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    Summary
    EudraCT Number:2010-024069-30
    Sponsor's Protocol Code Number:CD-IA-MEDI-545-1067/D2800L00004
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2011-05-04
    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 number2010-024069-30
    A.3Full title of the trial
    A Phase 2b, Dose-ranging Study to Evaluate the Efficacy and Safety of Sifalimumab in Adults with Systemic Lupus Erythematosus
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the optimum dose, the efficacy and the safety of sifalimumab in adult patients with Systemic Lupus Erythematosus, a disease of the immune system
    A.4.1Sponsor's protocol code numberCD-IA-MEDI-545-1067/D2800L00004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01283139
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation
    B.5.3.4CountrySweden
    B.5.6E-mailinformation.center@astrazeneca.com
    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 nameSifalimumab
    D.3.2Product code MEDI-545
    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 INNsifalimumab
    D.3.9.1CAS number 1006877-41-3
    D.3.9.2Current sponsor codeMEDI-545
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous 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
    Lupus, a disease of the immune system
    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 14.0
    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 study is to evaluate the efficacy of sifalimumab compared to placebo in subjects with chronic, moderately-to-severely active SLE with an inadequate response to SOC SLE at Day 365 (Week 52).
    E.2.2Secondary objectives of the trial
    1) To evaluate the effect of sifalimumab compared to placebo in reducing background oral corticosteroids dosage.
    2) To evaluate the effect of sifalimumab compared to placebo in improving inflammatory cutaneous lupus lesions.
    3) To evaluate the effect of sifalimumab compared to placebo in improving fatigue.
    4) To evaluate the safety profile of sifalimumab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Able tocomprehend and complete the informed consent, and all protocol-related subject assessments.
    2) Age 18-75 years.
    3) Written informed consent.
    4) Fulfils at least 4 of the 11 American College of Rheumatology (ACR) classification criteria for SLE, one of which must be: a) Significantly positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at central lab; OR b) Elevated anti-dsDNA or Sm antibody at screening as determined by central lab
    5) Weight ≥ 40.0 kg.
    6) Diagnosis of pediatric or adult SLE with chronic disease activity requiring ongoing treatment or observation for ≥ 24 weeks prior to screening.
    7) Receiving at least one of the following (at stable doses) prior to signing ICF through Day 1: a) prednisone (or equivalent) ≤ 20 mg/day for at least 2 weeks; b) one of the following for at least 8 weeks: azathioprine, an antimalarial, mycophenolate mofetil/ mycophenolic acid, weekly administrations of oral or SC methotrexate.
    8) External Adjudication Group confirmation of both: a) SLEDAI-2K score ≥ 6 points or ‘Clinical’ SLEDAI-2K score ≥ 6 points; b) At least one of the following: i) BILAG-2004 Index level A disease in ≥ 1 body/organ system ii) BILAG-2004 Index level B disease in ≥ 2 body/organ systems.
    9) Day 1 ‘Clinical’ SLEDAI-2K score ≥ screening “Clinical” SLEDAI-2K score.
    10) Physicians Global assessment (MDGA) ≥ 1.0 on a 0-3 scale at screening.
    11) Females of childbearing potential must use 2 effective methods of avoiding pregnancy from screening through 180 days after the final dose of investigational product unless surgically sterile, has a sterile male partner, is 1 year postmenopausal, or practices abstinence.
    12) Non-sterilized males must practice two effective contraceptive measures with a female of childbearing potential from Day 1 through at least 180 days after the last dose of investigational product has been administered.
    13) Females with an intact cervix must have documentation of a Pap smear and HPV
    testing with no documented malignancy within 24 weeks prior to Day 1.
    14) Willing to forego other forms of experimental treatment for SLE during the study.
    15) Meets various criteria for freedom from tuberculosis.
    16) Adequate peripheral venous access.
    E.4Principal exclusion criteria
    1) Any condition that would interfere with evaluation of the IMP or interpretation of subject safety or study results.
    2) Concurrent enrollment in any other study with an IMP within 4 weeks prior to Day 1 or within 5 half-lives of the IMP used in that study, whichever is longer.
    3) Employees of the study site or any other individuals involved with the study or immediate family members.
    4) Receipt of any of: a) any new oral prednisone therapy (or equivalent) or any change in current oral prednisone dose (or equivalent) from 2 weeks prior to signing of the ICF through Day 1; b) any new dose or change in current dose of any of the following anytime in the 8 weeks prior to signing of the ICF through Day 1: azathioprine; any antimalarial; mycophenolate mofetil/mycophenolic acid; oral methotrexate; or SC methotrexate.
    5) Receipt of any of the following: a) azathioprine > 150 mg/day; b) mycophenolate mofetil/mycophenolic acid > 3.0 grams/day; c) oral or SC methotrexate > 20 mg/week; d) any change in route of administration of oral or SC methotrexate anytime within the 8 weeks prior to signing of the ICF.
    6) Receipt of more than one dose of sifalimumab prior to screening.
    7) Receipt of a biologic agent within 5 half-lives or prior to loss of PD and/or clinical effect, whichever is longer, prior to signing of the ICF.
    8) A known history of allergy or reaction to any component of the IMP formulation or history of anaphylaxis to any human gamma globulin therapy.
    9) Receipt of more than one prescribed NSAID at an anti-inflammatory dose within 2 weeks (14 days) prior to Day 1; OR receipt of fluctuating doses of a prescribed NSAID within 2 weeks (14 days) prior to Day 1;.
    10) Receipt of any of the following: a) any live vaccine within 4 weeks prior to signing the ICF; b) oral anti-infectives (including antivirals) for active infection within 2 weeks prior to Day 1; c) BCG vaccine within 1 year of signing the ICF; d) any restricted medication (as listed in Appendix 3 of the protocol).
    11) Receipt of any of the following: a) etanercept ≤ 4 weeks prior to signing the ICF; b) adalimumab, infliximab, or golimumab ≤ 12 weeks prior to signing the ICF; c) rituximab or certolizumab pegol < 24 weeks prior to signing the ICF.
    12) Any fluctuation in hormone replacement therapy dose within 8 weeks of signing the ICF.
    13) Active severe or unstable neuropsychiatric SLE that would make the subject unsuitable for the study or unable to fully understand the ICF.
    14) Within 8 weeks prior to screening, active severe SLE-driven renal disease or unstable renal disease.
    15) A diagnosis (within 1 year) of mixed connective tissue disease or any history of overlap syndromes of SLE with rheumatoid arthritis, erosive arthritis, or scleroderma.
    16) History of, or current, inflammatory joint or skin disease other than SLE that could interfere with the inflammatory arthritis or skin assessments and confound the disease activity assessments.
    17) History of asthma that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to randomization.
    18) Known history of a primary immunodeficiency or an underlying condition such as HIV infection or splenectomy that predisposes to infection.
    19) Confirmed positive tests for hepatitis B surface antigen serology.
    20) Positive test for hepatitis C serology as confirmed by central laboratory.
    21) Any serious herpes infection at any time prior to randomization, including but not limited to disseminated herpes, herpes encephalitis, or ophthalmic herpes.
    22) Any herpes zoster infection that has not completely resolved within 12 weeks prior to signing of the ICF.
    23) Any of the following within 4 weeks prior to signing the ICF: a) clinically significant active infection; b) any infection requiring hospitalization or treatment with IV anti-infectives.
    24) Lactating or pregnant females or females who intend to become pregnant from initiation of screening through the 180-day safety follow-up period following last dose of IMP.
    25) Current evidence of alcohol, drug or chemical abuse, or a recent history of such abuse within 1 year of randomization.
    26) History of cancer, apart from basal cell carcinoma or cervical cancer treated with apparent success with curative therapy within 1 year of randomization.
    27) Major surgery within 8 weeks before signing the ICF or elective major surgery planned during the study period.
    28) Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to signing the ICF.
    29) At screening, any of the following: AST or ALT > 2.0 × ULN unless caused by myositis (with elevated CPK) associated with SLE; total bilirubin > ULN (unless due to Gilbert’s syndrome); serum creatinine > 2.0 mg/dL; protein/creatinine ratio > 2.0; neutrophil count < 1,000/μL; platelet count < 25,000/μL; hemoglobin < 8 g/dL; hemoglobin A1c > 8% at screening (diabetic subjects only).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint for this study is the proportion of subjects achieving a response in an SLE responder index [SRI (4)] at Day 365 in subjects with chronic moderately-to-severely active SLE.

    An SRI(4) Responder is defined as 1) a reduction in baseline SLEDAI-2K disease activity score of ≥ 4 points; and 2) no worsening of disease from baseline as measured by the MDGA (defined as an increase of ≥ 10% on a 0-3.0 VAS); and 3) no new BILAG-2004 Index A organ system score and no more than one new or worsening BILAG-2004 Index B organ system scores.

    There will be 6 primary comparisons for the primary endpoint. Sifalimumab 200 mg versus placebo, sifalimumab 600 mg versus placebo, and sifalimumab 1200 mg versus placebo will be compared for the overall population. The same 3 dose comparisons will also be performed for the subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening. The primary endpoint will be analyzed using a logistic regression model. The independent variables in the model will include treatment groups and stratification factors. The multiplicity adjustment for 3 dose comparisons within each of the 2 study populations, the overall population and the baseline gene signature positive subpopulation, will be done by performing a global test of all treatments prior to performing pairwise comparisons. No multiplicity adjustment for the 2 study populations is planned. An additional analysis with a more rigorous multiplicity adjustment approach may also be performed. The details of the multiplicity adjustments will be documented in the SAP that will be finalized prior to unblinding.

    Unless otherwise specified, the stratification factors will include geographic region (Latin America, Eastern Europe, and Asia vs. North America, Western Europe, and South Africa), SLEDAI-2K score at screening (< 10 points vs. ≥ 10 points), and the results of a diagnostic test for type I IFN signature in whole blood at screening using a 4-gene diagnostic test (positive vs. negative) for the overall population, and include geographic region and SLEDAI-2K score at screening only for subpopulation of subjects with a positive diagnostic test result for type I IFN signature at screening.
    The primary endpoint analysis will be conducted using the mITT Population. This analysis will also be conducted on the PP population as a sensitivity analysis.
    The dose-response trend based on SRI (4) at Day 365 will be tested using a Cochran-Armitage trend test. Other dose-response models may be evaluated. The details of the dose-response analysis will be described in the SAP.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 365
    E.5.2Secondary end point(s)
    The following secondary efficacy endpoints will be evaluated in the overall population of subjects with chronic, moderately-to-severely active SLE; and a subpopulation of subjects with a positive diagnostic test for type I IFN signature at screening.
    1) The proportion of subjects on ≥ 10 mg oral prednisone (or equivalent) at baseline who are able to taper ≤ 7.5mg/ day at Day 365 will be compared between treatment groups using logistic regression model.
    2) The proportion of subjects with an active CLASI score ≥ 10 at baseline who achieve a ≥ 4-point reduction at Day 365 will be compared between treatment groups using logistic regression model.
    3) The proportion of subjects who achieve a > 3-point reduction in the FACIT-FATIGUE Scale at Day 365 will be compared between treatment groups using logistic regression model.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 365
    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 No
    E.6.11Pharmacogenomic Yes
    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 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Brazil
    Canada
    Chile
    France
    Germany
    Hungary
    India
    Italy
    Mexico
    Netherlands
    Peru
    Philippines
    Poland
    Romania
    South Africa
    Spain
    Thailand
    United Kingdom
    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
    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 years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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: 517
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 217
    F.4.2.2In the whole clinical trial 544
    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)
    Subjects who are permanently discontinued from further receipt of investigational product regardless of the reason, will be followed for 180 days after the date of the last dose of investigational product.
    Subjects who participate in this study may have the option of entering a separate long-term safety study. This study is in the planning phase and a separate protocol will be submitted.
    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 Decision2011-05-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-08-05
    P. End of Trial
    P.End of Trial StatusOngoing
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