Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study

Timothy M Cox, Dominick Amato, Carla Em Hollak, Cecile Luzy, Mariabeth Silkey, Ruben Giorgino, Robert D Steiner, Miglustat Maintenance Study Group, Timothy M Cox, Dominick Amato, Carla Em Hollak, Cecile Luzy, Mariabeth Silkey, Ruben Giorgino, Robert D Steiner, Miglustat Maintenance Study Group

Abstract

Background: Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy.

Methods: Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count.

Results: Forty-two patients were enrolled (mean±SD age, 45.1±12.7 years; previous enzyme therapy duration 9.5±4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3-765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (-1.1%; 95%CI -6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, -0.95 (-1.38, -0.53) g/dL and -44.1 (-57.6, -30.7) ×109/L, respectively.

Conclusions: The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice.

Trial registration: Clinicaltrials.gov identifier NCT00319046.

Figures

Figure 1
Figure 1
Patient disposition.*All enrolled population; ‡full analysis population; **all patients with at least one post-baseline liver assessment (≥6 months) were included in primary endpoint analysis, including 11 patients who discontinued miglustat treatment prematurely; ††some patients had more than one of the listed reasons for non-inclusion in the per-protocol analysis; ‡‡Patient had documented symptomatic bone disease at screening and represented a protocol violation. Note: secondary efficacy evaluations based on full analysis population included different numbers of patients subject to data availability.
Figure 2
Figure 2
Absolute changes in primary and secondary efficacy parameters during 24 months of miglustat therapy (full analysis population). Changes from baseline in a) liver volume, b) spleen volume, c) hemoglobin concentration and d) platelet count. Data are mean absolute change from baseline (square points), with 95% confidence intervals (grey boxes) and minimum–maximum value ranges (solid vertical lines).

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