Trial to Evaluate the Efficacy and Safety of KM-819 Treatment to Slow the Progression of Multiple System Atrophy (MSA)

Study Overview
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Brief Summary
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This trial will the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA.

Detailed Description
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This is a randomized, double-blind, placebo-controlled phase II trial. This trial will be performed in two part: Main study and Ancillary study. Main Study: Following a 4-week screening period, subjects will be stratified by MSA subtype (MSA-P, -C [MSA-Parkinsonian type, MSA-cerebellar ataxia]) and randomly assigned in a 1:1 ratio either to KM-819 or Placebo groups. During a treatment period of 36 weeks, subjects will receive pills of either KM-819 or Placebo for oral administration every day from baseline visit. Following this, there will be a safety follow-up period at Week 40. Ancillary Study: This ancillary study will provide additional information on the continuing efficacy and safety of KM-819. Subjects in either treatment group in the main study who complete the study are eligible to participate in a follow-up, all-subjects-on-treatment (KM-819), open-label ancillary study. All subjects in the ancillary study will receive KM-819 for additional 36 weeks regardless of their treatment allocation during the main study. During a treatment period of 36 weeks, subjects will receive pills of KM-819 for oral administration every day from visit at Weeks 40.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of KM-819 Treatment to Slow the Progression of Multiple System Atrophy

Conditions
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Multiple System Atrophy

Intervention / Treatment
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* Drug: KM-819
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be diagnosed as probable or possible MSA, according to the second consensus criteria for diagnosis of MSA Patients who are able to visit the clinic during the study period to be in the study. ≥ 30 years and ≤ 80 years of age at the time of signing the Informed Consent Antiparkinsonian medications should be stable for, at least, one month before enrollment. Body Mass Index (BMI) range of 18.5 to 30 kg/m^2 inclusive at Screening Patient agrees to use acceptable contraceptive methods during the study For women, menopause, sterilization confirmed. For childbearing women, older than 40, and agreed with more than 2 methods of contraception below and agreed with no desire to be pregnant during and after the study, and, agreed with maintaining medically acceptable methods of contraception during for 90 days after the study. Cognitive ability for possible to make self-decision, understand and follow the instruction, to make written signature on consent form. If no ability to walk, patients must be accompanied by caregiver by wheelchair on schedule. Exclusion Criteria: A diagnosis of drug induced parkinsonism by typical neuroleptic treatment or haloperidol medication. Women who are pregnant or lactating History of suicide attempt. Any recent suicidal ideation (a level of 4 or 5) within the last 3 months prior to Day 1, or has a positive response ('Yes') to either question 4 or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS) at check-in (Day 1), or who is at significant risk to commit suicide, as judged by the Investigator using the C-SSRS at Screening. Febrile illness or symptomatic viral, bacterial (including upper respiratory infection) or fungal (non-cutaneous) infection. Any clinically significant abnormality following the Investigator's review of the physical examination and protocol-defined clinical laboratory tests at Screening or site check-in. Patient has a mean pulse rate < 40 Patient has a mean corrected QT interval using Fridericia's formula (QTcF) of > 430 msec (for males) and > 450 msec (for females). History of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart disease or a family history of Long QT Syndrome. Positive serology test for hepatitis B surface antigen (HBsAg), anti-hepatitis A virus (HAV), immunoglobulin M (IgM), anti-hepatitis C virus (HCV) or anti-human immunodeficiency virus (HIV). Known or suspected hypersensitivity to KM-819, or any components of the formulation(s) used. Patient has a serious medical or surgical condition. Patients unable to understand the consent form, and determined by investigator with too serious problems for participating in the study. Patients unable to visit the clinical site on schedule due to the no ability mobilize. Patients who had brain surgery history.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main Study: KM-819<br>Subjects will receive 400 mg of KM-819 orally from Week 0 to Week 36. | Drug: KM-819<br>* Subjects will receive KM-819 400 mg orally daily.<br>|
| Placebo Comparator: Main Study: Placebo<br>Subjects will receive visually identical placebo pills of KM-819 orally. | Drug: Placebo<br>* Subjects will receive Placebo orally daily.<br>|
| Experimental: Ancillary Study: KM-819<br>Subjects will receive 400 mg of KM-819 orally from Week 40 to Week 76. | Drug: KM-819<br>* Subjects will receive KM-819 400 mg orally daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from baseline in putaminal [18F]FP-CIT (18F-FP-CIT Positron Emission Tomography for Correlating Motor and Cognitive Symptoms of Parkinson's Disease) binding | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA. The putaminal [18F]FP-CIT binding will allow quantification of MSA progression during 36 weeks. | From Baseline to Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the Unified Multiple System Atrophy Rating Scale (UMSARS) scores (UMSARS I + II) | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA. The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. It is composed of four subscales: UMSARS-I (12 items) rates patient-reported functional disability (Historical Review), UMSARS-II (14 items) assesses motor impairment based on a clinical examination. Each item scores 0-4. UMSARS-I total score is 48 and UMSARS-II total score is 56. Higher scores on the UMSARS indicate greater disability. | From Baseline to Week 36 | 
| Change from baseline in the UMSARS I scores | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA. The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. It is composed of four subscales: UMSARS-I (12 items) rates patient-reported functional disability (Historical Review), UMSARS-II (14 items) assesses motor impairment based on a clinical examination. Each item scores 0-4. UMSARS-I total score is 48. Higher scores on the UMSARS indicate greater disability. | From Baseline to Week 36 | 
| Change from baseline in the UMSARS II scores | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA. The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. It is composed of four subscales: UMSARS-I (12 items) rates patient-reported functional disability (Historical Review), UMSARS-II (14 items) assesses motor impairment based on a clinical examination. Each item scores 0-4. UMSARS-II total score is 56. Higher scores on the UMSARS indicate greater disability. | From Baseline to Week 36 | 
| Percentage change from baseline in putaminal glucose metabolism | To evaluate the efficacy of KM-819 compared to placebo for slowing the putaminal of MSA, as measured by [18F]FDG PET (fluorodeoxyglucose (FDG)-positron emission tomography (PET)). | From Baseline to Week 36 | 
| Percentage change from baseline in cerebellar glucose metabolism | To further evaluate the efficacy of KM-819 compared to placebo for slowing the cerebellar progression of MSA, as measured by [18F]FDG PET. | From Baseline to Week 36 | 
| Change from baseline in the Unified Parkinson Disease Rating Scale (UPDRS) III score | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA, measured by clinical scales. The UPDRS is the most widely applied rating instrument for PD. The Total UPDRS III scale includes 18 items. Each item scores 0-4. UPDRS III total score is 72. The highest score refers to the most severe level of disability due to Parkinson's disease. | From Baseline to Week 36 | 
| Change from baseline in the Scale for the Assessment and Rating of Ataxia (SARA) score | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA, measured by clinical scales. The SARA is a tool for assessing ataxia. It has eight categories with an accumulative scores ranging from 0 (no ataxia) to 40 (most severe ataxia). The eight categories were: Gait (0-8 score); Stance (0-6 score); Sitting (0-4 score); Speech disturbance (0-6 score); Finger chase(0-4 score); Nose-finger test (0-4 score); Fast alternating hand movements (0-4 score); Heel-shin slide (0-4 score). Mild dependence: 5.5 or lower, Moderate dependence: 14.25 or lower, Maximal dependence: 23 of higher. | From Baseline to Week 36 | 
| Change from baseline in the Montreal Cognitive Assessment (MoCA) score | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA, measured by clinical scales. MoCA can be used to detect dementia in a clinical setting. A total score of 30 with over 26 is normal. The lower score refers the severe cognitive impairment. | From Baseline to Week 36 | 
| Change from baseline in the Beck's Depression Inventory (BDI-II) score | To evaluate the efficacy of KM-819 compared to placebo in subjects with MSA for slowing the progression of MSA, measured by clinical scales. The BDI-II is scored by summing the ratings for the 21 items. Each item is rated on a 4-point scale ranging from 0 to 3. The maximum total score is 63. Measures of 0-13: Minimal, 14-19: Mild, 20-28: Moderate, 29-63: Severe. | From Baseline to Week 36 | 
| Number of subjects with adverse events (AEs) and serious AEs (SAEs) | To evaluate the safety of KM-819 in subjects with MSA. | From Screening (Day -4) to Week 40 | 
| Maximum observed concentration (Cmax) | To describe the pharmacokinetics parameter (Cmax) of KM-819 using sparse PK sampling. | From Baseline to Week 36 | 
| Area under the concentration-time curve (AUC) | To describe the pharmacokinetics parameter (AUC) of KM-819 using sparse PK sampling. | From Baseline to Week 36 | 
| Time of maximum observed concentration (Tmax) | To describe the pharmacokinetics parameter (Tmax) of KM-819 using sparse PK sampling. | From Baseline to Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurodegenerative disorder, Fas-associated factor 1 (FAF1), autonomic dysfunction, KM-819