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    Summary
    EudraCT Number:2017-004554-42
    Sponsor's Protocol Code Number:TAMDMD
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-04-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2017-004554-42
    A.3Full title of the trial
    Tamoxifen in Duchenne muscular dystrophy:
    A multicenter, randomised, double-blind, placebo-controlled, phase 3 safety and efficacy 48-week trial

    Tamoxifen in Duchenne muscular dystrophy: A 48-week open label extension of a multicentre, randomised, double-blind, placebo-controlled, phase 3 safety and efficacy trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The study examines boys suffering from Duchenne muscular dystrophy. We are carrying out this study to examine the effect and tolerance of Tamoxifen in this disease.
    A.4.1Sponsor's protocol code numberTAMDMD
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03354039
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Basel Children's Hospital, Division of Neuropediatrics
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSwiss National Science Foundation (SNSF)
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportScientific and Technological Research Council of Turkey (TÜBİTAK)
    B.4.2CountryTurkey
    B.4.1Name of organisation providing supportFrench National Research Agency (ANF)
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportDuchenne UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportDuchenne Parent Project Netherlands
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportAssociation Monegasque contre les myopathies
    B.4.2CountryMonaco
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationmulti-service-monitoring
    B.5.2Functional name of contact pointDr. Josef Reisinger
    B.5.3 Address:
    B.5.3.1Street AddressAhornweg 8
    B.5.3.2Town/ cityBeratzhausen
    B.5.3.3Post code93176
    B.5.3.4CountryGermany
    B.5.4Telephone number+4994939592966
    B.5.5Fax number+4994939592967
    B.5.6E-mailjosef.reisinger@multi-service-monitoring.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tamoxifen 20mg Hexal® Filmtabletten
    D.2.1.1.2Name of the Marketing Authorisation holderHexal Ag, Industristraße 25, 83607 Holzkirchen
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTamoxifen
    D.3.9.1CAS number 54965-24-1
    D.3.9.3Other descriptive nameTAMOXIFEN CITRATE
    D.3.9.4EV Substance CodeSUB04672MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Duchenne muscular dystrophy
    E.1.1.1Medical condition in easily understood language
    Duchenne muscular dystrophy
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10013801
    E.1.2Term Duchenne muscular dystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To test if tamoxifen treatment, compared to placebo, reduces the progression of the disease in 6.5-12 years old ambulant DMD patients (Group A) by at least 50% (using the MFM D1 subscore as primary clinical endpoint).
    Furthermore, to test if tamoxifen treatment, compared to placebo, reduces the progression of the disease in 10-16 years old non-ambulant DMD patients (using the MFM D2 subscore as primary endpoint.)
    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. Therefore, disease progression during the OLE phase will be compared between both OLE treatment arms.
    E.2.2Secondary objectives of the trial
    Secondary clinical outcomes to assess muscle function:

    1. MFM total score, the D2, and D3 MFM subscores, North Star Ambulatory Assessment, proximal upper limb function from baseline to week 48 under TAM treatment compared to placebo.

    2. 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 TAM treatment compared to placebo.

    Secondary clinical outcomes to assess muscle force:

    3. Quantitative muscle testing (using Grip force) from baseline to week 48 under TAM treatment compared to placebo.

    Secondary surrogate marker to assess muscle degeneration:

    4. Quantitative muscle MRI including muscle fat fraction (MFF) and T2 times of thigh muscles visualised by MRI from baseline to week 48 under TAM treatment compared to placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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-Bickelsyndrome);
    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
    E.5 End points
    E.5.1Primary end point(s)
    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,
    - to run 10 m,
    - and to hop 10 times on one foot,

    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, Baseline, week 12, week 24, week 36, week 48, week 60 (OLE), week 72 (OLE), week 84 (OLE), week 96 (OLE)
    E.5.2Secondary end point(s)
    Secondary clinical outcomes to assess muscle function:
    - MFM total score, the D2, and D3 MFM subscores, North Star Ambulatory Assessment 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    MRI: Baseline, week 24, week 48, week 72, week 96
    Timed Function test, MFM: Screening, Baseline, week 12, week 24, week 36, week 48, week 60, week 72, week 84, week 96
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    Turkey
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 100
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 80
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Boys between 6,5 years and 16 years
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Depending on the safety and efficacy data obtained during the study, the sponsor plans an open-label extension study to provide tamoxifen access to all DMD patients enrolled in this study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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