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Comparison of Longitudinal Changes in Expiratory Respiratory Function Endpoints and Inspiratory Flow Reserve (IFR) in Patients with Duchenne Muscular Dystrophy (DMD)
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A1765 - Comparison of Longitudinal Changes in Expiratory Respiratory Function Endpoints and Inspiratory Flow Reserve (IFR) in Patients with Duchenne Muscular Dystrophy (DMD)
Author Block: J. Karafilidis1, H. Mayer2, M. Leinonen3, G. Buyse4; 1Santhera Pharmaceuticals, Burlington, MA, United States, 2Childrens Hosp of Philadelphia, Philadelphia, PA, United States, 3Consultant, Santhera Pharmaceuticals, Liestal, Switzerland, 4University Hospitals Leuven, Leuven, Belgium.
Background:
Disease progression in DMD has recently been well characterized for expiratory respiratory function endpoints, especially peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)1,2. When expressed as percent of predicted values, all these endpoints follow linear and parallel trajectories during the respiratory function decline phase. The predicted values fall from 80% to 30% between 10 and 20 years, at an approximate annual decline of 5%. However, the disease progression in inspiratory flow reserve3 (IFR) has not been documented and no prediction equations exist.
Methods:
The objective of this analysis is to compare the longitudinal changes in expiratory respiratory function endpoints and IFR and to investigate the influence of baseline characteristics on longitudinal changes in IFR. In the DELOS study, 64 DMD patients, age 10-18 years, not using concomitant glucocorticoids who were in the respiratory function decline phase were randomized to receive idebenone (900 mg/day) or placebo for 52 weeks4. Treatment differences between idebenone and placebo at Week 52 were estimated with Mixed Model for Repeated Measures (MMRM). To investigate the influence of baseline disease characteristics, age, height and previous use of glucocorticoids were included as additional fixed factors in the MMRM analysis of IFR.
Results:
As reported ealier3,4, idebenone had a favorable effect in both PEF and FEV1 (p-values ranging from 0.023 to 0.082) and in IFR (p=0.040 for original MMRM analysis). When the additional factors were included in the MMRM analysis for IFR, age was the only factor influencing the longitudinal changes in IFR in addition to the baseline IFR and idebenone treatment. A more robust treatment effect for IFR favoring idebenone was seen when the additional factors were included in the MMRM (difference idebenone vs placebo 7.7%; p=0.006).
Conclusion:
Although the IFR has not been shown to correlate with the expiratory respiratory function endpoints3, idebenone had a favorable effect on both IFR and the expiratory respiratory function. Baseline IFR, age and idebenone treatment influenced the longitudinal changes in IFR. When the baseline disease characteristics were included as covariates in the statistical model, a more robust treatment effect of idebenone was seen.
References:
1Mayer OH et al. Pediatr Pulmonol. 2015 May;50(5):487-94.
2Mayer OH et al. US Neurology. 2017;13(1):35-41.
3Buyse GM et al. Pediatr Pulmonol. 2017;52(4):508-15.
4Buyse GM et al. Lancet 2015;385:1748-57.
Author Block: J. Karafilidis1, H. Mayer2, M. Leinonen3, G. Buyse4; 1Santhera Pharmaceuticals, Burlington, MA, United States, 2Childrens Hosp of Philadelphia, Philadelphia, PA, United States, 3Consultant, Santhera Pharmaceuticals, Liestal, Switzerland, 4University Hospitals Leuven, Leuven, Belgium.
Background:
Disease progression in DMD has recently been well characterized for expiratory respiratory function endpoints, especially peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)1,2. When expressed as percent of predicted values, all these endpoints follow linear and parallel trajectories during the respiratory function decline phase. The predicted values fall from 80% to 30% between 10 and 20 years, at an approximate annual decline of 5%. However, the disease progression in inspiratory flow reserve3 (IFR) has not been documented and no prediction equations exist.
Methods:
The objective of this analysis is to compare the longitudinal changes in expiratory respiratory function endpoints and IFR and to investigate the influence of baseline characteristics on longitudinal changes in IFR. In the DELOS study, 64 DMD patients, age 10-18 years, not using concomitant glucocorticoids who were in the respiratory function decline phase were randomized to receive idebenone (900 mg/day) or placebo for 52 weeks4. Treatment differences between idebenone and placebo at Week 52 were estimated with Mixed Model for Repeated Measures (MMRM). To investigate the influence of baseline disease characteristics, age, height and previous use of glucocorticoids were included as additional fixed factors in the MMRM analysis of IFR.
Results:
As reported ealier3,4, idebenone had a favorable effect in both PEF and FEV1 (p-values ranging from 0.023 to 0.082) and in IFR (p=0.040 for original MMRM analysis). When the additional factors were included in the MMRM analysis for IFR, age was the only factor influencing the longitudinal changes in IFR in addition to the baseline IFR and idebenone treatment. A more robust treatment effect for IFR favoring idebenone was seen when the additional factors were included in the MMRM (difference idebenone vs placebo 7.7%; p=0.006).
Conclusion:
Although the IFR has not been shown to correlate with the expiratory respiratory function endpoints3, idebenone had a favorable effect on both IFR and the expiratory respiratory function. Baseline IFR, age and idebenone treatment influenced the longitudinal changes in IFR. When the baseline disease characteristics were included as covariates in the statistical model, a more robust treatment effect of idebenone was seen.
References:
1Mayer OH et al. Pediatr Pulmonol. 2015 May;50(5):487-94.
2Mayer OH et al. US Neurology. 2017;13(1):35-41.
3Buyse GM et al. Pediatr Pulmonol. 2017;52(4):508-15.
4Buyse GM et al. Lancet 2015;385:1748-57.
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