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Repurposed tamoxifen failed to delay disease progression as an adjunct to corticosteroids among boys with Duchenne muscular dystrophy (DMD), the phase III TAMDMD trial showed.

In an intention-to-treat population, no significant differences were observed from baseline to week 48 in D1 domain scores (measuring lying, sitting, and standing positions) of the Motor Function Measure, with changes of -3.05% in the tamoxifen group and -6.15% in the placebo group (P=0.33), reported Dirk Fischer, MD, of University Children's Hospital Basel in Switzerland, and co-authors.

There were also no significant differences between the tamoxifen and placebo groups in secondary efficacy outcomes, including changes in the Motor Function Measure total score, D2 and D3 subscores of the Motor Function Measure, the North Star Ambulatory Assessment, the Performance of Upper Limb test, timed function tests, and quantitative muscle tests, they noted in .

Quantitative MRI using fat fraction and T2 did not differ between tamoxifen and placebo after 48 weeks of treatment, nor were there any differences in the results of the Personal Adjustment and Role Skills Scale questionnaire.

"Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant," Fischer and colleagues wrote. "Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence."

Tamoxifen was safe and well tolerated in the study. The majority of adverse events were mild to moderate, and no fatalities occurred.

In designing this trial, the authors referred to published preclinical data for tamoxifen that showed efficacy in stabilizing biological membranes, inhibiting fibrosis and other potential beneficial effects. A also showed that tamoxifen increased muscle force generation, reduced muscle fatigue, and normalized locomotor activity.

Additionally, an open-label prospective showed a good safety profile in 13 children with DMD. A comparison of these participants with historical controls suggested that tamoxifen preserved motor function, leading Fischer and co-authors to design and complete the current phase III trial.

In an , Laurent Servais, MD, PhD, of the University of Oxford in England, wrote that "the negative result for tamoxifen in the phase III trial should not discourage the community from continuing the evaluation of inexpensive repositioned drugs that have the potential to treat individuals worldwide."

"It is important to keep in mind that the only drugs that unambiguously work so far for individuals with Duchenne muscular dystrophy are corticosteroids," he added.

The multicenter, double-blind was conducted at 12 centers in seven European countries from May 2018 to October 2020. Fischer and team randomized 79 ambulant boys ages 6.5 to 12 with a genetically confirmed diagnosis of DMD 1:1 to 20-mg tamoxifen or placebo as an oral tablet once daily. Additionally, patients received standard-of-care corticosteroids. The trial lasted 48 weeks with an end-of-study visit during week 60.

Baseline characteristics were similar between groups, but participants in the intervention group had a slightly higher mean age (9.2 vs 8.4 years) and body mass index (19.6 vs 18.6). Pharmacokinetic analysis of tamoxifen metabolites showed higher-than-expected participant compliance during the trial.

Fischer and co-authors noted that the primary efficacy outcome of motor function via the Motor Function Measure D1 subscore depends on patients' fatigue level and motivational state and is subject to inter-rater variability.

They also cited the study's selected timepoint and duration as a limitation: "The question arises as to whether a medical intervention should be done as early as possible, because the rapid decline of motor function following the relatively stable plateau phase in Duchenne muscular dystrophy might only be slowed with sufficient lead time of treatment," they wrote.

Fischer and team will address the question of treatment duration in an optional open-label extension phase of TAMDMD. Additionally, they plan to publish the results of Cohort 2, which contained non-ambulatory children, separately.

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