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    Summary
    EudraCT Number:2016-000287-42
    Sponsor's Protocol Code Number:I15015
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-06-08
    Trial results View 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 ConcernedFrance - ANSM
    A.2EudraCT number2016-000287-42
    A.3Full title of the trial
    A Multicentre Open label Phase II study of Daratumumab in AL Amyloidosis
    Patients not in VGPR or Better
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Amyloidosis Patients traitment
    A.3.2Name or abbreviated title of the trial where available
    AMYDARA
    A.4.1Sponsor's protocol code numberI15015
    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 SponsorCHU de Limoges
    B.1.3.4CountryFrance
    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 supportJANSSEN
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de Limoges
    B.5.2Functional name of contact pointClinical Trial Coordinator
    B.5.3 Address:
    B.5.3.1Street Address2 Avenue Martin Luther King
    B.5.3.2Town/ cityLimoges
    B.5.3.3Post code87042
    B.5.3.4CountryFrance
    B.5.4Telephone number0555058637
    B.5.5Fax number0555056649
    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 No
    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 nameHuMax-CD38
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDARATUMUMAB
    D.3.9.1CAS number 945721-28-8
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    AL Amyloidosis
    E.1.1.1Medical condition in easily understood language
    Amyloidosis
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level HLGT
    E.1.2Classification code 10035227
    E.1.2Term Plasma cell neoplasms
    E.1.2System Organ Class 10005329 - Blood and lymphatic system 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 Assess Overall Hematologic Response Rate (CR + VGPR) at the completion of 6 cycles of Daratumumab in patients with AL Amyloidosis not in CR or VGPR after any previous therapy
    E.2.2Secondary objectives of the trial
    •To determine safety and tolerability of Daratumumab (type, frequency, severity, and relationship of adverse events to study treatment).
    •To Assess in all patients according to their disease history
    oOverall Hematologic Response Rate (CR+VGPR+PR) at the completion of 1 and 3 the cycles (PR: 50% drop from dFLC at inclusion).
    oThe Overall Hematologic Response Rate including PR at the completion of 6 cycles
    othe duration of hematologic response
    othe rate of organ response and organ improvement, according to standard criteria
    othe time to hematologic and organ response
    othe hematologic disease progression free survival (PFS) and 1-year PFS
    othe overall survival (OS) and 1-year OS
    •Assess QoL using EORTC QLQ30, EQ5D-3L and Amyloidosis Symptoms Scale
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Histologic diagnosis of AL amyloidosis
    2.Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence of kappa or lambda light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement.
    3.Patients must be >=18 years of age
    4.Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
    5.Patients should have received at least one line with an alkylating agent and/or a proteasome inhibitor and dexamethasone and not be in VGPR or CR at the time of inclusion (patients who did not reach VGPR or patients who reached VGPR or better but have an hematological relapse can be included).
    6.Measurable hematologic disease: difference between involved and uninvolved FLC > 50 mg/L with an abnormal kappa/lambda ratio (with Freelite® test kits, The Binding Site)
    7.Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system)
    8.Wash out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies, whichever is longer,
    9.Adequate bone marrow function prior to 1st drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1st drug intake,
    10.Adequate organ function defined as:
    - Serum creatinine clearance (Cockcroft-Gault formula) >= 30 ml/min
    - Serum SGOT/AST or SGPT/ALT < 3.0 X Upper Limit Of The Normal Range (ULN)
    - Serum total bilirubin < 2.0 mg/dL, unless the patient has Gilbert’s syndrome where the direct bilirubin should then be < 2.0 mg/dL

    11.Women who are partners of men and with childbearing potential*(defined below) must be practicing a methods of birth control
    12.A woman with childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 14 days prior to dosing and the second within 48 hours prior to dosing, and remain on a highly effective method of birth control. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception,
    Highly effective methods :
    Intrauterine device (IUD), Hormonal (birth control pills, injections, implants), Tubal ligation, Partner’s vasectomy
    Additional effective methods :
    Male condom, Diaphragm, Cervical Cap
    Serum (urine in the case where serum is not possible in a timely manner) pregnancy test to be performed for all women of childbearing potential regularly during the therapy. In addition, a pregnancy test may be done at any time during the study at the discretion of the investigator if a subject misses a period or has unusual menstrual bleeding
    13.A woman of childbearing potential must remain on a highly effective method of birth control. Contraception must begin 4 weeks before initiating treatment with Daratumumab, during therapy, during dose interruptions and continuing for 3 months following discontinuation of Daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
    14.A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control e.g., condom with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study, and for 3 months following discontinuation of Daratumumab. The exception to this restriction is that if the subject’s female partner is surgically sterile, a second method of birth control is not required
    15.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
    16.Subjects affiliated with an appropriate social security system
    E.4Principal exclusion criteria
    1. 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
    2.Isolated soft tissue involvement
    3.Presence of non-AL amyloidosis
    4.Bone marrow plasma cells >30% on bone marrow aspirate at screening
    5.Cardiac mayo stage IIIb disease. (i.e. cardio mayo stage III with NT-proBNP >= 8500 ng/L
    6.Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment, except if a pacemaker has been implanted.
    7.Chronic atrial fibrillation
    8.Supine systolic blood pressure <100 mmHg
    9.Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen
    10.Clinically overt multiple myeloma with lytic bone lesions
    11.Patients with uncontrolled infection or active malignancy with the exception of
    -adequately treated basal cell or squamous cell skin cancer,
    -in situ cervical cancer
    -low grade (Gleason 3+3 or less) prostate cancer or in situ breast carcinoma if surgically treated
    -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 3 years.
    12. Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including:
    - NYHA functional classification IV congestive heart failure
    - LVEF (Left Ventricular Ejection Fraction) <45%
    - Uncontrolled angina, hypertension or arrhythmia
    - Myocardial infarction in the past 6 months
    13.Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy
    14.Subjects with known/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary artery disease)
    15.Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal
    16.Subject has known moderate or severe persistent asthma within the past 2 years (see APPENDIX 8), or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study)
    17.Previous anti-CD38 therapy
    18.Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy
    19.Known positive for HIV or active hepatitis B or C
    20.Refusal to consent or protected by legal regime
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the Overall Response Rate (CR+VGPR) at the completion of 6 cycles of Daratumumab in patients with AL Amyloidosis not in CR or VGPR after any previous therapy, using the new response criteria . The data used for the primary statistical analysis will be central laboratories data. Key parameters will be M-protein, serum free light chain values and ratio, and DIRA when applicable.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the completion of 6 cycles
    E.5.2Secondary end point(s)
    The safety and tolerability by type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams. Incidence of Treatment Emergent Adverses Events (TEAE), Serious Adverses Events (SAE) and laboratory abnormalities will be assed using NCI CCTAE V4.03
    • In all patients according to their disease history
    o the overall hematologic response rate (CR + VGPR + PR) at the completion of 1 and 3 cycles
    o the Overall Hematologic Response Rate including PR at the completion of 6 cycles
    o the duration of hematologic response
    o the time to hematologic disease progression
    o the rate of organ response and organ improvement, according to standard criteria
    o the time to hematologic and organ response
    o the hematologic disease progression free survival (PFS) and 1-year PFS
    o the overall survival (OS) and 1-year OS
    The data used for the primary statistical analysis will be central laboratories data. Key parameters will be M-protein, serum free light chain dosage and ratio, and DIRA when applicable.
    • QoL using EORTC QLQ30, EQ5D-3L, Amyloidosis Symptoms Scale
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety is evaluated at the strt of each cycle
    Responses at the completion of 1 and 3 cycles
    The Overall Hematologic Response Rate including PR at the completion of 6 cyclesPlease enter information in English and add any other language that is applicable
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned23
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    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 months0
    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.1.1.1In 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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 40
    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)
    After treatment discontinuation, follow-up will be made to the patient every 3 months for at least 2 years to inquire about the patient’s hematological and organ status, general health, and information on any antineoplastic therapies utilized since discontinuation of study treatment and to verify the occurrence of any secondary cancers
    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 Decision2016-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-14
    P. End of Trial
    P.End of Trial StatusCompleted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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