| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064060 |
| E.1.2 | Term | Multiple system atrophy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary 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.
- as measured by the change from baseline to Week 52.
- 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 TAK- 341 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.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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| E.4 | Principal 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). |
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| E.5 End points |
| E.5.1 | Primary 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.5.1.1 | Timepoint(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.5.2 | Secondary end point(s) |
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.
• Change from baseline to Week 52 on levels of CSF free αSYN with TAK- 341 compared with placebo.
• 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. |
|
| E.5.2.1 | Timepoint(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.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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.8.7 | Trial 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. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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