Agalsidase-Beta Therapy for Advanced Fabry Disease

A Randomized Trial

View larger version (35K): [in this window] [in a new window]   Figure 1. Study flow diagram.

View larger version (17K): [in this window] [in a new window]   Figure 2. Analyses of time to first clinical outcome. Dashed lines show Kaplan–Meier estimates of time to any clinical event (composite outcome). Solid lines show curves with adjustment for baseline proteinuria (urine protein–creatinine ratio), derived from a Cox regression analysis with baseline proteinuria added as a covariate to the regression equation (22, 23). Top. The time-to-event analyses for the composite end point for both treatment groups in the intention-to-treat population are shown. The unadjusted treatment-related hazard ratio associated with agalsidase beta was 0.57 (95% CI, 27.0 to 1.22; P = 0.14). With adjustment for baseline proteinuria, the hazard ratio was 0.47 (CI, 0.21 to 1.03; P = 0.06). Bottom. The time-to-event analyses for the composite end point for both treatment groups in the per-protocol population are shown. The unadjusted treatment-related hazard ratio associated with agalsidase beta was 0.54 (CI, 0.25 to 1.19; P = 0.12). With adjustment for baseline proteinuria, the hazard ratio was 0.39 (CI, 0.16 to 0.93; P = 0.034).

View larger version (12K): [in this window] [in a new window]   Figure 3. Hazard ratios for the primary end point stratified by median baseline serum creatinine level, estimated glomerular filtration rate (eGFR), and proteinuria. Proteinuria denotes the urine protein–creatinine ratio. The P values for formal tests for treatment interaction were as follows: baseline serum creatinine level, P = 0.16; baseline eGFR, P = 0.09; and baseline proteinuria, P = 0.54.

View larger version (16K): [in this window] [in a new window]   Appendix Figure. Longitudinal analysis of proteinuria in both groups. Data are shown as increases or decreases from baseline proteinuria (urinary protein–urinary creatinine ratio) for the placebo group (solid line) and the agalsidase-beta group (dashed line). A mixed model with fixed effects for treatment group, time, and treatment-by-time interactions, as well as random intercepts and slopes, for each patient over time was fit. The overall P value for treatment effect is 0.32.

View this table: [in this window] [in a new window]   Appendix Table. Adverse Events that Occurred without Regard to Causality in at Least 10% of Patients in the Agalsidase-Beta Group