Outcomes assessment in multiple sclerosis clinical trials: a critical analysis

Abstract

The feasibility and precision of clinical trials for the treatment of MS must be improved. Subsequent to the approval by the Food and Drug Administration of the United States of interferon beta-Ib as a safe and effective, though not curative, treatment for relapsing-remitting MS, the testing of other agents in this disease has been undertaken or is anticipated. This report summarises the discussions and recommendations of an international workshop held to review critically the elements of current MS therapeutic trials and to identify the most important aspects of clinical evaluation, study design and data analysis that would allow agents for MS to be tested as accurately, rapidly and economically as possible. While acknowledging the many uncertainties about the pathophysiology and natural history of MS, the workshop participants made recommendations about the preferred components to be used in the design of trials which may be different depending on the treatment goal and agent studied. It was concluded that the formulation of a useful clinical trial design must be based on specific guidelines for clinical scales and imaging for which task forces were recommended and subsequently appointed.

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

“…With more therapies available, it has become practically and ethically difficult to design and implement multiyear placebo-controlled randomized clinical trials. Shorter trials based on surrogate outcomes using fewer patients are of interest when determining a clinical outcome is impractical, inconvenient, uncomfortable, or intolerable for subjects [7][8][9][10]. Changes in MS brain lesion patterns determined by magnetic resonance imaging (MRI) reflect changes in underlying disease pathology [7][8][9]11], providing a strong theoretical basis for surrogacy.…”

Measuring Disability Progression with the Multiple Sclerosis Functional Composite

“…At this workshop, participants agreed that there was no optimal assessment measure available and recommended the development of a multidimensional assessment tool incorporating multiple clinically independent dimensions of MS, including cognitive function. 15 A task force was then appointed to recommend improved clinical outcome measures. This task force published important criteria for MS clinical trial outcome measures 16 and conducted a meta-analysis of quantitative measures of arm, leg, cognitive, and visual function from historic data collected in natural-history and clinical studies of MS. 17 This led to the development of the multiple sclerosis functional composite (MSFC).…”

Teste de destreza manual da caixa e blocos em indivíduos normais e em pacientes com esclerose múltipla

“…Por exemplo, esta escala dá grande ênfase às funções piramidais e cerebelares, sendo pouco sensível quando o escore varia de 2,0 a 4,0. Assim, um paciente com discreta paraparesia (escore 3 na função piramidal), que desenvolve fraqueza em membro superior provavelmente não terá alteração no escore, mesmo porque há muita subjetividade nestas avaliações 11,12 . Outra crítica a este procedimento é o fato de privilegiar o EDSS excessivamente as dificuldades à marcha, sintoma que muitos destes pacientes apresentam na evolução da doença, em detrimento da avaliação de eventual comprometimento dos membros superiores 11,13 .…”

“…Outra crítica a este procedimento é o fato de privilegiar o EDSS excessivamente as dificuldades à marcha, sintoma que muitos destes pacientes apresentam na evolução da doença, em detrimento da avaliação de eventual comprometimento dos membros superiores 11,13 . Finalmente, com certa frequên-cia, pacientes com EM apresentam surtos da doença com importante impacto na sua qualidade de vida devido à fadiga que é o sintoma predominante e não citado na escala de Kurtzke 12,13 . Outras escalas tem sido utilizadas para complementar a avaliação clínica destes pacientes, como a Neurological Rating Scale (NRS) 14 e a Escala Ambulatorial 15 porém, estas também priorizam o acometimento dos membros inferiores.…”