The NEW ENGLAND JOURNAL of MEDICINE
`
`
`
`‘
`
`ORIGINAL ARTICLE
`
`‘
`
`Oral Fingolimod (FTY720) for Relapsing
`Multiple Sclerosis
`
`Ludwig Kappos, M.D.,Jack Antel, M.D., Giancarlo Comi, M.D.,
`Xavier Montalban, M.D., Paul O'Connor, M.D., Chris H. Polman, M.D.,
`Tomas Haas, Ph.D., Alexander A. Korn, Ph.D., Goeril Karlsson, Ph.D.,
`
`and Ernst W. Radue, M.D., for the FTY720 D2201 Study Group":
`
`
`
`ABSTRACT
`
`BACKGROUND
`
`Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for
`the treatment of relapsing multiple sclerosis.
`
`METHODS
`
`We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg
`or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with
`magnetic resonance imaging (MRI) and clinical evaluations (core study, months
`0 to 6). The primary end point was the total number ofgadolinium-enhanced lesions
`recorded on T,-weighted MRI at monthly intervals for 6 months. In an extension
`study in which the investigators and patients remained unaware of the dose assign-
`ments (months 7 to 12), patients who received placebo underwent randomization
`again to one of the fingolimod doses.
`
`RESULTS
`
`A total of 255 patients completed the core study. The median total number ofgado-
`linium—enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion,
`P<0.001) and 5.0 mg of fmgolimod (3 lesions, P=0.006) than with placebo (5 le-
`sions). The annualized relapse rate was 0.77 in the placebo group, as compared
`with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the
`group given 5.0 mg of fingolimod (P: 0.01). For the 227 patients who completed
`the extension study, the number of gadolinium-enhanced lesions and relapse rates
`remained low in the groups that received continuous fingolimod, and both mea-
`sures decreased in patients who switched from placebo to fingolimod. Adverse
`events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clin-
`ically asymptomatic elevations of alanine aminotransferase levels were more fre-
`quent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the
`posterior reversible encephalopathy syndrome occurred in the 5.0—mg group. Fingo-
`limod was also associated with an initial reduction in the heart rate and a modest
`
`decrease in the forced expiratory volume in 1 second.
`
`CONCLUSIONS
`
`In this proof-of-concept study, fingolimod reduced the number of lesions detected
`on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation
`in larger, longer-term studies is warranted. (Clinicaltrialsgov numbers, NCT00333138
`[core study] and NCT00235430 [extension].)
`
`From the Departments of Neurology and
`Research. University Hospital. Basel.
`Switzerland (L K); Le Centre Universitaire
`de Santé McGill. Montreal Neurological
`Institute. McGill University. Montreal
`(j.A.); Neurology Clinic. San Raffaele
`Hospital. University Vita e Salute. Milan
`(G.C.); Neuroimmunology Unit, Hospital
`Vall d'Hebron, Barcelona (X.M.); Division
`of Neurology. St. Michael's Hospital.
`Toronto (P.O.); DepartmentofNeurology,
`Vrije Universiteit Medical Center. Am-
`sterdam (C.H.P.); Biostatistics and
`Statistical Reporting (T.H.) and Clinical
`Development and Medical Affairs (G.K.),
`Novartis Pharma. Basel. Switzerland;
`Clinical Development and Medical Affairs,
`Novartis Pharmaceuticals. East Hanover.
`NJ (A.A.K.); and Neuroradiology and MS-
`MRI Evaluation Center, University Hospital.
`Basel. Switzerland (EW.R.).Address reprint
`requests to Dr. Kappos atthe Departments
`of Neurology and Research, University
`Hospital. Petersgraben 4. 4031 Basel.
`Switzerland. or at ||rappos®uhbs.ch.
`
`*The members ofthe FI'Y720 D2201 Study
`Group are listed in the Appendix.
`
`N Engl] Med 2006;355:1124-40.
`Copyright o 2006 Massachusetts Medial sway.
`
`1124
`
`u ENGLJ ME!) 355;" WWW.NE’M.ORG SEPTEMBER 14, 2006
`
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`

`

`fingolimod therapy for multiple sclerosis
`
`Multiple sclerosis is the most com-
`
`mon nontraumatic cause of neurologic
`disability in young adults.1,2 It is gener-
`ally believed to be an autoimmune condition in
`which autoreactive T cells attack myelin sheaths,3
`leading to demyelination and axonal damage.4
`Currently approved immunomodulating treat-
`ments for multiple sclerosis (interferon beta and
`glatiramer acetate)5-8 reduce relapse rates by about
`30%.9 Both these drugs are administered either
`subcutaneously or intramuscularly, and interfer-
`ons are associated with systemic reactions in more
`than 60% of patients,10 with implications for ad-
`herence to treatment.11
`Fingolimod (FTY720, Novartis Pharma) is an
`oral sphingosine-1-phosphate receptor modula-
`tor. After rapid phosphorylation, fingolimod-P
`acts as a superagonist of the sphingosine-1-phos-
`phate-1 receptor on thymocytes and lymphocytes
`and induces aberrant internalization of this re-
`ceptor, thereby depriving these cells of a signal
`necessary to egress from secondary lymphoid tis-
`sues. The majority of circulating lymphocytes are
`thus sequestered in lymph nodes, reducing pe-
`ripheral lymphocyte counts and the recirculation
`of lymphocytes to the central nervous system.12-15
`Lymphocytes in secondary lymphoid organs and
`those remaining in blood continue to be func-
`tional. In laboratory animals, fingolimod does
`not impair memory T-cell activation or expan-
`sion in response to systemic viral infection.16 In
`animal models of multiple sclerosis, fingolimod
`prevents the onset of disease and reduces estab-
`lished neurologic deficits.12,17,18
`We conducted a double-blind, placebo-con-
`trolled, proof-of-concept clinical study to evalu-
`ate the efficacy and safety of fingolimod for the
`treatment of relapsing multiple sclerosis.
`
`Methods
`
`The steering-committee members and the spon-
`sors designed the study. The authors had access
`to all data, participated in the analysis and inter-
`pretation of data, and were members of the pub-
`lication committee. The academic authors vouch
`for the completeness and veracity of the data and
`analyses.
`
`Patients
`Eligible patients were 18 to 60 years of age and
`had a diagnosis of relapsing multiple sclerosis19
`
`and at least one of the following: two or more doc-
`umented relapses during the previous 2 years, one
`or more documented relapses in the year before
`enrollment, and one or more gadolinium-enhanced
`lesions detected on magnetic resonance imaging
`(MRI) at screening. Additional eligibility criteria
`included a score of 0 to 6 on the Expanded Dis-
`ability Status Scale (EDSS, on which scores range
`from 0 to 10, with higher scores indicating a great-
`er degree of disability)20 and neurologically sta-
`ble condition, with no evidence of relapse for at
`least 30 days before screening and during the
`screening and baseline phases. Exclusion criteria
`were use of corticosteroids (within the previous
`30 days), immunomodulatory therapy (within the
`previous 3 months), or immunosuppressive treat-
`ment (e.g., azathioprine or methotrexate within
`6 months, cyclophosphamide within 12 months,
`or mitoxantrone or cladribine within 24 months);
`a history of cardiac conditions that might increase
`the risk of a decrease in heart rate; a white-cell
`count of less than 3500 per cubic millimeter; and
`a lymphocyte count of less than 800 per cubic
`millimeter.
`The study adhered to the International Con-
`ference on Harmonization Guidelines for Good
`Clinical Practice21 and was conducted in accor-
`dance with the Declaration of Helsinki.22 An in-
`dependent external data and safety monitoring
`board evaluated adverse events and other safety
`data as well as clinical and MRI efficacy data. All
`patients gave written informed consent.
`
`Study Design and Randomization
`The study included a 6-month double-blind core
`study (months 0 to 6) and a 6-month extension
`study during which the investigators and patients
`were unaware of treatment assignments (months
`7 to 12).
`In the core study, patients were randomly as-
`signed, in a 1:1:1 ratio, to 1.25 mg of fingolimod,
`5.0 mg of fingolimod, or a matching placebo once
`daily; all drugs were given as capsules. Random-
`ization was stratified according to disease course
`(relapsing–remitting or secondary progressive)
`with the use of a centralized automated system
`that provided randomized packages of the study
`drug to each center. The medication was prepack-
`aged on the basis of a block size of 3 (1.25 mg,
`5.0 mg, and placebo); this information was not
`disclosed to investigators and monitors.
`After the core study, patients could continue
`
`n engl j med 355;11 www.nejm.org september 14, 2006
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`in the extension study. Participating patients re-
`ceived a new set of medication and were unaware
`of the treatment assignment; those who had re-
`ceived active treatment in the core study contin-
`ued with the same dose, and those who had re-
`ceived placebo were randomly assigned to receive
`1.25 or 5.0 mg of fingolimod.
`Study visits took place at screening, at base-
`line, on days 1 and 7, and then monthly for
`6 months. In the extension study, visits took
`place on day 1 and at months 9 and 12. MRI of
`the brain was performed at baseline, monthly for
`6 months, and at month 12, with the use of stan-
`dard, predefined acquisition settings. T1-weighted,
`T2-weighted, and proton and density sequences
`were obtained before the administration of gado-
`linium. T1-weighted sequences were also obtained
`after the administration of gadolinium. Vital signs
`were obtained at each visit, and laboratory and
`hematologic measures were obtained at base-
`line, day 1, and months 1, 3, 6, 9, and 12. Electro-
`cardiograms were obtained at baseline, on days
`1 and 7, and at months 1, 3, 6, and 12, and 24-hour
`Holter electrocardiographic monitoring was per-
`formed at selected sites at baseline, day 1, and
`month 3. Pulmonary-function tests, which in-
`cluded the forced expiratory volume in 1 second
`(FEV1), forced vital capacity (FVC), and carbon
`monoxide diffusion capacity, were performed at
`screening and months 6 and 12. These tests were
`introduced by means of a protocol amendment
`and thus were performed in a subgroup of pa-
`tients. Neurologic evaluations were performed at
`baseline and every 3 months thereafter with the
`use of the EDSS and the Multiple Sclerosis Func-
`tional Composite (MSFC, data not shown). Re-
`lapses were confirmed by the treating physician
`on the basis of an examination by the EDSS rater
`who was not otherwise involved in patient care.
`When warranted, relapses were managed by the
`treating physician according to a standardized
`scheme, with up to 1000 mg of methylpredniso-
`lone per day given intravenously for 3 to 5 days.
`
`Study End Points and Procedures
`As previously suggested for phase 2 proof-of-con-
`cept trials in relapsing multiple sclerosis,23,24
`the primary efficacy end point of the study was
`the total number of gadolinium-enhanced le-
`sions per patient recorded on T1-weighted MRI
`at monthly intervals for 6 months. Secondary
`
`MRI variables included the total volume of gado-
`linium-enhanced lesions per patient, the propor-
`tion of patients with gadolinium-enhanced le-
`sions, the total number of new lesions per patient
`on T2-weighted images, changes in lesion vol-
`ume on T2-weighted images, and brain volume
`from baseline to month 6.
`Clinical end points included the number of
`patients remaining free of relapse, the annual-
`ized relapse rate, and the time to the first relapse.
`Confirmed relapse was defined as the occurrence
`of new symptoms or worsening of previously sta-
`ble or improving symptoms and signs not asso-
`ciated with fever, lasting more than 24 hours and
`accompanied by an increase of at least half a
`point in the EDSS score or 1 point in the score for
`at least one of the functional systems (excluding
`the bowel and bladder and mental systems). Neu-
`rologic deterioration that was classified by the
`treating physician as a relapse but that did not
`fulfill these criteria was documented as an un-
`confirmed relapse. In the core study, we performed
`exploratory assessments of disability by compar-
`ing scores on the MSFC and EDSS at baseline with
`scores at month 6. For the extension study, values
`at baseline and month 6 were compared with
`values at month 12.
`MRI scans were assessed for quality and
`compliance at the MS-MRI Evaluation Center in
`Basel without the evaluators’ knowledge of treat-
`ment assignments or clinical results. Lesion vol-
`umes were measured with the use of an interac-
`tive digital-analysis program.25 Brain volume was
`measured with the Structural Image Evaluation
`Using Normalisation of Atrophy (SIENA) pro-
`gram.26 Neurologic assessments were performed
`by specially trained,27 independent neurologists
`who were unaware of the treatment assignments,
`were not involved in the everyday care of the pa-
`tients, and had no access to their medical records.
`Adverse events were assessed and reported at
`each visit (scheduled and unscheduled) by the
`treating physicians. Laboratory evaluations were
`undertaken at a central laboratory. Laboratory
`values that might have revealed the treatment as-
`signment (e.g., lymphocyte counts) were not dis-
`closed to treating physicians unless they exceeded
`prespecified safety limits. In cases of clinical ad-
`verse events or notable laboratory abnormalities,
`the dose of study medication was reduced or with-
`held at the discretion of the treating neurologist.
`
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`fingolimod therapy for multiple sclerosis
`
`Rechallenge after improvement was performed at
`the discretion of the treating neurologist.
`
`Statistical Analysis
`Statistical power and sample size were calculated
`on the basis of data from the Sylvia Lawry Centre
`for Multiple Sclerosis Research,28 with a nonpara-
`metric bootstrap method29 with a two-sided Wil-
`coxon rank-sum test and a 5% significance level.
`For a study with 80 patients per group, we esti-
`mated that the study would have a power of 78%
`if the number of post-baseline lesions on MRI was
`reduced by 50% in the fingolimod groups, as com-
`pared with the placebo group. Assuming that we
`would be able to evaluate data for more than 90%
`of patients, the enrollment of 72 patients with
`data that could be evaluated in each group would
`be sufficient to detect a significant treatment ef-
`fect of 50% with a power of 75%.
`As prespecified, MRI analyses were primar-
`ily performed in a population of patients who
`underwent randomization and who completed
`6 months of treatment, had no major protocol
`violations, and for whom MRI scans were avail-
`able at baseline and on three or more visits. Use
`of a per-protocol–like population for MRI anal-
`yses is appropriate for a proof-of-concept study.
`The intention-to-treat population comprised all
`patients who were randomly assigned to receive
`at least one dose of study medication and had at
`least one post-baseline MRI. MRI analyses were
`repeated for the intention-to-treat population to
`assess the sensitivity of the results with the popu-
`lation with data that could be evaluated. Clinical
`outcomes were evaluated in the intention-to-treat
`population. Safety analyses were undertaken for
`patients who were randomly assigned to receive
`at least one dose of study drug and completed at
`least one safety assessment. Adverse events were
`analyzed by means of Fisher’s exact test.
`MRI end points were compared among the
`groups with the use of nonparametric Wilcoxon
`rank-sum tests. The probability of a first con-
`firmed relapse was calculated by the Kaplan–Meier
`method, with between-group comparisons made
`with the log-rank test. Proportions of patients
`who were free of relapse at month 6 on the basis
`of Kaplan–Meier estimates were compared with
`the use of the z-test. We used a Poisson regres-
`sion model to compare annualized relapse rates.
`Baseline characteristics were assessed with Fish-
`
`er’s exact test for categorical variables and the
`Wilcoxon rank-sum test for continuous variables.
`P values are based on two-sided tests. No interim
`analysis was performed. No adjustments were
`made for multiple comparisons.
`When scans were missing, patients discon-
`tinued treatment, or MRI was performed within
`14 days after corticosteroid treatment and the
`results were therefore considered invalid, the
`median of number and volume of gadolinium-
`enhanced lesions and the number of new lesions
`on monthly T2-weighted scans available post-base-
`line was imputed. Each patient therefore had six
`complete scans, and the totals were compared
`among treatments with a nonparametric Wilcoxon
`rank-sum test. Additional analyses were performed
`with data from the intention-to-treat population
`and actual lesion counts only (i.e., without im-
`puted data). These analyses included Wilcoxon
`rank-sum tests for between-group comparisons
`of the average number of lesions per scan and
`per patient and generalized estimation equations30
`with the use of longitudinal data and adjustment
`for baseline covariates. The Wilcoxon signed-rank
`test was used for within-group comparisons of
`MRI outcomes in the extension study.
`
`R esults
`
`Patients
`Patients were recruited by investigators from 32
`centers in 10 European countries and Canada
`from May 2003 to April 2004. In the 12-month
`extension study, the assessment for the last pa-
`tient was completed in April 2005.
`Figure 1 shows the numbers of patients who
`were randomly assigned to the three study groups
`and who completed treatment. Baseline charac-
`teristics were similar among the three groups
`(Table 1).
`
`MRI Results in the Core Study
`The total cumulative numbers of lesions per
`patient on post-baseline, monthly gadolinium-
`enhanced, T1-weighted MRI scans were lower
`in both fingolimod groups than in the placebo
`group (P<0.001 for the 1.25-mg dose and P = 0.006
`for the 5.0-mg dose) (Table 2).
`At month 6, the proportion of patients who
`were free of gadolinium-enhanced lesions was
`greater in both fingolimod groups than in the
`
`n engl j med 355;11 www.nejm.org september 14, 2006
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`366 Patients assessed
`for eligibility
`
`85 Did not meet eligibility
`criteria
`
`281 Underwent randomization
`
`
`
`92 In intention-to-
`treat population
`
`6 Discontinued
`study drug
`
`11 Discontinued
`5 Discontinued
`study drug
`study drug
`
`
`86 Completed 6 mo
`of placebo
`
`88 Completed 6 mo of
`1.25mg dose offingolimod
`
`81 Completed 6 mo of
`5-mg dose offingolimod
`
`81 in Placebo
`group
`
`77 in S-rng group
`offingolimod
`
`1 Did not
`continue
`
`ofstudy drug
`
`40 Assigned to
`fingolimod, 1.25 mg,
`in extension study
`
`43 Assigned to
`fingolimod, 5 mg.
`in extension study
`
`87 Assigned to
`fingolimod, 1.25 mg.
`in extension study
`
`80 Assigned to
`fingolimod, 5 mg.
`in utension study
`
`4 Discontinued
`study dmg
`
`5 Discontinued
`study drug
`
`7 Discontinued
`study drug
`
`7 Discontinued
`study dmg
`
`36 Completed 12 mo
`ofstudy drug
`
`38 Completed 12 mo
`ofstudy drug
`
`80 Completed 12 mo
`of study dmg
`
`73 Completed 12 mo
`
`figure 1. Nunbers of Patients who Undawent Randomintion and Who Completed Treatment.
`Four patients did not have one or more scans available after baseline and therefore were not included in the intention-to-treat analysis.
`The most common reasons for premature discontinuation were adverse events and withdrawal of consent. In addition to the patients
`who prematurely discontinued study medication. 14 patients were etcluded from the population that could be evaluated because base-
`line and three post-baseline MRI scans were not available or the protocol was violated. These 14 patients completed the core study and
`were eligible to enter the extension phase.
`
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`fingolimod therapy for multiple sclerosis
`
`Table 1. Baseline Characteristics of the Patients.
`
`Characteristic
`Intention-to-treat population
`Age — yr
`Mean
`Range
`Age — no. (%)
`≤30 yr
`31–40 yr
`41–50 yr
`>50 yr
`Male sex — no. (%)
`Interval since first symptoms — yr
`Mean
`Range
`Course of disease — no. (%)
`Relapsing–remitting
`Secondary progressive
`No. of relapses in previous yr
`Mean
`Range
`No. of relapses in previous 2 yr
`Mean
`Range
`Time since most recent relapse — mo
`Mean
`Median (range)
`EDSS score*
`Mean
`Median (range)
`Primary MRI analysis population†
`No. of T1-weighted, gadolinium-enhanced lesions
`at baseline
`
`Mean
`Median (range)
`Patients with T1-weighted, gadolinium-enhanced
`lesions at baseline — no. (%)
`Volume of lesions at baseline — mm3
`T1-weighted, gadolinium-enhanced
`Mean
`Median (range)
`T2-weighted
`Mean
`Median (range)
`
`Placebo
`(N = 92)
`
`Fingolimod, 1.25 mg
`(N = 93)
`
`Fingolimod, 5.0 mg
`(N = 92)
`
`37.1
`19–56
`
`24 (26)
`33 (36)
`30 (33)
`5 (5)
`31 (34)
`
`8.4
`0.2–28.2
`
`83 (90)
`9 (10)
`
`1.2
`0–5
`
`1.8
`0–6
`
`38.0
`19–60
`
`23 (25)
`38 (41)
`21 (23)
`11 (12)
`23 (25)
`
`8.6
`0.3–50.2
`
`83 (89)
`10 (11)
`
`1.3
`0–5
`
`1.9
`0–8
`
`38.3
`18–59
`
`26 (28)
`26 (28)
`24 (26)
`16 (17)
`27 (29)
`
`9.5
`0.5–42.2
`
`80 (87)
`12 (13)
`
`1.3
`0–4
`
`1.9
`0–8
`
`9.2
`6.3 (2–95)
`
`7.3
`6.1 (1–26)
`
`6.3
`5.3 (0–26)
`
`2.6
`2.0 (0.0–6.5)
`
`2.7
`2.5 (0.0–6.0)
`
`2.5
`2.0 (0.0–6.0)
`
`2.8
`1.0 (0–47)
`41 (51)
`
`3.4
`0 (0–72)
`39 (47)
`
`2.8
`1.0 (0–54)
`44 (57)
`
`417
`16 (0–6341)
`
`232
`0 (0–3106)
`
`268
`32 (0–5002)
`
`8805
`5499 (123–62,218)
`
`10,219
`4237 (293–104,504)
`
`8722
`4750 (349–70,218)
`
`* Scores range from 0 to 10; higher scores indicate a greater degree of disability. Scores were available for 91 patients
`in the placebo group, 93 in the 1.25-mg group, and 91 in the 5.0-mg group.
`† Data were available for 81 patients in the placebo group, 83 in the 1.25-mg group, and 77 in the 5-mg group.
`
`n engl j med 355;11 www.nejm.org september 14, 2006
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`placebo group (P<0.001 for both comparisons),
`with a separation between the curves becoming
`evident from 2 months onward (Fig. 2A). With
`the exception of the change in brain volume from
`baseline, all secondary MRI end points differed
`significantly between the fingolimod groups and
`the placebo, in each case favoring treatment with
`fingolimod (Table 2).
`In the population with data that could be
`evaluated, only 1% of scans were missing or in-
`valid (i.e., with the use of imputed values), as
`compared with 6% in the intention-to-treat pop-
`ulation. When sensitivity analyses of data with
`and without imputation were performed for the
`
`intention-to-treat population, all MRI findings
`were similar to those in the population with
`data that could be evaluated and all significant
`differences were maintained.
`
`Clinical Outcomes in the Core Study
`Although the study was not powered to detect a
`treatment effect on the relapse end points, signifi-
`cant improvements over placebo were observed
`in the fingolimod groups, including a relative re-
`duction in the annualized relapse rate (by 53% in
`the 5.0-mg group and by 55% in the 1.25-mg
`group) (Table 2). In addition, the estimated time
`to a first relapse was significantly prolonged in
`
`Table 2. MRI and Clinical End Points at 6 Months in the Core Study.
`
`End Point
`
`Placebo
`
`Fingolimod, 1.25 mg Fingolimod, 5.0 mg
`
`P Value
`
`Primary MRI analysis population
`
`No. evaluated
`
`Total cumulative no. of
`gadolinium-enhanced lesions
`
`Mean ±SD
`
`Median (range)
`
`No. of gadolinium-enhanced lesions at 6 mo
`
`Mean ±SD
`
`Median (range)
`
`Patients free of gadolinium-enhanced
`lesions at 6 mo — no. (%)
`
`Total cumulative volume of
`gadolinium-enhanced lesions — mm3
`Mean ±SD
`
`1.25 mg vs.
`Placebo
`
`5.0 mg vs.
`Placebo
`
`81
`
`83
`
`77
`
`14.8±22.5
`
`5 (0–114)
`
`2.21±4.3
`
`1 (0–26)
`
`38 (47)
`
`8.4±23.7
`
`1 (0–182)
`
`1.29±5.8
`
`0 (0–48)
`
`64 (77)
`
`5.7±11.6
`
`3 (0–91)
`
`0.27±0.7
`
`0 (0–3)
`
`63 (82)
`
`<0.001
`
`0.006
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`1418±2349
`
`715±1658
`
`530±1260
`
`0.002
`
`0.009
`
`Median (range)
`
`335 (0 to 10,975)
`
`69 (0 to 9058)
`
`137 (0 to 7806)
`
`Volume of gadolinium-enhanced lesions at
`6 mo — mm3
`Mean ±SD
`
`242±641
`
`79±294
`
`34±98
`
`<0.001
`
`<0.001
`
`Median (range)
`
`17.2 (0 to 4232)
`
`0 (0 to 1772)
`
`0 (0 to 504)
`
`Total cumulative no. of new T2 lesions
`
`Mean ±SD
`
`Median (range)
`Change in T2 volume from baseline — mm3
`Mean
`
`6.4±9.2
`
`3 (0 to 45)
`
`3.0±8.6
`
`0 (0 to 66)
`
`1.9±2.6
`
`1 (0 to 13)
`
`<0.001
`
`<0.001
`
`+129
`
`−113
`
`−627
`
`0.10
`
`<0.001
`
`Median (range)
`
`−16 (−5056 to 6801)
`
`−97 (−4916 to 4050) −220 (−10,041 to 5734)
`
`Change in brain volume from baseline
`
`Mean
`
`Median (range)
`
`
`
`1130
`
`−0.31
`
`−0.22
`
`−0.40
`
`0.77
`
`0.20
`
`−0.15 (−3.2 to 1.5)
`
`−0.29 (−1.3 to 1.4)
`
`−0.34 (−1.9 to 1.0)
`
`n engl j med 355;11 www.nejm.org september 14, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on April 23, 2019. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`Page 7 of 17
`
`

`

`FINGOLIMOD THERAPY FOR MULTIPLE SCLEROSIS
`
`the fingolimod groups (Fig. 2B). Inclusion ofun-
`confirmed relapses yielded similar results. There
`were no significant differences in disability (EDSS
`scores) at 12 months between the fingolimod
`groups and the placebo group (Table 2).
`
`EXTENSION STUDY
`
`from placebo to fmgolimod (Table 3). Other MRI
`variables consistently showed that fmgolimod
`continued to have a marked effect on inflamma-
`
`tory activity, as reflected by MRI findings (Table
`3). At month 12, more than 80% of patients who
`received fmgolimod were free of gadolinium-
`enhanced lesions.
`
`0f the 255 patients who completed the core
`study, 250 (98%) continued in the extension study
`(Fig. 1). A total of227 ofthese 250 patients (91%)
`completed the 6—month extension study, for a to—
`tal of 12 months in the overall study.
`At month 12, the number of gadolinium-
`enhanced lesions remained low in the two groups
`of patients who received continuous treatment
`with fmgolimod, whereas the number decreased
`significantly among the patients who switched
`
`Among patients who switched from placebo
`to fingolimod, the annualized relapse rate was
`lower during the period of treatment with fingo-
`limod (Table 3). The relapse rates in the groups
`of patients who received continuous fingolimod
`remained low during months 7 to 12, with overall
`12-month relapse rates of 0.31 and 0.29 for the
`1.25-mg dose and the 5.0-mg dose, respectively.
`In both groups of patients who received con-
`tinuous fingolimod, 79% were free of relapse at
`
`Fingoimod, 1.25 mg
`
`Fingolimod, 5.0 mg
`
`P Value
`
`1.25 mg vs. 5.0 mg vs.
`Placebo
`
`Clinical (intention-wheat population)
`No. evaluated
`
`Annualized relapse rate
`
`Relative reduction in relapse rate vs.
`placebo — 96 (95% CI)*
`
`Patients free of relapse at 6 m0— 961‘
`
`Confirmed relapses — no.
`
`All relapses — no.
`
`Confirmed relapses with complete clinical
`recovery— no. (96)
`
`Patients who received corticosteroid therapy
`
`No. (96)
`
`Cumulative dose (mg/kg of body weight)
`
`No. of hospitalizations due to relapse
`EDSS scorej:
`Mean
`
`93
`
`0.35
`
`92
`
`0.36
`
`55 (18 to 75)
`
`53 (14 to 74)
`
`66
`
`34
`
`40
`
`86
`
`16
`
`21
`
`86
`
`16
`
`18
`
`12 (35)
`
`12 (75)
`
`7 (44)
`
`23 (25)
`
`2372
`
`4
`
`2.7
`
`11(12)
`848
`
`2
`
`2.6
`
`10 (11)
`725
`
`1
`
`2.6
`
`Placebo
`
`Median (range)
`
`2.3 (0 to 7.0)
`
`2.0 (o to 6.5)
`
`2.0 (0 to 6.0)
`
`Categorical change from baseline in EDSS
`score— no./total no. (96);
`
`Improved or stable
`Worse
`
`71/89 (80)
`
`18/89 (20)
`
`84/93 (90)
`
`9/93 (10)
`
`75/88 (85)
`
`13/88 (15)
`
`* Data are from the Poisson regression model. Cl denotes confidence interval.
`1- Data are Kaplan—Meier estimates.
`1: Scores range from 0 to 10; higher scores indicate a higher degree of disability.
`s The change in the EDSS score could not be calculated for seven patients because of missing scores at baseline, at 6 months. or both.
`Improvement was defined as a decrease of 1.0 point or more. stable condition as a change of no more than half a point, and worsening
`as an increase of 1.0 point or more.
`
`N ENGL) MED 355;" www.NE)u.onc sznsunn 14, 2006
`
`1131
`
`Page 8 of 17
`
`TheNewEnglandJomnalofMedidne
`DownloadedfiomnejmosgonAprilB,2019.Fotpusomluseonly.Noodietuseswitlxmtpermission.
`Copyright02006MassaclnnemMedicalSocietyAllrigh8reserved
`
`

`

`
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`Fingolimod, 5 mg
`(N=77)
`P<0.0l
`
`Fingolimod, 1.25 mg
`(N=83)
`P<0.0l
`
`
`
`PatientsFreeofLesions(36)
`
`
`
`
`
`Fingolimod, 1.25 mg (N=93)
`P=0.007
`
`Fingolimod, 5 mg
`(N=92)
`9:091
`
`g “
`
`39
`
`'
`'68
`
`The study medication was discontinued because
`of adverse events in four patients who received
`placebo, in five patients who received 1.25 mg of
`fmgolimod, and in eight patients who received
`5.0 mg offmgolimod. The incidence of serious ad-
`verse events was similar among the study groups
`(Table 4); no patient died.
`The overall incidence of adverse events in the
`
`extension study was lower than that in the core
`study, with nasopharyngiu's, influenza, and head-
`ache reported most frequently (Table 5). No in-
`fections were reported as serious adverse events
`in the core study. 'IWO infections were reported
`as serious adverse events during the extension:
`one case of facial herpes zoster in a patient who
`switched from placebo to fingolimod at a dose
`of 5.0 mg and one case of enterocolitis in a pa-
`tient who switched from placebo to fingolimod
`at a dose of 1.25 mg.
`In the core study, after 10 weeks of treatment
`with fmgolimod at a dose of 5.0 mg, the poste-
`rior reversible encephalopathy syndrome devel-
`oped in a 52-year-old woman. This syndrome was
`characterized clinically by headache, acute corti-
`cal blindness, ophthalmoplegia, dysarthria, and
`ataxia. MRI showed diffuse areas of hyperin-
`tensity in the occipital region and brain stem on
`Tz-weighted scans — findings consistent with
`the presence of posterior reversible encephalopa-
`thy syndrome”,32 The patient did not have a his-
`tory of hypertension or renal disease. Neurologic
`symptoms and the hyperintense areas on MRI
`began to improve 72 hours after the discontinu-
`ation of treatment, leaving a residual right hom-
`onymous hemianopia corresponding to a left oc-
`cipital hyperintensity and mild ataxia, which did
`not change after 15 months of follow-up.
`Clinically asymptomatic lymphopenia and in-
`creases in liver enzyme levels (mainly alanine
`aminotransferase) were the most common labo-
`ratory abnormalities. Peripheral-blood lympho-
`cyte counts decreased rapidly to approximately
`20 to 30% of the baseline value in both fmgoli-
`mod groups. During the core study, an increase
`in the alanine aminotransferase level to three or
`
`more times the upper limit of the normal range
`(290 U per liter in women and 2117 U per liter
`in men) was more frequent with fingolimod (in
`10% of the patients who received 1.25 mg and in
`12% of those who received 5 mg) than with pla-
`cebo (1%; P=0.02 and P<0.005, respectively). Ele-
`vations ofaspartate aminotransferase levels were
`
`E
`
`I?K
`
`g.
`
`3E
`
`40
`
`60
`
`80
`
`IN 120
`
`140
`
`160
`
`180
`
`200
`
`'l‘lmeloFirleonfirmed Rdapse (days)
`
`Figure 2. Proportion of Pah'ents who Were Free ofGadolinium-Enhanced
`Lesions on T,-Weigllted MRI at 0 to 6 Months (Panel A) and the Estimated
`Time to a First Confirmed Relapse (Panel B).
`P values are for each fingolimod dose as compared with placebo.
`
`month 12, whereas 65 to 67% were free ofrelapse
`in the groups given placebo and fmgolimod. The
`EDSS scores did not worsen during 12 months
`of treatment.
`
`ADVERSE EVENTS
`
`In the core study, the incidence of adverse events
`was higher in the group of patients who received
`fmgolimod at a dose of 5.0 mg per day than in
`the group that received the 1.25-mg dose and the
`placebo group (Table 4). Frequently reported ad-
`verse events associated with fmgolimod were na-
`sopharyngitis and dyspnea (both mainly in the
`group of p