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

      1 , 2 , 1 , 2

      Drug Design, Development and Therapy

      Dove Medical Press

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          Abstract

          Dear editor We read with interest the report by Goláň 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.

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          Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomized Study Evaluating Regression of Ventricular Enlargement.

          The study was done to evaluate reliability of echocardiographic left ventricular (LV) mass. Echocardiographic estimation of LV mass is affected by several sources of variability. We assessed intrapatient reliability of LV mass measurements in 183 hypertensive patients (68% men, 65 +/- 9 years) enrolled in the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) trial after a screening echocardiogram (ECHO) showed LV hypertrophy. A second ECHO was repeated at randomization (45 +/- 25 days later). Two-dimensional (2D)-guided M-mode or 2D linear measurements of LV cavity and wall dimensions were verified by one experienced reader. Mean LV mass was similar at first and second ECHO (243 +/- 53 vs. 241 +/- 54 g) and showed high reliability as estimated by intraclass correlation coefficient (RHO) = 0.93. Within-patient 5th, 10th, 90th and 95th percentiles of between-study difference in LV mass were -32 g, -28 g, +25 g and +35 g. Mean LV mass fell less from the first to the second ECHO than expected from a formula to predict regression to the mean (2 +/- 19 vs. 17 +/- 12 g, p or = 95% or > or = 80% likelihood of being true change.
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            Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease

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              Randomized clinical trials

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                02 November 2015
                : 9
                : 5873-5875
                Affiliations
                [1 ]Department of Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
                [2 ]Department of Nephrology, Instituto Reina Sofia de Investigación Nefrológica, Madrid, Spain
                [1 ]Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
                [2 ]Shire, Lexington, MA, USA
                Author notes
                Correspondence: Alberto Ortiz, Unidad de Dialisis, IIS-Fundacion Jimenez Diaz, Av Reyes católicos 2, 28040 Madrid, Spain, Email aortiz@ 123456fjd.es
                Correspondence: Lubor Goláň, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, U nemocnice 2, 128 00 Prague 2, Czech Republic, Tel +420 2 2496 6711, Fax +420 2 2491 5413, Email lubor.golan@ 123456vfn.cz
                Article
                dddt-9-5873
                10.2147/DDDT.S93371
                4636096
                © 2015 Ortiz and Sanchez-Niño. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Letter

                Pharmacology & Pharmaceutical medicine

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