Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

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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