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    Summary
    EudraCT Number:2010-022395-31
    Sponsor's Protocol Code Number:AC-004-EU
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2011-11-10
    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 ConcernedUK - MHRA
    A.2EudraCT number2010-022395-31
    A.3Full title of the trial
    A randomized open-label multicenter phase III trial of Melphalan and Dexamethasone (MDex) versus Bortezomib, Melphalan and Dexamethasone (BMDex) for untreated patients with systemic light-chain (AL) amyloidosis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MDex vs BMDex in systemic light-chain (AL) amyloidosis [abnormal condition of depositing proteins known as amyloid in tissues and organs of the body]
    A.3.2Name or abbreviated title of the trial where available
    MDex vs BMDex in systemic light-chain (AL) amyloidosis
    A.4.1Sponsor's protocol code numberAC-004-EU
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01277016
    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 SponsorEuropean Myeloma Network
    B.1.3.4CountryDenmark
    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 supportEuropean Myeoloma Network
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College Medical School (Royal Free Campus)
    B.5.2Functional name of contact pointAsutosh Wechalekar
    B.5.3 Address:
    B.5.3.1Street AddressNational Amylodosis Centre, Rowland Hill stree
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeNW3 2PF
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44-207-433-2758
    B.5.5Fax number+44-207-433-2817
    B.5.6E-mailawechale@medsch.ucl.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorEuropean Myeloma Network Datacenter
    B.1.3.4CountryItaly
    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 supportEuropean Myeloma Network
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 VELCADE
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.1Product nameBortezomib
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Systemic light-chain (AL) amyloidosis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10002022
    E.1.2Term Amyloidosis
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare haematologic response (reduction in the abnormal protein level in the blood) after 3 cycles in patients treated with melphalan and dexamathasone (MDex) Or MDex plus bortezomib (BMDex).

    Haematologic (clonal) response is the rate of complete response (CR) + partial response (PR) defined according to the criteria of the International Society for Amyloidosis consensus.
    E.2.2Secondary objectives of the trial
    Secondary research objectives include comparing in patients treated with MDex or BMDex:
    ** complete haematologic response rate after 3 cycles and after completion of therapy;
    ** haematologic response rate at completion of therapy;
    ** organ response rates at 3, 6, 9 and 12 months;
    ** treatment-related mortality;
    ** toxicity;
    ** overall and progression-free survival;
    ** time to hematologic and organ response;
    ** quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ** Histologic diagnosis of amyloidosis.
    ** Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence of light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement.
    ** Not eligible for ASCT with melphalan 200 mg/m2 . (Patients who are eligible for SCT with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization)
    ** Patients must be ≥18 years of age
    ** ECOG performance status 0,1 or 2
    ** Measurable disease; at least one of the following criteria:
    - monoclonal protein >10 g/L in serum,
    - amyloid-forming (involved) FLC >75 mg/L,
    - difference between involved and uninvolved FLC >50 mg/L,
    - bone marrow with a clonal predominance
    ** Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system)
    ** Hemoglobin ≥11 g/dL, absolute neutrophil count ≥1500/μL, platelets ≥140,000/μL
    ** Total bilirubin <2.5 mg/dL, alkaline phosphatase <5 × u.l.n., ALT <3 × u.l.n
    ** Estimated glomerular filtration rate (eGFR) by the MDRD formula >30 ml/min
    ** Only patients who are informed of the investigational nature of this study and sign and give written informed consent in accordance with institutional, national and European guidelines are eligible to participate
    ** Women must be either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
    ** Men must agree to use an acceptable method for contraception for the duration of the study.
    E.4Principal exclusion criteria
    ** Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis.
    ** Isolated soft tissue involvement.
    ** Presence of non-AL amyloidosis.
    ** Previous treatment for plasma cell disease. A single previous cycle of dexamethasone or steroid equivalent (maximum cumulative dexamethasone dose 160 mg) is allowed; in this case baseline data must be obtained after steroid administration. Previous stem cell harvest is allowed, provided that mobilization is performed with G-CSF only.
    ** Bone marrow plasma cells >30%.
    ** Cardiac stage III disease: both cTnT > 0.035 ng/mL (or in place of cTnT the cTnI > 0.10 ng/mL) AND simultaneous NT-proBNP >332 ng/L.
    ** Repetitive ventricular arrhythmias on 24h Holter ECG in spite of anti-arrhythmic treatment.
    ** Chronic atrial fibrillation
    ** Supine systolic blood pressure <100 mmHg or symptomatic orthostatic hypotension or clinically important autonomic disease
    ** Grade 3 sensory or grade 1 painful peripheral neuropathy.
    ** Patients with AL who are eligible for ASCT with 200 mg/m2 of melphalan. These are patients <65 years of age, without cardiac involvement (determined according to the consensus criteria), with eGFR >51mL/min, left ventricular ejection fraction >45%, and bilirubin <2.0 mg/dL. Patients who are eligible for SCT with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization.
    ** Pregnant or nursing women.
    ** Clinically overt multiple myeloma with lytic bone lesions
    ** Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
    ** Patients with medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure, or myocardial infarction within the previous 6 months are not eligible.
    ** HIV positive
    ** Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study.
    ** Patients with hypersensitivity to bortezomib, boron or mannitol.
    E.5 End points
    E.5.1Primary end point(s)
    Haematological response (complete response and partial response) after three treatment cycles.
    E.5.2Secondary end point(s)
    To compare in patients treated with MDex or BMDex:
    ** complete hematologic response rate after 3 cycles and after completion of therapy;
    ** hematologic response rate at completion of therapy;
    ** organ response rates at 3, 6, 9 and 12 months;
    ** treatment-related mortality;
    ** toxicity;
    ** overall and progression-free survival;
    ** time to hematologic and organ response;
    ** quality of life
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Melphalan/dexamethasone without Bortezomib
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Denmark
    France
    Germany
    Greece
    Italy
    Netherlands
    Norway
    Spain
    Sweden
    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
    The study will be completed when all subjects have completed 24 months of trial treatment and follow-up, or have withdrawn from the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    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)
    Participants will continue to receive appropriate clinical treatment for their condition at the end of the study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-26
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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