Use of a wearable device to assess sleep and motor function in Duchenne muscular dystrophy

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

10.21203/rs.2.10085/v2 ◽

2019 ◽

Author(s):

Sara Nagy ◽

Patricia Hafner ◽

Simone Schmidt ◽

Daniela Rubino-Nacht ◽

Sabine Schädelin ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Motor Function ◽

Open Label ◽

Phase 3 ◽

Double Blind ◽

Safety And Efficacy ◽

Open Label Extension ◽

To Receive ◽

Function Measure

Abstract 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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Recombinant human insulin‐like growth factor‐1 therapy for 6 months improves growth but not motor function in boys with Duchenne muscular dystrophy

Muscle & Nerve ◽

10.1002/mus.26846 ◽

2020 ◽

Vol 61 (5) ◽

pp. 623-631

Author(s):

Meilan M. Rutter ◽

Brenda L. Wong ◽

James J. Collins ◽

Hemant Sawnani ◽

Michael D. Taylor ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Growth Factor ◽

Muscular Dystrophy ◽

Motor Function ◽

Human Insulin ◽

Insulin Like Growth Factor ◽

Recombinant Human Insulin

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Editorial: Motor Function Measure in Duchenne Muscular Dystrophy

European Journal of Paediatric Neurology ◽

10.1016/j.ejpn.2022.01.007 ◽

2022 ◽

Author(s):

Imelda JM. de Groot

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Motor Function ◽

Function Measure

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Characteristics of Disease Progression and Genetic Correlation in Ambulatory Iranian Boys With Duchenne Muscular Dystrophy

10.21203/rs.3.rs-185817/v1 ◽

2021 ◽

Author(s):

Gholamreza Zamani ◽

Sareh Hosseinpour ◽

Mahmoud Reza Ashrafi ◽

Mahmoud Mohammadi ◽

Reza Shervin Badv ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Motor Function ◽

Pediatric Population ◽

Disease Onset ◽

Clinical History ◽

Disease Diagnosis ◽

The Mean ◽

Mutation Type

Abstract Introduction: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations are progressive muscle weakness, impairment in walking and motor function leading to loss of ambulation by age of 13 years. Molecular studies are standard tests for diagnosis. This article describes the status of disease progression and genetic pattern in the Iranian affected boys and furthermore, concerns to find a correlation between the genotype and motor function phenotype of them. Methods This study was performed on 152 DMD patients. Clinical history including disease phenotype, steroid therapy data and the NorthStar Ambulatory Assessment (NSAA) score were all collected. Molecular diagnoses were confirmed by multiplex ligation dependent probe amplification and Next Generation Sequencing tests. Results We studied a total of 152 Iranian DMD patients. The mean age at disease onset was 4.04 ± 2.00 year and the mean age at diagnosis was 5.05 ± 2.08 year. The mean age of loss of ambulatory was 10.9 year. Contracture was seen in 38.9 %. The overall mean of NSAA total score versus age of the patients peaked at 4 year with mean NSAA score of 24. We assessed the yearly changes in the NSAA linear score for all cases based on mutation type and exon site. We found deletion mutation in 79.1%, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon was deletion exon 44 in our patients (5.3%) and the most common multiexon deletion was 45–50 and 45–52 exon equally with 4.6%. This study did not show any correlation between age at disease onset, loss of ambulation age and wheelchair dependency with mutation type but a correlation between contracture with mutation type was found. A significant deference in NSAA score were seen between deletion and nonsense groups at the age of 3 year (P = 0.036) and 3.5 years (p = 0.04). We couldn’t find any correlation among phenotype and Exon site. 91.1% had a history of corticosteroid taking and 54.1% of patient had compliance with rehabilitation. Conclusion This study has demonstrated the phenotype and mutational features of DMD boys and provide information of the disease natural motor history, disease progression and disease diagnosis with the management status of DMD in Iran. Achieved data will encourage the development of clinical trials and advance future molecular therapies in Iran.

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