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    Summary
    EudraCT Number:2018-002471-18
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-06-19
    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 number2018-002471-18
    A.3Full title of the trial
    The clinical effectiveness and cost effectiveness of clozapine for inpatients with borderline personality disorder: randomised controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clozapine in the treatment of borderline personality disorder
    A.3.2Name or abbreviated title of the trial where available
    CALMED
    A.4.1Sponsor's protocol code number
    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 SponsorImperial College London
    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 Health Technology Assessment Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College London
    B.5.2Functional name of contact pointMike Crawford
    B.5.3 Address:
    B.5.3.1Street AddressDu Cane Road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW12 0NN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02083834161
    B.5.6E-mailm.crawford@imperial.ac.uk
    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 Clozaril
    D.2.1.1.2Name of the Marketing Authorisation holderMylan Products Ltd.
    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 nameClozaril
    D.3.4Pharmaceutical form Capsule
    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 INNclozapine
    D.3.9.1CAS number 5786-21-0
    D.3.9.3Other descriptive name 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine
    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 number12.5 to 400
    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
    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
    Borderline Personality Disorder
    E.1.1.1Medical condition in easily understood language
    Borderline Personality Disorder
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10006034
    E.1.2Term Borderline personality disorder
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    For people receiving inpatient treatment for borderline personality disorder who have not responded well to usual care (including at least three months taking another antipsychotic drug), does the addition of clozapine to their usual care lead to improved mental health six months later, compared to adding a placebo to their usual care?
    E.2.2Secondary objectives of the trial
    For people receiving inpatient treatment for borderline personality disorder who have not responded well to usual care, does the addition of clozapine lead to greater improvements in health-related quality of life, greater reductions in aggression, suicidal behaviour, and use of services compared to adding a placebo?
    Does the addition of clozapine provide a cost-effective treatment compared to the addition of a placebo?
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria:
    1) Aged 18 years or over
    2) Currently an inpatient on a mental health unit
    3) Meeting DSM-IV diagnostic criteria for borderline personality disorder
    4) Failure to make an adequate clinical response to taking antipsychotic medication other than clozapine for at least three months
    5) Have a satisfactory pre-treatment full blood count (white blood cell count >=3.5 and absolute neutrophil count >=2.0)
    6) Have had their weight and blood glucose recoded in their clinical records
    E.4Principal exclusion criteria
    We will exclude those who:
    1) have a current clinical diagnosis of schizophrenia, or bipolar I disorder
    2) prescribed clozapine within the last two weeks
    3) are known to be pregnant, trying to conceive, breastfeeding, or a woman of childbearing potential and is not using a highly
    effective birth control.
    4) are due to be discharged from the unit within the following two weeks
    5) are unable to speak sufficient English to complete the baseline assessment
    6) are unwilling or unable to provide written informed consent to take part in the study
    7) are unable to undergo regular blood tests
    8) have a contraindication to clozapine or other listed condition, namely:
    9) have a known history of primary bone marrow disorders or impaired bone marrow function
    10) severe renal or cardiac disorders (e.g. myocarditis), or a known history of cardiac illness or abnormal cardiac findings on physical examination
    11) have hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
    12) have hypersensitivity to
    -Magnesium stearate
    -Silica, colloidal anhydrous
    -Povidone K30
    -Talc
    -Maize starch
    -Lactose monohydrate
    13) have a known history of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy)
    14) have a history of clozapine-induced agranulocytosis
    15) have uncontrolled epilepsy
    16) have alcoholic and other toxic psychoses, drug intoxication, comatose conditions
    17) Have circulatory collapse and/or CNS depression of any cause
    18) Have active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure
    19) Have paralytic ileus
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is total score on the Zanarini rating scale for Borderline Personality Disorder (ZAN-BPD) at six months (primary end point) to assess this.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Six months
    E.5.2Secondary end point(s)
    Secondary outcomes
    i. Total score on the Zanarini rating scale for Borderline Personality Disorder at three months.
    ii. General mental health using the Brief Psychiatric Rating Scale (BPRS) at three and six months.
    iii. Incidence and severity of suicidal behaviour using the Acts of Deliberate
    Self-Harm Inventory.
    iv. Level of aggressive behaviour using the Overt-Aggression Scale-Modified
    v. Health related quality of life using the EQ-5D-5L.
    vi. Side effects of medication using the Antipsychotic Non-Neurological Side Effects Scale (ANNSERS) and motor and extrapyramidal side effects using the Extrapyramidal Side Effects Scale.
    vii. Incidence of withdrawal of trial medication due to adverse effects.
    viii. Medication adherence at three and six months using the Brief Adherence Rating Scale.
    ix. Resource use collected using a modified version of the Adult Service Use Schedule and by examining clinical records at six, 12 and 18 months, This will include detailed information about length of inpatient treatment and type of ward (high, medium, low secure, Psychiatric Intensive Care, general adult etc.), contacts with community mental health services and emergency medical services, and the type and dose of psychotropic medication that people are prescribed.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Three, six, 12 and 18 months.
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned8
    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
    Last visit last subject
    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 months11
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days31
    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: 219
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state222
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 222
    F.4.2.2In the whole clinical trial 222
    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)
    Following a participant’s six month assessment, a letter will be sent to the referring clinician informing them of the participant’s trial arm allocation. Where a participant has completed the participation period in full, this will allow for arrangements to be made for the participant to continue on clozapine if appropriate and desired. While no further clozapine will be supplied by the sponsor, prescribers will continue to be able to prescribe off-licence clozapine for the participant.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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