Discussion
deteriorating cognitive functioning, neuronopathic MPS II, deteriorating cognitive function
GCA
PRAS methodology has been developed to overcome the limitations of norm-based ability test scores in characterizing absolute changes over time in cognitive development [After 1 year of treatment, the idursulfase-IT group included a greater proportion of patients with above-average or average cognitive growth rates in DAS-II GCA scores and a lower proportion of patients with deteriorating cognitive functioning than the no idursulfase-IT group. Differences in the distribution of cognitive categories at 1 year did not reach statistical significance in the overall population but did reach statistical significance for the subpopulation aged younger than 6 years at phase 2/3 baseline in this post hoc analysis. Importantly, PRAS analyses allowed the differentiation of patients with declines in GCA scores after 1 year of treatment into the three categories of below-average, plateauing, and deteriorating cognitive functioning, revealing that approximately three times as many patients (proportionally) in the no idursulfase-IT group had deteriorating cognitive functioning after 1 year than patients in the idursulfase-IT group (Table At 2 years, both treatment groups were receiving idursulfase-IT in the extension study. Differences between treatment groups were less pronounced at 2 years than at 1 year, and did not reach statistical significance in either the overall population or the subpopulation younger than 6 years of age. However, many patients remained in the same cognitive category from 1 to 2 years.The findings from PRAS analyses support and extend the results from the primary analyses of the phase 2/3 trial and extension study [An analysis of the same trial and extension study data that categorized patients younger than 6 years old at baseline into three cognitive development categories (above-average, average, or below-average) based on their DAS-II GCA scores alone has also been reported previously [Differences in the proportions of patients with missing data from 1 to 2 years in the two treatment groups may have affected the results. For example, the increase in the proportion of patients with missing data from 1 to 2 years in the delayed idursulfase-IT group mainly comprised patients who had been in the deteriorating cognitive category at 1 year, leading to a possible misinterpretation that the proportion of patients with deteriorating cognitive function had declined. However, approximately half of the patients in the early idursulfase-IT group and most of those in the delayed idursulfase-IT group remained in the same cognitive category at 1 year and 2 years. Moreover, patients typically moved to an adjacent category, with few patients having substantial changes in their cognitive status. The cognitive category with the greatest proportion of patients was that in which DAS-II GCA score cognitive growth rates were average (i.e., they were matching the trajectory of age-matched norms), and this remained the case at 1 year and 2 years.These results should be considered in the context of current knowledge of the natural history of neuronopathic MPS II [Other limitations of the present analysis include those inherent to all post hoc analyses. The duration of follow-up, small sample sizes, and missing data for some patients, particularly at the 2-year timepoint, limit the conclusions that can be drawn regarding patterns and differences between groups and over time. While we considered a difference of > 10 points between endpoint and baseline GCA scores (relative change) or between endpoint GCA score and PRAS (absolute change) to be clinically and statistically meaningful based on our previous analysis, we acknowledge the limitations of this cut-off-based method, which should be taken into account in its application [It is also important to understand the meaning and value of PRAS in the context of other types of scores from cognitive ability tests. Although norm-based scores cannot be used in isolation to evaluate absolute change, other types of scores such as raw scores or item-response theory (IRT)-based scores (e.g., Rasch-scaled scores; referred to as ability scores for the DAS-II subtests) can be used to evaluate absolute change in individual or sample scores over time [Change in raw or IRT-based scores corresponds directly to participant performance on items within a subtest and is straightforward to calculate. However, unlike PRAS (which have meaning based on norm values), raw or IRT-based scores do not have inherent functional or clinical meaning. Thus, reliable and meaningful within-patient change values for raw or IRT-based scores would need to be established for the use of a subtest as a primary endpoint in a clinical trial (and would differ from one subtest to another) [Future large-scale, long-term studies are required to fully assess the role of PRAS methodology in assessing specific profiles of cognitive function in patients with neurodegenerative conditions such as neuronopathic MPS II. When assessing cognitive function over the long term (> 24 months, i.e., a longer time period than in the present study), a combination of PRAS methodology and other established approaches is likely to be required for optimal interpretation of cognitive scores [