Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy

Study Overview
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Brief Summary
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Multiple system atrophy (MSA) is a fetal, rare neurodegenerative disease presenting with parksinonism, autonomic dysfunction, and cerebellar ataxia. Numerous anti-parkinsonism agents have been developed. However, no medication has yet been proven effective for the symptomatic or even causative treatment in cerebellar ataxia. To our knowledge, cerebellar N-methyl-D- aspartic acid (NMDA) receptors play a special role in the modulation of motor learning and coordination. Tllsh2910, a NMDA modulator, has been found to attenuate the ataxic gait in the mouse model. Here, we designed a large-scale double-blind randomized controlled, cross-over phase III trial to investigate the efficacy of Tllsh2910 in neurodegenerative ataxic patients and the association of gut microbiota change.

Detailed Description
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The study is terminated prematurely due to project replanning and difficulty in recruitment during the pandemic. The overall sample size is not adequate to meet the requirement of estimated power. The statistical results will be investigated. No severe drug-related adverse events were reported during the study period.

Official Title
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Gut Microbiota Alteration and Improvement of Ataxia in Patients of Multiple System Atrophy Treating With Tllsh2910 - a Randomized, Placebo-controlled, Double-blinded, Cross-over, Single-center Clinical Trial

Conditions
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Ataxia, Cerebellar, Multiple System Atrophy

Intervention / Treatment
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* Drug: Tllsh2910
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Clinically confirmed cerebellar ataxia with a SARA total score ≥ 3 (range 0-40). 2. Clinical diagnosis of probable or possible MSA-C. 3. Patients older than 18 years old and younger than 80 years old. Exclusion Criteria: 1. Major systemic diseases such as hepatic, renal or heart failure, malignancy, stroke. 2. Concomitant medication which inhibit CYP2C19 enzyme such as Clopidogrel, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, fluoxetine, fluvoxamine, ticlopidine. 3. Pregnancy and/or breastfeeding. 4. Acute diseases that might interfere with the trial.

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tllsh2910 to placebo<br>Tllsh2910 160mg per day for 12 weeks with wash-out period 12 weeks and subsequent placebos for 12 weeks. | Drug: Tllsh2910<br>* Tllsh2910 80mg twice per day orally for 12 weeks<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Placebo to Tllsh2910<br>Placebos for 12 weeks with wash-out period 12 weeks and subsequent Tllsh2910 160mg per day for 12 weeks | Drug: Tllsh2910<br>* Tllsh2910 80mg twice per day orally for 12 weeks<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| =Scale for the assessment and rating of ataxia (SARA) score | SARA is an 8-item performance based scale with gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternative hand movements, and heel-shin slide, yielding a total score of 0 (no ataxia) to 40 (most severe ataxia). The change in the SARA score will be recorded from period-level baseline to the end of the 12-week, 24-week, 36-week treatment period. | Baseline, 12 weeks, 24 weeks, 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| International Cooperative Ataxia Rating Scale (ICARS) score | ICARS is an 19-item performance based scale with 4 subscales of postural and gait disturbances, kinetic function, speech disorders, and oculomotor disorders, yielding a total score of 0 (no ataxia) to 100 (most severe ataxia). The change in the ICARS score will be measured from period-level baseline to the end of the 12-week, 24-week, 36-week treatment period. | Baseline, 12 weeks, 24 weeks, 36 weeks | 
| Unified multiple system atrophy rating scale (UMSARS) Part II score | UMSARS is an validated 26-items scale for multiple system atrophy with 4 subscales of historical review, motor examination scale, autonomic examination, and global disability scale. The Part II is a performance based subscale, yield a total score of 0 (no motor impairment) to 56 (most severe motor impairment). The change in the UMSARS Part-II score will be measured from period-level baseline to the end of the 12-week, 24-week, 36-week treatment period. | Baseline, 12 weeks, 24 weeks, 36 weeks | 
| The composition change of gut microbiota | The gut microbiota will be measured at baseline and 12th weeks. | Baseline, 12 weeks | 
| The change of total time needed for a 8-meter walking test | Total time of 8-meter walking test will be measured from period-level baeline to the end of the 12-week, 24-week, and 36-week. | Baseline, 12 weeks, 24 weeks, 36 weeks | 
| The change of the World Health Organization Quality of Life (WHOQOL-BREF) scale | The WHOQOL-BREF scale is a 28-item questionnaire about quality of life. The change of WHOQOL-BREF scores will be measured at baseline, 12-week, 24-week, and 36-week. | Baseline, 12 weeks, 24 weeks, 36 weeks | 
| The total time needed for 9 hole peg test | The total time needed for 9 hole peg test will be measured at the baseline, 12-week, 24-week, and 36-week. | Baseline, 12 weeks, 24 weeks, 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple system atrophy, cerebellar ataxia, NMDA, microbiota