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T.P.1.03 Gait pattern assessment over 200 m in Duchenne muscular dystrophy (DMD)
Abstracts / Neuromuscular Disorders 18 (2008) 724–833 1 Washington University School of Medicine, Department of Neurology, St. Louis, United States; 2 Erasmus Medical Center, Sophia, Rotterdam, The Netherlands; 3 University of Pittsburgh, Department of Neurology, Pittsburgh, United States; 4 Children’s National Medical Center, Washington, DC, United States; 5 Institut de Myologie, Groupe Hospitalier PitieSalpetriere, Paris, France; 6 Tower Hematology Oncology, Beverly Hills, United States; 7 Mount Sinai School of Medicine, New York, United States; 8 Genzyme Corporation, Cambridge, United States
Background: The 6 min walk test (6MWT) is a well-established measure of functional endurance used to evaluate treatment-related change in clinical studies of cardiac and pulmonary disease: its appropriateness in neuromuscular disease trials has not been established. Objective: The objective of this study was to assess the effect of alglucosidase alfa treatment on functional endurance in a randomized, double-blind, placebo controlled study of children and adults with Pompe disease. Improvement in the 6MWT was a co-primary endpoint. Methods: Ninety ambulatory patients with Pompe disease (age 10–70 years) were randomized to receive intravenous (IV) infusions of alglucosidase alfa at 20 mg/kg of body weight or placebo every other week for 78 weeks. The 6MWT was administered by licensed physical therapists according to American Thoracic Society guidelines twice on consecutive days at 12-week intervals. Reliability training was performed prior to the Baseline and Week 52 assessments. Results: The coefficient of variation for the distance walked in the two tests was 2.3% with an ICC of 0.99 at Baseline and 1.9% with an ICC of 0.98 at Week 52. Thirty-one of 90 subjects (34.4%) used an assistive device to complete the test. Mean distance walked at Baseline was 327.4 m (SD = 128.0) or 50.1% predicted (41–626 m). By Week 78, an estimated mean absolute difference of 28.1 ± 13.1 m was observed in 6MWT distance (p = .0342) in favor of alglucosidase alfa vs. placebo. The 6MWT results correlated with leg muscle strength, r = .43, p < .001, and pulmonary function, r = .32, p = .002. Conclusion: The 6MWT was demonstrated reliable, valid and sensitive to the effect of alglucosidase alfa on the walking ability of children and adults with Pompe disease when compared to placebo. These findings support the use of the 6MWT as an endpoint in clinical studies in neuromuscular disease. doi:10.1016/j.nmd.2008.06.053
T.P.1.02 The 6 min walk test (6MWT) as a clinical trial outcome measure in Duchenne/Becker Muscular Dystrophy (DMD/BMD) C.M. McDonald 1; E.K. Henricson 1; J.J. Han 1; A.R. Nicorici 1; R.T. Abresch 1; L.A. Atkinson 2; A.L. Reha 2; G.L. Elfring 2; L.L. Miller 2 1 University of California, Davis Medical Center, Sacramento, CA, United States; 2 PTC Therapeutics, South Plainfield, NJ, United States Background: Lack of clinically meaningful outcome measures has been an obstacle to the development of new treatments for DMD/BMD. We conducted an observational study to evaluate the use of the 6MWT in DMD and have adopted the 6MWT as the primary outcome measure in an ongoing Phase 2b, double-blind, randomized trial of PTC124 in DMD/BMD. Methods: In the observational study, we enrolled ambulatory boys with DMD (n = 16) and healthy boys (n = 25). The age range was 4–12 years old. Boys with DMD were tested and re tested 8 days apart using a modified American Thoracic Society 6MWT; healthy controls were tested once. Reliability with repeat testing at longer time intervals is being pursued. Results: Median (range) distance traveled was 350 m (125–450 m) for boys with DMD and 626 m (range = 479–754 m) for healthy boys (p < 0.0002, t-test). All boys maintained a consistent velocity; the median (range) change in velocity between Minute 1 and Minute 6 was 9% ( 24% to +22%) for boys with DMD and 2% ( 20% to +18%) for healthy boys. Median (range) resting heart rate was 97 b/min (81–119 b/min) for boys with DMD and 83 b/min (59–108 b/min) for healthy boys at baseline (p < 0.0003, t-test) and 108 b/min (84–135 b/min) for boys with
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DMD and 111 b/min (73–145 b/min) for healthy boys after activity (p < 0.0002, t-test for change comparison). Nine accidental falls occurred in 5/16 (31%) boys with DMD compared with 4 falls in 3/25 (12%) healthy boys. After a fall, median (range) time to resume walking in boys with DMD was 2 s (1–7 s). All boys completed testing without injury. Available repeat testing and Phase 2b baseline 6MWT data will also be presented. Conclusion: Boys with DMD can complete the 6MWT at a steady, selfselected, fast walking pace. Distance and velocity clearly differentiate DMD boys from healthy boys. The test can be performed safely, without injury, and with minimal interruption from falls. The 6MWT provides a direct assessment of ambulatory function, thus offering a clinically meaningful outcome measure for use in registration-directed DMD therapeutic trials. doi:10.1016/j.nmd.2008.06.054
T.P.1.03 Gait pattern assessment over 200 m in Duchenne muscular dystrophy (DMD) P.Y. Jeannet 1; R. Ganea 2; V. Spehrs-Ciaffi 1; N.M. Goemans 3; K. Aminian 2; A. Paraschiv-Ionescu 2 1 Pediatric Neuromuscular Center, CHUV, Pediatrics, Lausanne, Switzerland; 2 Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), Laboratory of Movement Analysis and Measurement, Lausanne, Switzerland; 3 University Hospital Gasthuisberg, Pediatrics, Leuven, Belgium Introduction: In the face of new therapeutic perspectives for neuromuscular disorders, new tools are needed to better evaluate patients’ motor function. This study assesses the characteristics of the gait pattern of DMD children during free walking over 200 m while wearing miniaturized gyroscopes on each leg as compared with healthy controls. Method: Seventeen DMD patients (aged 8.1 ± 2 years) and 5 controls were assessed while walking a 200 m straight path at a self-determined normal pace. The gyroscopes measured cadence (CAD = steps/min), stride velocity (SV = m/s), peak shank angular velocity (PSAV = deg/s) and double support (DST = % of gait cycle time). Stride-to-stride variability of each of these gait parameters was calculated using median absolute deviation (MAD), defined as the median of the absolute difference between the sample values and their median value. Results: Mean CAD, SV and PSAV were lower for DMD patients (124 ± 18 steps/min, 0.88 ± 0.2 m/s and 398 ± 85 deg/s, respectively) compared to healthy controls (132 ± 16 steps/min, 1.2 ± 0.04 m/s and 474 ± 57 deg/s). PSAV decreased linearly with age in DMD patients. The DS phase (a marker of pathological gait) increased linearly after age 6 and was overall prolonged in DMD patients (23 ± 8%) compared to control (18 ± 6%). During the last 100 m, the variability of gait rhythm (calculated as MAD of PSAV) increased for DMD patients (29 ± 10 deg/s) compared to control (18 ± 8 deg/s), this variability also increased linearly with age in DMD patients. Conclusions: As expected this study shows that gait parameters in DMD patients are overall lower than in controls. More importantly, these preliminary results suggest that in DMD some gait parameters (such as PSAV and PSAV variability) worsen linearly with disease severity but also during a 200 m walking distance (further data is being collected). This assessment tool potentially provides a new objective assessment of disability, disease progression and possibly fatigue in neuromuscular disorders. doi:10.1016/j.nmd.2008.06.055
T.P.1.04 The falling factors of children with DMD ¨ . Yilmaz 1; A. Karaduman 1; H. Topaloglu 2 I. Alemdaroglu 1; O 1 Hacettepe University, Faculty of Health Sciences, Ankara, Turkey; 2 Hacettepe University, Children’s Hospital, Unit of Pediatric Neurology, Ankara, Turkey
Background: The 6 min walk test (6MWT) is a well-established measure of functional endurance used to evaluate treatment-related change in clinical studies of cardiac and pulmonary disease: its appropriateness in neuromuscular disease trials has not been established. Objective: The objective of this study was to assess the effect of alglucosidase alfa treatment on functional endurance in a randomized, double-blind, placebo controlled study of children and adults with Pompe disease. Improvement in the 6MWT was a co-primary endpoint. Methods: Ninety ambulatory patients with Pompe disease (age 10–70 years) were randomized to receive intravenous (IV) infusions of alglucosidase alfa at 20 mg/kg of body weight or placebo every other week for 78 weeks. The 6MWT was administered by licensed physical therapists according to American Thoracic Society guidelines twice on consecutive days at 12-week intervals. Reliability training was performed prior to the Baseline and Week 52 assessments. Results: The coefficient of variation for the distance walked in the two tests was 2.3% with an ICC of 0.99 at Baseline and 1.9% with an ICC of 0.98 at Week 52. Thirty-one of 90 subjects (34.4%) used an assistive device to complete the test. Mean distance walked at Baseline was 327.4 m (SD = 128.0) or 50.1% predicted (41–626 m). By Week 78, an estimated mean absolute difference of 28.1 ± 13.1 m was observed in 6MWT distance (p = .0342) in favor of alglucosidase alfa vs. placebo. The 6MWT results correlated with leg muscle strength, r = .43, p < .001, and pulmonary function, r = .32, p = .002. Conclusion: The 6MWT was demonstrated reliable, valid and sensitive to the effect of alglucosidase alfa on the walking ability of children and adults with Pompe disease when compared to placebo. These findings support the use of the 6MWT as an endpoint in clinical studies in neuromuscular disease. doi:10.1016/j.nmd.2008.06.053
T.P.1.02 The 6 min walk test (6MWT) as a clinical trial outcome measure in Duchenne/Becker Muscular Dystrophy (DMD/BMD) C.M. McDonald 1; E.K. Henricson 1; J.J. Han 1; A.R. Nicorici 1; R.T. Abresch 1; L.A. Atkinson 2; A.L. Reha 2; G.L. Elfring 2; L.L. Miller 2 1 University of California, Davis Medical Center, Sacramento, CA, United States; 2 PTC Therapeutics, South Plainfield, NJ, United States Background: Lack of clinically meaningful outcome measures has been an obstacle to the development of new treatments for DMD/BMD. We conducted an observational study to evaluate the use of the 6MWT in DMD and have adopted the 6MWT as the primary outcome measure in an ongoing Phase 2b, double-blind, randomized trial of PTC124 in DMD/BMD. Methods: In the observational study, we enrolled ambulatory boys with DMD (n = 16) and healthy boys (n = 25). The age range was 4–12 years old. Boys with DMD were tested and re tested 8 days apart using a modified American Thoracic Society 6MWT; healthy controls were tested once. Reliability with repeat testing at longer time intervals is being pursued. Results: Median (range) distance traveled was 350 m (125–450 m) for boys with DMD and 626 m (range = 479–754 m) for healthy boys (p < 0.0002, t-test). All boys maintained a consistent velocity; the median (range) change in velocity between Minute 1 and Minute 6 was 9% ( 24% to +22%) for boys with DMD and 2% ( 20% to +18%) for healthy boys. Median (range) resting heart rate was 97 b/min (81–119 b/min) for boys with DMD and 83 b/min (59–108 b/min) for healthy boys at baseline (p < 0.0003, t-test) and 108 b/min (84–135 b/min) for boys with
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DMD and 111 b/min (73–145 b/min) for healthy boys after activity (p < 0.0002, t-test for change comparison). Nine accidental falls occurred in 5/16 (31%) boys with DMD compared with 4 falls in 3/25 (12%) healthy boys. After a fall, median (range) time to resume walking in boys with DMD was 2 s (1–7 s). All boys completed testing without injury. Available repeat testing and Phase 2b baseline 6MWT data will also be presented. Conclusion: Boys with DMD can complete the 6MWT at a steady, selfselected, fast walking pace. Distance and velocity clearly differentiate DMD boys from healthy boys. The test can be performed safely, without injury, and with minimal interruption from falls. The 6MWT provides a direct assessment of ambulatory function, thus offering a clinically meaningful outcome measure for use in registration-directed DMD therapeutic trials. doi:10.1016/j.nmd.2008.06.054
T.P.1.03 Gait pattern assessment over 200 m in Duchenne muscular dystrophy (DMD) P.Y. Jeannet 1; R. Ganea 2; V. Spehrs-Ciaffi 1; N.M. Goemans 3; K. Aminian 2; A. Paraschiv-Ionescu 2 1 Pediatric Neuromuscular Center, CHUV, Pediatrics, Lausanne, Switzerland; 2 Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), Laboratory of Movement Analysis and Measurement, Lausanne, Switzerland; 3 University Hospital Gasthuisberg, Pediatrics, Leuven, Belgium Introduction: In the face of new therapeutic perspectives for neuromuscular disorders, new tools are needed to better evaluate patients’ motor function. This study assesses the characteristics of the gait pattern of DMD children during free walking over 200 m while wearing miniaturized gyroscopes on each leg as compared with healthy controls. Method: Seventeen DMD patients (aged 8.1 ± 2 years) and 5 controls were assessed while walking a 200 m straight path at a self-determined normal pace. The gyroscopes measured cadence (CAD = steps/min), stride velocity (SV = m/s), peak shank angular velocity (PSAV = deg/s) and double support (DST = % of gait cycle time). Stride-to-stride variability of each of these gait parameters was calculated using median absolute deviation (MAD), defined as the median of the absolute difference between the sample values and their median value. Results: Mean CAD, SV and PSAV were lower for DMD patients (124 ± 18 steps/min, 0.88 ± 0.2 m/s and 398 ± 85 deg/s, respectively) compared to healthy controls (132 ± 16 steps/min, 1.2 ± 0.04 m/s and 474 ± 57 deg/s). PSAV decreased linearly with age in DMD patients. The DS phase (a marker of pathological gait) increased linearly after age 6 and was overall prolonged in DMD patients (23 ± 8%) compared to control (18 ± 6%). During the last 100 m, the variability of gait rhythm (calculated as MAD of PSAV) increased for DMD patients (29 ± 10 deg/s) compared to control (18 ± 8 deg/s), this variability also increased linearly with age in DMD patients. Conclusions: As expected this study shows that gait parameters in DMD patients are overall lower than in controls. More importantly, these preliminary results suggest that in DMD some gait parameters (such as PSAV and PSAV variability) worsen linearly with disease severity but also during a 200 m walking distance (further data is being collected). This assessment tool potentially provides a new objective assessment of disability, disease progression and possibly fatigue in neuromuscular disorders. doi:10.1016/j.nmd.2008.06.055
T.P.1.04 The falling factors of children with DMD ¨ . Yilmaz 1; A. Karaduman 1; H. Topaloglu 2 I. Alemdaroglu 1; O 1 Hacettepe University, Faculty of Health Sciences, Ankara, Turkey; 2 Hacettepe University, Children’s Hospital, Unit of Pediatric Neurology, Ankara, Turkey