Efficacy of Idebenone to Preserve Respiratory Function above Clinically Meaningful Thresholds for Forced Vital Capacity (FVC) in Patients with Duchenne Muscular Dystrophy

Oscar H Mayer, Mika Leinonen, Christian Rummey, Thomas Meier, Gunnar M Buyse, DELOS Study Group, Oscar H Mayer, Mika Leinonen, Christian Rummey, Thomas Meier, Gunnar M Buyse, DELOS Study Group

Abstract

Background: Patients with DMD experience progressive restrictive respiratory disease and eventual respiratory failure. Standard of care guidelines command changes in disease management when forced vital capacity percent of predicted (FVC% p) falls below clinically relevant thresholds. The Phase 3 DELOS trial in patients with DMD demonstrated that idebenone reduces the loss of peak expiratory flow and FVC compared to placebo (Buyse GM, et al.; Lancet 2015; 385 : 1748-57).

Objective: Post-hoc analyses were conducted to assess whether treatment with idebenone could reduce the risk of patients dropping below clinically meaningful thresholds of FVC% p.

Methods: The DELOS trial enrolled DMD patients 10-18 years of age not using glucocorticoids to receive idebenone (N = 31) or placebo (N = 33) for 12 months. Change from baseline in FVC and FVC% p was assessed by hospital spirometry and analyzed by mixed model of repeated measures and slope analysis and proportions of patients falling below clinically meaningful thresholds of FVC% p were compared.

Results: The change over 1 year in FVC and FVC% p showed a consistent pattern in favor of idebenone treatment across multiple analysis methods and fewer patients in the idebenone group declined by a margin of 10% or more in FVC and FVC% p compared to placebo. There were also fewer patients in the idebenone group (15%) with a decline below FVC% p of 50% compared to the placebo group (25%) and fewer patients in the idebenone group (28%) showed a decline below FVC% p of 50% or 40% or 30% compared to the placebo group (43%).

Conclusions: These data added to the consistency and clinical meaningfulness of findings from the DELOS trial showing that idebenone can slow the loss of pulmonary function in patients with DMD.

Keywords: Duchenne muscular dystrophy; Pulmonary function; forced vital capacity; idebenone; respiration.

Figures

Fig.1
Fig.1
Kaplan-Meier analysis for the time to 10% relative decline in FVC% p (persistent event analysis).
Fig.2
Fig.2
Kaplan-Meier analysis for the time to decline below 50% of FVC% p from baseline to week 52 (persistent event analysis).
Fig.3
Fig.3
Kaplan-Meier analysis for time to decline below any of the 50%, 40% or 30% thresholds for FVC% p from baseline to week 52 (persistent event analysis).

References

    1. Mah JK, Korngut L, Dykeman J, et al. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 2014;24:482–91.
    1. McDonald CM, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil. 1995;74:S70–92.
    1. Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to Duchenne muscular dystrophy and spinal muscular atrophy. Pediatr Pulmonol. 2000;29:141–50.
    1. Simonds AK. Respiratory complications of the muscular dystrophies. Semin Respir Crit Care Med. 2002;23:231–8.
    1. Bourke SC. Respiratory involvement in neuromuscular disease. Clin Med (Lond). 2014;14:72–75.
    1. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med. 2004;170:456–65.
    1. Finder J, et al. Pulmonary endpoints in duchenne muscular dystrophy: A workshop summary. American Journal of Respiratory and Critical Care Medicine (epub ahead of print). 2017.
    1. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2001;164:2191–4.
    1. McDonald CM, et al. Longitudinal pulmonary function test outcome measures in Duchenne muscular dystrophy: Long-term natural history with ad without glucocorticoids. (submitted). 2017.
    1. Mayer OH, Finkel RS, Rummey C, et al. Characterization of pulmonary function in Duchenne muscular dystrophy. Pediatr Pulmonol. 2015;50:487–94.
    1. Mayer OH, Henricson EK, McDonald CM, Buyse GM. Advances in pulmonary care in duchenne muscular dystrophy. US Neurology. 2017;13:35–41.
    1. McDonald CM, Henricson EK, Abresch RT, et al. The cooperative international neuromuscular research group Duchenne natural history study- a longitudinal investigation in the era of glucocorticoid therapy: Design of protocol and the methods used. Muscle Nerve. 2013;48:32–54.
    1. LoMauro A, D’Angelo MG, Aliverti A. Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: Current and emerging options. Therapeutics and Clinical Risk Management. 2015;11:1475–88.
    1. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part Implementation of multidisciplinary care. Lancet Neurol. 2010;9:177–189.
    1. Landfeldt E, Peter Lindgrenc P, Bell CF, et al. Compliance to care guidelines for Duchenne Muscular Dystrophy. Journal of Neuromuscular Diseases. 2015;2:63–72.
    1. Rodger S, Katherine L, Woods KL, et al. Adult care for Duchenne muscular dystrophy in the UK. J Neurol. 2015;262:629–41.
    1. Birnkrant DJ, Panitch HB, Benditt JO, et al. American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Chest. 2007;132:1977–86.
    1. Humbertclaude V, Hamroun D, Bezzou K, et al. Motor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials. Eur J Paediatr Neurol. 2012;16:149–60.
    1. Birnkrant DJ, Bushby KM, Amin RS, et al. The respiratory management of patients with duchenne muscular dystrophy: A DMD care considerations working group specialty article. Pediatr Pulmonol. 2010;45:739–4.
    1. Buyse GM, Voit T, Schara U, et al. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): A double-blind randomised placebo-controlled phase 3 trial. Lancet. 2015;385:1748–57.
    1. Buyse GM, Voit T, Schara U, et al. Treatment effect of idebenone on inspiratory function in patients with Duchenne muscular dystrophy. Pediatr Pulmonol. 2017;52(4):508–15.
    1. McDonald CM, Meier T, Voit T, et al. Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy. Neuromuscul Disord. 2016;26:473–80.
    1. American Thoracic Society/European Respiratory S. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166:518–624.
    1. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159:179–87.
    1. Gauld LM, Kappers J, et al. Prediction of childhood pulmonary function using ulna length. Am J Respir Crit Care Med. 2003;168:804–9.
    1. Gauld LM, Kappers J, Carlin JB, Robertson CF. Height prediction from ulna length. Dev Med Child Neurol. 2004;46:475–80.
    1. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82.
    1. Meier T, Rummey C, Leinonen M, et al. Characterization of pulmonary function in 10–18 year old patients with Duchenne muscular dystrophy. Neuromuscul Disord. 2017;27:307–14.
    1. Brooke MH, Fenichel GM, Griggs RC, et al. Duchenne muscular dystrophy: Patterns of clinical progression and effects of supportive therapy. Neurology. 1989;39:475–81.
    1. du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184:1382–9.
    1. Richeldi L. Assessing the treatment effect from multiple trials in idiopathic pulmonary fibrosis. Eur Respir Rev. 2012;21:147–51.
    1. Henricson EK, Abresch RT, Cnaan A, et al. The cooperative international neuromuscular research group Duchenne natural history study: Glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013;48:55–67.
    1. Noble PW, Albera C, Bradford WZ. Pirfenidone in patients with idiopathic pulmonary fibrosis. (CAPACITY): Two randomised trials. Lancet. 2011;377:1760–69.
    1. Richeldi L, Ryerson CJ, Lee JS, et al. Relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis. Thorax. 2012;67:407–11.
    1. Sawnani H, Thampratankul L, Szczesniak RD, et al. Sleep disordered breathing in young boys with Duchenne muscular dystrophy. J Pediatr. 2015;166:640–645.

Source: PubMed

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