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    Summary
    EudraCT Number:2022-000336-28
    Sponsor's Protocol Code Number:TAK3412001
    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:2022-08-01
    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 number2022-000336-28
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous TAK-341 in Subjects With Multiple System Atrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to evaluate Efficacy, Safety, Tolerability and Effects of TAK-341 in the human body in patients with Multiple System Atrophy
    A.4.1Sponsor's protocol code numberTAK3412001
    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 SponsorTakeda Development Center Americas, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTakeda Development Center Americas, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Development Center Americas, Inc.
    B.5.2Functional name of contact pointGlobal Development Operations
    B.5.3 Address:
    B.5.3.1Street Address95 Hayden Avenue
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number13148072639
    B.5.6E-mailandrew.janis@takeda.com
    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 No
    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 nameTAK-341
    D.3.2Product code TAK-341
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInfusion (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot assigned
    D.3.9.1CAS number Not assigned
    D.3.9.2Current sponsor codeTAK-341
    D.3.9.3Other descriptive nameHuman IgG1 monoclonal antibody against alpha-synuclein
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 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 infusion
    D.8.4Route of administration of the placeboInfusion (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple System Atrophy
    E.1.1.1Medical condition in easily understood language
    Uncommon disease caused by the progressive loss of nerve cells in the brain which leads to tremors, slow movement, muscle rigidity, and postural instability
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10064060
    E.1.2Term Multiple system atrophy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of TAK-341 versus placebo, as measured by the change from baseline to Week 52 on UMSARS Part I, minus the sexual function item, with collapse of the normal and mild ratings on each item.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of TAK-341 vs placebo:
    - as measured by the change from baseline to Week 52 on the 11-item UMSARS .
    - as measured by the change from baseline to Week 52 on the total UMSARS (UMSARS Part I + Part II).
    - as measured by the change from baseline to Week 52 on the Part I UMSARS minus the sexual function item (without collapse of ratings of scale items).
    - as measured by the change from baseline to Week 52 on the Part II UMSARS.
    - CGI-S) score
    - on the Scales for Outcomes in Parkinson’s Disease -Autonomic Dysfunction (SCOPA-AUT).
    - as measured by overall survival at 52 weeks.
    - To assess the serum PK and CSF concentrations of TAK-341 in subjects
    with MSA.
    - Change from baseline to Week 52 on levels of CSF free αSYN with TAK341 compared with placebo
    - Serum PK parameters, if feasible, will include but not be limited to
    Cmax, Tmax, Area under serum concentration-time
    - CSF concentrations of TAK-341
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject (or, when applicable, the subject’s legally acceptable representative) signs an informed (e)consent form indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. (additionally for subjects in Germany or Austria: the subject has been informed of the nature, significance, and
    implications of the clinical study and is willing and able to understand and fully comply with study procedures and requirements (including
    digital tools and applications) in the opinion of the investigator. If the subject becomes incompetent over the course of the study, a legally
    authorized court-appointed representative or an appointed agent in health matters (ie, legally acceptable representative) will need to be
    identified and the subject will need to provide assent, in accordance with the local regulations, guidelines, and the IRB/IEC to provide informed
    consent on the subject's behalf to continue in the clinical study).

    2. The subject is an outpatient of either sex, at least 40 years old, at the time of consent.

    3. Subjects must, in the opinion of the investigator, be able to participate in all scheduled evaluations, likely to be compliant, and likely to complete all required tests, including neuroimaging brain scans and lumbar punctures.

    4. The subject has a body mass index ≥18 and ≤35 kg/m2 at screening.

    5. The subject has a diagnosis of possible or probable MSA using the modified Gilman et al, 2008 diagnostic criteria.

    6. The subject’s onset of first MSA symptoms (including parkinsonism, cerebellar symptoms, orthostatic or urinary symptoms) occurred ≤4 years before screening as assessed by the investigator..

    7. The subject’s anticipated life expectancy is ≥3 years, per investigator judgment.

    8. The subject has an UMSARS Part I score of ≤21, and additionally has:

    a) Severity score ≤2 on the swallowing item (#2) at screening visit
    (Visit 1).
    b) Severity score ≤2 on the ambulation item (#7) at screening visit
    (Visit 1).
    c) Severity score ≤2 on the falling item (#8) at screening visit
    (Visit 1).

    9. The subject has an UMSARS Part IV disability score ≤3 at screening visit
    (Visit 1).

    10. Subject has a MoCA ≥18. Additionally, subject has sufficiently intact cognition to complete study and follow study instructions, per investigator´s judgment.

    11. A male subject who is nonsterilized (fertile) and sexually active with a female partner of childbearing potential is eligible to participate if he agrees to use a barrier method of contraception (ie, condom with or without spermicide) from the signing of informed (e)consent throughout the study and for 90 days plus 5 half-lives (total of 190 days) after the last dose. In addition, they must be advised not to donate sperm during
    this period. The female partner of a male subject should also be advised to use a highly effective method of contraception.


    12. Female subjects are eligible to participate if (a) they are not pregnant or nursing and (b) they are of nonchildbearing potential or agree to use highly effective contraception from the signing of informed consent throughout the study and for 30 days plus 5 half-lives (total of 130 days) after the last dose of study drug.
    E.4Principal exclusion criteria
    1. The subject has serious or unstable clinically significant illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic or autoimmune (eg, multiple sclerosis), hematologic, or other major disease, which, in the judgment of the investigator, is poorly controlled or otherwise likely to deteriorate, compromises the subject’s safety or ability to complete the study, or compromises the interpretation of the study results.
    2. The subject has medical problems (neurological, visual, orthopedic, psychiatric) that may significantly interfere with completion of the study or interpretation of study endpoints or may confound diagnosis.
    3. The subject has a disorder that is likely to interfere with drug disposition and elimination.
    4. In the opinion of the investigator, the subject has a diagnosis of depression or other psychiatric disorder, as defined by DSM-5, AND this disorder is poorly controlled and of sufficient severity to interfere with completion of the study or interpretation of the endpoints.
    5. The subject is considered by the investigator to be a imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within the past year before screening.
    6. The subject has a history of alcohol or substance use disorder (except tobacco use disorder), as defined by the DSM-5, within 1 year before screening or between screening and randomization
    7. The subject has positive finding on an alcohol or illicit drug screen.
    8. The subject has undergone surgery for the treatment of MSA (eg, pallidotomy, deep brain stimulation, fetal tissue transplantation).
    9. History of epilepsy or seizures, except self-limited febrile childhood seizures.
    10. Contraindication to lumbar puncture (as assessed by the Investigator). A subject whose CSF cannot be collected will be excluded.
    11. The subject has hypersensitivity to TAK-341 or any excipients used in its formulation.
    12. Subject has a history of cancer in the past 5 years (does not apply to participants with carcinoma in situ that has been resolved without
    further treatment, or basal cell carcinoma; these subjects may be included after approval by the sponsor or designee).
    13. Clinically significant abnormality at screening or between screening and randomization in physical examination findings, vital signs, electrocardiograms (ECGs), or clinical laboratory test results
    14.Presence of any of contraindications to MRI as assessed by the Investigator.
    15. Ophthalmic abnormalities
    16. At the screening visit: estimated glomerular filtration rate (determined with the Chronic Kidney Disease Epidemiology Collaboration equation) <50 mL/min; QT interval with Fridericia correction method >450 ms for male subjects and >470 ms for female subjects; a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >1.5 × the upper limit of normal.
    17. Clinically significant vital sign abnormalities at screening or Visit 2 (Day 1), defined as (a) systolic blood pressure ≥160 mm Hg, (b) diastolic blood pressure ≥90 mm Hg (blood pressure assessed with the subject at rest in the seated position; may be repeated up to 3 times), or (c) pulse rate <45 or >100 beats per minute (subject at rest in the seated position; may be repeated up to 3 times).
    18. Positive hepatitis B surface antigen test result, known or suspected active hepatitis C infection, or known history of HIV infection.
    19. Brain MRI showing clinically significant evidence of malignant, ischemic, hemorrhagic, demyelinating, structural, or degenerative brain disease (other than MSA) that may confound diagnosis or compromise subject safety during the study, or the subject has findings that compromise the safety of lumbar puncture.
    20. Current blood clotting or bleeding disorder
    21. Poor venous access
    22. Participation in another study investigating active or passive immunization against αSYN for Parkinson disease or MSA, , (unless
    subject's assignment to placebo is documented).
    23. The subject has had immunoglobulin G therapy for any reason within 6 months before screening.
    24. Participation in a previous study of a disease-modifying therapy (with proven receipt of active treatment)
    25. Any investigational compound being received that may not have completely washed out before the screening visit or may affect the safety or efficacy evaluations.
    26. Positive pregnancy test result at screening.
    27. The subject is an immediate family member, is a study site employee, or is in a dependent relationship (eg, as a spouse, parent, child, or sibling) with a study site employee who is involved in the conduct of this study
    28. Donation of 400 mL or more of his or her blood volume within 90 days before the start of the screening visit.
    29. Austrian participants without capacity of consent (ie, ability to understand and process information relevant to making an informed,
    voluntary decision to participate in research).
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to Week 52 on UMSARS Part I, minus the sexual function item, with collapse of the normal and mild ratings on each item with TAK-341 compared with placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to week 52. Please refer to protocol Appendix A for all subjects and Appendix B for additional home visits for subjects in the early PK cohort
    E.5.2Secondary end point(s)
    -Serum PK parameters, if feasible, will include but not be limited to the following:
    – Cmax.
    – tmax.
    – Area under the serum concentration-time curve during a dosing interval (AUCτ).

    CSF concentrations of TAK-341.

    Change from baseline to Week 52 on the 11-item UMSARS specified by Palma et al. 2021 al 2021 with TAK-341 compared with placebo.

    Change from baseline to Week 52 on the UMSARS total score (UMSARS Part I + Part II) with TAK-341 compared with placebo.

    Change from baseline to Week 52 on the UMSARS Part I score minus the sexual function item (without collapse of ratings of scale items) with TAK-341 compared with placebo.

    Change from baseline to Week 52 on the UMSARS Part II score with TAK-341 compared with placebo.

    Change from baseline to Week 52 on the CGI-S score with TAK-341 compared with placebo.

    Change from baseline to Week 52 on the SCOPA-AUT total score with TAK-341 compared with placebo.

    Overall survival at 52 weeks with TAK-341 compared with placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to week 52. Please refer to protocol Appendix A for all subjects and Appendix B for additional home visits for subjects in the early PK cohort
    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 No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Japan
    United Kingdom
    United States
    Austria
    Denmark
    France
    Germany
    Italy
    Portugal
    Spain
    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
    The end of the study is defined as the date of the last visit of the last subject participating in the study. The final analyses for the primary endpoint and single final CSR will be conducted after all subjects enrolled in the study have had the opportunity to complete 52 weeks of treatment (total of 13 infusions) with TAK-341.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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: 76
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 62
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 138
    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)
    The subject should be returned to the care of a physician and standard therapies as required.

    If an open-label extension study is conducted, subjects will be given the opportunity to enroll to continue receiving TAK-341 if they have, in the opinion of the investigator and confirmed by the sponsor, experienced a clinically important benefit fromTAK-341 that they received in the study, if they have no alternative therapeutic option, and if they would be harmed without continued access.

    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 Decision2022-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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