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    Summary
    EudraCT Number:2021-006706-69
    Sponsor's Protocol Code Number:DUAG9V1.03_10.06.2022
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-01-03
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2021-006706-69
    A.3Full title of the trial
    Lithium versus cariprazine in the acute phase treatment of bipolar depression: a pragmatic head-to-head open, randomized multicenter study. The 9th study of the Danish University Antidepressant Group (DUAG 9).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Lithium versus cariprazine in the treatment of bipolar depression
    A.4.1Sponsor's protocol code numberDUAG9V1.03_10.06.2022
    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 SponsorPsychiatry – Aalborg University Hospital, Unit for Psychiatric Research
    B.1.3.4CountryDenmark
    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 supportDanske Regioner
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportRegion Nordjylland
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPsychiatry - Aalborg University Hospital
    B.5.2Functional name of contact pointUnit for Psychiatric Research
    B.5.3 Address:
    B.5.3.1Street AddressMoelleparkvej 10
    B.5.3.2Town/ cityAalborg
    B.5.3.3Post code9000
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4597643000
    B.5.6E-mailren@rn.dk
    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 Reagila
    D.2.1.1.2Name of the Marketing Authorisation holderRecordati AB (Europe) and Geodon Richter (Intl)
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 nameCariprazine
    D.3.4Pharmaceutical form Capsule, hard
    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 INNcariprazine
    D.3.9.1CAS number 839712-12-8
    D.3.9.4EV Substance CodeSUB34830
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Litarex
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA A/S in Denmark (Actavis Gropu PTC represented in Denmark by the former))
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 namelithium citrate
    D.3.4Pharmaceutical form Tablet
    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 INNlitarex
    D.3.9.3Other descriptive nameLITHIUM CITRATE
    D.3.9.4EV Substance CodeSUB195420
    D.3.10 Strength
    D.3.10.1Concentration unit mmol millimole(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Bipolar disorder, current depressive episode.
    -Bipolar affektiv lidelse, aktuel depressiv episode
    E.1.1.1Medical condition in easily understood language
    Patients with a diagnoses of bipolar disorder who have a depressive episode
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10004911
    E.1.2Term Bipolar affective disorder, depressed
    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
    The primary aim is to investigate whether cariprazine is superior to lithium or vice versa in the acute treatment of patients with bipolar type 1 or 2 patients in a current depressive episode measured as change on the Hamilton Depression Scale, 6 item version (HDS-6) (Bech et al. 1981, O’Sullivan et al. 1997) from baseline to 8 weeks of treatment.
    E.2.2Secondary objectives of the trial
    Secondarily, we aimed at comparing the two study medications on various other clinically relevant variables as defined in the Methods section. These include depressive and manic symptomatology, sleep patterns, general well-being, cognitive function, social functioning and suicidal ideation.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A) A diagnosis of bipolar disorder, type 1 or type 2, and a current episode of depression according to DSM-5, verified by a shortened Mini-International Neuropsychiatric Interview (MINI) (Sheehan 1998). The current depressive episode should be without mixed features according to DSM-5.
    B) Severity of depression: A score of at least 21 on the self-reported Major Depression Inventory (MDI) (Bech et al. 2015)
    C) No start or dose increase of psychotropic medication (except for benzodiazepines and benzodiazepine-like drugs (zopiclone, zolpidem, and melatonin)) in the two weeks prior to inclusion.
    D) No new start of formalized psychotherapy sessions, excluding psychoeducation, during the 4 weeks prior to inclusion.
    E) Age criteria: Subjects must be at least 18 years old and below 65 at the time of randomization.
    F) The duration of the current depressive episode must be between 4 and 52 weeks as judged by the investigator at the time of randomization.
    G) Clinical uncertainty (Geddes et al. 2016) regarding which of the alternatives, cariprazine and lithium, would be the better choice in the specific case, implying that both drugs are considered equally relevant, taken the clinical circumstances of the individual patient into account. (If for example the patient has a history of lithium intolerance it is likely that cariprazine a priori might be the better choice and the patient should be excluded).

    H) Female participants should be sterile or non-fertile or, in case of being fertile, they must have a negative pregnancy test AND use safe anticonception. The safe anticonception is defined by The Danish Medicines Agency as intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections). To be considered as sterile or non-fertile, one must be surgically sterilized (bilateral tubectomy, hysterectomy or bilateral ovariectomy) or be postmenopausal defined as absence of menses in at least 12 months before inclusion. A blood sample of FSH is obtained to confirm menopause unless beyond reasonable doubt (e.g., age over 60 or menopause for several years).

    I) Signed document of informed consent.
    E.4Principal exclusion criteria
    A) Prior or ongoing treatment of the current depressive episode with either lithium or cariprazine.
    B) ECT within the current depressive episode.
    C) A score of MAS > 6.
    D) A diagnosis of dementia.
    E) High risk of non-adherence at the investigator’s discretion.
    F) Not understanding the Danish language as judged by the investigator
    G) Psychiatric coercion in the form of forced admission or detainment OR sentence to forensic psychiatric care.
    H) Presence of clinically relevant delusions, hallucinations or other psychotic symptoms as judged by the investigator.
    I) Suicidality according to C-SSRS with a positive response to question 4 or 5 or upon investigator’s discretion.
    J) Medical conditions like cancer, kidney failure, epilepsy, deep brain stimulation device, or other medical conditions interfering with study the outcome and safety as judged by investigator’s discretion.
    K) Current harmful use or dependency of alcohol or drugs according to DSM-5.
    L) Known allergy to any of the substances in the study medication
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the difference in differences (DID) between cariprazine and lithium in HDS-6 from baseline to planned endpoint at 8 weeks or to premature endpoint for those not completing the study, based on the mITT population. The HDS-6 is chosen as the primary scale because of its superior psychometric properties regarding one-dimensionality (in terms of measuring severity of depression) and its high degree of sensitivity to change in depression severity (Licht et al. 2005, Timmerby et al. 2017, Østergaard et al. 2016).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 8 weeks post baseline or to premature endpoint for those not completing the study, based on the modified intention to treat (mITT) population.
    E.5.2Secondary end point(s)
    All secondary outcomes are based on the mITT population unless otherwise specified.
    • Difference-in-differences for the following secondary continuous measures: HDS-17, MAS, MES, MADRS, YMRS, ASRM-14, MADRS, MDI, WHO-5, SCIP, COBRA, FAST, PSQI, CGI-S, CGI-I, C-SSRS, accumulated benzodiazepine dose as diazepam equivalents (DSKP), and time to all-causes discontinuation or study endpoint. A Per Protocol analysis at 8 weeks is performed for all continuous secondary outcomes.

    • Difference-in-differences (baseline to 8 weeks) in HDS-6 for the PP8 population.

    • Between-groups difference in proportion of responders and remitters at week 4 and 8. Responders are defined as subjects with a reduction of at least 50 % in their HDS-6 scores between baseline and the endpoint of interest. Remitters are defined as subjects with HDS-6 score below 5 at the endpoint of interest. Both are measured at 4 weeks or at a premature endpoint before (LOCF) and at 8 weeks or at a premature endpoint before (LOCF). Outcomes are also reported for completers only, at 4 and 8 weeks. Response and remission as defined by HDS-6 score do not take co-existing hypomanic/manic symptoms into account, even if these lead to exclusion.

    • Between-groups difference in proportion of responders and remitters at week 4 and 8 as above but with response and remission defined by HDS-6 score as well as having a MAS <7 at planned or premature endpoint.

    • Between-groups difference in the proportion of patients with ‘acceptable wellbeing’, defined as the subject reporting ≥50 on the WHO-5 questionnaire at endpoint.
    • Between-groups difference in proportion of switches to mania/hypomania with or without mixed features, defined as mania/hypomania after DSM-5 or symptoms requiring treatment (switch or response occurring at any time in the study period). Switch is only considered as a premature endpoint if the mania requires treatment as outlined below “Criteria for premature discontinuation for individual subjects (premature endpoints)”.

    • Between-groups difference in “(switch to mania or hypomania) / (response) -ratio”, defined as the number of subjects switching to mania or hypomania (as defined above) divided by the total number of responders, including those responders switching to mania (switch or response occurring at any time in the study period).

    • Between-group differences in reason for and time to all cause treatment discontinuation (lack of effect, lack of tolerability, lost to follow-up, or other cause).

    • Between-group difference in treatment compliance. Treatment compliance is defined as the proportion of received treatments out of the planned until drop-out or end of study.

    • Between-group difference for the ITT population in reasons for premature discontinuation, time to all cause discontinuation, treatment expectation, adverse events, and serious adverse events.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 8 weeks post baseline or to premature endpoint for those not completing the study, based on the modified intention to treat (mITT) population unless specified otherwise above inE.5.2.
    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 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 Yes
    E.6.13.1Other scope of the trial description
    This is a pragmatic superiority study to investigate wether there is no significant difference in the change in the Hamilton Depression Scale, 6 item version (HDS-6) (Bech et al. 1981, O’Sullivan et al. 1997) from baseline to 8 weeks of treatment between the two treatment arms (H0 hypothesis).
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    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 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
    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 months20
    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: 122
    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 state122
    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)
    Study participants who wish to continue either lithium or cariprazine can discuss this with the physician responsible for their treatment.

    The investigator will follow study participants with side effects that persist after the study is finished.

    In case the patient wishes to dropout, the next rating session will be performed if possible. It is recommended that study participants discuss further treatment with the treating physician responsible for this.

    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 Danish University Antidepressant Group
    G.4.3.4Network Country Denmark
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-02-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-06-22
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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