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Dear editor  We read with interest the report by Golaň et al on the “Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease”.1 Based on the reported results, the authors conclude that no efficacy or safety differences were found when the approved every-other-week (EOW) dosage of agalsidase alfa was increased to weekly administration. However, the key question is whether the study, as designed and performed, could have had a different outcome. Estimation of the sample size was based on the 1999 report by Palmieri et al.2 Table 3 in this publication indicates that the sample size per group needed to detect a change in left ventricular mass (LVM) of 5 g/m2.7 assuming a 5% type I error rate and an 80% power is 19.2 This would yield a total sample size of 38. The authors state that the sample size calculations assumed a 10% dropout rate, but this assumption did not appear to result in a 10% increase in sample size to 42. In addition to this failure to increase the sample size in order to account for a 10% dropout, the real dropout was even higher than 10%. Thus, the dropout rate in the 0.2 mg/kg/2 weeks group was 25% (5/20) when including real dropouts and patients with missing end-of-study assessment of the primary end point (left ventricular mass index [LVMI]). Thus, according to the authors’ estimates, the study was underpowered to detect differences. The ability to detect differences may have been further compromised by the heterogeneity of the patient population. Thus, for the main analysis, males and females were grouped together. However, the response to therapy appears to be divergent between males and females. The least squares mean (LSM) difference (0.2 mg/kg weekly minus EOW) was −7.6 g/m2 for males and +7.85 g/m2 for females. Indeed, the −7.76 value observed in males was outside the 95% confidence interval for the LSM difference in females (−2.55 to 18.25). In this regard, the study was theoretically powered to detect a 5 g/m2.7 treatment difference in the primary efficacy end point for the whole group. Both sex subgroups exceeded this difference but in opposite directions, thus further limiting the power of the study when results from both sexes were added. Some important information that may help better interpret the study is missing. Thus, the standard deviation for the baseline and 53-week LVMI data is not reported. There is also no information on the baseline LVMI values of the patients for whom 53-week data are available. We suggest that the conclusion be modified to state that no efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration, but the study was underpowered to detect such differences.

Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy was underpowered