Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 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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Long‐term safety and efficacy of tofogliflozin as add‐on to insulin in patients with type 2 diabetes: Results from a 52‐week, multicentre, randomized, double‐blind, open‐label extension, Phase 4 study in Japan (J‐STEP/INS)

Diabetes Obesity and Metabolism ◽

10.1111/dom.13213 ◽

2018 ◽

Vol 20 (5) ◽

pp. 1176-1185 ◽

Cited By ~ 11

Author(s):

Yasuo Terauchi ◽

Masahiro Tamura ◽

Masayuki Senda ◽

Ryoji Gunji ◽

Kohei Kaku

Keyword(s):

Type 2 Diabetes ◽

Extension Phase ◽

Open Label ◽

Double Blind ◽

Safety And Efficacy ◽

Open Label Extension

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A 6-month open-label extension study of the safety and efficacy of subcutaneous belimumab in patients with systemic lupus erythematosus

Lupus ◽

10.1177/0961203318777634 ◽

2018 ◽

Vol 27 (9) ◽

pp. 1489-1498 ◽

Cited By ~ 8

Author(s):

A Doria ◽

D Bass ◽

A Schwarting ◽

A Hammer ◽

D Gordon ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Group Versus ◽

Extension Phase ◽

Systemic Lupus ◽

Open Label ◽

Double Blind ◽

Safety And Efficacy ◽

Open Label Extension ◽

Open Label Phase

Objective To evaluate the safety, tolerability and efficacy of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE) beyond 1 year. Methods This was a 24-week, open-label extension following a 52-week, double-blind, placebo-controlled trial of belimumab SC. Patients who completed the double-blind phase were eligible to enter the open-label phase. All patients received weekly belimumab 200 mg SC plus standard SLE therapy. Outcome measures included safety and efficacy (SLE Response Index (SRI) and SLE Flare Index (SFI) rates), and changes in biomarker and B cell levels. Results Of 677 patients who completed the 52-week, double-blind phase, 662 entered the open-label phase; 206 had previously received placebo and 456 had previously received belimumab. Despite differences in total belimumab exposure (24 weeks in the placebo-to-belimumab group versus 76 weeks in the belimumab group), the proportions of patients experiencing more than one adverse event (AE) or a serious AE in the open-label phase were similar between groups (placebo-to-belimumab: 51.5 and 6.8%; belimumab: 48.2 and 5.5%, respectively). Most AEs were mild/moderate in severity. Efficacy was maintained through the extension phase. An SRI response was achieved by 16.1% of patients in the placebo-to-belimumab group and 76.3% patients in the belimumab group. Furthermore, 1.0% of patients in the placebo-to-belimumab group and 2.6% of patients in the belimumab group experienced a severe SFI flare. Conclusion Belimumab SC was well tolerated and efficacy was maintained during the extension phase of this study. The safety profile of belimumab SC is consistent with that of previous experience with belimumab. Trial registration ClinicalTrials.gov identifier: NCT01484496

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Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Neuromuscular Disorders ◽

10.1016/j.nmd.2021.02.001 ◽

2021 ◽

Author(s):

Richard S. Finkel ◽

Erika Finanger ◽

Krista Vandenborne ◽

H. Lee Sweeney ◽

Gihan Tennekoon ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Phase 2 ◽

Open Label ◽

Open Label Extension ◽

Disease Modifying ◽

Extension Trial

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Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

Neurology ◽

10.1212/wnl.0000000000009233 ◽

2020 ◽

Vol 94 (21) ◽

pp. e2270-e2282 ◽

Cited By ~ 25

Author(s):

Diane E. Frank ◽

Frederick J. Schnell ◽

Cody Akana ◽

Saleh H. El-Husayni ◽

Cody A. Desjardins ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Western Blot ◽

Exon Skipping ◽

Study Drug ◽

Dose Titration ◽

Open Label ◽

Double Blind ◽

Dystrophin Protein ◽

Muscle Biopsies

ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrials.gov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

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