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    Summary
    EudraCT Number:2007-003698-13
    Sponsor's Protocol Code Number:27646
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-01-08
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2007-003698-13
    A.3Full title of the trial
    A randomised, double-blind, placebo-controlled, multicentre prospective dose-finding Phase II/III study with atacicept given subcutaneously to subjects having recently experienced a flare of systemic lupus erythematosus (SLE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Atacicept Phase II/III in Generalized Systemic Lupus Erythematosus (APRIL SLE)
    A.3.2Name or abbreviated title of the trial where available
    Atacicept in generalised SLE Phase II/III
    A.4.1Sponsor's protocol code number27646
    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 SponsorMerck Serono S.A. Geneva. An affiliate of Merck KGaA, Darmstadt, Germany
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Serono S.A. Geneva.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Serono S.A. Geneva. An affiliate of Merck KGaA, Darmstadt, Germany
    B.5.2Functional name of contact pointCommunication center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Straße 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 6151 72 5200
    B.5.5Fax number+49 6151 72 2000
    B.5.6E-mailservice@merck.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 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 nameAtacicept
    D.3.2Product code TACI-Fc5
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAtacicept
    D.3.9.1CAS number 845264-92-8
    D.3.9.3Other descriptive nameTACI-Fc5
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number75 to 150
    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 Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Systemic Lupus Erythematosus
    E.1.1.1Medical condition in easily understood language
    Systemic Lupus Erythematosus (SLE) is a chronic (long term) autoimmune disease of unknown cause. SLE often involves chronic inflammation (pain and swelling) and organs can be damaged.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10042945
    E.1.2Term Systemic lupus erythematosus
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue 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 of this trial is to evaluate the efficacy of atacicept compared to placebo in preventing new flares in subjects with SLE.
    E.2.2Secondary objectives of the trial
    Secondary objectives of the trial are:
    - To evaluate the safety and tolerability profile of atacicept in treated subjects with SLE,
    - To confirm the optimal dose of atacicept for treatment of subjects with SLE,
    - To gain further information on the effect of atacicept on relevant markers specific to its mechanism of action (MoA) and their correlation to disease activity/progression,
    - To further characterise the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of atacicept, and
    - To identify genetic and genomic variations associated with drug response and disease activity/progression.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of SLE satisfying at least 4 out of the 11 ACR criteria at the time of diagnosis, with a disease duration of at least six months.
    2. Active SLE with at least one BILAG A or B score at initial screening (excluding a single B due to haematological values) requiring a change in the dose of corticosteroids.
    3. Positive antinuclear antibody (ANA) test results (HEp-2 ANA ≥1:80 and/or anti dsDNA ≥30 IU/mL) (subjects will be tested at screening).
    4. Male or female ≥16 years of age.
    5. Written informed consent, given before any study-related procedure. Subjects must have read and understood the Informed Consent Form, must fully understand the requirements of the study and must be willing to comply with all study visits and assessments. For subjects under the age of legal majority (according to local law), the subject and a legal guardian must read and sign the informed consent.
    6. Female subjects must be willing to avoid pregnancy by using an adequate method of contraception for 4 weeks prior to Study Day 1, during the trial and 24 weeks after the last dose of study medication. This requirement does not apply to surgically sterile subjects or to subjects who are post-menopausal for at least 2 years. Adequate contraception is defined as two barrier methods, or one barrier method with a spermicide, or an intrauterine device or use of a female hormonal contraceptive.
    7. Women of childbearing potential must have a negative serum pregnancy test at initial screening and at the end of screening before dosing. For the purpose of this study, women of childbearing potential are defined as all female subjects after puberty unless they are post-menopausal for at least 2 years or surgically sterile.

    In addition, to be eligible for inclusion into this trial, subjects must fulfil the following criteria at the end of the initial flare treatment period:
    8. Improvement of the qualifying BILAG A or B flare to BILAG C or D within 10 weeks after commencing steroid treatment.
    9. Use of an appropriate steroid regimen for the qualifying flare during the screening period, with stability of the dose at 7.5 mg of prednisone or equivalent for 2 weeks after improvement to BILAG C or D.
    10. No other new BILAG A or B at an assessment performed following confirmation of stable steroid dose.
    E.4Principal exclusion criteria
    1. Any condition, including laboratory findings and findings in the medical history or in the pre-study assessments, that constitutes a risk or a contraindication for participation to the study in the opinion of the Investigator or that could interfere with study objectives, conduct or evaluation.
    2. Active moderate to severe glomerulonephritis
    3. Active central nervous system SLE deemed to be severe or progressive and/or associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with the protocol.
    4. Comorbidities requiring systemic corticosteroid therapy (such as asthma or inflammatory bowel disease) and/or preventing engagement in study conduct.
    5. Any history of treatment with rituximab, abatacept or belimumab.
    6. Introduction of azathioprine, hydroxychloroquine, chloroquine, or methotrexate within 2 months before initial screening or increase in the dose regimen of any of these medications within 2 months before initial screening.
    7. Initiation of any immunosuppressive drug within 3 months before initial screening.
    8. Participation in any interventional clinical trial within the last 28 days or within 5 half-lives of the investigated compound (whichever is longer) before initial screening.
    9. Treatment with cyclophosphamide mycophenolate mofetil or a calcineurin inhibitor within 3 months before initial screening.
    10. Treatment with leflunomide, 6-mercaptopurine or thalidomide within 3 months before initial screening.
    11. Active infection with herpes zoster or Epstein-Barr virus at initial screening.
    12. Positive HIV serology (subjects will be tested at screening).
    13. Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (subjects will be tested at screening).
    14. History or presence of tuberculosis infection without documentation of adequate treatment, or treatment that occurred in the past year. Subjects should be evaluated and screened for tuberculosis according to national or local recommendations.
    15. Known active clinically significant acute or chronic infection, or any major episode of infection requiring hospitalisation or treatment with parenteral anti-infectives within 4 weeks of baseline or completion of oral anti-infectives within 2 weeks prior to screening.
    16. Diagnosis or family history of Creutzfeldt-Jakob disease (CJD).
    17. History or presence of uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.
    18. History of cancer, except for adequately treated basal cell carcinoma of the skin, cervical dysplasia or carcinoma in situ of the skin or the cervix.
    19. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase (AP) level > 2.5 x ULN, or total bilirubin > 1.5 x ULN.
    20. Clinically significant abnormality in any haematological test (e.g. haemoglobin < 5.5 mmol/L, WBC < 2.5 x 10^9/L, platelets < 75 x 10^9/L) unless attributable to active SLE.
    21. Serum immunoglobulin G below 6 g/L.
    22. Clinically significant abnormality on chest X-ray performed within 3 months of initial screening or on ECGs performed at initial screening unless attributable to active SLE.
    23. Hypersensitivity to any of the components of the formulated atacicept.
    24. Immunisation with live vaccines or Ig treatment within 1 month before Study Day 1.
    25. Planned major surgery during the trial period (including follow-up).
    26. Active alcohol or drug abuse or history of alcohol or drug abuse in the last 6 months.
    27. Breastfeeding or pregnancy.
    28. History of any demyelinating disease, such as MS or ON.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint of this trial is the proportion of subjects experiencing a new flare (as defined by a British Isles Lupus Assessment Group [BILAG] score of A or B) during the 52-week treatment period following randomisation.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From Study Day (SD) 1 until Week 52 or early termination.
    E.5.2Secondary end point(s)
    1. Time to new flare from randomization (main secondary endpoint)
    2. Proportions of subjects within each of the following ordinal response categories at Week 52; No flare, first new flare scored as BILAG B and first new flare scored as BILAG A.
    3. Proportion of subjects with a new flare (BILAG A or B) within the initial 24 weeks after randomisation.
    4. Corticosteroid exposure post-randomisation
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Randomisation to week 52 or early termination
    2. Week 52
    3. Randomisation to Week 24
    4. Randomisation to Week 52
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    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) 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 trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Argentina
    Australia
    Brazil
    Chile
    Croatia
    India
    Israel
    Korea, Republic of
    Lebanon
    Malaysia
    Mexico
    Peru
    Philippines
    Serbia
    Switzerland
    Taiwan
    United States
    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
    For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock. This provides for a single and conservative definition across all trial sites.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months10
    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.1.3Elderly (>=65 years) Yes
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 175
    F.4.2.2In the whole clinical trial 510
    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)
    Expected standard of care treatment of that condition as per judgement of the treating physician.
    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 Decision2008-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-04-01
    P. End of Trial
    P.End of Trial StatusCompleted
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