`0·18 (0·13 to 0·23)
`77·6% (72·9 to 81.6)
`
`30 (8%)
`8·00% (5·66 to 11·24)
`0·70 (0·40 to 1·23)
`30%
`
`–0·14 (–0·25 to –0·02)
`
`0·15 (0·52)
`
`–9·3% (–19·6 to –0·2)
`
`176/363 (48%)
`
`<0·0001
`
`<0·0001
`
`0·22
`
`0·97
`
`0·01
`
`0·31
`
`0·04
`
`26/366 (7%)
`
`<0·0001
`
`–0·867% (–1·470 to –0·254) <0·0001
`
`279 (74%)
`2·36 (1·62 to 3·43)
`139/360 (39%)
`
`<0·0001
`
`1·75 (1·17 to 2·61)
`
`0·006
`
`Bayer Schering Pharma participated in the design and
`oversight of the trial. Clinical investigators collaborated
`with the sponsor to design and oversee the trial. The
`sponsor did the statistical analyses. All authors had full
`access to data, participated in the analyses, wrote the
`manuscript, had fi nal responsibility for the decision to
`submit for publication, and vouch for the accuracy and
`completeness of the results.
`
`Results
`563 (97%) of 581 patients who were randomly assigned
`received at least one dose of study drug and 526 (93%) of
`these patients completed the study on assigned treatment
`(fi gure 1). Baseline char acteristics were typical for an
`early, active relapsing-remitting multiple sclerosis
`population (table 1). 17 (5%) of 376 patients received
`aciclovir with the fi rst course of alemtuzumab and
`243 (66%) of 370 patients received aciclovir with the
`second course of alemtuzumab.
`Alemtuzumab reduced the rate of relapse compared
`with interferon beta 1a (table 2). More patients were
`relapse-free at 2 years in the alemtuzumab group than
`were relapse-free in the interferon beta 1a group
`(table 2, fi gure 2).
`Rates of sustained accumulation of disability did not
`diff er between groups (table 2, fi gure 2). Mean EDSS
`score improved from baseline by 0·14 points in both
`groups (table 2). Based on the prespecifi ed plan of
`sequential testing of secondary endpoints to control for
`multiple comparisons, the diff erence in MSFC change
`over 24 months was not regarded as signifi cant (table 2,
`fi gure 3).
`lesion volume by
`in T2-hyperintense
`Decreases
`24 months did not diff er between groups (table 2, fi gure 3).
`Compared with interferon beta 1a, alemtuzumab reduced
`the proportions of patients with gadolinium-enhancing
`and new or enlarging T2-hyperintense lesions, and slowed
`brain volume loss by about 40% (table 2, fi gure 3).
`More patients remained free from clinical disease
`activity and combined clinical and radiological disease
`activity in the alemtuzumab group than in the interferon
`beta 1a group (table 2).
`Masking was successful for 5172 (>99%) of 5193 EDSS
`assessments. Only 15 (3%) of 563 patients had one or
`more assessments done by an unmasked rater.
`Sensitivity analyses, including exclusion of unmasked
`assessments, supported the absence of eff ect of rater
`unmasking on study results (appendix). The relapse
`adjudication panel confi rmed 121 (81%) of 149 suspected
`relapses for patients in the alemtuzumab group and
`125 (85%) of 147 suspected relapses for patients in the
`interferon beta 1a group.
`Much the same proportions of patients in the two
`treatment groups had adverse events (92–96%), most of
`which were mild to moderate in severity (table 3). The most
`frequently reported adverse events with alemtuzumab
`were infusion-associated reactions (headache, rash, and
`
`Data are n (%), mean (SD), median (IQR), or n/n assessed (%), unless otherwise stated. EDSS=expanded disability status
`scale. MSFC=multiple sclerosis functional composite. *Kaplan-Meier estimates. †As per the prespecifi ed plan for
`sequential testing of the four secondary endpoints and the non-signifi cant fi ndings for changes over 24 months in EDSS
`and T2-hyperintense lesion volume, this diff erence was not regarded as signifi cant. §Prespecifi ed tertiary endpoint.
`
`Table 2: Clinical and MRI outcomes
`
`1822
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`Articles
`
`Interferon beta 1a
`Alemtuzumab
`
`Hazard ratio 0·45 (95% CI 0·33–0·61); p<0·0001
`
`3
`
`175
`366
`
`6
`
`156
`358
`
`9
`
`137
`340
`
`12
`
`127
`321
`
`15
`
`118
`313
`
`18
`
`116
`306
`
`21
`
`109
`299
`
`24
`
`101
`287
`
`Hazard ratio 0·70 (95% CI 0·40–1·23); p=0·2173
`
`3
`
`185
`376
`
`6
`
`181
`372
`
`9
`
`15
`
`12
`Follow-up (months)
`177
`170
`164
`368
`363
`357
`
`18
`
`162
`352
`
`21
`
`158
`345
`
`24
`
`149
`336
`
`A
`100
`95
`90
`85
`80
`75
`70
`65
`60
`55
`50
`0
`
`0
`
`Relapse-free survival (%)
`
`187
`376
`
`Number at risk
`Interferon beta 1a
`Alemtuzumab
`B
`20
`18
`16
`14
`12
`10
`8
`
`0246
`
`0
`
`Patients with sustained accumulation
`
`of disability (%)
`
`Number at risk
`Interferon beta 1a
`Alemtuzumab
`
`187
`376
`
`Figure 2: Clinical effi cacy outcome measures
`Kaplan-Meier estimates of time to fi rst relapse (A) and sustained accumulation of disability, confi rmed over
`6 months and measured by the expanded disability status scale (B).
`
`Between 11 months and 22 months after start of alem-
`tuzu mab treatment, three patients developed im mune
`thrombocytopenia that was classifi ed as serious. One
`patient with disease that was refractory to steroids and
`intravenous gammaglobulin responded to rituxi mab.
`Another patient gradually developed thrombo cytopenia
`and, after reaching 2×10⁹ per L, was treated with platelet
`transfusions, corticosteroids, and intra venous gamma-
`globulin, and recovered. A third patient had an initial
`platelet drop that resolved spon taneously, recurred
`6 months later, and responded to prednisolone. One
`patient in the interferon beta 1a group developed mild
`persistent idiopathic thrombo cytopenia, which did not
`need treatment.
`During safety follow-up, one patient who received a
`third alemtuzumab treatment after the study ended
`developed glomerulonephritis with haematuria, pro-
`tein uria, and slightly elevated anti-glomerular basement
`membrane antibody (maximum 38·53 U/mL; normal
`<20 U/mL) but normal or near-normal serial creatinine
`concentrations. The patient was treated with plasma-
`pheresis, cyclophosphamide, and intravenous steroids,
`
`pyrexia) and relapse of multiple sclerosis. The most
`frequently reported adverse events with interferon beta
`1a were fl u-like illness, relapse of multiple sclerosis,
`and headache. The most common serious adverse event
`for both groups was relapse of multiple sclerosis.
`Overall, 51 (14%) of 376 patients in the alemtuzumab
`group and 14 (8%) of 187 patients in the interferon beta
`1a group had serious adverse events other than relapse
`of multiple sclerosis. Fewer patients in the alem-
`tuzumab group than in the interferon beta 1a group
`discontinued treatment or study participation because
`of an adverse event (fi gure 1). One patient in the
`alemtuzumab group died during the study because of
`an automobile accident, and one died because of sepsis
`after the study.
`338 (90%) of 376 patients treated with alemtuzumab
`had infusion-associated reactions; 12 (3%) had serious
`reactions (table 3). Infusion-associated reactions were
`less common during the second treatment course. One
`patient was reported to have had an anaphylactic shock
`with the fi rst infusion, which was later reclassifi ed by the
`investigator as non-anaphylactoid hypotension. Another
`patient developed angio-oedema during the fi rst course
`of alemtuzumab. Both patients received the second
`course of alemtuzumab without adverse reactions.
`Infections, which were more frequent in the alemtu-
`zumab group than in the interferon beta 1a group
`(table 3), were predominantly (98%) mild or moderate in
`severity. No infection occurring during the study led to
`discontin uation of treatment or study participation, and
`no infections were life-threatening or fatal. The most
`common infections in patients treated with alemtuzumab
`were upper respiratory, urinary tract, and herpetic. One
`patient treated with alemtuzumab was from a region
`endemic for tuberculosis, and developed pulmonary
`tuberculosis, which resolved with standard treatment. In
`the month after the 12 month alemtuzumab course,
`three (1%) of 243 patients receiving aciclovir had a
`herpetic
`infection, compared with
`four
`(3%) of
`127 patients not receiving aciclovir.
`Because autoimmune disorders have previously been
`reported after alemtuzumab treatment, we rigorously
`monitored for these adverse events (table 3). Most thyroid-
`associated adverse events were mild or moderate in
`severity. The infant of a patient with Graves’ disease
`treated with alemtuzumab had neonatal thyrotoxicosis,
`probably from passive transfer of maternal autoantibody,
`and was treated medically without sequelae. Subse quently,
`the mother also developed thyrotoxi cosis, which was
`treated medically, and ophthalmopathy which was
`managed without ophthalmic surgery. Ultimately, she
`underwent thyroidectomy. After completion of the phase 3
`trial, another patient developed Graves’ hyperthyroidism
`and Coombs-positive autoimmune haemolytic anaemia
`15 months after the second course of alemtuzumab. After
`treatment with oral corticosteroids, carbimazole, and folic
`acid, she recovered without sequelae.
`
`www.thelancet.com Vol 380 November 24, 2012
`
`1823
`
`MYLAN PHARMS. INC. EXHIBIT 1110 PAGE 5
`
`

`
`Interferon beta 1a
`(n=187)
`
`Alemtuzumab
`(n=376)
`
`1784 (4·94)
`172 (92%)
`11 (6%)
`
`33 (0·09)
`27 (14%)
`13 (7%)
`14 (7%)
`0
`
`All adverse events
`Events (events per person-year)
`Patients with ≥1 event
`Study drug discontinuation
`because of adverse event*
`Serious adverse events
`Events (events per person-year)
`Patients with ≥1 event
`Multiple sclerosis relapse†
`Excluding MS relapses†
`Deaths
`Infusion-associated reactions
`NA
`Any event
`Events aff ecting >10% in alemtuzumab group
`Headache
`NA
`Rash
`NA
`Pyrexia
`NA
`Nausea
`NA
`Urticaria
`NA
`Flushing
`NA
`Chills
`NA
`Serious adverse events
`NA
`Atrial fi brillation
`NA
`Incorrect dose administered
`NA
`Hypotension
`NA
`Bradycardia
`NA
`Sinus bradycardia
`NA
`Sinus tachycardia
`NA
`Tachycardia
`NA
`Nausea
`NA
`Chest discomfort
`NA
`Pyrexia
`NA
`Anaphylactic shock‡
`NA
`Myalgia
`NA
`Brain stem syndrome
`NA
`Headache
`NA
`Migraine
`NA
`Pleurisy
`NA
`Throat tightness
`NA
`Angio-oedema
`NA
`Urticaria
`NA
`
`5829 (7·73)
`361 (96%)
`5 (1%)
`
`98 (0·13)
`69 (18%)
`19 (5%)
`51 (14%)
`1 (<1%)
`
`338 (90%)
`
`160 (43%)
`155 (41%)
`125 (33%)
`51 (14%)
`43 (11%)
`43 (11%)
`38 (10%)
`12 (3%)
`2 (1%)
`2 (1%)
`2 (1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`(Continues in next column)
`
`and continues to receive low-dose oral steroids and
`cyclo phosphamide. 6 months after the study (19 months
`after
`last
`receiving alemtuzumab), one patient
`developed pre sumed autoimmune pan cyto penia, which
`resolved with platelet
`transfusion, corticosteroids,
`intra venous gamma globulin, and fi lgrastim. After
`hospital discharge, the patient did not comply with
`prescribed corticosteroid therapy, and 8 days later
`developed fever, mucocutaneous bleeding, and sepsis
`from which he died.
`
`Interferon beta 1a
`Alemtuzumab
`
`3
`
`186
`376
`
`6
`
`184
`373
`
`9
`
`179
`375
`
`12
`
`179
`375
`
`15
`
`177
`372
`
`18
`
`173
`372
`
`21
`
`173
`366
`
`24
`
`173
`366
`
`Articles
`
`A
`
`2·2
`
`2·1
`
`2·0
`
`1·9
`
`1·8
`
`1·7
`
`0
`
`EDSS score
`
`Number of observations
`Interferon beta 1a
`Alemtuzumab
`
`187
`376
`
`B
`
`0·20
`
`0·10
`
`0
`
`MSFC Z score
`
`–0·10
`
`0
`
`Number of observations
`Interferon beta 1a
`Alemtuzumab
`
`186
`375
`
`6
`
`182
`369
`
`12
`Follow-up (months)
`
`178
`373
`
`18
`
`172
`368
`
`24
`
`172
`363
`
`Brain
`parenchymal
`fraction
`
`0
`–0·1
`–0·2
`–0·3
`–0·4
`–0·5
`–0·6
`–0·7
`–0·8
`–0·9
`–1·0
`–1·1
`–1·2
`–1·3
`–1·4
`–1·5
`–1·6
`–1·7
`–1·8
`
`Median change (%)
`
`T2 lesion volume
`
`0
`
`–1
`
`–2
`
`–3
`
`–4
`
`–5
`
`–6
`
`–7
`
`–8
`
`–9
`
`–10
`
`–11
`
`–12
`
`Median change (%)
`
`Interferon beta 1a
`Alemtuzumab
`
`Gadolinium-
`enhancing
`lesions
`
`New
`enlarging
`T2 lesions
`
`C
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Patients with lesions (%)
`
`Figure 3: Secondary and exploratory clinical and MRI outcome measures
`(A) Mean change of expanded disability status scale (EDSS) from baseline; bars show 95% CIs. (B) Mean change
`from baseline in multiple sclerosis functional composite (MSFC) Z score; bars show 95% CIs. (C) Patients with
`gadolinium-enhancing lesions at 24 months, new or enlarging T2-hyperintense lesions from baseline to
`24 months, median percentage change in T2-hyperintense lesion volume from baseline to 24 months, and
`median percentage change in the brain parenchymal fraction measure of normalised brain volume from
`baseline to 24 months.
`
`1824
`
`www.thelancet.com Vol 380 November 24, 2012
`
`MYLAN PHARMS. INC. EXHIBIT 1110 PAGE 6
`
`

`
`Articles
`
`Interferon beta 1a
`(n=187)
`
`Alemtuzumab
`(n=376)
`
`Interferon beta 1a
`(n=187)
`
`Alemtuzumab
`(n=376)
`
`0
`
`0
`
`(Continued from previous column)
`Blood and lymphatic system disorders
`Any event
`36 (19%)
`Serious adverse events
`0
`Immune thrombocytopenic
`0
`purpura
`Agranulocytosis
`Malignant disease
`Thyroid cancer
`Liver toxicity
`Any event
`Serious adverse events
`Administration-site reactions
`87 (47%)
`Any event
`Other events aff ecting >10% of patients in any group||
`General condition
`Fatigue
`Infl uenza like illness
`Injection site erythema
`Nervous system disorders
`35 (19%)
`Headache
`73 (39%)
`Multiple sclerosis relapse†
`Skin and subcutaneous tissue disorders
`Rash
`7 (4%)
`
`32 (17%)
`1 (1%)
`
`16 (9%)
`43 (23%)
`46 (25%)
`
`66 (18%)
`5 (1%)
`3 (1%)
`
`2 (1%)
`
`2 (1%)
`
`15 (4%)
`0
`
`19 (5%)
`
`50 (13%)
`11 (3%)
`0
`
`86 (23%)
`80 (21%)
`
`44 (12%)
`
`(Continued from previous column)
`Infections
`Any events
`Events aff ecting >10% in any group
`Nasopharyngitis
`Urinary tract infection
`Herpes viral infections
`Herpes simplex§
`Herpes zoster
`Herpes v