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    Summary
    EudraCT Number:2022-001997-70
    Sponsor's Protocol Code Number:EXCELLENCE/0421/0543v1
    National Competent Authority:Cyprus - MoH-Ph.S
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-11-17
    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 ConcernedCyprus - MoH-Ph.S
    A.2EudraCT number2022-001997-70
    A.3Full title of the trial
    Efficacy of Ketamine for the Prevention of Relapse in Patients with Opioid-Use Disorders (OUD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of ketamine to prevent relapse in opioid addicts
    A.3.2Name or abbreviated title of the trial where available
    PROUD
    A.4.1Sponsor's protocol code numberEXCELLENCE/0421/0543v1
    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 of Cyprus
    B.1.3.4CountryCyprus
    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 supportResearch and Innovation Foundation
    B.4.2CountryCyprus
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Cyprus
    B.5.2Functional name of contact pointPanos Zanos
    B.5.3 Address:
    B.5.3.1Street Address1 Panepistimiou Avenue
    B.5.3.2Town/ cityNicosia
    B.5.3.3Post code2109
    B.5.3.4CountryCyprus
    B.5.4Telephone number+35722892243
    B.5.6E-mailzanos.panos@ucy.ac.cy
    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 Ketamin Inresa 10 ml Solution for injection 500 mg 50 mg/ml
    D.2.1.1.2Name of the Marketing Authorisation holderInresa Arzneimittel GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameKetamin Inresa 10 ml Solution for injection 500 mg 50 mg/ml
    D.3.4Pharmaceutical form Solution for injection
    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.3.9.2Current sponsor codeNot Applicable
    D.3.9.3Other descriptive nameKETAMINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB02830MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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
    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
    Methadone and buprenorphine comprise a first-line, evidence-based opioid substitution treatment (OST) for OUD patients. Unfortunately, retention and adherence to OST treatment is currently a major challenge in the treatment of OUDs. Another major challenge for opioid addicts who are recovering from addiction is the maintenance of a drug-free state due to the negative affect associated with protracted opioid abstinence, including depression, anhedonia, and anxiety.
    E.1.1.1Medical condition in easily understood language
    Opioid addiction is a chronic, relapsing brain disorder causing high rates of mortality, primarily due to overdose incidences.
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10019935
    E.1.2Term Heroin addiction
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10030900
    E.1.2Term Opium addiction
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012378
    E.1.2Term Depression
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10057840
    E.1.2Term Major depression
    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
    The long-term aim of the project is to identify novel, faster-acting medications for (i) promoting retention to the opioid substitution treatment, (ii) reversing/preventing comorbid affective disorders and (iii) maintain opioid abstinence in abstaining opioid dependent patients. In addition, PROUD aims to identify novel biomarkers predicting vulnerability to relapse to opioid-taking during abstinence. Our studies will contribute to improved treatment strategies for prevention of relapse to opioid use following long-term abstinence in patients.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    (i) age between 18 to 65 years old;
    (ii) daily use of illicit opioids
    (iii) fulfillment of DSM-5/ICD-10 criteria for moderate-to-severe opioid or heroin use disorder;
    (iii) acceptance into maintenance care for treatment of opioid or heroin use disorder;
    (iv) retained in buprenorphine/naloxone treatment since their intake on the preceding day;
    (v) achieved a PHQ-9 score of at least 10 points.
    E.4Principal exclusion criteria
    (i) electrocardiogram (ECG) findings of tachycardia, prior myocardial infarction, myocardial ischemia, or aberrant conduction; (iii) baseline urine drug test positive for benzodiazepine, methadone, or buprenorphine; (iv) self-report of recent prescribed or illicit benzodiazepine use (“Xanies”, or “bars”); (v) urine screen positive for pregnancy; (vi) hypertension, defined by a systolic blood pressure (SBP) > 140 mmHg or a diastolic blood pressure (DBP) > 90 mmHg; (vii) clinically significant abnormal laboratory values, physical exam findings or self-reported medical conditions for which a transient increase in blood pressure could be significantly detrimental (e.g., cardiovascular disease); (viii) any clinically significant abnormal findings from health and physical examination; (ix) any indication of serious mental illness or psychiatric disorder from the attending’s evaluation notes.

    Additionally:

    (i) subjects who meet DSM-5 criteria for current bipolar disorder; (ii) subjects who meet DSM-5 criteria for current or history of psychotic spectrum disorders; (iii) past or current presence of psychotic symptoms, or diagnosis of a lifetime psychotic disorder including schizophrenia or schizoaffective disorder; (iv) current or previous recreational use of ketamine or PCP.
    E.5 End points
    E.5.1Primary end point(s)
    * We will assess the efficacy of a two-week regimen of subanesthetic antidepressant doses of ketamine (0.5 mg/kg) as an adjunct treatment to: (i) Improve OST treatment retention; (ii) reverse comorbid negative affective behaviors (including depression, anhedonia, suicidal thoughts and anxiety); (iii) prolong/maintain abstinence, in abstaining opioid addicts undergoing opioid-substitution treatment (OST).

    * Emotion regulation ability (as indexed via heart rate variability; HRV), stress response biomarkers (norepinephrine, epinephrine (catecholamines), adrenocorticotrophic hormone (ACTH) and cortisol) and changes in neural activity (measured via EEG spectral analysis) will be assessed in OUD patients prior and after exposure to a mild psychological stressor, prior to quitting opioids. The aim here is to examine whether these psycho-bio-neurophysiological markers alone or their reciprocal interactions can predict: (i) vulnerability to relapse to opioid-taking during abstinence in placebo-treated patients; (ii) ketamine’s treatment outcomes in the patient treatment group that will receive ketamine infusions.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study and after the end of ketamine administration
    E.5.2Secondary end point(s)
    * Using EEG measurements, we will assess whether changes in cortical neural activity after administration of ketamine are associated or can predict ketamine’s efficacy to improve OST treatment retention, reverse comorbid negative affective behaviors and prolong/maintain abstinence.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Prior to ketamine administration and 1 day after administration
    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 No
    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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    End of the trial will be 9 months after the last ketamine infusion, when the subjects will be assessed for relapse and be assessed for some additional clinical signs
    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: 60
    F.1.3Elderly (>=65 years) No
    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 state60
    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)
    Patients will be given instructions on the signs of relapse to opioids and they will be provided with points of contact for further help if they feel they have cravings to use opioids after abstinence
    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 Decision2022-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-28
    P. End of Trial
    P.End of Trial StatusOngoing
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