Tamoxifen in Duchenne Muscular Dystrophy

A randomised, double blind, placebo controlled, 48-week clinical trial with a core population (group A) of 79 ambulant 6.5 to 12 years old Duchenne's muscular dystrophy (DMD) patients that are under stable standard treatment of care with glucocorticoids. Furthermore, the investigators plan to include 6-20 non-ambulant patients who do not receive glucocorticoids (as parallel group B), 10 to 16 years old, to obtain efficacy and safety data in a broader DMD population. All patients will receive 20 mg of tamoxifen (TAM) or placebo once daily during 48 weeks.

An open label extension (OLE) trial for participants of the TAMDMD main study will be performed. All TAMDMD patients on TAM or placebo are offered to enter this OLE.

This is a 48-week multicentre, parallel, randomised, double-blind, placebo controlled phase 3 safety and efficacy trial. There are two treatment arms: Tamoxifen (verum) and placebo (control), with treatment allocation of 1:1.

The investigators plan to screen at least 79 and to enroll at least 71 ambulant DMD patients aged between 6.5 and 12 years (group A) and 6 - 20 non-ambulant DMD patients aged between 10 and 16 years (group B). In order to reach statistical power, 60 ambulant patients (group A) need to complete the trial. Treatment with 20 mg Tamoxifen once daily will be given for the total trial duration of 48 weeks.

Only patients with glucocorticoids (standard treatment of care) will be included in group A (ambulant patients) and only non-glucocorticoid users in group B. At baseline as well as at the end of the study clinical, laboratory, and MRI measurements will be performed. These include the Motor Function Measure (MFM) scale, timed function tests, the 6 minute walking distance, quantitative muscle testing (QMT) and quantitative thigh muscle MRI, questionnaires. A physical examination, an ECG, vital signs as well as safety laboratory blood analyses will be performed at every visit. Furthermore, an x-ray of the hand and a dual energy x-ray absorptiometry (DEXA)-scan will be performed at baseline and at the end of the study.

An open label extension (OLE) trial for participants of the TAMDMD main study will be performed. All TAMDMD patients on TAM or placebo are offered to enter this OLE. All OLE patients will receive 20 mg of TAM daily during 48 weeks. The same study specific assessments as in the double-blind randomized phase will be performed during the OLE phase

Eligibility Criteria:
Inclusion Criteria:

Group A (ambulant patients)

* Documented diagnosis of DMD by mutation analysis in the dystrophin gene or by substantially reduced levels of dystrophin protein (i.e. absent or \<5% of normal) on Western blot or immunostaining
* Stable treatment with glucocorticoids \>6 months (no significant change in dosage (\>0.2mg/kg)) at screening; dosing adaptations according to weight change are allowed
* Male gender
* 6.5 to 12 years of age at time of screening
* weight \>20kg
* ambulant patients
* able to walk at least 350 meters in 6 minute walking distance test without assistance at screening
* MFM D1 subdomain of the MFM scale \>40% at screening
* Ability to provide informed consent and to comply with study requirements
* Patients harbouring a nonsense mutation treatable with the approved drug ataluren should be under stable ataluren treatment for at least 3 months or in case of nontolerance being off ataluren treatment for at least 3 months before screening

Group B (non-ambulant patients)

* Documented diagnosis of DMD by mutation analysis in the dystrophin gene or by substantially reduced levels of dystrophin protein (i.e. absent or \<5% of normal) on Western blot or immunostaining
* Not using glucocorticoids for \>6 months
* Male gender
* Non-ambulant patients (walking distance less than 10 meters)
* 10 to 16 years of age at time of screening
* Ability to provide informed consent and to comply with study requirements

Open label extension

- Recent participation and completion of TAMDMD study

Exclusion Criteria:

* Known individual hypersensitivity or allergy to tamoxifen or other ingredients/excipients of IMP
* Female gender
* Use of tamoxifen or testosterone within the last 3 months
* Known or suspected malignancy
* Other chronic disease or clinically relevant limitation of renal, liver or heart function
* Known or suspected non-compliance
* Any injury which may impact functional testing, e.g. upper or lower limb fracture
* Planned or expected spinal fusion surgery during the study period (as judged by the Investigator; i.e. due to rapid progressing scoliosis), previous spinal fusion surgery is allowed if it took place more than 6 months prior to screening.
* Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders of the participant/parents (as judged by the investigator)
* Concomitant participation in any other interventional trial (and up to 3 months prior to screening)
* Use of CYP2D6 inhibitors or of CYP3A4 inducers (apart from glucocorticoids), platelet aggregation inhibitors and coumarin-type anti-coagulants
* Use of drugs metabolized by CYP2C9, such as phenprocoumon, phenytoin, warfarin, celecoxib, fluvastatin, ginko biloba, St. John's wort and sulfamethoxazol
* Galactosemia (lack of galactose-1-phosphat-uridylyltransferase or UDP-galactose-4-epimerase or galactokinase; Fanconi-Bickel-syndrome); congenital lack of lactase; glucose-galactose malabsorption
* Presence of one or more of the following eye disorders: cataract, retinopathia, optic neuropathy, alteration of the cornea
* Presence of one or more of the following laboratory abnormalities: anaemia, thrombocytopenia, leukopenia, neutropenia or agranulocytosis

Group A:

* Glucocorticoid naïve patients
* Start of glucocorticoid treatment or change in dosage \<6 month prior to screening (dosing adaptations according to weight change are allowed)

Group B:

* Glucocorticoid treated patients or patients that stopped glucocorticoid treatment \<6 month prior to screening
* Assisted ventilation of any kind necessary