F Vermeulen1, C Le Camus2, J C Davies3, D Bilton4, D Milenković5, K De Boeck6. 1. Cystic Fibrosis Reference Centre, University Hospital of Leuven, Leuven, Belgium. Electronic address: francois.vermeulen@uzleuven.be. 2. Vertex Pharmaceuticals Inc., Cambridge, MA, United States. 3. Imperial College London, United Kingdom; Paediatric Respiratory Medicine and Department of Cystic Fibrosis , Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom. 4. Imperial College London, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom. 5. London School of Hygiene and Tropical Medicine, London, United Kingdom. 6. Cystic Fibrosis Reference Centre, University Hospital of Leuven, Leuven, Belgium.
Abstract
INTRODUCTION:Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. METHODS: In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial. RESULTS:Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. CONCLUSION: Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.
RCT Entities:
INTRODUCTION:Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. METHODS: In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial. RESULTS: Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. CONCLUSION: Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.
Authors: Edith T Zemanick; Michael W Konstan; Donald R VanDevanter; Steven M Rowe; J P Clancy; Katherine Odem-Davis; Michelle Skalland; Nicole Mayer-Hamblett Journal: J Cyst Fibros Date: 2021-02-08 Impact factor: 5.482
Authors: Tyler R Ray; Maja Ivanovic; Paul M Curtis; Daniel Franklin; Kerem Guventurk; William J Jeang; Joseph Chafetz; Hannah Gaertner; Grace Young; Steve Rebollo; Jeffrey B Model; Stephen P Lee; John Ciraldo; Jonathan T Reeder; Aurélie Hourlier-Fargette; Amay J Bandodkar; Jungil Choi; Alexander J Aranyosi; Roozbeh Ghaffari; Susanna A McColley; Shannon Haymond; John A Rogers Journal: Sci Transl Med Date: 2021-03-31 Impact factor: 17.956