To test if tamoxifen treatment, compared to placebo, reduces the progression of the disease in 6.5-12 years old ambulant DMD patients by at least 50% (using the MFM D1 subscore as primary clinical endpoint in group A patients).To test if tamoxifen…
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Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Outcome
Group A: The primary efficacy outcome will be the change of motor function
under TAM treatment compared to placebo. This will be assessed by the motor
function measure (MFM) D1 subscore (standing and transfers) in ambulant
patients.
For the MFM D1 subscore several exercises that will be scored have to be done
by the patients such as:- to sit up on a mat (without support of upper limbs),
- to stand up from sitting on a mat,
- to sit down on the chair from standing,
- to walk forward 10 steps on both heels,
- to walk forward 10 steps on a straight line,
- torun10m,
- and to hop 10 times on one foot,
The MFM is a validated assessment tool used to measure proximal and distal
motor function in both ambulant and non-ambulant patients with neuromuscular
disorders as recommended by the EMA in trials for DMD (Bérard et al. 2005). The
instruction manual, validation examinations and other publications using the
MFM can be downloaded from the MFM- website (www.mfm-nmd.org). This score also
seems to be particularly interesting because of its relation to loss of
ambulation and its responsiveness to short-term changes. Therefore, the results
suggest to use the MFM D1 subscore as the primary endpoint for the selected
population of ambulant DMD patients. Ambulant DMD patients show a rapid decline
of about -17.2% per year of the D1 subscore and a D1 subscore of 40% is
predictive for loss of ambulation 1 year later (Bushby & Connor 2011).
Recently, Bonati et al, (2015) demonstrated that among all analysed clinical
measures, the MFM D1 subscore showed the most significant decline in ambulant
DMD patients older than 7 years, resulting in the highest effect size and power
(Bonati et al. 2015).
Group B: The primary efficacy outcome in this group will be the motor function
from baseline to week 48 under TAM treatment compared to placebo. This will be
assessed by the motor function measure (MFM) D2 subscore in non-ambulant
patients allowing a partial extrapolation and comparison of MFM D2 values
between group A and group B. Note that the MFM D1 subscore in non-ambulant
patients is usually 0%; therefore the MFM D1 subscore is not suitable for this
population.
For the MFM D2 subscore several exercises that will be scored have to be done
by the patients such as:
- from supine on a mat to raise the head and maintain the raised position
- from supine on a mat to raise one hand and move it to the opposite shoulder
- from seated on the chair to raise the head from fully flexed position and
maintain the raised position
- from seated on the chair to place the two forearms and/or the hands on the
table at the same time without moving the trunk.
Secondary outcome
Secondary clinical outcomes to assess muscle function:
- MFM total score, the D2, and D3 MFM subscores, North Star Ambulatory
Assessment, proximal upper limb function from baseline to week 48 under
tamoxifen treatment compared to placebo.
- Timed function tests (6 minute walking distance in meter, 10 meter walking
time in seconds, time to rise from lying on the floor / supine up in seconds,)
from baseline to week 48 under tamoxifen treatment compared to placebo.
Secondary clinical outcomes to assess muscle force:
- Quantitative muscle testing (using Grip force) from baseline to week 48 under
tamoxifen treatment compared to placebo.
Secondary surrogate marker to assess muscle degeneration:
- Quantitative muscle MRI including muscle fat fraction (MFF) and T2 times of
thigh muscles visualised by MRI from baseline to week 48 under tamoxifen
treatment compared to placebo.
Outcomes and endpoints of the OLE part are the same as in the RCT (Randomized
Controlled Trial) part of the trial
Background summary
Duchenne muscular dystrophy (DMD) is a rare disease and the most common
hereditary muscular dystrophy. It is characterized by progressive muscle
wasting, respiratory and cardiac impairments and premature death. This disease
only affects boys since the defective gene is located on the X chromosome. The
incidence is 1 in 3*500 to 6*000 male live births (Ricotti et al. 2016). In
Europe there are about 30*000 affected patients. About one third of the boys
affected by DMD do not have a family history of the disease because the DMD
gene has undergone a spontaneous mutation. Symptoms usually begin before the
age of six years. Children with DMD have difficulties in standing up, walking
and climbing stairs. Most boys need a wheelchair at about age 12. Moreover,
muscle wasting continues and affects other muscles including the diaphragm and
the heart, leading to reduced respiratory and cardiac functions; patients often
die in their 20ies. Adequate care and support prolong life expectancy to the
early 30ies but quality of life is severely reduced due to an evolving
pathology including cardiomyopathy and artificial respiration in the late
stages of the disease (Verheart et al. 2011). With the exception of
glucocorticoids, there is no treatment that improves quality of life and
long-term survival time of DMD patients. Glucocorticoids (mainly prednisolone
or deflazacort) are prescribed to most DMD patients; they reduce inflammation
TAMDMD, version 3.0 of 04.04.2018 Page 20 of 94
and excessive Ca2+ influx in dystrophic muscle fibres (Ruegg et al. 2012). At
the therapeutic level, glucocorticoids prolong the age of ambulation and
slightly increase quality and duration of life (Manzur et al. 2008). However,
glucocorticoids have many undesirable effects, notably retarding growth, which
can lead to drug cessation in some patients. Therefore, an alternative therapy
is urgently needed that efficiently counteracts the disease symptoms, possibly
by interfering with the pathological signalling cascade, and causes fewer
undesirable effects.
The DMD gene codes for a protein called dystrophin that links a transmembrane
protein complex with the extracellular matrix with enzymes mediating
intracellular signalling, such as nitric oxide synthase, kinases and
phosphatases on one hand, and with numerous ion channels, pumps and exchangers
on the other hand. Through a not yet fully understood mechanism of action,
dystrophin affects ion channels and participates in regulating the influx of
Ca2+ ions into the cell. When dystrophin is absent, Ca2+ influx is increased
leading to cell death via necrosis or apoptosis. Increased cytosolic Ca2+
levels were reported in muscle biopsies from DMD patients and in the muscles of
mdx mice, a mouse model for DMD, implicating it as a main driver of the
pathology. Increased Ca2+ influx through either store- operated channels or
stretch-activated channels was reported to be involved in such an increment.
Therapies targeting these subsets of channels have shown clear benefits in mdx
mice; however, proof of principle in DMD patients has yet to be established
(Ruegg et al. 2012).
Study objective
To test if tamoxifen treatment, compared to placebo, reduces the progression of
the disease in 6.5-12 years old ambulant DMD patients by at least 50% (using
the MFM D1 subscore as primary clinical endpoint in group A patients).
To test if tamoxifen treatment, compared to placebo, reduces the progression of
the disease in 10-16 years old non-ambulant DMD patients not treated with
glucocorticoids (using the MFM D2 subscore as primary endpoint.)
Open Label Extension study:
The main objective of the OLE part of this study is to test if earlier
initiation compared to delayed start of tamoxifen treatment reduces the
progression of the disease and to evaluate long-term efficacy and safety.
Post OLE Observation: During the Post OLE Observation it will be investigated
whether disease progression increases after discontinuation of TAM
Study design
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.
We 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 16 * 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 MFM scale, timed
function tests, the 6 minute walking distance, quantitative muscle testing
(QMT), quantitative thigh muscle MRI and 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
DEXA-scan will be performed at baseline and at the end of the study.
The Open label extension study will be extended for 48 weeks. All subjects will
receive 20mg of Tamoxifen on a daily base.
Week 48 from the RCT (Randomized Controlled Trial) will be the first visit (V1)
for the OLE trial. The study design is similar as the RCT trial, subjects on
site visits (from V1 to V5, V2 will be a phone visit, similar to the previous
trial) will occur every 12 weeks up to Week 96, a FU visit (V6) will take place
at V108
Post OLE Observation:
The Open label Extension study will be extended with 2 years with an
Observational non interventional phase, during this phase the subjects will
receive the medication the local physician is prescribing, the subject will not
receive tamoxifen from the sponsor. During the observation phase, data will be
collected from examinations that are routinely performed by the subjects
physician.
Intervention
Procedures at each visit
A pre-screening form has to be completed for each patient and sent to sponsor
by fax for approval at least 20 days before the planned screening visit.
During the study visits asessments according to the study flow chart will be
performed and data collected is captured in the patients* source documents.
After the visit this data is entered in the eCRF by a study nurse/study
coordinator.The PARS III questionnaire has to be completed by a parent/legal
representative during the study visit.
Basically, the physical as well as the physiotherapeutical examinations are
part of the standard medical care in DMD patients. Usually, the MRI, the
completion of the questionnaire and the DEXA and x-ray bone age determination
(if applicable, in selected sites) are study specific examinations and not
routine treatment in this disease.
1. Screening visit (Visit 0, Week -4, ±16 days)
After signing the informed consent form, the inclusion and exclusion criteria
are verified. If the criteria are fulfilled the patient will be enrolled in the
study. During this visit the following procedures will be performed.
- Informed consent
- Demographics
- Medical history
- Check inclusion/exclusion criteria
- Concomitant therapy
- Physical examination, incl. anthropometric measurements
- Vital signs, ECG
- Physiotherapeutical evaluation
- Safety blood analyses
In case of screening failure due to exclusion criteria the patient can be
re-screened once for this study.
2. Baseline visit (Visit 1, Week 0)
During this visit the following procedures will be performed:
- Check inclusion/exclusion criteria
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements and Tanner staging
- Vital signs, ECG
- Ophthalmological examination (visual acuity and slit-lamp examination)
- DEXA scan and x-ray bone age determination (in selected sites only)
- Wells score for DVT
- Physiotherapeutical evaluation
- MRI
- Patient reported outcome measures
- Safety blood analyses and biomarkers I
- Randomisation (if the patient still qualifies for the study, he will be
randomised and receive study medication)
- Dispense study medication
- Raven's Coloured Progressive Matrices test
3. Telephone call (Week 6, ±7 days)
The patient will be contacted by phone and asked about his health, according to
the questionnaire in appendix 6.
4 .Visit 2, 3 and 4 (Week 12, ±16 days; Week 24, ±16 days; Week 36, ±16 days)
During these visits the following procedures will be performed:
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements (and Tanner staging
at visit 3)
- Vital signs, ECG
- Ophthalmological examination at visit 3
- Wells score for DVT
- Physiotherapeutical evaluation
- (MRI and patient reported outcome measures at visit 3)
- Safety blood analyses (and biomarkers I at visit 3)
- Collection of study medication
- Dispense of study medication
5. End of Study visit (Visit 5, Week 48, ±16 days)
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements and Tanner staging
- Vital signs, ECG
- Ophthalmological examination
- DEXA scan and x-ray bone age determination (in selected sites only)
- Wells score for DVT
- Physiotherapeutical evaluation
- MRI
- Safety blood analyses and biomarkers I and II
- Collection of study medication
- Raven's Coloured Progressive Matrices
6. Follow-up Telephone call (Week 52, ±7 days)
The patient will be contacted by phone and asked about his health, according to
the questionnaire in appendix 11. In case an adverse event has occurred in the
time from visit 5 to the follow-up phone call, the patient will be asked to
come to the site to undergo physical and if applicable further additional
examination within one week, respectively as soon as possible (in case of
hospitalization etc.).
Ophthalmological examination, physiotherapeutical examination, MRI, X-ray bone
age determination and DEXA have to be performed within one week following the
visit date.
1.Start of Open Label Extension visit (Visit 1OLE, Week 48)
- Concomitant therapy*
- Physical examination, incl. anthropometric measurements and Tanner staging*
- Vital signs, ECG*
- Ophthalmological examination*
- DEXA scan and x-ray bone age determination (in selected sites only)*
- Wells score for DVT*
- Physiotherapeutical evaluation*
- MRI
- Safety blood analyses and biomarkers I and II*
- Raven's Coloured Progressive Matrices*
- Check inclusion/exclusion criteria
- Dispense study medication
*will be assessed in the context of the end of study visit (visit 5)
2. Visits 2OLE and 4OLE (Week 60, ±16 days, Week 84, ±16 days)
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements
- Vital signs, ECG
- Wells score for DVT
- Safety blood analyses I (total amount of blood taken 7.4 ml)
- -Collection of study medication
- Dispense study medication
- Physiotherapeutical evaluation
3.Visit 3OLE (Week 72, ±16 days)
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements and Tanner staging
- Vital signs, ECG
- Ophthalmological examination at visit 3
- Wells score for DVT
- Physiotherapeutical evaluation
- MRI and patient reported outcome measures
- Safety blood analyses (total amount of blood taken 7.4 ml)
- Collection of study medication
- Dispense of study medication
4. End of Open label extension visit (Visit 5OLE, Week 96, ±16 days)
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements and Tanner staging
- Vital signs, ECG
- Ophthalmological examination
- DEXA scan and x-ray bone age determination (in selected sites only)
- Wells score for DVT
- Physiotherapeutical evaluation
- MRI
- Safety blood analyses (total amount of blood taken 7.4 ml)
- Collection of study medication
- Raven's Coloured Progressive Matrices
5. Follow-up visit (Visit 6OLE, Week 108, ±14 days)
- Capture adverse events
- Concomitant therapy
- Physical examination, incl. anthropometric measurements
- Vital signs, ECG
- Wells score for DVT
- Safety blood analyses (total amount of blood taken 7.4 ml
Post OLE Observation: the data will be generated from routine examinations
performed by the local physician.
The following data will be generated:
- Further intake of Tamoxifen
- Concomitant therapy
- Participation in other clinical trials
- Physiotherapeutic Evaluations: results of 6-minutes walk test, North Star
Ambulatory Assessment (NSAA) or Motor Function Measurement (MFM if NSAA is not
applicable)
Study burden and risks
Tamoxifen (TAM) is a selective estrogen receptor modulator and has been used
for more than 35 years to treat estrogen receptor positive breast cancer. In
adults it is usually given at a dose of 20mg per day. There is abundant safety
information on the use of TAM in adults and adolescents but less on
pre-pubertal children. TAM therapy has been used for decades for the management
of pubertal gynecomastia using doses of 10 * 20 mg per day (Dermann et al 2008,
Eugster et al 2003, Kreher et al 2005, Pollack et al 1997). Even though
randomised controlled trials were not included and some studies had
methodological flaws, a systematic review on a total of 164 publications showed
some promising results. No clinical side-effects were reported or observed
(Lapid et al 2013). Importantly, in these studies, TAM did not alter the
acquisition of male sexual traits. Therefore, it appears that a trial on boys
of the age group 6.5-12 years and older can be carried out with a low risk of
undesirable effects. DMD patients under steroid medication exhibit reduced
growth and altered bone quality, which correlates with more frequent fractures.
It should be noted that this reduction in stature might be counted among the
effects of glucocorticoids. In contrast, TAM prevents bone loss (Starnes et al
2007, Vogel et al 2006) and has shown to increase the height of short boys
through decreasing the rate of bone maturation (Kreher et al 2005). Dorchies et
al (2013) demonstrated that very low levels of TAM and TAM metabolites (10-30
nM) are sufficient to cause major therapeutic effects on the dystrophic mouse,
which is encouraging in the perspective of this clinical application. It is
possible that therapeutic TAM concentrations might be reached using lower than
standard TAM regimen. The benefits elicited by the Eisomers of TAM metabolites,
which were produced in substantial amounts in dystrophic mice (Dahmane et al.
2010), but are barely detectable in humans (Murdter et al 2011), deserve
attention. This could result in lower than expected benefits in
DMD-patients.Undesirable effects:
Only the very common (>1/10) and the common (>1/100 to <1/10) and to boys
relevant undesirable effects will be reported in the study protocol. For more
information please refer to the SmPC.
Very common: fluid retention, hot flushes, nausea, skin rash, and fatigue.
Common: anemia, increase in serum triglycerides, vomiting, diarrhea,
constipation, light-headedness, headache, ischemic cerebro-vascular events,
sensory disturbances including paresthesia and dysgeusia, cataracts,
retinopathy, changes in liver enzyme levels, fatty liver, alopecia, myalgia,
leg cramp, hypersensitivity reactions, thromboembolic events including deep
vein thrombosis, microvascular thrombosis and pulmonary embolism.
Spitalstrasse 33
Basel - CH 4031
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Spitalstrasse 33
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Listed location countries
Age
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 non tolerance 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
requirements7S8S9S
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 (as judged by the Investigator)
- 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 month 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, celecobix, 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 steroid treatment <6
month prior to screening
- Participation in any other interventional trial
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004554-42-NL |
| ClinicalTrials.gov | NCT03354039 |
| CCMO | NL66050.091.18 |