Given the results from the phase-1 study, the ability of rhIDU to reduce storage and improve MPS I disease was demonstrated, but these data were not sufficient to obtain registration in the United States. The approval on a single pivotal trial can be achieved based on FDA guidelines, but the type of endpoints, the nature of the control group, the size of the trial, the multiple site design, and the degree of statistical persuasiveness need to be sufficient to meet expectations. Although phase-1 data were highly significant with p < 0.001 for both endpoints, the primary endpoints were considered surrogates and were not validated or proven to be likely to predicting clinical benefit. Given the limited published data on these endpoints during BMT, it was not possible to develop a sufficient body of literature and data to support the relevance of these measures of lysosomal storage to predict clinical outcome. Without a placebo control group, the secondary clinical endpoints could not be considered adequately controlled enough to demonstrate that improvements were not subject to bias during assessments. Based on these issues, a randomized, placebo-controlled, multicenter study was designed using clinical primary endpoints.
The phase-3 study was designed as a randomized, double-blind, placebo-controlled study in 45 MPS I patients treated with weekly infusions of Aldurazyme over a 26-week period . The patient population was restricted to patients over 5 years of age and was predominantly Hurler-Scheie in phenotype. The primary endpoints were the change between baseline and week-26 in the forced vital capacity (FVC), and the 6-min walk test. FVC is a measure of lung capacity, which is severely restricted in MPS I patients such that respiratory insufficiency is a common contributor to death. The 6-min walk test is commonly used in congestive heart failure studies as a measure of endurance. In MPS I, the 6-min walk distance can be severely restricted due to a combination of factors that includes poor respiratory function, cardiac disease, and joint stiffness and pain. In addition to these endpoints, secondary endpoints in the study were liver size, sleep apnea, shoulder flexion, and the Health Assessment Questionnaire (child and adult versions). Other endpoints included urinary GAG excretion, joint range of motion, visual acuity, and quality of life measures.
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