Tamoxifen in Duchenne Muscular Dystrophy (TAMDMD)

University Hospital Basel

Status and phase

Completed

Phase 3

Conditions

Duchenne Muscular Dystrophy

Treatments

Drug: Tamoxifen

Drug: Matching placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT03354039

TAMDMD

Details and patient eligibility

About

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.

Full description

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

Enrollment

93 patients

Sex

Male

Ages

78 months to 16 years old

Volunteers

No Healthy Volunteers

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