Multiple sclerosis is a complex disease that presents numerous challenges in selecting appropriate measurements for a given clinical trial. These challenges can include:
- Handling inflammation and relapses versus degeneration and progression
- A lack of understanding in the underlying pathophysiology
- Therapies designed for delivery early in the disease intended to prevent disability later
- Symptoms that don’t directly correlate to disease activity.
Because of the wide array of challenges, it can be tough to determine what should be measured as part of a clinical study.
One of the first steps in selecting an outcome or endpoint is understanding who the study is trying to convince. Neurologists, patients, regulators, and payors are all going to have a different perspective. Neurologists prefer measurements that they are familiar with, like the Expanded Disability Status Scale (EDSS). For patients, it’s important to demonstrate that the therapy will make them feel better and improve their quality of life. Regulators want to see efficacy demonstrated through validated scales and a well-established safety profile. Payors are interested value and cost-effectiveness.
The type of therapy and the trial design will also influence which assessments and outcomes measures are most appropriate. MS can present with a broad range of symptoms, and it may make sense to only measure symptoms that the therapy is expected to improve. The duration of the trial also needs to be considered. Some endpoints aren’t likely to show a clinically meaningful difference in short duration trials. The control arm of the study is also a consideration. Placebo controlled trials are likely to show a larger treatment effect, so if a comparator control is needed, you may need a more sensitive instrument.
There are a number of potential endpoints that can be used in MS studies. The table below summarizes some commonly used assessments.
|Expanded Disability Status Scale (EDSS)||Quantifies disability in MS patients and can be used to monitor changes over time|
|Symbol Digit Modalities Test (SDMT)||Cognitive measure sensitive to slowed processing of information common in MS|
|Timed 25-Foot Walk (T25-FW)||Measures mobility and leg function based on a timed 25-foot walk|
|9-Hole Peg Test (9-HPT)||Quantifies upper extremity function|
|Low Contrast Letter Acuity (LCLA)||Assesses visual disability in multiple sclerosis|
|Annualized Relapse Rate||The average number of relapses a group of patients in a study have in one year|
|Magnetic Resonance Imaging (MRI)||MRIs can be used to measure brain volume loss, inflammation, lesion load, and lesion activity. Typically used in conjunction with clinical measures.|
|Optical Coherence Tomography (OCT)||Rapid, inexpensive imaging technique measuring retinal thinning which is correlates to both visual function and global MS disability scores.|
|Evoked Potentials||Assesses the speed of message delivery from the sensory nerves to the brain. Often used in the diagnosis of MS.|
|Multiple Sclerosis Impact Scale (MSIS-29)||Patient-based outcome measure of the impact of multiple sclerosis|
|Multiple Sclerosis Rating Scale Revised (MSRS-R)||Patient-reported assessment of functional status|
|Multiple Sclerosis Individual Outcome Assessment (MSIOA)||Monitors patients’ perspective on how much emotional or psychological distress their symptoms cause them|
|Multiple Sclerosis Functioning Composite (MSFC)||Reflects varied clinical expressions of MS|
Traditionally, phase III trials have used EDSS and relapse rate as primary measures with various MRI scan measures used as secondary outcomes. The EDSS is the most widely used assessment and is also often used as part of the inclusion criteria for a trial. However, it does have limitations, which increasingly leads researchers to consider other measures or additional measures. The EDSS is not particularly sensitive and it can be difficult to show a significant change over the duration of a typical clinical trial. Additionally, a number of domains like cognition, mood, and quality of life are not assessed, yet improvement in these areas is very important to patients.
Relapse rate is another traditional outcome measure. Relapse rate is effective at demonstrating short-term efficacy, but relapse rates only partially correlate with worsening disability over time. There are a number of newer assessments such as the MSIS29, MSFC, and the MSIOA that are designed to provide more information on the domains that aren’t captured by the earlier assessments and that reflect patient concerns about activities of daily living and quality of life. The MSIOA was developed to address the need for a patient-centric account of their symptoms. It captures the patient’s perspective on the amount of emotional or psychological distress their symptoms cause. Patients, regulators, and payers increasingly are interested in patient-centered symptom outcomes in addition to traditional measures of disease activity.
Depending on the therapy, the intended population, and stage of development there are numerous assessments which may be considered for clinical trials in MS. Need help determining the right outcomes assessments and endpoints for your program? Contact us.
References and Additional Information
National Multiple Sclerosis Website– https://www.nationalmssociety.org/
van Munster, C.E.P., Uitdehaag, B.M.J. Outcome Measures in Clinical Trials for Multiple Sclerosis. CNS Drugs 31, 217–236 (2017). https://doi.org/10.1007/s40263-017-0412-5
Gray, O., McDonnell, G., & Hawkins, S. (2009). Tried and tested: the psychometric properties of the multiple sclerosis impact scale (MSIS-29) in a population-based study. Multiple Sclerosis Journal, 15(1), 75–80. https://doi.org/10.1177/1352458508096872