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    Summary
    EudraCT Number:2009-015165-31
    Sponsor's Protocol Code Number:EME-08/43/39
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-06-18
    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 ConcernedUK - MHRA
    A.2EudraCT number2009-015165-31
    A.3Full title of the trial
    Antiglucocorticoid augmentation of antiDepressants in Depression: a double-blind, randomised, placebo-controlled, parallel-group trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to determine whether the addition of Metyrapone increases effects of anti-depressants in patients with depression.
    A.3.2Name or abbreviated title of the trial where available
    Antiglucocorticoid augmentation of antiDepressants in Depression (ADD Study)
    A.4.1Sponsor's protocol code numberEME-08/43/39
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN45338259
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01375920
    A.5.4Other Identifiers
    Name:CT.govNumber:NCT01375920
    Name:NIHR CSPNumber:38766
    Name:NIHRNumber:7801
    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 SponsorNorthumberland, Tyne and Wear NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    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 supportNIHR Efficacy, Mechanism and Evaluation Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Metyrapone
    D.2.1.1.2Name of the Marketing Authorisation holderAlliance Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMetyrapone
    D.3.4Pharmaceutical form Capsule, soft
    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 INNMetyrapone
    D.3.9.1CAS number 54-36-4
    D.3.9.2Current sponsor code2010NEAMH001
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    depression
    E.1.1.1Medical condition in easily understood language
    depression
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The principal research question/objective is to determine whether Metyrapone 500 mg taken orally twice a day, versus a dummy pill (which will look exactly the same as the real medication), added to a patient's current anti-depressant, is effective in treating depression in a UK primary care and outpatient setting.
    E.2.2Secondary objectives of the trial
    The secondary research questions/objectives are to: - determine how big the clinical effect of Metyrapone is in practice in the UK. - assess whether the response to Metyrapone is sustained for up to 6 weeks after the course of treatment has finished. - assess whether Metyrapone augmentation improves patients' quality of life. - assess how well Metyrapone is tolerated. - identify factors that may predict response to this treatment and clarify the biological processes involved in its action. In subsamples: - to determine whether attention and memory improve with Metyrapone treatment and to examine if improvements occur just in specific cognitive tasks that provide information as to how it may be working. - to determine whether EEG predictors of conventional antidepressant response predict response to Metyrapone augmentation. - to clarify differences in the activity of certain brain regions in response to different cognitive challenges between patients w
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patient should be suffering from a DSM-IV major depressive episode, as described below: 1. Severity of depression. - Hamilton Depression Rating Scale (HDRS17) score of 18, or greater (rated using the GRID-HAMD), consistent with a moderate to severe episode. The stability of the clinical state will also be confirmed with a two week baseline lead in period (week -2 to 0). - A repeat HDRS17 score at time 0 is required to be 18 or greater. 2. Treatment refractoriness. - Assessed using Massachusetts General Hospital (MGH) staging method. This defines minimum effective doses of all currently available antidepressants and an "adequate trial" as being for at least six weeks. For the trial to be considered a "failure", it must have been considered by the clinical team to have been ineffective rather than the drug not taken or not tolerated. - Failure to respond to at least the second trial of an antidepressant. (This equates to a minimum score of two on MGH staging. The maximum MGH score for inclusion in the study will be 10. A study in the UK has shown mean MGH scores in primary care patients of less than one, in secondary care mental health settings of around five and eleven in a population of patients referred to a tertiary centre (Dr D Christmas, Dundee, Personal Communication). 3. Current anti-depressant treatment - At trial entry, patients must be taking monotherapy or combination antidepressant therapy that includes a serotonergic drug (an SSRI, a tertiary amine tricyclic, venlafaxine, duloxetine or mirtazepine). They must not be on noradrenergic anti-depressant monotherapy (eg. with lofepramine, imipramine or reboxetine). At the point of randomisation, patients must have been on their current anti-depressant medication, at the current dose, for a minimum of four weeks. 4. Aged 18-65 - Patients will be included who are aged 18-65. For the mechanistic substudies the upper age limit is 60. For the healthy controls (inclusion criteria): 1. Currently psychiatrically well confirmed through SCID interview. 2. HDRS17 score of five or less 3. No current psychotropic medication 4. No past history of psychiatric illness as revealed by SCID interview, or requiring any treatment (formal psychotherapy or psychotropic medication) 5. No first degree family history of psychiatric illness 6. Aged 18-60
    E.4Principal exclusion criteria
    1. Any other DSM IV Axis I disorder, other than an anxiety disorder unless the depressive episode is considered to be secondary to the anxiety disorder, confirmed using the Structured Clinical Interview for DSM (SCID). 2. Physical co-morbidity which would render the use of Metyrapone inappropriate, including untreated hypothyroidism, disorders of steroid production, current, severe cardiac failure, current, severe or frequent angina, current renal failure or myocardial infarction within the last year. 3. Pregnancy - determined by history and, if indicated, urine pregnancy test. 4. Mothers who are breastfeeding. 5. Use of concomitant medication that would interfere in a pharmacodynamic or pharmacokinetic manner with Metyrapone. 6. Dependence on alcohol or other drug in the past 12 months, and/or current harmful use of alcohol or other drug. 7. Recently having taken part in another research study that could interfere with the results of this one. For the healthy controls: 1. Any DSM IV Axis I disorder. 2. Any physical ill health which would render the use of Metyrapone inappropriate, including untreated hypothyroidism, disorders of steroid production, current, severe cardiac failure, current, severe or frequent angina, current renal failure or myocardial infarction within the last year. 3. Pregnancy - determined by history and if indicated, urine pregnancy test. 4. Mothers who are breastfeeding. 5. Use of any medication that would interfere in a pharmacodynamic or pharmacokinetic manner with Metyrapone. 6. Dependence on alcohol or other drug in the past 12 months and/or current harmful use of alcohol or other drug.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure will be the change in Montgomery-Asberg Depression Rating Scale (MADRS) from week 0 to week 5.
    E.5.1.1Timepoint(s) of evaluation of this end point
    All patients will be assessed at randomisation (week 0), and 2 weeks after the end of treatment, (week +5).
    E.5.2Secondary end point(s)
    Secondary outcomes related to mood will be the MADRS measured at time 0, +3, +5, +8, +16 and + 24 weeks relative to baseline. Additional secondary outcome measures of symptomatology include the Clinical Anxiety Scale (CAS), an observer rated scale of current anxiety, and the Beck Depressive Inventory (BDI) and State Trait Anxiety Inventory (STAI), which are patient-rated scales of depression and anxiety.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The Clinical Anxiety Scale, Beck Depressive Inventory and State Trait Anxiety Inventory will be conducted at the following timepoints: weeks 0, +3, +5, +8, +16, +24.
    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 No
    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 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 concerned5
    E.8.5The trial involves multiple Member States No
    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
    The end of the trial will be the last patient's last visit(LVLS).
    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 months37
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 190
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state190
    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)
    The study drug will not be available to patients at the end of the study. This will be made clear when the patient is given information about the study and before consent is obtained. Patients will continue to receive standard care after the study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Mental Health Research Network (North East Hub)
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-04-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-06-30
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