Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Despite promising preclinical data, this RCT (n=78) did not meet prespecified primary endpoint, with no statistically significant effect of tamoxifen vs placebo on change from baseline to week 48 in scores on D1 domain of Motor Function Measure (-3·05% vs –6·15%, placebo; p=0.33)
Source:
The Lancet Neurology
SPS commentary:
The researchers conducted this study based on data showing that tamoxifen increased muscle force generation, reduced muscle fatigue, and normalisation of locomotor activity in the Duchenne muscular dystrophy mouse model (mdx). In this paper, they report the results in ambulant participants (group A); results in non-ambulant participants (group B) will be analysed and presented separately.
A commentary notes that despite this disappointing result, two positive conclusions can be drawn from this trial. First, academic investigators, supported by a broad community, were able to fund and conduct a large international trial to investigate the effect of a drug with no potential for financial gain. Second, they reported these negative results, which is of utmost importance, as over the past 15 years, several promising results from phase 1 and phase 2 trials could not be reproduced in double-blind, placebo-controlled studies, examples being the antisense oligonucleotide drisapersen, the coenzyme Q-derived idebenone, and the nuclear factor κ-light-chain-enhancer of activated B cells inhibitor edasalonexent. It highlights that “blaming clinical trial design or clinical outcome for negative results in phase 3 trials ignores that no outcome measure or clinical trial design will make a non-efficacious drug efficacious.” It also highlights that an additional takeaway from this trial is that the management of expectations generated by phase 1 trials and the objective interpretation of early efficacy signals are a collective responsibility, with caution needed when claiming efficacy on basis of short, open-label, uncontrolled phase 1 trials and the tempering of the enthusiastic presentation of data from these early-phase trials. It suggests that investigators and sponsors should work with the patient community to avoid false claims in social media that overstate the benefits of a drug. It calls for early-phase trials to be properly designed to capture efficacy signals as objectively as possible, and to control for bias, to avoid conducting large phase 3 trials with little chance of showing efficacy. It concludes that the negative result for tamoxifen should not discourage the community from continuing the evaluation of inexpensive repositioned drugs but it is important to keep in mind that the only drugs that work so far in Duchenne muscular dystrophy are corticosteroids.