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    EudraCT Number:2021-000862-14
    Sponsor's Protocol Code Number:A-bipolar
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-01
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2021-000862-14
    A.3Full title of the trial
    Effects of low dose Aspirin in bipolar disorder – a randomized controlled trial (the A-Bipolar RCT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of low dose Aspirin in bipolar disorder – a randomized controlled trial
    A.4.1Sponsor's protocol code numberA-bipolar
    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 SponsorCopenhagen Affective Disorder research Center (CADIC),
    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 supportRegion Hovedstadens Psykiatri
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCopenhagen Affective Disorder research Center (CADIC),
    B.5.2Functional name of contact pointCaroline Fussing Bruun
    B.5.3 Address:
    B.5.3.1Street AddressHovedvejen 13, 1. sal, bygning 18, Nordre Fasanvej 57
    B.5.3.2Town/ cityFrederiksberg, Copenhagen
    B.5.3.3Post code2000
    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. name Hjertemagnyl
    D. of the Marketing Authorisation holderTakeda Pharma A/S
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.11 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Bipolar disorder
    E.1.1.1Medical condition in easily understood language
    Bipolar disorder is a common psychiatric disorder, formerly known as manio-depressive disorder.It has a life-long course characterized by high risk of recurrence of manic and depressive episodes.
    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 10004935
    E.1.2Term Bipolar affective disorder, unspecified
    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 objective of the present study is to conduct an RCT investigating whether add-on low-dose Aspirin versus placebo add-on to standard treatment improves mood stabilization and other critical patient outcomes in subjects with BD, and whether its principal effects are antimanic, antidepressant or prophylactic against relapse.

    Primary hypothesis:
    Add on low dose aspirin versus placebo to standard treatment improves mood stabilization in BD
    E.2.2Secondary objectives of the trial
    Secondary hypothesis:
    II. Associations between inflammatory markers and BD and treatment allocation
    a. Baseline inflammatory marker levels (hsCRP, cytokines ( IL-6, IL-10, IL-18, TNFr-alpha, etc., and hsCRP) and other inflammation-related biomarkers (oxidative stress, hair cortisol and gut microbiome composition) predict or moderate clinical improvement following treatment with low dose aspirin vs. placebo at t=3 months and t=6 months
    b. Changes in inflammatory markers represent indirect mediators of response, i.e. 1) allocated treatment affect inflammatory markers levels at t=3 months and t=6 months, and 2) inflammatory markers changes at t=3 months and t=6 months are associated with clinical outcome measures.

    III. Allocated treatment (low-dose aspirin versus placebo) improves cognition at t=3 months and t=6 months compared to t=0.

    IV. Baseline (before randomization) inflammatory marker levels are increased or altered in BD patients compared to HC
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Bipolar disorder (type 1 or 2), with diagnoses confirmed by SCAN interview.
    - Age 18-65 years
    - Speaks and writes Danish at a level equal to mother tongue
    - Habile (i.e. able to give informed consent)
    E.4Principal exclusion criteria
    - Chronic kidney disease with GFR 0-10 ml/min
    - Severe cardiac insufficiency (NYHA IIIb-IV)
    - History of gastric ulcers, gastro-intestinal bleeding or other pathological bleeding tendency (thrombocytopenia, hemophilia, vitamin K deficiency)
    - Asthma or other allergic symptoms developed after intake of salicylates, paracetamol or other NSAID or any of the excipients
    - Patients already on aspirin or other NSAID, anticoagulants or SSRIs.
    - For fertile females:
    o Reluctance to use effective contraception (IUD or hormonal contraception) during enrollment, including a safety period of one week following last medication day/trial completion
    o Pregnancy; pregnancy ruled out by HCG test before enrollment
    o Breastfeeding
    - Planned major surgery during trial period . If a subject has scheduled major surgery (i.e. with bleeding risk), enrollment will be postponed until this is completed
    E.5 End points
    E.5.1Primary end point(s)
    Mood stabilization will be measured by a mood instability score reflecting the daily variability in self-monitored mood as described in section
    E.5.1.1Timepoint(s) of evaluation of this end point
    Trial participation will include three visits (with an optional fourth visit for a subgroup of patients): An assessment at inclusion/baseline (T=0), one after three months (T=3), one after six months (T=6), and, for a subset of patients enrolled within the first trial year, we will also include an assessment at twelve months (T=12). Scheduling of the visits will be done as follows:
    T=0: Represents enrollment/baseline. The first trial week (week 1) begins immediately after enrollment.
    T=3: Can be scheduled in trial week 11-13, i.e. a two-week interval placed midway.
    T=6: Can be sheduled in trial week 23-25
    T=12: Can be scheduled in trial week 47-49

    The primary end point will be evaluated at T=3, T=6 and T=12
    E.5.2Secondary end point(s)
    Secondary/additional endpoints:

    2. Associations between inflammatory markers and BD and treatment allocation:
    Level of inflammatory activity will be assessed by measuring inflammatory blood marker levels and other inflammation-related biomarkers (urinary oxidative stress, hair cortisol and gut microbiome composition):
    - Blood based biomarkers: High sensitive CRP (hsCRP), IL-6, IL-10, IL-18, TNF-alpha and BDNF.
    - Other inflammation-related biomarkers:
    o Urinary oxidative stress biomarker levels (oxidized nucleosides 8-oxodG and 9-oxoGuo)
    o Gut microbiome composition
    o Hair cortisol concentration

    3. Allocated treatment (low-dose aspirin versus placebo) improves cognition at t=3 months and t=6 months compared to t=0
    Cognition will be assessed by neuropsychological testing according to our newly developed Internet-based Cognition Assessment Tool (ICAT), which is self-administered by trial subjects in their home setting at start, midway and end of the RCT. The ICAT contains a set of five short tasks, representing different cognitive domains. Each subtest/task results in a score summing up to a total score.

    4. Baseline (before randomization) inflammatory marker levels are increased or altered in BD subjects compared to healthy controls
    As described above

    5. Additional endpoints
    a. Self-rated or observer-rated
    - Other daily self-reported smartphone-based data including daily activity level and sleep, as recently reported
    - Clinically rated observer-based scores at start, midway and end of the 6-month trial on the following three scales: Hamilton Depression Scale-6 items (HAM-D6) (being more sensitive in RCTs than the HAM-D17, the Young Mania Rating Scale (YMRS) and the Functional Assessment Short Test (FAST) (a 24-item interviewer-administered interview concerning autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal relationships and leisure time)
    - Self-assessed scores on the following questionnaires: Quality of life according to WHO Quality of Life-BREF (WHOQoL), general well-being according to the WHO (Five) well-being index and perceived stress according to Cohen’s Perceived stress scale (PSS).
    b. Automatically smartphone-generated data on:
    - Physical activity measured by an accelerometer every 5 min
    - Social activity expressed as numbers of outgoing and incoming calls and text messages/24h
    - Voice features like variance, pitch etc., defined numerically, as described by Faurholt-Jepsen et al.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary end points will be evaluated at T=3, T=6 and T=12 with baseline values at T=0 as reference
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    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. 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 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
    Definition of the end of trial is the last visit of the 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 months6
    E.8.9.1In the Member State concerned days0
    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: 225
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state250
    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)
    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 Decision2021-04-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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