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

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

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.

Study Overview

• Status: Terminated
• Conditions: Multiple System Atrophy; Ataxia, Cerebellar
• Intervention / Treatment: Drug: Placebo; Drug: Tllsh2910

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 3

Contacts and Locations

Study Locations

• Taiwan
  • Taipei city, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Chun-Hwei Tai, National Taiwan University Hospital (NTUH)

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2019
• Primary Completion (Actual): April 3, 2023
• Study Completion (Actual): April 3, 2023

Study Registration Dates

• First Submitted: March 24, 2019
• First Submitted That Met QC Criteria: April 2, 2019
• First Posted (Actual): April 3, 2019

Study Record Updates

• Last Update Posted (Actual): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 5, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: multiple system atrophy, cerebellar ataxia, NMDA, microbiota
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Dyskinesias; Autonomic Nervous System Diseases; Primary Dysautonomias; Hypotension; Cerebellar Diseases; Atrophy; Ataxia; Multiple System Atrophy; Shy-Drager Syndrome; Cerebellar Ataxia
• Other Study ID Numbers: 201810015MINC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No