Trial Information

Retrospective and Prospective Validation of DS3 Severity Score System for Adults With Type 1 Gaucher Disease (GD1)

GD1 is a prototypical lysosomal storage disorder and the first disorder to have compelling
evidence of successful treatment with enzyme replacement therapy. The common clinical
manifestations are hematologic cytopenias, hepatomegaly, splenomegaly, and a spectrum of
skeletal pathologies. Disease expression is diverse. The rate and extent of disease
progression are variable and often independent of the age at which symptoms are first
reported1. Despite a long history of treatment efficacy2, there is significant heterogeneity
of response among patients with regard to the maximum improvement in hematologic, visceral,
bone, and other manifestations and the dynamic speed of response during therapy1-3. There
have been few well-designed studies that comprehensively annotate phenotypic variation over
time or measure treatment efficacy and dose response. In part, this is attributable to lack
of a validated disease severity scoring system for GD1 to standardize the monitoring of
progression and treatment response and to define patient cohorts in clinical studies.

DS3 is a method of expressing an integrated assessment of the burden of disease in a given
patient. It can be used to monitor patient status, determine endpoints in clinical studies,
classify disease phenotypes and compare patients with the same disease. Although frequently
referred to as 'disease severity indices,' DS3 instruments may also include measures of
disease activity and damage. DS3s utilize a minimal data set to score the patient in a
comprehensive manner. They usually are structured as a group of domains (often according to
organ system) that are populated with non-redundant items that are valid, reliable, use
feasible, standardized methods of assessment, and that are variably weighted based on
associated morbidity and mortality. A DS3 for adult GD1 patients was recently developed and
subjected to successful preliminary testing for validity, reliability and feasibility4. With
respect to changes over time, a minimal clinically important difference was defined.
Construct validity has been partially demonstrated. Using 20 patient profiles from the
International Collaborative Gaucher Group (ICGG) Gaucher Registry, the instrument was shown
to correlate very well with the "gold standard" clinical global impression scale. However,
larger scale testing in a population that is representative of the world wide distribution
of GD1 phenotypes (including splenectomy patients) is needed and predictive validity has yet
to be determined. Moreover, the DS3 has not yet been correlated with disease-specific
measures of response such as achievement of therapeutic goals or broadly used biomarkers.
Combining retrospective and prospective analysis, this study is designed to address these
issues