Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial

Ebers, George C.; Traboulsee, Anthony; Li, D; Langdon, Dawn; Reder, Anthony T.; Goodin, Douglas S.; Bogumil, Timon; Beckmann, Karola; Wolf, Christian; Konieczny, A

doi:10.1136/jnnp.2009.204123

Cited by 119 publications

(92 citation statements)

References 33 publications

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“…Furthermore, the medications taken after the end of the pivotal study did not differ systematically. 18 Taken together, these observations support the notion that there is a survival advantage after early exposure to IFN␤-1b.…”

Section: Discussionsupporting

confidence: 77%

“…27 We observed this in our own work: the death rate in the unidentified patient cohort in the 16Y-LTF study (18.4% [7 of 38]) was higher than that observed in the identified cohort (10.7% [35 of 328]). 18 Moreover, the 5 years between the 16Y-LTF and 21Y-LTF studies resulted in a doubling of the number of observed deaths (35 vs 81 deaths), increasing the precision of the estimates. The results of the 21Y-LTF study extend the treatment benefits first suggested in the 16Y-LTF study.…”

Section: Discussionmentioning

confidence: 99%

“…Deceased patients therefore represented 18.4% (7 of 38) of those unidentified patients in the 16Y-LTF cohort, a higher proportion than the 10.7% (35 of 328) originally reported. 18 The median time from pivotal trial randomization to 21Y-LTF was 21.1 years. There were no notable differences in baseline characteristics among the groups at the start of the RCT for the 366 patients identified at 21Y-LTF (table e-1).…”

Section: Patient Identification and Baseline Characteristicsmentioning

confidence: 99%

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Survival in MS

Goodin¹,

Reder²,

Ebers³

et al. 2012

Neurology

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222

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Objective: To examine the effects of interferon beta (IFN␤)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. Methods:For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFN␤-1b 250 g and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-totreat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.Results: After a median of 21.1 years from RCT enrollment, 98.4% (366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFN␤-1b 250 g showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p ϭ 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFN␤-1b 250 g-treated patients (46.0% among IFN␤-1b 50 g-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. Conclusions:There was a significant survival advantage in this cohort of patients receiving early IFN␤-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFN␤-1b benefit on all-cause mortality. Classification of Evidence:This study provides Class III evidence that early treatment with IFN␤-1b is associated with prolonged survival in initially treatment-naive patients with relapsingremitting multiple sclerosis. Neurology Multiple sclerosis (MS) is a chronic, inflammatory disease of the CNS with a lifelong course, necessitating outcome assessments over both the short term and long term.1 However, randomized clinical trials (RCTs) have typically focused only on short-term outcomes such as clinical measures of relapse and physical disability, as well as MRI measures of disease activity and severity.2-8 Although survival is the ultimate long-term outcome, to date mortality in patients with MS treated with disease-modifying therapy (DMT) has not been well-studied, largely because of the length and completeness of observation needed. 9 *These authors contributed equally to this work.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Patient Identification and Baseline Characteristicsmentioning

confidence: 99%

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Survival in MS

Goodin¹,

Reder²,

Ebers³

et al. 2012

Neurology

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222

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“…Here, we will describe only the longest running of these follow up trials as an example. To address the question of long term survival in MS patients, the 16 year and 21 year Long Term Follow-up investigators evaluated a cohort of participants from the pivotal IFNB Multiple Sclerosis Study Group trial, which evaluated the use of IFNB-1b SC 50 mcg, 250 mcg QOD vs placebo [57,58]. In the 21 year long term follow up study, the investigators were able to identify 366 of the original 372 participants.…”

Section: Long Term Follow Upmentioning

confidence: 99%

Interferon Beta and Glatiramer Acetate Therapy

McGraw

Lublin

2013

Neurotherapeutics

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“…They reduce relapses by approximately 30%, though evidence they truly affect the long-term outcome of MS is sparse. 4,5 These drugs have also been trialled in patients who have experienced a single attack or 'clinically isolated syndrome' (CIS) (ie before MS has been confirmed), in the hope treatment would delay or even prevent the development of MS. All these studies showed similar results: a statistically significant delay in the time to development of MS. Sounds impressive?…”

Section: Modern Approaches To Multiple Sclerosis Martin Wilsonmentioning

confidence: 99%

Modern approaches to multiple sclerosis

Wilson

2011

Clinical Medicine

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This article will summarise aspects of 'modern approaches to multiple sclerosis (MS)' , focusing on areas where there has been significant change in practice within the last decade, and in particular the new therapeutic agents available for relapsing MS which have posed new dilemmas for neurologists prescribing disease modifying therapies (DMT) for the condition.The basics: aetiology, pathology, and classification MS is a common cause of neurological disability in young and middle age adults, second only to trauma in the UK. Approximately 80,000 individuals in the UK have MS. MS is considered to be a predominantly autoimmune, T-cell mediated disease occurring in genetically predisposed individuals after one or more environmental 'triggers' . The identity of the trigger(s) remains unknown, but currently favoured candidates include childhood Epstein-Barr virus infection, and low vitamin D levels. The result is the onset, usually in adulthood, of lesions affecting the white matter of the central nervous system (CNS), as in the brain, spinal cord and optic nerves. The pathology is characterised by demyelination and axonal loss in the CNS white matter (Fig 1). 1 MS is classified into subtypes according to a simple, but useful scheme: it is purely clinical, based upon the observations of the patient's pattern of disease (Fig 2).Most patients present with a relapsing-remitting disease (RRMS), with relapses ('attacks') followed by recovery (partial or complete), with marked variability in both severity of relapses, and interval between them. A large proportion of patients with RRMS will eventually develop 'secondary progressive' disease (SPMS), characterised by a reduction or cessation of acute relapses but instead a gradual worsening of disability (Fig 2). The length of time spent in the relapsing phase is markedly variable, but once secondary progression is established the rate of progression is fairly predictable, and essentially irreversible. 2 There are no DMT for progressive forms of MS. Diagnosis of multiple sclerosisThe diagnosis of MS (in its relapsing forms) has long been based upon clinical observation of 'lesions disseminated in both space and time': that is to say, symptoms and signs (consistent with inflammatory demyelination) occurring in different areas of the CNS and at different times (for example an optic neuritis in 2001 and partial myelitis in 2003). The diagnosis is usually confirmed by typical abnormalities on magnetic resonance imaging (MRI) of the brain (Fig 3) and/or cord: other investigations including lumbar puncture, evoked responses and blood testing can all be useful if the clinical or radiological presentation is atypical.The current 'McDonald criteria' 3 have introduced one significant change to the way we can confirm a diagnosis: although still crucial to demonstrate 'dissemination in time' , this can now be done radiologically rather than clinically. In other words, following a first attack of demyelination (for example optic neuritis), and with an abnormal MRI scan, the clinician and ...

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Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial

Cited by 119 publications

References 33 publications

Survival in MS

Survival in MS

Interferon Beta and Glatiramer Acetate Therapy

Modern approaches to multiple sclerosis

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