Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. FINDINGS: Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. INTERPRETATION: Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. 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. 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. FUNDING: Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.

Implementation of Motor Function Measure score percentile curves - Predicting motor function loss in Duchenne muscular dystrophy.

The Motor Function Measure is a standardized scoring system to evaluate motor function and monitor disease progression in neuromuscular diseases such as Duchenne muscular dystrophy. There are no available reference percentile curves for this measure. The aim of this analysis was to generate Motor Function Measure percentile curves for ambulant and non-ambulant patients affected by Duchenne Muscular Dystrophy, providing the opportunity to better evaluate the status and progression of an individual patient compared to other patients in the same age group. Data of patients aged between 6 and 15 years (819 measurements) was obtained from the international Motor Function Measure database. Age-dependent percentile curves were estimated using a "Generalized additive model for location, scale and shape" as suggested by the World Health Organisation Multicentre Growth Reference Study Group. Percentile curves for the Motor Function Measure total score and its sub-scores for patients with and without treatment with glucocorticoids are presented. Mean scores decline with age. Patients treated with glucocorticoids have higher mean values compared to glucocorticoid-naïve patients at the same age. The percentile curves with the online tool extend the clinical utility of the Motor Function Measure by facilitating the interpretation of individual standing and disease progression.

Health-related quality of life, self-reported impairments and activities of daily living in relation to muscle function in post-polio syndrome.

BACKGROUND: The symptoms of post-polio syndrome (PPS) and its resulting disabilities can affect quality of life and the ability to perform daily activities. No study has comprehensively analysed how various patient-reported outcome measures (PROMs) are associated with objectively assessed physical function in patients with PPS. AIM: To investigate health-related quality of life (HRQOL), self-reported impairments and activities of daily living during 6 months and evaluate their association with clinical muscle function outcomes in individuals with PPS. METHODS: Twenty-seven patients with PPS were included in the study. At baseline and 6 months, patients were administered PROMs measuring HRQOL (WHOQOL-BREF), self-reported impairments related to PPS (SIPP-RS) and activities of daily living (IBM-FRS). Clinical muscle function outcomes included 6 min walking distance (6MWD) and motor function measure (MFM). RESULTS: There were no changes in self-reported impairments (25.52 to 24.93, p = 0.40), activities of daily living (33.89 to 33.30, p = 0.20), 6MWD (391.52 to 401.85, p = 0.30) and MFM (83.87 to 85.46, p = 0.14) during 6 months, while the HRQOL psychological health decreased during this period (76.85 to 72.38, p = 0.05). A strong association was found between activities of daily living and clinical muscle function outcomes (6MWD: ß = 0.02, 95% CI: 0.02;0.03, t = 6.88, p < 0.01; MFM: ß = 0.25, 95% CI: 0.17;0.33, t = 6.69, p < 0.01). Self-reported impairments and HRQOL domains were not associated with the clinical muscle outcomes. CONCLUSIONS: Study findings indicate that objectively measured walking and motor abilities do not reflect patient's perspectives of their HRQOL and impairment due to PPS. More research is needed to assess changes over time and capture clinically meaningful changes in individuals with PPS and to increase the understanding of how the patient's perspective of disability measured by PROMs is related to objectively measured walking and motor abilities. TRIAL REGISTRATION: ClinicalTrials.gov Identifier ( NCT02801071 ) registered June 15, 2016.

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

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 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/DESIGN: At 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. DISCUSSION: The 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 REGISTRATION: ClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.

Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy.

While the number of new treatment options tested in patients with Duchenne muscular dystrophy (DMD) is increasing, there is still no defining of the most reliable assessments regarding therapeutic efficacy. We present clinical and radiological outcome measures used in ambulatory patients participating in our trial "Treatment with L-citrulline and metformin in Duchenne muscular dystrophy". The motor function measure is a validated test in patients with neuromuscular disorders that consists of 32 items and assesses all three dimensions of motor performance including standing and transfer (D1 subscore), axial and proximal motor function (D2 subscore), and distal motor function (D3 subscore). The test shows high intra- and inter-rater variability but only when strictly following guidelines of the materials, examination steps, and calculation of scores. The 6-minute walk test, timed 10-meter walk/run test, and supine-up time are commonly used timed functional tests that also sufficiently monitor changes in muscle function; however, they strongly depend on patient collaboration. Quantitative MRI is an objective and sensitive biomarker to detect subclinical changes, though the examination costs may be a reason for its limited use. In this study, a high correlation between all clinical assessments and quantitative MRI scans was found. The combinational use of these methods provides a better understanding about disease progression; however, longitudinal studies are needed to validate their reliability.

Timed function tests, motor function measure, and quantitative thigh muscle MRI in ambulant children with Duchenne muscular dystrophy: A cross-sectional analysis.

The development of new therapeutic agents for the treatment of Duchenne muscular dystrophy has put a focus on defining outcome measures most sensitive to capture treatment effects. This cross-sectional analysis investigates the relation between validated clinical assessments such as the 6-minute walk test, motor function measure and quantitative muscle MRI of thigh muscles in ambulant Duchenne muscular dystrophy patients, aged 6.5 to 10.8 years (mean 8.2, SD 1.1). Quantitative muscle MRI included the mean fat fraction using a 2-point Dixon technique, and transverse relaxation time (T2) measurements. All clinical assessments were highly significantly inter-correlated with p < 0.001. The strongest correlation with the motor function measure and its D1-subscore was shown by the 6-minute walk test. Clinical assessments showed no correlation with age. Importantly, quantitative muscle MRI values significantly correlated with all clinical assessments with the extensors showing the strongest correlation. In contrast to the clinical assessments, quantitative muscle MRI values were highly significantly correlated with age. In conclusion, the motor function measure and timed function tests measure disease severity in a highly comparable fashion and all tests correlated with quantitative muscle MRI values quantifying fatty muscle degeneration.

Treatment with L-citrulline in patients with post-polio syndrome: study protocol for a single-center, randomised, placebo-controlled, double-blind trial.

BACKGROUND: Post-polio syndrome (PPS) is a condition that affects polio survivors years after recovery from an initial acute infection by the Poliomyelitis virus. Most often, patients who suffered from polio start to experience gradual new weakening in muscles, a gradual decrease in the size of muscles (muscle atrophy) and fatigue years after the acute illness. L-citrulline is known to change muscular metabolism synthesis by raising nitric oxide (NO) levels and increasing protein synthesis. This investigator-initiated, randomised, placebo-controlled, double-blind, trial aims to demonstrate that L-citrulline positively influences muscle function and increases muscular energy production in patients with PPS. METHODS/DESIGN: Thirty ambulant PPS patients will be recruited in Switzerland. Patients will be randomly allocated to one of the two arms of the study (placebo:verum 1:1). After a 24-week run-in phase to observe natural disease history and progression, participants will be treated either with L-citrulline or placebo for 24 weeks. The primary endpoint is change in the 6-min Walking Distance Test. Secondary endpoints will include motor function measure, quantitative muscle force, quantitative muscle magnetic resonance imaging and magnetic resonance spectroscopy and serum biomarker laboratory analysis DISCUSSION: The aim of this phase IIa trial is to determine if treatment with L-citrulline shows a positive effect on clinical function and paraclinical biomarkers in PPS. If treatment with L-citrulline shows positive effects, this might represent a cost-efficient symptomatic therapy for PPS patients. TRIAL REGISTRATION: ClinicalTrial.gov, ID: NCT02801071 . Registered on 6 June 2016.