Efficacy Of Oral Trehalose In Spinocerebellar Ataxia 3

Study Overview
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Brief Summary
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This study evaluates the effectiveness of oral trehalose in alleviating the neuropathological and motor behaviour deficits among patients with SCA3. A total of 40 participants with SCA3 will be recruited, with 20 participants to be administered with trehalose while another 20 participants to be administered with a maltose placebo.

Detailed Description
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Spinocerebellar ataxia 3 (SCA3) is a rare form of inherited neurodegenerative disease involving progressive degeneration of spinocerebellar tract. SCA3 is characterised by increasingly worsening cerebellar function leading to gait abnormalities and poor coordination, dysarthria, and abnormal eye movements. Non-ataxia features include pyramidal and extrapyramidal manifestations, sensorimotor, neuropsychological and psychiatric symptoms. This is attributed to the role of cerebellum in motor, cognitive and affective processing (i.e. cerebellar cognitive and affective syndrome; CCAS), as well as its extensive connection with cerebral structures. Trehalose is an omnipotent disaccharide molecule found in lower and higher life forms except in vertebrates. It has an amorphous (i.e. non-reducing) property, which is shown in its high hydrophilicity, chemical stability and strong resistance to denaturation / breakdown by heat, acid or enzyme. It is also shown to help refold partially denatured protein, thereby stabilizes protein aggregates, including those of polyglutamine, in vivo as well as in vitro. This has provided an avenue in which trehalose as a therapeutic agent for neurodegenerative disorders with pathological changes of protein aggregates. In this study, a double-blinded randomised controlled trial (RCT) will be employed. A total of 40 patients with SCA3 will be randomly allocated to oral trehalose group and a placebo group (20 participants for each arm). With regards to clinical outcomes, motor and cognitive performances will be assessed to infer the efficacy of trehalose. Likewise, structural, resting-state fMRI (i.e. functional connectivity), and MR spectroscopy (i.e. metabolism), will be used as imaging biomarkers in this study.

Official Title
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A Randomised Controlled Trial on the Clinical Efficacy of Oral Trehalose in Patients With Spinocerebellar Ataxia 3: Clinical & FMRI Correlation

Conditions
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Spinocerebellar Ataxia Type 3

Intervention / Treatment
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* Dietary Supplement: Trehalose
* Dietary Supplement: Maltose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 85 years old. Genetically confirmed SCA 3 diagnosis. Presence of progressive cerebellar syndrome (i.e. symptomatic) and genetic confirmation of SCA 3 in one of the immediate family members with similar clinical syndrome. Able to read, speak, and understand English or Malay. Exclusion Criteria: Diagnosis of Diabetes Mellitus Type 1 or Type 2 Presence of any concomitant neurological condition that might interfere with clinical measures used in this study. Presence of contraindication or hypersensitivity to trehalose. Use of stimulant / medication, caffeine, and tobacco within less than 24 hours washout period prior to assessment and / or scan. Presence of severe visual and / or auditory perceptual deficits. MRI contra-indications: claustrophobia, pregnancy, electronic implants (e.g. pacemaker) in the body, aneurysm clip, and current or past employment as machinists, welders or metal workers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Interventional Model Description: This study will employ a double-blind randomised controlled trial (RCT) with two arms. Patients with SCA3 will be randomly allocated to oral trehalose group and a maltose placebo group. A total of 20 participants will be allocated to each group. There is a possibility of including other types of SCA at later stage of the study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trehalose<br>Trehalose powder form to be dissolved in water, to be consumed by mouth, every day for 3 months. | Dietary Supplement: Trehalose<br>* A disaccharide sugar usually used as food preservative, but for this study it is given at a higher dose<br>|
| Placebo Comparator: Maltose placebo<br>Isocaloric maltose powder form to be dissolved in water, to be consumed by mouth, every day for 3 months. | Dietary Supplement: Maltose<br>* Maltose power<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from Baseline Scale for Ataxia Rating Assessment (SARA) at 3 months, 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | An 8-item scale to quantify the severity of ataxia with a scoring of 0 (no ataxia) to 40 (most severe ataxia). Total time taken for test administration is estimated at 10 minutes. | Baseline, 3 months, and 6 months, as well as 3, 6, 9, and 12 months post-treatment follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from Baseline Spinocerebellar Ataxia Functional Index (SCAFI) at 3 months and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | A validated multi-modal assessment tool that is composed of: a) timed 8 metre walk (8MW); b) the 9-hole peg test (9HPT); and c) the rate of PATA repetition over 10 seconds (PATA) to rate speech performance. Total time taken for test administration is estimated at 10 minutes. | Baseline, 3 months, and 6 months, as well as 3, 6, 9, and 12 months post-treatment follow-up. | 
| Changes from Baseline Inventory of Non-Ataxia Symptoms (INAS) at 3 months and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | A validated scale assessing non-cerebellar signs with a scoring of 0 (no non-ataxia sign) to 16 (all assessed systems affected). Total time taken for test administration is estimated at 10 minutes. | Baseline, 3 months, and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | 
| Changes from Baseline Cerebellar Cognitive & Affective Syndrome (CCAS) Scale at 3 months and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | CCAS Scale is a brief cognitive screening tool to help identify CCAS in patients with cerebellar impairment. It derives a total score of 120 as a continuous measure; as well as an ordinal measure in accordance to the number of failed tests: 1) Possible CCAS = 1 failed test; 2) Probable CCAS = 2 failed tests; Definite CCAS = 3 or more failed tests. Four different forms were available to minimize the practice effect. Total time taken for test administration is estimated at 10 minutes. | Baseline, 3 months, and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | 
| Changes from Baseline Wechsler Adult Intelligence Scale (WAIS - 4) at 3 months and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | WAIS - 4 is an IQ test designed to measure intelligence and cognitive ability in adults and older adolescents. The selected subtests are Matrix Reasoning, Digit Span, and Coding. These subtests are used to measure abstract reasoning, WM, and processing speed respectively. These index and subtests have good reliability | Baseline, 3 months, and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | 
| Changes from Baseline Delis-Kaplan Executive Function System (D - KEFS) at 3 months and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | D - KEFS is a neuropsychological battery designed to measure various subdomains of executive function from 8 - 89 years old. The selected subtests are: Tower Test, Trail Making Test (TMT), Colour-Word Interference Test (CWIT). These tests measure planning, set-shifting, and inhibition abilities respectively. | Baseline, 3 months, and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | 
| Changes from Baseline Repeatable Battery for the Assessment of Neuropsychological Status Update (RBANS Update) at 3 months and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | RBANS Update is a neuropsychological battery designed to measure 5 neuropsychological domains from 12:0 - 89:11 years old. The selected subtests are: Figure Copy and Figure Recall. These tests measure visual construction, visual memory, and language abilities respectively. | Baseline, 3 months, and 6 months; as well as 3, 6, 9, and 12 months post-treatment follow-up. | 
| Changes from Baseline Resting state fMRI at 3 months. | The level of measurement of oxy-Hb (activation level) is continuous; greater oxy-Hb (mM.mm) indicates greater activation. | Baseline and 3 months | 
| Changes from Magnetic resonance spectroscopy at 3 months. | The level of measurement of N-Acetyl Aspartate (NAA; metabolism) is continuous; greater NAA (ppm) indicates greater metabolism. | Baseline and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinocerebellar ataxia Type 3, Cerebellar Cognitive and Affective Syndrome, Trehalose, Neuropsychology, Magnetic resonance imaging