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    Summary
    EudraCT Number:2015-000222-11
    Sponsor's Protocol Code Number:1
    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:2020-07-30
    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 number2015-000222-11
    A.3Full title of the trial
    A phase II, randomised, double-blind, placebo- controlled, multi-site, parallel group clinical trial to examine ketamine as a pharmacological treatment for alcohol dependence in an alcohol dependent population.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    KARE: Ketamine for reduction of Alcoholic Relapse
    A.3.2Name or abbreviated title of the trial where available
    KARE: Ketamine for reduction of Alcoholic Relapse Version 1
    A.4.1Sponsor's protocol code number1
    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 SponsorUniversity 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 supportMedical Research Council
    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 Ketalar
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer 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 nameKetalar
    D.3.4Pharmaceutical form Solution for injection/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 INNKetamine
    D.3.9.1CAS number 6740-88-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 placeboSolution for injection/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
    Severe Alcohol Use Disorder
    E.1.1.1Medical condition in easily understood language
    Alcoholism
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10001585
    E.1.2Term Alcohol abuse chronic
    E.1.2System Organ Class 100000004873
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1) To obtain preliminary data on whether ketamine is effective in promoting and prolonging abstinence in patients with severe alcohol use disorder following detoxification.



    2) To assess safety and tolerability of ketamine in severe alcohol use disorder.
    E.2.2Secondary objectives of the trial
    1) To make an early assessment on likely compliance to a combined ketamine and relapse prevention based psychological therapy



    2) To obtain preliminary data as to whether ketamine alone is as effective as a combined ketamine and psychological therapy treatment.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    18 - 60 years old



    Meet either a) DSM-5 criteria for severe alcohol use disorder and b) DSM-IV criteria for alcohol dependence



    Currently abstinent (breathlyser BAC level 0.02 and negative urine drug and alcohol screen)



    Minimum of mild depression(>14 on Beck Depression Inventory-II)



    Capacity to give informed consent as defined by GCP guidelines



    Willing and able to wear a SCRAM-X bracelet for 6 months



    Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 6 weeks after treatment discontinuation and inform the trial if pregnancy occurs



    Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment and on day of first treatment.
    E.4Principal exclusion criteria
    Currently taking any other relapse prevention medication or anti-depressants



    Uncontrolled hypertension, systolic 140mm Hg or greater and diastolic 90mm Hg or greater



    < 16 or > 35 BMI



    History of psychosis, or in a first-degree relative; co-morbid current psychiatric diagnosis excluding depression as identified by DSM-5 or DSM-IV SCID



    Previous or current diagnosis of substance dependence / severe substance misuse disorder



    History of neuropsychological difficulties



    One or more previous confirmed seizures



    Currently taking daily prescribed medication contraindicated in the Summary of Product Characteristics with ketamine:

    Barbiturates and/or narcotics

    Halogenated anaesthetics

    Atracurium and tubocurarine

    Central nervous system (CNS) depressants (e.g. phenothiazines, sedating H1 – blockers or skeletal muscle relaxants)

    Anxiolytics, sedatives and hypnotics

    Thiopental, thyroid hormones

    Antihypertensive agents

    Theophylline and methylxanthine

    OR psychotropic drug use at screening assessment or during treatment weeks



    Liver function tests > 3 times normal levels



    Where there are "Special warnings or precautions for use" according to the Summary of Product Characteristics where risk vs benefit ratio is not in favour of giving ketamine, with assessment made by physical examination by medically qualified trial personnel, self-report or inspection of the medical notes:

    Acute intermittent porphyria

    Dehydration or hypovolemia

    Hyperthyroidism, or patients receiving thyroid replacement

    Pulmonary or upper respiratory tract infection

    Severe Coronary artery disease, Cerebrovascular accident or cerebral trauma

    Diabetes

    Known glaucoma or globe injuries

    Cirrhosis

    Epilepsy

    Neurological condition/brain damage

    Intracranial mass lesions, presence of head injury or hydrocephalus



    Suicidal ideation



    Not willing to use effective contraception or (females) take pregnancy test



    Allergic reaction to ketamine



    > 10 previous detoxifications from alcohol



    Pregnant or Breastfeeding



    Allergies to excipients of Investigational Medicinal Product and placebo



    Use of another investigational medicinal product that is likely to interfere with the study medication within 3 months of study enrolment
    E.5 End points
    E.5.1Primary end point(s)
    Relapse rates at 6 months and percentage days abstinent at 6 months, indexed by the SCRAM-X bracelet and patient reports on the time line follow back scale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    As an interim analysis with regarding to trial continuation, attrition among participants receiving ketamine only will be determined; the trial will be discontinued if more than 21/24 (88%) of participants who were randomised to ketamine are lost to follow-up at 3 months. Only aggregate data will be provided to the statistician at 3-month follow-up to ensure that treatment arm allocation will remain concealed. Due to the short duration of follow-up, no interim analyses for the primary or secondary outcomes are planned. From a safety perspective, adverse events will be monitored by the TSC and any concerns will be addressed.
    E.5.2Secondary end point(s)
    Number of days of continuous abstinence 3 months (SCRAM-X and Time-line follow back)

    Percentage days abstinent at 3 months (SCRAM-X and timeline follow-back)

    State mood (Profile of Mood states)

    Depression (Beck Depression Inventory; Hamilton Depression Scale)

    Anxiety (Speilberger Trait Anxiety Inventory)

    Psychotic symptoms (Brief Psychiatric Rating Scale; Psychotomimetic States Inventory)

    Cigarette smoking (Fagerstrom Smoking)

    Craving (Visual Aanalogue Scales)

    Quality of Life (SF-12)

    Episodic Memory (Prose Recall)

    Delay discounting

    Response Inhibition (Stop Signal Reaction time)

    Working Memory

    Hippocampal Functioning (Pattern Recognition Test)

    Adverse Effects (Adverse Effects VAS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    These endpoints will be evaluated following trial end when all patients have 6 month follow up data.
    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 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) 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 Yes
    E.8.2.3.1Comparator description
    Saline (NaCl 0.9%, 50 mls solution)
    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.8.4.1Number of sites anticipated in Member State concerned2
    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 No
    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 follow-up visit of the last participant at approximately 24 weeks post baseline.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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.1.1Number 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: 96
    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 state96
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    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)
    There is no plan to allow continued treatment with ketamine. Patients will be made aware of this before agreeing to participate via the PIS and screening consultation. After the final visit, we will refer Patients back to their GP or Clinic where they will routinely continue with their follow up. If Patients would like to receive further assistance or advice about their alcohol use we will help them locate further services that are available to them.

    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 Decision2015-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-02-07
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