Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial

Lublin, Fred; Miller, David H.; Freedman, Mark S.; Cree, Bruce A.C.; Wolinsky, Jerry S.; Weiner, Howard L.; Lubetzki, Catherine; Hartung, Hans‐Peter; Montalbán, Xavier; Uitdehaag, Bernard M. J.; Merschhemke, Martin; Li, Bingbing; Putzki, Norman; Liu, Fonda C; Häring, Dieter A.; Kappos, Ludwig

doi:10.1016/s0140-6736(15)01314-8

Cited by 398 publications

(354 citation statements)

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“…At baseline, the placebo population ( n = 487) had a median age of 49 years, median of 5.7 years since onset of symptoms, median Expanded Disability Status Scale (EDSS)10 score of 4.5; and 13% of patients had gadolinium‐enhancing T1 (Gd+) lesions. Over the ≥3‐year course of the study, there was a mean of 0.5 new/enlarging T2 lesions per patient per year, and 8% of patients experienced a relapse 1. The study found no significant difference between fingolimod 0.5 mg and placebo for the composite primary endpoint, 3‐month confirmed disability progression according to worsening of any one of: EDSS, 25‐foot timed‐walk test (25'TWT),11 or nine‐hole peg test (9‐HPT) 11, 12.…”

Section: Methodsmentioning

confidence: 99%

“…Fingolimod reduced the risk of disability worsening in relapsing‐remitting MS (RRMS) and consistently reduced brain volume loss by more than 30% compared with placebo or interferon‐beta in three randomized, controlled clinical trials 7, 8, 9. In PPMS, however, fingolimod treatment did not reduce disability worsening or brain volume loss, perhaps suggesting differences in pathogenesis of both disability progression and brain volume loss between RRMS and PPMS 1. The question arises whether normalized brain volume and brain volume loss are associated with disability progression in PPMS.…”

Section: Introductionmentioning

confidence: 99%

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Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692).MethodsMagnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease‐burden covariates.ResultsBaseline normalized brain volume was predictive of disability worsening: Risk of 3‐month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log‐rank test: P = 0.0297). Moreover, on‐study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium‐enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001).InterpretationBaseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti‐inflammatory treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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“…Five years after disease onset she was enrolled in the phase III trial of fingolimod 0.5 mg/day in PPMS (INFORMS) 1. She had never been treated with a DMT before.…”

Section: Case Reportmentioning

confidence: 99%

“…It has also undergone a phase III trial in people with progressive MS (pwPMS) failing to show efficacy on the primary endpoint 1. A key mechanism of action of fingolimod is believed to be sequestering of pathogenic lymphocytes in lymph nodes2 thereby preventing entry into the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis

Alvarez-Gonzalez

Adams

Mathews

et al. 2017

Ann Clin Transl Neurol

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Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium‐enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short‐term safety issues or adverse events.

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“…Preventing progression is an essential treatment goal in PPMS, a goal that drugs tested in previous clinical studies failed to achieve 2, 3, 4. Ascertaining the absence of progression in both clinical trials and clinical practice requires reliable and comprehensive measures of disease progression.…”

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confidence: 99%

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

Wolinsky

Montalbán

Hauser

et al. 2018

Annals of Neurology

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ObjectiveNo evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo‐controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post‐hoc analysis.MethodsThe proportion of patients with NEPAD (no evidence of progression [NEP; no 12‐week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12‐week confirmed progression of ≥20% on the Timed 25‐Foot Walk test and 9‐Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium‐enhancing lesions], and no protocol‐defined relapse) from baseline to week 120 was determined in ocrelizumab‐ (600 mg; n = 465) and placebo‐treated (n = 234) patients.ResultsThe majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab‐treated compared to 9.4% and 29.1% placebo‐treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07–4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17–1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes.InterpretationCompared to placebo, ocrelizumab enhanced 3‐fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527–536

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Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial

Abstract: Novartis Pharma AG.

Cited by 398 publications

References 28 publications

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

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