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    Summary
    EudraCT Number:2015-003957-16
    Sponsor's Protocol Code Number:ZonMw80-83600-98-3074
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-08-30
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-003957-16
    A.3Full title of the trial
    A randomised controlled trial of oral S-ketamine as add-on medication for patients with treatment-resistant major depressive disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Oral ketamine for treating depression
    Orale ketamine als aanvullende behandeling bij patiënten met een therapieresistente depressie
    A.3.2Name or abbreviated title of the trial where available
    Oral S-ketamine for treating depression
    A.4.1Sponsor's protocol code numberZonMw80-83600-98-3074
    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 Medical Centre Groningen
    B.1.3.4CountryNetherlands
    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 supportZonMw
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Centre Groningen
    B.5.2Functional name of contact pointUniversity Centre of Psychiatry
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713 GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031503618880
    B.5.6E-mailketaminestudie@umcg.nl
    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.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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.3.4Pharmaceutical 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 INNEsketamine
    D.3.9.1CAS number 33795-24-3
    D.3.9.3Other descriptive nameESKETAMINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB25825
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEsketamine
    D.3.9.1CAS number 33795-24-3
    D.3.9.3Other descriptive nameESKETAMINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB25811
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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
    Treatment resistant major depressive disorder
    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 proposed study aims to examine the antidepressant efficacy of oral S-ketamine augmentation in patients with treatment resistant depression, treated with regular antidepressants in a double-blind randomised controlled trial.
    E.2.2Secondary objectives of the trial
    Secondary questions involve the effects of oral S-ketamine on sleep, autobiographical memory, pain, anxiety, anhedonia, suicidal ideation, nicotine dependence, quality of life and consumption of medical care, as well as a detailed assessment of possible side effects caused by the ketamine treatment. Brain activation, brain blood flow and volume parameters, neuroplasticity, glutamate and glutamine concentrations in the brain, biomarkers, and the genotype of the CYP enzyme(s) involved in the metabolism of ketamine will be assessed, to develop a better understanding of the mechanisms of action and metabolism of S-ketamine. Furthermore, the study will also investigate the duration of effects after discontinuation of S-ketamine add-on treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all the following criteria:
    - Male or female, age range: 18 to 80 years;
    - Signed informed consent;
    - Good understanding of spoken and written Dutch;
    - DSM-5 diagnosis of MDD, first or recurrent episode, ascertained by the Mini International Neuropsychiatry Interview (MINI-plus);
    - TRD, defined as nonresponse to at least 3 different classes of antidepressants during lifetime, all given in an adequate dose (i.e. defined daily dose) for at least 4 weeks;
    - At least moderately severe depression, defined by a score higher than 18 on HDRS17;
    - Current treatment with an officially approved antidepressant medicine.
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation:
    - Bipolar depression or depression with psychotic features, according to the DSM-5;
    - Previous or comorbid schizophrenia spectrum or other psychotic disorder according to the DSM-5, not including MDD with psychotic features;
    - Comorbid severe personality disorder according to the DSM-5, that is the main reason for treatment;
    - Previous or comorbid moderate or severe dependence of alcohol or drugs according to the DSM-5, not including tobacco-related and caffeine-related disorders;
    - Recent (within the last 4 weeks) or current use of cannabis or any other non-prescribed psychoactive compounds, including Saint John’s wort;
    - Relevant neurological disorder, such as dementia or epilepsy;
    - Recent (within the last 4 weeks) change of antidepressant treatment;
    - ECT sessions or any other antidepressant treatment change planned for the period of the study;
    - Active suicidal intent, defined by scores higher than 2 on HDRS17 for suicidal ideation;
    - (Suspected) pregnancy, insufficient contraception or lactation. If there is any doubt, a pregnancy test is performed;
    - Recent (within the last 4 weeks) or current use of benzodiazepine and benzodiazepine-like agents (zolpidem, zopiclone) in excess of 2 mg lorazepam or an equivalent per day;
    - Recent (within the last 4 weeks) or current use of somatic medication that commonly affects mood, like oral corticosteroids;
    - Presence of any contra-indication for ketamine use, such as increased intracranial pressure, recent myocardial infarction or other relevant cardiac problems, severe hypertension, severe hyperthyroidism, severe liver problems, severe kidney problems, or the use of medication that ketamine interacts with on a major level, such as monoamine oxidase inhibitors;
    - Vision or hearing problems that cannot be corrected and that interfere with the ability to comply with treatments and/or assessments;
    - Mental incompetence to provide informed consent, based on the judgment of the general practitioner or treating psychiatrist of the participant;
    - Inability to comply with treatments and/or assessments, based on the judgment of the general practitioner or treating psychiatrist of the participant.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this trial is to examine the antidepressant efficacy of oral S-ketamine augmentation in patients with TRD. This will be measured by the following main study endpoints at the end of treatment: 1) change in symptom severity, expressed as a change in total score on the HDRS17; 2) response, defined as ≥ 50% decrease in total score on the HDRS17; 3) partial response, defined as 25-49% decrease in total score on the HDRS17.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of treatment (week 6)
    E.5.2Secondary end point(s)
    The secondary objectives of this trial will be measured by the following secondary study endpoints:
    - HDRS17 changes in total sum score after the discontinuation of treatment;
    - IDS-SR changes in total sum score during and after the discontinuation of treatment;
    - HDRS17 changes and IDS-SR changes in symptom dimension scores during and after the discontinuation of treatment;
    - BSS changes in total sum score during and after the discontinuation of treatment;
    - SHAPS changes in total sum score during and after the discontinuation of treatment;
    - fMRI reward task changes in total sum score during treatment;
    - CGI severity changes and CGI improvement scores during and after the discontinuation of treatment;
    - BAI changes in total sum score during and after the discontinuation of treatment;
    - GCPS changes in item scores during and after the discontinuation of treatment;
    - FTND changes in total sum score during and after the discontinuation of treatment;
    - AMT changes in total specific sum score during and after the discontinuation of treatment;
    - EQ-5D-5L changes in total sum score calculated using the Dutch tariff and in VAS score, during and after the discontinuation of treatment;
    - Changes of brain activation in the prefrontal cortex, limbic structures, insula and default mode network during treatment;
    - Changes of the prefrontal cortex and limbic structures volumes during treatment;
    - Changes of glutamate and glutamine concentrations in the anterior cingulate cortex of the brain during treatment;
    - Changes of blood flow in the brain during treatment;
    - Changes of biomarker patterns in blood and urine during and after the discontinuation of treatment;
    - Changes in gene expression patterns, measured by the use of RNA, during and after the discontinuation of treatment;
    - SAFTEE changes in total sum score and item scores during and after the discontinuation of treatment;
    - ISDI changes in symptom dimension scores during and after the discontinuation of treatment;
    - QPE changes in total sum score and symptom dimensions scores during and after the discontinuation of treatment;
    - DSS changes in total sum score during and after the discontinuation of treatment;
    - Body weight changes during and after the discontinuation of treatment;
    - Blood pressure changes during and after the discontinuation of treatment;
    - Liver enzyme level changes during treatment;
    - Incremental costs per additional percentage point of patients recovered from depression, with recovery assessed by the means of the HDRS17, and defined as a more than 50% decrease in score from week 1 to week 6 and 10;
    - Incremental costs per QALY gained, with QALYs assessed by means of the EQ-5D-5L and calculated over the 10 week study period;
    - Expected changes in the flows of expenditure in the Dutch health care system after the adoption of ketamine as a new intervention for treatment resistant depression;
    - Report on new pharmacokinetics knowledge of S-ketamine and norketamine after oral administration;
    - Report on associations between S-ketamine and norketamine pharmacokinetics and changes on the HDRS17;
    - Report on new genotype knowledge of the CYP enzyme(s) involved in the metabolism of S-ketamine.
    E.5.2.1Timepoint(s) of evaluation of this end point
    There will be different timepoints for the secondary end points:
    - During treatment (week 0 - week 6);
    - At the end of treatment (week 6);
    - At follow-up (week 7, 8 and 10);
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 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
    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 months
    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.1.1.1In 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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 118
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 Information not present in EudraCT
    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 state128
    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)
    After the final follow-up, an open-label off-label extension treatment with ketamine will be offered to participants who have completed the placebo controlled period, and whom have not remitted during the study or whom have relapsed during follow-up. This open-label treatment is not part of this 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 Academisch Medisch Centrum
    G.4.3.4Network Country Netherlands
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Erasmus Medisch Centrum
    G.4.3.4Network Country Netherlands
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation St. Anna Ziekenhuis
    G.4.3.4Network Country Netherlands
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-08-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-29
    P. End of Trial
    P.End of Trial StatusOngoing
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