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    Summary
    EudraCT Number:2017-004624-30
    Sponsor's Protocol Code Number:TOC17_01
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-11-27
    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 ConcernedSweden - MPA
    A.2EudraCT number2017-004624-30
    A.3Full title of the trial
    Modulating proinflammatory processes using tocilizumab in major depressive disorder
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The role of brain inflammation in depression
    A.4.1Sponsor's protocol code numberTOC17_01
    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 SponsorLinköping University
    B.1.3.4CountrySweden
    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 Östergötland
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLinköping University
    B.5.2Functional name of contact pointLinköping University
    B.5.3 Address:
    B.5.3.1Street AddressCenter for Social and Affective Neuroscience
    B.5.3.2Town/ cityLinköping
    B.5.3.3Post code58183
    B.5.3.4CountrySweden
    B.5.6E-mailmarkus.heilig@liu.se
    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 RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number162
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    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
    To examine the effects of administering tocilizumab on CNS-level biomarkers of inflammation in Major depressive disorder
    E.2.2Secondary objectives of the trial
    To examine the effects of administering tocilizumab on depressive symptomatology

    As an exploratory objective:
    To explore whether the depressive and proinflammatory processes examined in the protocol are in any systematic way related to metabolic state, as indexed by visceral fat measured using a novel MRI procedure.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    General inclusions (evaluated through screening under separate protocol 2017/345-32)
    1. Age 18 – 65
    2. Working knowledge of Swedish
    3. Current MDD episode as determined by MINI screening

    Tocilizumab augmentation-protocol related inclusions
    1. Willingness to provide informed consent (including consent to use baseline data from protocol 2017/345-32), and ability to do so, as evidenced by clinical assessment and a MMSE score ≥ 24
    2. Serum IL-6 levels above upper limit of reference interval (evaluated under separate protocol 2017/345-32)
    3. Women of childbearing potential (WOCBP) must agree to use a method of contraception that is highly effective for the duration of the study and for 3 months after the intake of the investigational medicinal product. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.
    E.4Principal exclusion criteria
    General exclusions (evaluated under separate protocol 2017/345-32):
    1. Any medical condition that, in the judgment of the study physician, after appropriate consults if needed, accounts for the symptoms of depression, such as, for example, hypothyroidism, severe anemia, etc.
    2. Standard clinical contraindication to MRI scanning of the head according to MRI checklist in Region Östergötland, following additional exams and evaluation by radiologist if needed.
    3. Pregnancy
    4. Any medical condition that, in the judgment of the study physician and after appropriate consults if needed, is likely to influence cerebral blood flow or gross-level brain activity/anatomy, such as for instance:
    a. type-1 diabetes
    b. cardiovascular or respiratory disease
    c. history of significant head injury
    d. hyper-/hypothyroidism
    e. epilepsy
    5. Current DSM-5 diagnosis of a substance use disorder (moderate – severe, corresponding to DSM-IV substance dependence; not including nicotine), as determined by the MINI interview
    6. Current DSM-5 diagnosis of a psychotic disorder (except MDD episode with mood congruent psychotic symptoms)
    7. Use of prescription or over-the-counter drugs that could interfere with the objectives of the study (such as ongoing use of steroidal and non-steroidal anti-inflammatory drugs)
    8. Additional medication exclusions:
    a. For antidepressants
    i. new medications started within one month prior to study (two months, in the case of fluoxetine)
    ii. increase in dose within one month prior to study
    b. For antipsychotics
    i. changed dosage within one month prior to study
    c. For antiepileptic drugs
    i. changed dosage within two months prior to study
    d. For mood stabilizers (e.g., lithium)
    i. changed dosage within two months prior to study

    Tocilizumab augmentation-protocol related exclusions:
    1. Presence, as evaluated by laboratory testing and appropriate specialist consult if needed, of multiple sclerosis, inflammatory bowel disease, or human immunodeficiency virus.
    2. Recent (within past month) immunization or plan to receive immunization during the duration of the study.
    3. Lactation
    4. A history of, or current tuberculosis as determined by history, physical exam, blood tests and chest X-rays.
    5. A history of, or current severe herpes infection (severe genital herpes, herpes zoster, or herpes encephalitis).
    6. Having a high risk of tuberculosis exposure as confirmed by interview
    7. Presence of interstitial pulmonary disease (including but not limited to primary or secondary pulmonary fibrosis or sarcoidosis), as determined by history, physical exam and chest X-ray.
    8. Presence of hepatitis B or C as determined by laboratory testing
    9. Systemic or serious fungal infection
    10. A history of clinically significant recurrence of viral or bacterial infections, as determined from medical records and interview will lead to appropriate specialist consult to determine whether it constitutes a significantly increased risk for administration of tocilizumab, and thus should be exclusionary.
    11. A history of cancer— excluding basal cell or squamous cell carcinoma of the skin—determined from interview and medical records
    12. Epilepsy or history of seizures
    13. Clinically significant cardiovascular disease, unless stable under treatment
    14. Abnormal thyroid-stimulating hormone levels (TSH <0.4 or >5.0mIU/L), unless patient is adequately substituted
    15. Abnormal liver function tests (ALAT or ASAT >3x upper level of normal (ULN); if ALAT or ASAT > 1.5x ULN but < 3x ULN, participant will be included but monitored during and beyond study completion until ALAT and/or ASAT < 1.5x ULN.
    16. Low absolute neutrophil count (<2.0 x 109/L)
    17. Abnormal white blood cell count (<4.5 or > 10.09 / L)
    18. Low platelet count (<145.0 x 109/L).
    19. Elevated temperature ≥37.9oC or physical signs of infection (for example as assessed by CRP analysis)
    20. Currently taking escitalopram or having taken it previously for more than four weeks consecutively during the current depressive episode without change in clinical status
    21. Contra-indications to escitalopram
    a. known allergy to the active substance
    b. concomitant or recent (within two weeks) use of non-selective, irreversible monoaminooxidase (MAO) inhibitors
    c. concomitant or recent (within two weeks) use of reversible MAO-A inhibitors (e.g. moklobemid) or the reversible non-selective MAO inhibitor linezolid.
    d. known QT interval prolongation
    i. concomitant use of drugs that prolong QT interval
    E.5 End points
    E.5.1Primary end point(s)
    The co-primary outcome measures will be change from baseline in central nervous system biomarkers of inflammation, as measured by
    1) the free-water fraction on the post-augmentation MR-scan; and
    2) levels of CSF pro-inflammatory cytokines.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) the free-water fraction on the post-augmentation MR-scan: at Visit 6, i.e one week after last administration of IMP
    2) levels of CSF pro-inflammatory cytokines: at Visit 7, i.e the last visit of the study
    E.5.2Secondary end point(s)
    The secondary outcome will be change from baseline in levels of depressive symptomatology over time, as measured by the MADRS ratings acquired at Visits 2-6.
    E.5.2.1Timepoint(s) of evaluation of this end point
    measured by the MADRS ratings acquired at Visits 2-6 (i.e once a week during 5 weeks, starting the same day as first injection of IMP and ends one week after last injection of IMP)
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months24
    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: 61
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state66
    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)
    Once participation in the study has ended, we will ensure that continued antidepressive treatment is provided either through the research clinic, or another care provider to whom we may refer the patient.
    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 Decision2018-01-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-11-05
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