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

Abstract

BackgroundDuchenne 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 being 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 antioxidant actions and regulatory roles in the calcium homeostasis besides its antitumor activity. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo-controlled phase III 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/designAt least 71 ambulant and up to 20 nonambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20 mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered tamoxifen for a 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 nonambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative magnetic resonance imaging of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed.DiscussionThe aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and nonambulant patients with DMD over 48 weeks. Motor function measures comprise 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.Trial registrationClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

“…In the past, a high dosage regimen of halofuginone, an anti-parasitic molecule used in veterinary medicine, combined with GCs led to the death of a DMD patient and abrogation of the clinical trial in 2016 [77]. One possible explanation could be found in the synergy between halofuginone and GCs [90][91][92][93]. When considering polypharmacy in DMD, exploring molecular interactions is of great importance in avoiding life-threatening drug combinations.…”

“…When blocking an entire pathway, such as the TGF-β, TLR, JAK/STAT or the glucose metabolism pathway, many other functions in the cell will be affected with repercussions in the cellular activity, which can be noticed as side-effects in patients (Tables 1-8). Inhibition of the TGF-β pathway seems to often produce side-effects (Table 5) [85,[92][93][94][95]. Although some molecules have not yet been tested in clinical trials with DMD patients, such as losartan, suramin, and decorin, the potential side-effects make these molecules less attractive.…”

“…A Phase clinical trial III (TAMDMD, NCT03354039, EudraCT Number: 2017-004554-42) is ongoing in Europe and should be completed in June 2020. Patients receive in both trials also GCs [92]. The antiparasitic molecule halofuginone (HT-100) inhibited mdx muscle and diaphragm fibrosis [93,94].…”

Current Pharmacological Strategies for Duchenne Muscular Dystrophy

“…Tamoxifen (TAM) is a selective estrogen receptor modulator that can either mimic or antagonize estrogens in a tissue-dependent manner ( Dorchies et al, 2013 ). TAM can elevate the level of pro-inflammatory cytokines and growth factors involved in muscle regeneration and fibrosis, such as TGF-β, insulin-like growth factor 1 (IGF1) and osteopontin ( Nagy et al, 2019 ). And then leads to an increased capacity of muscle-purified mitochondria to buffer cytosolic calcium ( Nagy et al, 2019 ).…”

Recent advances of glucocorticoids in the treatment of Duchenne muscular dystrophy (Review)

“…This suggests that denosumab merits further testing as an effective drug for the treatment of osteoporosis in patients with DMD. Tamixofen was evaluated for the treatment of DMD in a multicenter, randomized, placebo-controlled, double-blind phase 3 trial, which found that 20 mg tamoxifen daily for 48 weeks slowed the progression of ambulant and non-ambulant DMD ( 38 ). In another phase 3 trial, the DMD Long-term Idebenone Study (DELOS) trial, idebenone was shown to reduce the loss of peak expiratory flow and FVC in patients with DMD in comparison with placebo ( 39 ).…”