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    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2006-004679-36
    Sponsor's Protocol Code Number:052015-001
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2006-10-09
    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 ConcernedGermany - BfArM
    A.2EudraCT number2006-004679-36
    A.3Full title of the trial
    Prospective, open-label, multicenter, international study of mifepristone for symptomatic treatment of Cushing's syndrome caused by ectopic Adrenal Corticotrophin Hormone (ACTH) secretion.
    A.3.2Name or abbreviated title of the trial where available
    HRA052015 in EAS
    A.4.1Sponsor's protocol code number052015-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00422201
    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 SponsorLaboratoire HRA Pharma
    B.1.3.4CountryFrance
    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 supportLaboratoire HRA Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLaboratoire HRA Pharma
    B.5.2Functional name of contact pointLaboratoire HRA Pharma
    B.5.3 Address:
    B.5.3.1Street Address15 rue Béranger
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75003
    B.5.3.4CountryFrance
    B.5.4Telephone number+33140331130
    B.5.5Fax number+33142770465
    B.5.6E-mailinfo-produit@hra-pharma.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/298
    D.3 Description of the IMP
    D.3.2Product code HRA052015
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmifepristone
    D.3.9.1CAS number 84371-65-3
    D.3.9.3Other descriptive name17β-hydroxy-11β-(4-dimethylaminophenyl)17α-(prop-1-ynyl)estra-4,9-dien-3-one
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of Cushing's syndrome caused by ectopic Adrenal Corticotrophin Hormone (ACTH) secretion.
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10011652
    E.1.2Term Cushing's syndrome
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10014146
    E.1.2Term Ectopic ACTH syndrome
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to demonstrate that daily administration of mifepristone in subjects with Cushing’s syndrome caused by ectopic ACTH secretion will improve or normalize the glucocorticoid-dependent glycemic disorders as well as a list of predefined symptoms attributable to the Cushing’s syndrome.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to assess the impact of long-term administration of mifepristone on the other symptoms of Cushing syndrome, the steady state pharmacokinetic profile of the agent and the safety of the agent.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects will be included if they have ALL of the three following criteria:
    1. Hypercortisolism from Cushing’s syndrome caused by ectopic ACTH secretion confirmed by:
    - Inferior petrosal sinus sampling (IPSS) with a central to peripheral ACTH ratio of less than 2.0 before CRH administration and less than 3.0 after CRH administration.
    - or biopsy with ACTH immunoreactivity.
    - or presence of a tumor evidenced by imaging combined with both a negative CRH test and a negative 8 mg dexamethasone suppression test.
    No major change in tumor status/anti-tumor therapy should be expected during the study
    AND
    2. Glycemic disorder that is considered to be caused or worsened by the hypercortisolism.
    Glycemic disorders will be defined and categorized at pre-inclusion as follows:
    o Known diabetes defined by
     fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dL)
     or treated diabetes. In addition, treatment should be stable, i.e.
    - for thiazolidinediones, patients must have been on stable therapy for at least four months prior to study entry
    - for all other diabetes treatments, patients must have been on stable therapy for at least two weeks prior to study entry, for insulin the dose should be stable as long as possible before study entry
    o Diabetes diagnosed at pre-inclusion visit and defined by:
     2-hour glucose plasma level after 75 g OGTT ≥ 11.1 mmol/L (200 mg/dL)
    o Impaired Glucose Tolerance (IGT) defined at pre-inclusion visit by:
     2-hour glucose plasma level after 75 g OGTT ≥ 7.8 mmol/L (140 mg/dL) and < 11 mmol/L (200 mg/dL)
    o Impaired Fasting Glucose (IFG) defined at pre-inclusion visit by:
     fasting plasma glucose level ≥ 5.5 mmol/L (100 mg/dL) and < 7 mmol/L (126 mg/dL)
    AND
    3. At least one of the following clinical symptoms attributable to the Cushing’s syndrome:
    o Increased weight gain ≥ 5% within 1 year
    o Overweight defined by BMI > 25 kg/m2
    o Truncal obesity defined by waist circumference ≥ 94 cm for men or ≥ 80 cm for women (IDF definition) and/or documented by truncal fat mass at DEXA scan
    o Depression (treated or not) defined by a BDI-II score > 1
    o Proximal muscle weakness as assessed by straight leg lift clinical test < 120 sec
    o Bruising evaluated at clinical examination and with photos if possible
    o Violaceous striae evaluated at clinical examination and with photos if possible
    o Facial plethora evaluated at clinical examination and with photos if possible
    o Dorsocervical fat pad evaluated at clinical examination and with photos if possible

    In addition, the following criteria should be met:
    - Written informed consent to participate in the study (including taking photos)
    - Female subjects should be sterilized, post-menopausal, sexually inactive or willing to use barrier methods of contraception throughout the study.
    - Subject willing to return to investigational site during the full course of the study
    - Age in the range of 18 to 85 years inclusive
    E.4Principal exclusion criteria
    - Evidence for Cushing’s disease as judged by positive inferior petrosal sinus sampling or a lesion on pituitary MRI with positive CRH test
    - Suspected or known adrenocortical cancer or adenomas, as judged by ACTH values < 10 pg/ml and adrenal mass
    - Subjects with cyclic Cushing’s syndrome defined by any measurement of Urinary Free Cortisol over the previous 2 months < 2 times the upper normal limit
    - Children (age less than 18) and patients over 85 years
    - Pregnant or lactating women. A urinary pregnancy test will be performed in women of childbearing potential unless they have a history of menopause prior to Cushing’s syndrome or hysterectomy
    - Life expectancy less than two months
    - Surgery planned within 8 weeks after inclusion, especially bilateral adrenalectomy
    - Uncontrolled diabetes (plasma glucose > 15.0 mmol/ (270 mg/dL) and/or HbA1c > 10%)
    - Uncontrolled hypertension (blood pressure > 180/110 mmHg)
    - Recent (less than two weeks prior to inclusion) initiation of corrective treatments for depression
    - Clinically significantly impaired cardiovascular function (e.g. stage IV cardiac failure)
    - Severe liver disease (liver enzymes ≥ 3 x the institutional upper limit of normal range)
    - Severe renal impairment (serum creatinine ≥ 2.2 mg/dl or creatinine clearance < 30 ml/min)
    - Severe hypokalemia (plasma K < 3.0 mm/L).
    - Uncontrolled severe active infection
    - In women, known endometrial cancer, history of endometrial hyperplasia or vaginal bleeding of unknown cause
    - Premenopausal women with hemorrhagic disorders or on anticoagulants
    - Recent (less than two weeks prior to inclusion) initiation of or significant change in dose of anti-tumor therapy
    - Previous treatment with approved or experimental steroidogenesis inhibitors, somatostatin analogues within one week of admission (eight weeks for patients on octreotide LAR or on lanreotide autogel).
    - Plasma mitotane concentration > 5 µg/ml
    - Impaired mental capacity or markedly abnormal psychiatric evaluation that precludes informed consent
    - Body weight over 136 kg, which is the limit for the tables used in the scanning areas
    - Inherited porphyria
    - Positive pregnancy test at inclusion
    - Use of antiretroviral agents, midazolam, cabergoline, erythromycin, or grapefruit juice within two weeks of the study
    E.5 End points
    E.5.1Primary end point(s)
    Patients will be considered to be responders if they meet the following criteria at primary evaluation visit:
    - Improvement or normalization of glycemic disorders
    AND
    - Global improvement of the predefined list of clinical symptoms attributable to the Cushing’s syndrome
    • Criteria for improvement or normalization of glycemic disorders
    A. For diabetic patients (known or diagnosed at pre-inclusion visit)
    - Decrease in HbA1c > 0.3%
    B. For patients with IGT
    - Normalization of OGTT (2-hour glucose plasma level after 75 g OGTT < 7.8 mmol/L (140 mg/dL)
    D. For patients with IFG
    If impaired fasting glucose is also associated with impaired glucose tolerance during OGTT at pre-inclusion:
    - Normalization of OGTT (2-hour glucose plasma level after 75 g OGTT < 7.8 mmol/L (140 mg/dL)
    If impaired fasting glycemia is associated with normal OGTT at pre-inclusion (except at T0):
    - Normalization of fasting plasma glucose (fasting plasma glucose < 5.5 mmol/L (100 mg/dL)

    • Criteria for global improvement of clinical symptoms attributable to the Cushing’s syndrome
    - Weight
    - Body Mass Index
    - Truncal obesity (waist circumference, DEXAscan)
    - Depression (Beck scale); depression will be used as endpoint only for those subjects on stable anti-depressant therapy for at least two months prior to study entry
    - Proximal muscle weakness
    - Bruising
    - Violaceous striae
    - Facial plethora
    - Dorsocervical fat pad
    For each parameter, comparison with baseline will be made and scored as follows:
    • No modification: 0
    • Improvement or normalization: 1
    • Worsening: - 1
    If one of these symptoms was not present at inclusion but appears while the patient is on study drug, it will be scored -1
    The sum of the 10 scores will be made and overall evaluation of the Cushing’ syndrome symptoms will be classified in 2 categories:
    • Improvement or normalization if the sum > 0
    • No improvement or worsening if the sum ≤ 0
    The scoring of each symptom will be performed by the DSMB on the basis of predefined rules.
    E.5.2Secondary end point(s)
    Secondary efficacy variables
    Changes with respect to inclusion visit in the following parameters will be documented for each subject.
    • Secondary glycemic disorder parameters
    A. For diabetic patients
    - Improvement of the following parameters: glycemic profile, fasting blood glucose, fructosamine, 2-hour OGTT (for diabetics diagnosed at screening)
    - Number of anti-diabetics treatment or dose of anti-diabetics treatment for diabetic patients already on diabetes treatment at inclusion
    - Doses of insulin for insulin-treated patients
    B. For patients with IGT
    - HbA1c
    - Fructosamine
    C. For patients with IFG
    - HbA1c
    - Fructosamine
    D. For all patients
    - Fasting plasma insulin
    - Area Under the Curve of OGTT results when OGTT performed
    - HOMA index
    • Investigator’s assessment on patient’s overall profile evolution from baseline
    • Blood pressure:
    o The mean value of the 2 last measurements will be calculated
    o The number of antihypertensive treatments (number of active ingredient per therapeutic class) will be counted
    • Body composition (in particular leg, arm and sub-total fat mass) as determined by DEXA scan
    • Metabolic syndrome (according to NCEP and IDF definitions)
    • Fatigue (MFI-20)
    • Quality of life (SF-36v2™)
    • Impaired cognition/memory (MMSE™)
    • Laboratory Variables: hormones (LH, FSH, TSH, free T3, free T4, SHBG, CBG, estradiol in women, total testosterone in men) biochemistry, haematology, urinalysis
    • Osteocalcin
    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 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) Yes
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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
    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 years5
    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 years5
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 35
    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)
    Total duration of treatment will not exceed 12 months. At the end of 12-month treatment, investigators may petition to extend treatment on a case-by-case basis.
    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 Decision2007-04-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-12-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-04-04
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