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BMD
602
Abstracts / Neuromuscular Disorders 19 (2009) 543–660
the ongoing Phase 2b registration trial may represent a clinically meaningful benefit to boys with DMD/BMD. doi:10.1016/j.nmd.2009.06.184
M.P.3.04 Assessment of StepWatchTM activity monitoring in phase 2b study of ataluren (PTC124TM) in nmDMD/BMD C. McDonald1, K. Coleman 2, E. Henricson 1, R.T. Abresch 1, M. Eagle 3, J. Florence 4, E. Gappmaier 5, A.M. Glanzman 6, A. Reha 7, G.L. Elfring 7, L.L. Miller 7, L. Atkinson 7 1
University of California, Davis School of Medicine, Davis, CA, United States, 2 Orthocare Innovations, Seattle, WA, United States, 3 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom, 4 Washington University School of Medicine, St. Louis, MO, United States, 5 University of Utah, Salt Lake City, UT, United States, 6 Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 7 PTC Therapeutics, Inc., South Plainfield, NJ, United States Background: A Phase 2b, international, multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study is assessing the efficacy and safety of ataluren in 174 patients with nonsense mutation Duchenne/Becker muscular dystrophy (nmDMD/BMD). Methods: Pretreatment evaluations in this study included an in-clinic 6-minute walk test (6MWT) followed by 4–7 days of at-home StepWatch activity monitoring (SAM), each performed twice 6 weeks apart. Subjects wore the SAM device continuously from waking to bedtime. Results: 6MWT and SAM data are available for 164 subjects (ages 5–20 years) with P4 days of SAM recording. Mean [SD] average daily step count was 5236 [2012]. When comparing 5-11 yearold boys (n = 146) with nmDMD/BMD in this study vs historical healthy boys (n = 26) of the same age range, boys with nmDMD/ BMD had lower mean [SD] average daily step count (5461 [1421] for nmDMD/BMD vs 7780 [2538] for controls); % of time spent at medium (15 [7] vs 31 [4]) and high (3 [5] vs 15 [5]) activity; and maximum continuous 20-minute effort (20 [5] vs 44 [9]), 30-minute effort (15 [3] vs 38 [9]), and 60-minute effort (8 [2] vs 28 [7]) steps/ minute. Boys with nmDMD/BMD had higher % of time spent at low activity (82 [12] vs 51 [7]). For all SAM parameters, reliability was high for 137 subjects with test-retest data (range r = 0.73–0.81). Mean average daily step count correlated moderately (r = 0.53) with 6-minute walk distance (6MWD) (n = 162). When assessed by the study stratification factors, mean [SD] average daily step count was 4211 [2077] and 5935 [1640] for boys with baseline 6MWD <350 m vs P350 m, respectively; 4159 [1890] and 6073[1690] for boys P9 vs <9 years, respectively; and 4904 [1732] and 5345 [2109] for corticosteroid non-users vs users, respectively. Conclusion: At-home activity is impaired in boys with nmDMD/BMD, can be reliably assessed by SAM, and correlates with factors known to affect disease severity. doi:10.1016/j.nmd.2009.06.185
M.P.3.05 Use of a novel system for grading timed function test performance in phase 2b study of ataluren (PTC124TM) in nonsense mutation Duchenne and Becker muscular dystrophy (nmDMD/ BMD) M. Elfring 1, R.T. Abresch 2, J. Florence3, E. Gappmaier 4, A.M. Glanzman 5, E. Henricson 2, A. Reha 6, G.L. Elfring 6, L.L. Miller 6, L. Atkinson 6
1
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom, 2 University of California, Davis School of Medicine, Davis, CA, United States, 3 Washington University School of Medicine, St. Louis, MO, United States, 4 University of Utah, Salt Lake City, UT, United States, 5 Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 6 PTC Therapeutics, Inc., South Plainfield, NJ, United States Background: A Phase 2b, randomized, double-blinded, placebocontrolled study is assessing the efficacy and safety of ataluren in 174 patients (ages 5–20 years) with nmDMD/BMD. Screening and baseline evaluations (6 weeks apart) included 6-minute walk distance (6MWD); timed function tests (TFTs) (10-meter walk/run, 4stair climb, 4-stair descent, stand from supine); and myometry (shoulder abduction, elbow and knee flexion/extension). In addition, a new method was used to grade how TFTs were performed. Methods: Based on recognized movement patterns reflective of disease progression and the clinical effects of corticosteroid usage in DMD/ BMD, a TFT method grading system was devised. Grades ranged from non-performance (0) to normal performance (6). Clinical evaluators were given in-person training, written manuals, and video examples. TFT method grading was performed simultaneously with TFTs. Results: Median [range] TFT method grades were 5 (able to pick up speed but runs with a double stance phase) [2–6] for 10-meter walk/run; 3 (climbs 1 foot at a time, with both feet on a step before moving to the next step, using 1 arm on 1 handrail) [1–5] for 4-stair climb; 2 (descends 1 foot at a time, with both feet on a step before moving to the next step, requires both arms on 1 or both handrails) [1–5] for 4-stair descent; and 4 (half Gowers’) [1–6] for stand from supine. TFT method grade test-retest reliability was high (range r = .75 to.83). Lesser performance (lower grade) correlated with higher TFT times (range r = .69 to .53). However, grading differentiated ability in boys with similarly fast TFT times. TFT method grade correlated better with 6MWD (range r = .63 to.70) and knee extension (range r = .54 to.67) than with other myometry parameters (range r = .10 to.49). Conclusion: TFT method grades are reliable and correlate appropriately with other clinical measures, while providing additional clinically meaningful information about functional ability in boys with DMD/BMD. doi:10.1016/j.nmd.2009.06.186
M.P.3.06 Quantification of upper limb activity in non ambulant boys with Duchenne muscular dystrophy using accelerometry: A proof-ofconcept study L. Servais, A. Canal, J.Y. Hogrel, T. Voit Hôpital de la Pitié Salpétrière, Institut de Myologie, Paris, France Disease progression in ambulant boys with Duchenne muscular dystrophy (DMD) is frequently assessed by the 6-minutes walk test, which is also used as a primary outcome measure of ongoing therapeutic trials. There is currently no standardized method to assess upper limb function in non-ambulatory patients, which complicates trials in these cohorts. Upper limb function may be assessed by direct muscular strength measurement, either by clinical test that still have to be standardized and validated, or by activity monitoring. This latter approach is probably the more strongly correlated with patient’s quality of life. Measurement of upper limb activity by accelerometry in nonambulatory patients presents different technical requirements. The accelerometer must be as light as possible, wireless, able to indicate its spatial orientation in order to discriminate acceleration from
Abstracts / Neuromuscular Disorders 19 (2009) 543–660
the ongoing Phase 2b registration trial may represent a clinically meaningful benefit to boys with DMD/BMD. doi:10.1016/j.nmd.2009.06.184
M.P.3.04 Assessment of StepWatchTM activity monitoring in phase 2b study of ataluren (PTC124TM) in nmDMD/BMD C. McDonald1, K. Coleman 2, E. Henricson 1, R.T. Abresch 1, M. Eagle 3, J. Florence 4, E. Gappmaier 5, A.M. Glanzman 6, A. Reha 7, G.L. Elfring 7, L.L. Miller 7, L. Atkinson 7 1
University of California, Davis School of Medicine, Davis, CA, United States, 2 Orthocare Innovations, Seattle, WA, United States, 3 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom, 4 Washington University School of Medicine, St. Louis, MO, United States, 5 University of Utah, Salt Lake City, UT, United States, 6 Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 7 PTC Therapeutics, Inc., South Plainfield, NJ, United States Background: A Phase 2b, international, multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study is assessing the efficacy and safety of ataluren in 174 patients with nonsense mutation Duchenne/Becker muscular dystrophy (nmDMD/BMD). Methods: Pretreatment evaluations in this study included an in-clinic 6-minute walk test (6MWT) followed by 4–7 days of at-home StepWatch activity monitoring (SAM), each performed twice 6 weeks apart. Subjects wore the SAM device continuously from waking to bedtime. Results: 6MWT and SAM data are available for 164 subjects (ages 5–20 years) with P4 days of SAM recording. Mean [SD] average daily step count was 5236 [2012]. When comparing 5-11 yearold boys (n = 146) with nmDMD/BMD in this study vs historical healthy boys (n = 26) of the same age range, boys with nmDMD/ BMD had lower mean [SD] average daily step count (5461 [1421] for nmDMD/BMD vs 7780 [2538] for controls); % of time spent at medium (15 [7] vs 31 [4]) and high (3 [5] vs 15 [5]) activity; and maximum continuous 20-minute effort (20 [5] vs 44 [9]), 30-minute effort (15 [3] vs 38 [9]), and 60-minute effort (8 [2] vs 28 [7]) steps/ minute. Boys with nmDMD/BMD had higher % of time spent at low activity (82 [12] vs 51 [7]). For all SAM parameters, reliability was high for 137 subjects with test-retest data (range r = 0.73–0.81). Mean average daily step count correlated moderately (r = 0.53) with 6-minute walk distance (6MWD) (n = 162). When assessed by the study stratification factors, mean [SD] average daily step count was 4211 [2077] and 5935 [1640] for boys with baseline 6MWD <350 m vs P350 m, respectively; 4159 [1890] and 6073[1690] for boys P9 vs <9 years, respectively; and 4904 [1732] and 5345 [2109] for corticosteroid non-users vs users, respectively. Conclusion: At-home activity is impaired in boys with nmDMD/BMD, can be reliably assessed by SAM, and correlates with factors known to affect disease severity. doi:10.1016/j.nmd.2009.06.185
M.P.3.05 Use of a novel system for grading timed function test performance in phase 2b study of ataluren (PTC124TM) in nonsense mutation Duchenne and Becker muscular dystrophy (nmDMD/ BMD) M. Elfring 1, R.T. Abresch 2, J. Florence3, E. Gappmaier 4, A.M. Glanzman 5, E. Henricson 2, A. Reha 6, G.L. Elfring 6, L.L. Miller 6, L. Atkinson 6
1
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom, 2 University of California, Davis School of Medicine, Davis, CA, United States, 3 Washington University School of Medicine, St. Louis, MO, United States, 4 University of Utah, Salt Lake City, UT, United States, 5 Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 6 PTC Therapeutics, Inc., South Plainfield, NJ, United States Background: A Phase 2b, randomized, double-blinded, placebocontrolled study is assessing the efficacy and safety of ataluren in 174 patients (ages 5–20 years) with nmDMD/BMD. Screening and baseline evaluations (6 weeks apart) included 6-minute walk distance (6MWD); timed function tests (TFTs) (10-meter walk/run, 4stair climb, 4-stair descent, stand from supine); and myometry (shoulder abduction, elbow and knee flexion/extension). In addition, a new method was used to grade how TFTs were performed. Methods: Based on recognized movement patterns reflective of disease progression and the clinical effects of corticosteroid usage in DMD/ BMD, a TFT method grading system was devised. Grades ranged from non-performance (0) to normal performance (6). Clinical evaluators were given in-person training, written manuals, and video examples. TFT method grading was performed simultaneously with TFTs. Results: Median [range] TFT method grades were 5 (able to pick up speed but runs with a double stance phase) [2–6] for 10-meter walk/run; 3 (climbs 1 foot at a time, with both feet on a step before moving to the next step, using 1 arm on 1 handrail) [1–5] for 4-stair climb; 2 (descends 1 foot at a time, with both feet on a step before moving to the next step, requires both arms on 1 or both handrails) [1–5] for 4-stair descent; and 4 (half Gowers’) [1–6] for stand from supine. TFT method grade test-retest reliability was high (range r = .75 to.83). Lesser performance (lower grade) correlated with higher TFT times (range r = .69 to .53). However, grading differentiated ability in boys with similarly fast TFT times. TFT method grade correlated better with 6MWD (range r = .63 to.70) and knee extension (range r = .54 to.67) than with other myometry parameters (range r = .10 to.49). Conclusion: TFT method grades are reliable and correlate appropriately with other clinical measures, while providing additional clinically meaningful information about functional ability in boys with DMD/BMD. doi:10.1016/j.nmd.2009.06.186
M.P.3.06 Quantification of upper limb activity in non ambulant boys with Duchenne muscular dystrophy using accelerometry: A proof-ofconcept study L. Servais, A. Canal, J.Y. Hogrel, T. Voit Hôpital de la Pitié Salpétrière, Institut de Myologie, Paris, France Disease progression in ambulant boys with Duchenne muscular dystrophy (DMD) is frequently assessed by the 6-minutes walk test, which is also used as a primary outcome measure of ongoing therapeutic trials. There is currently no standardized method to assess upper limb function in non-ambulatory patients, which complicates trials in these cohorts. Upper limb function may be assessed by direct muscular strength measurement, either by clinical test that still have to be standardized and validated, or by activity monitoring. This latter approach is probably the more strongly correlated with patient’s quality of life. Measurement of upper limb activity by accelerometry in nonambulatory patients presents different technical requirements. The accelerometer must be as light as possible, wireless, able to indicate its spatial orientation in order to discriminate acceleration from