Multiple Sclerosis
Numerous drugs have been tested and proven to be effective in defeating or at least controlling the inflammatory phase of MS, with little or unknown independent effect on the neurodegenerative component. IFNβ-1b belongs to this group of drugs.
Clinical and Imaging Parameters to Measure Disease Progression and Drug Efficacy in Multiple Sclerosis Clinical Measures
The main clinical metrics used thus far for measuring IFNβ-1b’s effect in MS are:
• relapse rate; • proportion of relapse-free patients; • severity of relapse; •
• •
They permit the identification and computation of acute and chronic WM lesions (see details later). These measures are currently mostly employed in clinical trials. WM lesion identification and computation is a sensitive method for assessing disease progression and at the same time is highly reproducible across different centres. Non-conventional MRI techniques allow one to obtain quantitative measurements of brain and spinal cord normal-appearing WM (NAWM), normal-appearing GM and lesions. One such technique is magnetization transfer imaging (MTI). Quantities derived from MTI, namely magnetization transfer ratios (MTRs), are considered to indirectly reflect the amount of demyelination and axonal loss within visible lesions as well as in regions of normal-appearing tissue and lesions.
disability progression according to the Expanded Disability Status Scale (EDSS);15
proportion of patients free from EDSS change; and change in MS functional composite (MSFC) score.16
The meaning of clinical relapses was clarified earlier in this article. With respect to severity, the following measures are considered indicative of disease severity.
• extent of functional recovery; • •
need to use steroid medication and/or hospitalize the patient; and number of days of hospitalization.
Numerous clinical scales are used to measure physical, cognitive and emotional disability of MS patients. Nevertheless, the ones commonly employed thus far are the EDSS and the MSFC scale.
The EDSS scale ranges from 0 to 10 with 0.5-step increases and quantifies MS-induced disability in the pyramidal, cerebellar, brainstem, sensory, bowel, bladder, visual and cerebral functional systems. EDSS steps 1 to 4.5 are indicative of MS patients who have independent walking ability. EDSS steps 5 to 9.5 are defined by severe impairment to ambulation. A sustained progression is defined as any change ≥1 for EDSS scores ≤5 and any change ≥0.5 for EDSS scores ≤5.5. The variables most commonly used to identify drug effects are: the proportion of patients who remain free from disability progression over three- or six-month time windows; time to sustained disability progression; group- and/or within-person differences over time in median EDSS scores.
The MSFC is a 3D scale that measures cognitive function, leg function/ambulation, arm/hand motor and co-ordination functions. The scale produces values that are translated into z-scores in reference to normative values. These scores are used for group comparisons or for within-person comparison over a set time period.
Imaging Measures
The use of MRI provides a number of measurable disease parameters by means of which disease progression can be monitored. This is achieved with the use of conventional and non-conventional MRI techniques.17 Conventional MRI techniques include T1-w and T2-w spin echo images.
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Compared with conventional MRI techniques, non-conventional ones offer several challenges when one attempts their application in large multicenter clinical trials. First, scanning time may considerably increase. Second, results may suffer inter-center variability, therefore being poorly reproducible. Third, sophisticated image post-processing may be required for some of the non-conventional techniques, rendering their application in large clinical trials unpractical. To date, besides limited applications, which will be discussed later in the course of this review, no studies have attempted to investigate the effects of IFNβ-1b on MRI quantities derived from measurements on normal-appearing tissue and lesions.
A third image technique that is considered a non-conventional MRI technique but reflects the application of advanced post-processing analysis in conventional sequences, is the measurement of brain volume and its changes over time. Such a measurement is achieved by quantifying the so-called brain parenchyma fraction (BPF). This is given by the ratio of the sum of the WM and GM volumes over the volume of the entire brain, i.e. (WM+GM)/(WM+GM+CSF). The concept behind the application of BPF is that as the ventricles enlarge due to brain tissue shrinkage, the BPF decreases. BPF measurements have been successfully applied in large clinical trials.18
Types of Study Design
Different types of study design have been used in MS to detect the effect of IFNβ-1b. Study type depends upon two main factors:
• the number of subjects needed to treat in order to detect a significant effect on the chosen primary outcome measure; and
•
ethical motivations that over time limit the possibility of assigning patients to the placebo control arm.
Two main types of study designs have been used to identify the effect of IFNβ-1b in MS thus far: randomized controlled trials (RCTs) and baseline versus therapy (BVT) studies.
Randomized Controlled Trials
In RCTs patients are randomly allocated to the ‘intervention’ or placebo group and both investigators and patients are blind with respect to the compounds administered. This type of study design provides important data regarding the efficacy of IFNβ-1b compared with placebo in reducing the number and severity of clinical relapses as well as newly-formed lesions on MRI.
US NEUROLOGY
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