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    Summary
    EudraCT Number:2014-001232-11
    Sponsor's Protocol Code Number:200622
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-09
    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 ConcernedGermany - PEI
    A.2EudraCT number2014-001232-11
    A.3Full title of the trial
    Study 200622: A randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of mepolizumab in the treatment of adolescent and adult subjects with severe hypereosinophilic syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of mepolizumab vs. placebo in patients with HES who receive standard therapy
    A.4.1Sponsor's protocol code number200622
    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 SponsorGlaxoSmithKline Research & Development Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportGlaxoSmithKline Research & Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointGSK Clinical Support Help Desk
    B.5.3 Address:
    B.5.3.1Street Address1-3 Iron Bridge Road, Stockley Park West
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 0800 783 9733
    B.5.5Fax numberNot Applicable
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 Yes
    D.2.1.1.1Trade name Nucala
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Trading Services Limited
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/213
    D.3 Description of the IMP
    D.3.1Product nameNucala
    D.3.2Product code SB240563
    D.3.4Pharmaceutical form Lyophilisate for 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 INNMEPOLIZUMAB
    D.3.9.1CAS number 196078-29-2
    D.3.9.2Current sponsor codeSB240563
    D.3.9.3Other descriptive nameMEPOLIZUMAB
    D.3.9.4EV Substance CodeSUB21650
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 placeboLyophilisate for solution 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
    severe hypereosinophilic syndrome
    E.1.1.1Medical condition in easily understood language
    Hypereosinophilic syndrome (HES)
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10048643
    E.1.2Term Hypereosinophilic syndrome
    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 demonstrate the efficacy of mepolizumab compared with placebo based on maintenance of control of HES symptoms during the treatment period.
    E.2.2Secondary objectives of the trial
    To demonstrate supportive evidence of the benefit of mepolizumab compared with placebo based on other measures of efficacy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    INFORMED CONSENT
    1.Capable of giving signed informed consent/assent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

    AGE
    2. 12 years of age or older, at the time of signing the informed consent/assent

    TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
    3. Subjects who have been diagnosed with HES for at least 6 months at randomization. HES diagnosis is based on signs or symptoms of organ system involvement and/or dysfunction that can be directly related to:
    -blood eosinophilia of >1,500 eosinophils/μL on at least two occasions, and/or
    -tissue eosinophilia
    documented prior to Visit 2 without a discernible secondary cause
    Tissue eosinophilia is defined as a history of one or more of the following:
    -The percentage of eosinophils exceeds 20% of all nucleated cells in bone marrow sections.
    -In the opinion of a pathologist, tissue infiltration by eosinophils is extensive when compared with the normal physiologic range, compared with other inflammatory cells, or both.
    -A specific stain directed against an established eosinophil granule protein reveals extensive extracellular deposition of eosinophilderived proteins indicative of local eosinophil activation
    4. A history of two or more HES flares within the past 12 months prior to screening. Historical HES flares are defined as documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an escalation in therapy. At least one HES flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare.
    5. Subjects must have blood eosinophil count ≥1000 cells/μL present in the sample collected during screening (within 4 weeks prior to randomization).
    6. Subjects must be on a stable dose of HES therapy for the 4 weeks prior to
    randomization. HES therapy includes but is not limited to oralcorticosteroid (OCS), immunosuppressive, and cytotoxic therapy.

    SEX
    7. Male or female
    A female subject is eligible to participate if she is not pregnant, not lactating, and at least one of the following conditions applies:
    a. Females of non-reproductive potential (FNRP) defined as:
    - Post-menopausal women (including all women over 60 years of age, see below), OR
    Pre-menopausal females with one of the following procedures documented and no plans to utilize reproductive techniques (e.g., in vitro fertilization or donor embryo transfer:
    - Bilateral tubal ligation or salpingectomy
    - Hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
    - Hysterectomy
    - Bilateral Oophorectomy (surgical menopause)
    - Post-Menopause
    - Females 60 years of age or older
    - Menopause is the phase associated with complete cessation of menstrual cycles and implies the loss of reproductive potential by ovarian failure. This typically occurs around 50 years of age, although it may occur earlier or later. A practical definition accepts menopause after 1 year without menses with an appropriate clinical profile, e.g., age appropriate, >45 years, in the absence of hormone replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g., leuprolide treatment).
    - In questionable cases for women < 60 years of age, a blood sample with simultaneous follicle stimulating hormone and estradiol falling into the central laboratory’s postmenopausal reference range is confirmatory (these levels need to be adjusted for specific laboratories/assays)
    - Females under 60 years of age, who are on HRT and wish to continue, and whose menopausal status is in doubt, are required to use a highly effective method to avoid pregnancy, as outlined in the protocol.
    Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.
    Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a highly effective method to avoid pregnancy. If laboratory values for FSH and estradiol are drawn and the results do not confirm menopause on a potential subject that otherwise met the specifications for being post-menopausal defined above without question, the subject may still enrol in the study as a FNRP if approved by the GSK Medical Monitor and the safety
    physician.
    b. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (see Section 12.5) from 30 days prior to the first
    dose of study medication and until 4 months after the last dose of study treatment.
    The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
    E.4Principal exclusion criteria
    CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)
    1. Life-threatening HES or life-threatening HES co-morbidities: Imminently lifethreatening
    HES disease severity such that the likelihood of death is high unless the course of the disease is interrupted within 12 weeks prior to randomization.

    2. Other concurrent medical conditions that may affect the subject’s safety:
    Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological, respiratory or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment.

    3. Eosinophilia of unknown clinical significance

    4. 12-lead ECG finding:
    QTc > 450 msec or QTc > 480 msec in subjects with bundle branch block
    An abnormal ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant and would impact the subject’s participation during the study based on the evaluation of the Investigator.
    NOTE: 12-lead ECG results at screening with the over-read by the centralized independent cardiologist must be received prior to assessing eligibility at Visit 2 by the Investigator.

    5. Subjects with documented history of any clinically significant cardiac damage prior to screening that, in the opinion of the investigator, would impact the subject’s participation during the study.

    6. Liver abnormality/disease:
    -ALT >2.5xULN or ALT>5xULN if documented HES with liver manifestations
    -Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
    -Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
    NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
    NOTE: Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria.

    DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
    7. Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)
    8. Malignancy:
    -Subjects with a history of or current lymphoma
    -Subjects with current malignancy or previous history of cancer in remission for less than 12 months prior to randomization. Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded

    9. FIP1L1-PDGFR alpha Status: Subjects who test positive for the FIP1L1-PDGFR alpha fusion tyrosine kinase gene translocation
    Blood sampling is required for all subjects at screening for this test unless the documented result is available

    10. Infection:
    -Subjects with chronic or ongoing active infections requiring systemic treatment, as well as subjects who have experienced clinically significant infections due to viruses, bacteria, and fungi within 4 weeks prior to randomization
    -Subjects with a pre-existing helminthes infestation within 6 months prior to randomization.

    11. Subjects with a known immunodeficiency, other than that explained by the use of OCS or other therapy taken for HES

    12. Other laboratory abnormalities: Evidence of clinically significant abnormality in the
    hematological, biochemical or urinalysis screen from the sample collected at screening, that could put the subject’s safety at risk by participating in the study, as judged by the investigator

    CONCOMITANT MEDICATIONS
    13. Subjects who have previously received mepolizumab in the 4 months prior to randomization

    14. Subjects receiving any of the following:
    -Intravenous or subcutaneous corticosteroids in the 4-week period prior to randomization
    -Any other monoclonal antibodies within 30 days or 5 half-lives, whichever is longer, of randomization

    15. Other investigational product/clinical study:
    -Subjects who have received treatment with an investigational agent within the past 30 days or 5 drug half-lives whichever is longer, prior to randomization. The term “investigational” applies to any drug not approved for sale in the country in which it is being used or investigational formulations of marketed products
    -Subjects who are currently participating in any other interventional clinical study

    CONTRAINDICATIONS
    16. Subjects who are not responsive to OCS based on clinical response or blood eosinophil counts

    17. Subjects with any history of hypersensitivity to any monoclonal antibody (including mepolizumab) or any steroid or steroid-containing product.

    RELEVANT HABITS
    18. Subjects with a known or suspected history of alcohol or substance abuse at screening which in the opinion of the investigator could interfere with the subject’s proper completion of the protocol requirement.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who experience an HES flare during the 32-week study treatment period
    E.5.1.1Timepoint(s) of evaluation of this end point
    During 32 weeks starting randomization
    E.5.2Secondary end point(s)
    (1) Time to first HES flare;
    (2) Proportion of subjects who experience an HES flare during Week 20 through Week 32;
    (3) Rate of HES flares;
    (4) Change from baseline in fatigue severity based on Brief Fatigue Inventory (BFI) item 3 (worst level of fatigue during past 24 hours) at Week 32
    E.5.2.1Timepoint(s) of evaluation of this end point
    (1) & (3) During 32 weeks starting randomization;
    (2) During 20-32 weeks after randomization;
    (4) At 32 weeks after randomization
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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 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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    France
    Germany
    Italy
    Mexico
    Poland
    Romania
    Russian Federation
    Spain
    Sweden
    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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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 Yes
    F.1.1Number of subjects for this age range: 8
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 8
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 104
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 120
    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 complete the protocol-specified assessments for the 32-week period from randomization (Section 4.3) will be evaluated, and if eligible, may be enrolled into an extension study to receive open-label mepolizumab.
    The investigator is responsible for ensuring that consideration has been given to the poststudy care of the subject’s medical condition, whether or not GSK is providing specific
    post-study treatment.
    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 Decision2016-11-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-08
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