Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

doi:10.1016/S0140-6736(09)61259-9

The Lancet

Volume 374, Issue 9700, 31 October–6 November 2009, Pages 1503-1511

https://doi.org/10.1016/S0140-6736(09)61259-9 Get rights and content

Summary

Background

Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis.

Methods

In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224.

Findings

All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0·55, 95% CI 0·40–0·77; p=0·0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]).

Interpretation

Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI.

Funding

Teva Pharmaceutical Industries, Israel.

Introduction

Multiple sclerosis is an inflammatory demyelinating disease of the CNS with axonal injury and loss, which are closely associated with the acute inflammatory phase of lesion development. The extent of axonal injury correlates with the degree of inflammation, which depends on disease duration and clinical categorisation.¹ Clinically isolated syndrome is the term commonly used for a neurological attack, lasting at least 24 h, which is presumably caused by inflammatory demyelination in one or more sites of the CNS. Patients who present with clinically isolated syndrome do not have evidence of the dissemination in time or space that is required for diagnosis of multiple sclerosis,² but have a variable risk to develop this disease.1, 3, 4

Pathological and MRI studies, especially those using new techniques exploring structural nervous damage, have shown that irreversible axonal damage is already detectable at the first attack of multiple sclerosis, probably because of the inflammation-induced axonal transection produced in the acute lesions.5, 6, 7, 8 Moreover, the amount of inflammatory activity at clinical presentation of the disease has some predictive value for long-term disability.⁹ Thus, some investigators have suggested early treatment with disease-modifying drugs to prevent or delay the initiation or progression of irreversible neuronal damage.1, 10, 11 Six disease-modifying drugs are approved for use in relapsing forms of this disease.¹² Of these drugs, intramuscular interferon beta-1a¹³ and subcutaneous interferon beta-1b¹⁴ have been approved for reducing risk and delaying time to a second demyelinating event in patients with clinically isolated syndrome.

Glatiramer acetate (Copaxone) is approved for reduction in the frequency of relapses in patients with relapsing-remitting multiple sclerosis. Daily subcutaneous injection of glatiramer acetate reduces relapse rate, MRI activity, and disease burden.15, 16, 17 On the basis of glatiramer acetate's mechanism of action, its proven efficacy, and favourable safety profile, this drug was regarded as a promising candidate for the treatment of patients with clinically isolated syndrome. The PreCISe (early glatiramer acetate treatment in delaying conversion to clinically definite multiple sclerosis in subjects Presenting with a Clinically Isolated Syndrome) study was therefore designed to assess the effect of glatiramer acetate compared with placebo on the time to clinically definite multiple sclerosis.

Section snippets

Study design and patients

The PreCISe trial was a randomised, double-blind, placebo-controlled, parallel group phase 3 study. It was undertaken in 16 countries worldwide, in 80 sites from the USA, Europe, Argentina, Australia, and New Zealand.

Enrolment started in January, 2004, and was completed in January, 2006. Patients aged between 18 and 45 years inclusive, with one unifocal neurological event, and positive brain MRI at screening scan were included. Brain MRI was positive if there were at least two cerebral lesions

Results

Figure 1 shows the trial profile. 619 patients were screened; 138 were defined by the EEC as screening failures. 243 patients were randomly assigned to receive glatiramer acetate 20 mg and 238 to receive placebo (figure 1). 193 (40%) patients were still in the double-blind, placebo-controlled phase at the cut-off date of the interim analysis. 230 (48%) patients had completed the placebo-controlled phase either because of conversion to clinically definite multiple sclerosis (n=162; 34%) or after

Discussion

Findings from this study have shown that early treatment with glatiramer acetate for patients with clinically isolated syndrome, who are at high risk of developing multiple sclerosis, significantly reduced the frequency of conversion to clinically definite disease and delayed the occurrence of a second attack. The robustness of the positive results was emphasised by the concomitant efficacy of glatiramer acetate in reducing all the MRI measures of disease activity.

The concomitant efficacy

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Estos cambios han motivado la presente actualización del consenso mediante metodología Delphi, con el objetivo de reflejar el nuevo paradigma de manejo del paciente con EM basándose en la evidencia científica y la experiencia clínica de los participantes.
Entre las principales conclusiones destacan como recomendaciones: iniciar TME inmunomodulador en el síndrome radiológico aislado con actividad radiológica persistente, evaluar la perspectiva del paciente y abandonar la terminología «líneas de tratamiento» en la clasificación de los TME (consenso mayor del 90%). Tras el diagnóstico de EM la elección del primer TME debería considerar la presencia/ausencia de factores de mal pronóstico (epidemiológicos, clínicos, radiológicos y biomarcadores) para la aparición de nuevos brotes o progresión de discapacidad, pudiendo plantear desde el inicio TME de alta eficacia.
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In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants.
The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term “lines of therapy” no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset.
Consensus recommendations for diagnosis and treatment of Multiple Sclerosis: 2023 revision of the MENACTRIMS guidelines
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With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.
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Although MS is a relatively common CNS disease, treatment modalities for MS are not always easily accessible and the available ones being expensive, MS often poses a significant financial burden on the patients and their families. Being a chronic disease, it also leads to problems with daily functioning and loss or lack of employment, overburdening the caregiver. These problems could be overcome with a better understanding of the disease, its risk factors, pathology, and diagnostic and therapeutic approaches. There are studies that have led to improvement in the management of MS, and there are ongoing studies that need to be applied clinically and therapeutically to see any additional significant advances in the future.
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Lesions in the periventricular, (juxta)cortical, and infratentorial region, as visible on brain MRI, are part of the diagnostic criteria for Multiple sclerosis (MS) whereas lesions in the subcortical region are currently only a marker of disease activity. It is unknown whether MS lesions follow individual spatial patterns or whether they occur in a random manner across diagnostic regions.
First, to describe cross-sectionally the spatial lesion patterns in patients with MS. Second, to investigate the spatial association of new lesions and lesions at baseline across diagnostic regions.
Experienced neuroradiologists analyzed brain MRI (3D, 3T) in a cohort of 330 early MS patients. Lesions at baseline and new solitary lesions after two years were segmented (manually and by consensus) and classified as periventricular, (juxta)cortical, or infratentorial (diagnostic regions) or subcortical—with or without Gadolinium-enhancement. Gadolinium enhancement of lesions in the different regions was compared by Chi square test. New lesions in the four regions served as dependent variable in four zero-inflated Poisson models each with the six independent variables of lesions in the four regions at baseline, age and gender.
At baseline, lesions were most often observed in the subcortical region (mean 13.0 lesions/patient), while lesion volume was highest in the periventricular region (mean 2287 µl/patient). Subcortical lesions were less likely to show gadolinium enhancement (3.1 %) than juxtacortical (4.3 %), periventricular (5.3 %) or infratentorial lesions (7.2 %). Age was inversely correlated with new periventricular, juxtacortical and subcortical lesions. New lesions in the periventricular, juxtacortical and infratentorial region showed a significant autocorrelative behavior being positively related to the number of lesions in the respective regions at baseline. New lesions in the subcortical region showed a different behavior with a positive association with baseline periventricular lesions and a negative association with baseline infratentorial lesions.
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NCT04877457

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ArticlesEffect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Lancet Neurol

Lancet Neurol

J Neuroimmunol

Lancet

Lancet Neurol

Clinically isolated syndromes. Predicting and delaying multiple sclerosis

Neurology

Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald” criteria

Ann Neurol

Axonal transection in the lesions of multiple sclerosis

N Engl J Med

Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time

Brain

The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA

J Neurol

Simple and complex movement-associated functional MRI changes in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis

Hum Brain Mapp

Future Therapies in multiple sclerosis. Early treatment

Neurol Sci

Evidence of axonal damage in the early stages of multiple sclerosis and itsrelevance to disability

Arch Neurol

Articles
Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial