RESUMEN
BACKGROUND AND PURPOSE: Although the number of enhancing lesions is the typical outcome measure of choice in clinical trials in MS, a potentially more sensitive and statistically more powerful outcome measure is the volume of enhancing lesions. In this study, we assessed the distribution and statistical power of the volume of enhancing brain lesions as an outcome measure by means of their required sample size, and we compared the results with the number of enhancing lesions. MATERIAL AND METHODS: First, a literature search was performed to compare the effects of treatment on the number and volume of enhancing lesions. Then, a statistical model was proposed to describe the distribution of the volume of enhancing lesions in 2 datasets of patients with RRMS, and sample sizes for enhancing-lesion volume as primary outcome measure were calculated. RESULTS: A mixture of the binomial and Weibull distribution was determined to model enhancing-lesion volumes in patients. Sample size calculations for enhancing-lesion volumes showed that approximately 94 patients per arm would be required to detect a combination of 20% decrease in lesion volume and 20% increase in patients without enhancing lesions, whereas calculations for enhancing-lesion counts showed that approximately 129 patients would be required to detect a 50% decrease. CONCLUSIONS: The mixture of the binomial and Weibull distribution is a suitable approach in modeling new enhancing-lesion volumes in MS and yielded feasible sample size estimates for clinical trials, showing lesion volumes to be an advantageous outcome measure compared with lesion counts in terms of statistical power.
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Ensayos Clínicos como Asunto/métodos , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/estadística & datos numéricos , Modelos Estadísticos , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Adulto , Encéfalo/patología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Simulación por Computador , Interpretación Estadística de Datos , Femenino , Humanos , Aumento de la Imagen/métodos , Masculino , Modelos Biológicos , Esclerosis Múltiple/epidemiología , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
Interferon-ß (IFNß) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNß treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNß compared with patients carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNß treatment (P=0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P=0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNß treatment and MRI-based non-responder status was observed (P=0.103 and P=0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P=0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNß therapy that might have relevance as biomarker to predict the response to IFNß in multiple sclerosis.
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Factores Reguladores del Interferón/genética , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Biomarcadores , Estudios de Cohortes , Femenino , Expresión Génica , Variación Genética , Genotipo , Humanos , Interferón beta/farmacología , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple Recurrente-Remitente/genética , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
Magnetization transfer ratio (MTR) is a sensitive parameter to quantify the integrity of myelinated white matter in patients with multiple sclerosis. Lesional MTR decreases in the acute phase due to demyelination, and subsequently shows recovery depending on the degree of remyelination in the absence of axonal loss. Recovery of average lesion MTR therefore might prove a viable outcome measure to assess the effect of remyelinating agents. Our objective was to determine the required sample size for phase II multicentre clinical trials using the recovery of average lesion MTR as primary outcome measure. With 7-monthly MRI scans, the MTR evolution of 349 new enhancing lesions before and after enhancement was assessed in 32 MS patients from 5 centres. Multilevel models were fitted to the data yielding estimates for the variance components, which were applied in power calculations. Sample sizes were determined for placebo-controlled, multicentre trials using lesional MTR recovery post-enhancement as primary outcome measure. Average lesion MTR decreased slightly in the build-up to enhancement, decreased dramatically during enhancement and showed recovery in the period after cessation. The power calculations showed that for a power of 80%, approximately 136 patients per trial (mean number of 6 lesions per patient) are required to detect a 30% increase in lesional MTR post-enhancement compared with placebo, whereas 48 subjects are required to detect a 50% increase in lesional MTR compared with placebo. Recovery of lesion MTR is a feasible outcome measure for future multicentre clinical trials measuring the effect of remyelinating agents.
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Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/patología , Fibras Nerviosas Mielínicas/patología , Adulto , Distribución de Chi-Cuadrado , Ensayos Clínicos como Asunto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
INTRODUCTION: Cerebral atrophy is a compound measure of the neurodegenerative component of multiple sclerosis (MS) and a conceivable outcome measure for clinical trials monitoring the effect of neuroprotective agents. In this study, we evaluate the rate of cerebral atrophy in a 6-month period, investigate the predictive and explanatory value of other magnetic resonance imaging (MRI) measures in relation to cerebral atrophy, and determine sample sizes for future short-term clinical trials using cerebral atrophy as primary outcome measure. METHODS: One hundred thirty-five relapsing-remitting multiple sclerosis patients underwent six monthly MRI scans from which the percentage brain volume change (PBVC) and the number and volume of gadolinium (Gd)-enhancing lesions, T2 lesions, and persistent black holes (PBH) were determined. By means of multiple linear regression analysis, the relationship between focal MRI variables and PBVC was assessed. Sample size calculations were performed for all patients and subgroups selected for enhancement or a high T2 lesion load at baseline. RESULTS: A significant atrophy occurred over 6 months (PBVC = -0.33%, SE = 0.061, p < 0.0001). The number of baseline T2 lesions (p = 0.024), the on-study Gd-enhancing lesion volume (p = 0.044), and the number of on-study PBHs (p = 0.003) were associated with an increased rate of atrophy. For a 50% decrease in rate of atrophy, the sample size calculations showed that approximately 283 patients per arm are required in an unselected sampled population and 185 patients per arm are required in a selected population. CONCLUSION: Within a 6-month period, significant atrophy can be detected and on-study associations of PBVC and PBHs emphasizes axonal loss to be a driving mechanism. Application as primary outcome measure in short-term clinical trials with feasible sample size requires a potent drug to obtain sufficient power.
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Encéfalo/patología , Interferón beta/uso terapéutico , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Evaluación de Resultado en la Atención de Salud/métodos , Adyuvantes Inmunológicos/uso terapéutico , Adulto , Atrofia/tratamiento farmacológico , Atrofia/patología , Encéfalo/efectos de los fármacos , Estudios de Factibilidad , Femenino , Humanos , Interferón beta-1a , Estudios Longitudinales , Masculino , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
BACKGROUND: MRI is often used as primary outcome measure in phase II clinical trials in multiple sclerosis (MS). Since persistent T1 hypointense lesions are a surrogate parameter for axonal damage and demyelination, they may serve as a marker for monitoring the efficacy of neuroprotective drugs. At present, a power analysis using black hole (BH) evolution as primary outcome measure has not been performed. OBJECTIVE: To assess the feasibility of using BH evolution on serial brain MR images as primary outcome measure in proof of concept studies in MS. METHODS: MRI-data obtained from 169 active RRMS patients were analysed for BH evolution by determining the cumulative number of contrast enhancing lesions (CEL) evolving into a persistent black hole (PBH) after 3 months. With a parametric simulation procedure, based on a statistical distribution fitting the data, sample sizes were calculated. RESULTS: 21.2% of the total number of CELs observed during the study period evolved into a PBH. Ring enhancing lesions evolved most frequently into a PBH (59.4%), followed by lesions larger than 10 mm (57.4%) and periventricular CELs (30.6%). The simulation procedure, based on the statistical negative binomial (NB) model resulted in a sample sizes between 200 subjects and 30 subjects per arm, for treatment effects ranging from 50% to 90% reduction of the number of CELs evolving into a PBH, respectively. CONCLUSION: To perform a MRI monitored phase II clinical trial with a feasible sample size, using the evolution of CELs into PBHs as primary outcome parameter, a potent drug is required to obtain sufficient power.