6 August 2019
Using CANTAB to enhance pro-cognitive clinical trials in multiple sclerosis
Accurate outcome measures and suitable patient recruitment will be vital to the success of pro-cognitive treatment trials in multiple sclerosis (MS). In this article, we highlight the sensitivity of various CANTAB tasks to cognitive dysfunction in MS, and discuss the advantages of using these computerised assessments over paper-and-pencil based tests. We also consider how CANTAB tasks can be used to screen prospective participants for specific types and severities of cognitive impairment in order to gauge their suitability for inclusion in pro-cognitive intervention trials.
Cognitive impairment is a common and debilitating aspect of multiple sclerosis (MS) that can adversely affect an individual’s social and vocational functioning and quality of life. There are currently no regulatory approved treatments for the amelioration of cognitive dysfunction in MS, though many hope that the wealth of ongoing research and increasing recognition of the importance of this issue may lead to a major breakthrough in the coming years.
Prior to the upcoming ECTRIMS conference in Stockholm, Dr Jack Cotter (Senior Scientist at Cambridge Cognition) answered a number of common questions regarding the CANTAB platform and the ways in which it can help to enhance the accuracy and efficiency of clinical trials in MS.
What is CANTAB?
The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a collection of highly sensitive computerised tasks that can be used to assess many of the core aspects of cognition. Originally developed at the University of Cambridge, these tests have been used in over 2200+ peer-reviewed publications across a range of clinical and non-clinical populations and study designs (accessible via our online bibliography). Importantly, task performance has been shown to correlate with brain structure and function, as well as real-world functional outcomes. The CANTAB platform is also regulatory and HIPAA compliant for administering cognitive tests in clinical trials and has been included in regulatory submissions as both a primary and/or secondary endpoint by a number of major pharmaceutical companies.
What is the acceptability and feasibility of CANTAB for patients with MS?
A number of published studies have demonstrated that CANTAB tasks are sensitive to deficits across all of the key domains of cognition most commonly affected in MS, including measures of memory, executive function, processing speed and attention (e.g. Foong et al., 1997; Giedraitiene & Kaubrys, 2019; Muhlert et al., 2014). Evidence has shown that these tests are sensitive to deficits even among younger patients in the earliest stages of the illness, exhibiting minimal levels of physical disability (Cabeça et al., 2018). We have also recently demonstrated that brief touchscreen cognitive assessment using CANTAB tasks can be used to detect domain-specific cognitive impairment in MS patients attending routine clinical appointments (Cotter et al., 2018). Among ninety MS patients who underwent a fifteen-minute cognitive screening as part of their standard clinical assessments, CANTAB tests detected cognitive impairment in at least one of five cognitive domains among 44% of the sample, a figure comparable with previous studies that used much longer and more resource-intensive cognitive test batteries.
What are the advantages of using computerised cognitive assessments above traditional paper and pencil?
Paper-and-pencil based assessments are typically time-consuming, requiring specialist resources and a trained rater to administer and interpret the results of the tests. While a number of cognitive batteries have been developed specifically for use in patients with MS, these suffer from many of these limitations. In contrast, computerised CANTAB tasks offer a number of practical benefits, including;
- Automated instructions (available in a range of languages) and practice trials, standardizing the administration process and allowing tasks to be largely self-administered by participants.
- The touchscreen platform also ensures accurate response scoring, enabling precise assessment of subtle measures (such as reaction times), and permitting the simultaneous assessment of multiple aspects of cognition using single tasks.
- Abstract stimuli and multiple parallel forms limit learning effects, while many CANTAB tasks are also adaptive to individual performance to avoid floor and ceiling effects.
- Importantly, these tasks have been shown to be very well tolerated by patients, even among elderly individuals.
- Blinded data reports can be downloaded online at any time by nominated individuals in a range of formats.
- Additional patient and clinician-reported outcome measures can also be integrated into the system in order to harmonise data collection.
How can CANTAB identify the right patients for clinical trials?
Though cognitive dysfunction is common among patients with MS, not all individuals experience cognitive decline. Inclusion of those patients without a clinically significant deficit in cognitive performance could inflate baseline scores, and reduce the scope to see improvement between treatment and placebo groups. There is also an argument that exposing cognitively normal patients to investigational drugs represents an unnecessary and unethical risk, particularly given that polypharmacy is already common among patients with MS. This suggests a need to screen prospective participants in order to identify those with a deficit within a relevant cognitive domain, ideally based on the hypothesised mechanism of action of the study drug and the domains of cognition thought most likely to be improved. Using our CANTAB Recruit software, prospective participant’s test scores can be compared to our large normative database to provide an indication of their cognitive performance relative to age, gender and education-matched individuals in the general population, allowing you to quantify their level of impairment before entering the trial.
What support is available for designing and analysing MS trials?
Our expert in-house scientists and statisticians can provide advice to help optimise your trial design and the selection of cognitive endpoints, as well as the analysis and interpretation of your CANTAB data. Please get in touch so we can discuss your specific requirements.
Are there mobile and wearable applications of CANTAB for high-frequency testing?
Major advances in digital technologies over the last decade have made enhanced patient monitoring a realistic possibility. Many of these technologies (such as smartphones) are widely available and habitually used throughout the world, including many low and middle-income countries, offering highly scalable opportunities to enhance clinical research and treatment globally. We believe that MS is an area particularly suited to digital monitoring, given the day-to-day fluctuations in physical, psychological and cognitive symptoms commonly experienced in this patient group that may be missed through infrequent clinical assessments. In addition to our iPad-based CANTAB system, we are currently developing a selection of brief, smartphone and wearable-based cognitive tasks and patient questionnaires for daily use in clinical research studies. These have been successfully used in a number of recent industry-funded projects and hold significant promise for collecting high-frequency, ecologically valid patient data in the ‘real world’.
Cabeça HLS, Rocha LC, Sabbá AF, Tomás AM, Bento-Torres NVO, Anthony DC, Diniz CWP. The subtleties of cognitive decline in multiple sclerosis: an exploratory study using hierarchichal cluster analysis of CANTAB results. BMC Neurology 2018;18(1):140.
Cotter J, Vithanage N, Colville S, Lyle D, Cranley D, Cormack F, Barnett JH, Murray K, Pal S. Investigating domain-specific cognitive impairment among patients with multiple sclerosis using touchscreen cognitive testing in routine clinical care. Frontiers in Neurology 2018;9:331.
Foong J, Rozewicz L, Quaghebeur G, Davie CA, Kartsounis LD, Thompson AJ, Miller DH, Ron MA. Executive function in multiple sclerosis. The role of frontal lobe pathology. Brain 1997;120(1):15-26.
Giedraitiene N, Kaubrys G. Distinctive pattern of cognitive disorders during multiple sclerosis relapse and recovery based on computerized CANTAB tests. Frontiers in Neurology 2019;10:572.
Muhlert N, Atzori M, De Vita E, Thomas DL, Samson RS, Wheeler-Kingshott CA, Geurts JJ, Miller DH, Thompson AJ, Ciccarelli O. Memory in multiple sclerosis is linked to glutamate concentration in grey matter regions. Journal of Neurology, Neurosurgery and Psychiatry 2014;85(8):833-9.
Dr Jack Cotter, Senior Scientist