Corticosteroids in Duchenne muscular dystrophy: impact on the motor function measure sensitivity to change and implications for clinical trials

Schreiber, Audrey; Brochard, Sylvain; Rippert, Pascal; Fontaine-Carbonnel, S.; Payán, C.; Poirot, I.; Hamroun, Dalil; Vuillerot, Carole

doi:10.1111/dmcn.13590

Cited by 25 publications

(19 citation statements)

References 25 publications

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“…We also investigated possible relationships between timed immersion mouth and nose expiration and age, motor and respiratory functions. Motor and respiratory functions deteriorated in MD patients in oneyear follow-up, as observed in previous studies [21,22]. However, timed immersion expiration did not deteriorate.…”

Section: Discussionsupporting

confidence: 85%

Timed immersion expiration measures in patients with muscular dystrophies

et al. 2020

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Introduction: Muscular dystrophies (MD) cause muscle weakness, affecting motor and respiratory functions. Aquatic activities maintain strength and ventilatory function and may require immersion expiration control.Objectives: (1) To describe the evolution of timed immersion expiration in patients with MD in one-year follow-up.(2) to describe motor and respiratory outcomes in one-year follow-up. (3) to investigate possible relationships between timed immersion expiration and age, motor and respiratory functions.Method: Fifty-seven patients with MD (12-35 years, Vignos scale 2-8) were evaluated twice, with one-year interval. Immersion expiration control was timed with a chronometer. Motor function was assessed by Motor Function Measure. The respiratory function was evaluated by spirometry. Analysis of variance compared assessments and Pearson tests investigated relationships between variables and age. Results: Motor and respiratory functions decreased (p < 0.001) but timed immersion expiration was maintained. Timed immersion expiration was not correlated to motor and respiratory functions. Conclusion:As patients maintained timed immersion expiration in the one-year follow-up, aquatic therapy might be a facilitator for people with MD.

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Section: Discussionsupporting

confidence: 85%

Timed immersion expiration measures in patients with muscular dystrophies

et al. 2020

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“…The reliability of the MFM has been examined in several studies. It is described as being sensitive to treatment response [32] and to disease progression even within as short a period as 3 months [33, 34]. The D1 domain of the MFM, assessing standing and transfer, was shown to be the most powerful parameter to detect clinical decline compared to D2 and D3 domains [35].…”

Section: Methodsmentioning

confidence: 99%

“…Since the D1 domain remains around 0% in patients who have lost ambulation it cannot be applied to monitor disease progression or treatment response in nonambulant patients. In contrast, the D2 and D3 domains are more suitable for nonambulant patients as these assess the retained upper limb functions [29, 32, 33]. The D2 domain in particular was shown to be informative, with a decrease of 9.4% per year in nonambulant patients [33].…”

Section: Methodsmentioning

confidence: 99%

Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

Nagy

Hafner

Schmidt

et al. 2019

Trials

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BackgroundDuchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently being tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows antioxidant actions and regulatory roles in the calcium homeostasis besides its antitumor activity. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo-controlled phase III trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open-label extension of the study will be offered to all participants.Methods/designAt least 71 ambulant and up to 20 nonambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20 mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered tamoxifen for a further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in nonambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative magnetic resonance imaging of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed.DiscussionThe aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and nonambulant patients with DMD over 48 weeks. Motor function measures comprise the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open-label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double-blind phase) compared to a delayed start can reduce disease progression more efficiently.Trial registrationClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.

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“…The reliability of the MFM has been examined in several studies. It is described to be sensitive to treatment response 32 , and to disease progression even within as short periods as 3 months [33][34] . The D1 domain of the MFM, assessing standing and transfer, was shown to be the most powerful parameter to detect clinical decline compared to D2 and D3 domains 35 .…”

Section: Change Of D1 Domain Of Motor Function Under Tamoxifen Comparmentioning

confidence: 99%

Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

Nagy¹,

Hafner

Schmidt

et al. 2019

Preprint

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BACKGROUND Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows besides its antitumor activity also antioxidant actions and regulatory roles in the calcium homeostasis. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo controlled phase 3 trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open label extension of the study will be offered to all participants. METHODS/DESIGN At least 71 ambulant and up to 20 non-ambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered to receive tamoxifen for further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in non-ambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative MRI of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed. DISCUSSION The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and non-ambulant DMD patients over 48 weeks. Motor function measure comprises the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double blind phase) compared to a delayed start can reduce disease progression more efficiently.

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Corticosteroids in Duchenne muscular dystrophy: impact on the motor function measure sensitivity to change and implications for clinical trials

Abstract: Corticosteroids have a quantitative impact on muscle strength 6 to 24 months after starting treatment. Motor function measure is a valid outcome measure in Duchenne muscular dystrophy patients under corticosteroid treatment.

Cited by 25 publications

References 25 publications

Timed immersion expiration measures in patients with muscular dystrophies

Timed immersion expiration measures in patients with muscular dystrophies

Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial

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