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Efficacy Of Oral Trehalose In Spinocerebellar Ataxia 3

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ClinicalTrials.gov Identifier: NCT04399265
Recruitment Status : Recruiting
First Posted : May 22, 2020
Last Update Posted : September 11, 2020
Sponsor:
Collaborator:
Radboud University
Information provided by (Responsible Party):
Dr Norlinah Mohamed Ibrahim, National University of Malaysia

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Spinocerebellar Ataxia Type 3 Dietary Supplement: Trehalose Dietary Supplement: Maltose Not Applicable

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Outcomes Assessor)
Masking Description: Patients with SCA 3 will be randomised into the active treatment group and placebo group to which they are blinded from their group allocation. Likewise, the outcome assessor will be blinded from the patient's group status.
Primary Purpose: Treatment
Official Title: A Randomised Controlled Trial on the Clinical Efficacy of Oral Trehalose in Patients With Spinocerebellar Ataxia 3: Clinical & FMRI Correlation
Actual Study Start Date : February 24, 2020
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : February 23, 2022


Arm Intervention/treatment
Experimental: Trehalose
Trehalose powder form to be dissolved in water, to be consumed by mouth, every day for 3 months.
Dietary Supplement: Trehalose
A disaccharide sugar usually used as food preservative, but for this study it is given at a higher dose

Placebo Comparator: Maltose placebo
Isocaloric maltose powder form to be dissolved in water, to be consumed by mouth, every day for 3 months.
Dietary Supplement: Maltose
Maltose power




Primary Outcome Measures :
  1. Changes from Baseline Scale for Ataxia Rating Assessment (SARA) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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.


Secondary Outcome Measures :
  1. Changes from Baseline Spinocerebellar Ataxia Functional Index (SCAFI) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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.

  2. Changes from Baseline Inventory of Non-Ataxia Symptoms (INAS) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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.

  3. Changes from Baseline Cerebellar Cognitive & Affective Syndrome (CCAS) Scale at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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.

  4. Changes from Baseline Wechsler Adult Intelligence Scale (WAIS - 4) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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

  5. Changes from Baseline Delis-Kaplan Executive Function System (D - KEFS) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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.

  6. Changes from Baseline Repeatable Battery for the Assessment of Neuropsychological Status Update (RBANS Update) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    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.

  7. Changes from Baseline Resting state fMRI at 3 months. [ Time Frame: Baseline and 3 months ]
    The level of measurement of oxy-Hb (activation level) is continuous; greater oxy-Hb (mM.mm) indicates greater activation.

  8. Changes from Magnetic resonance spectroscopy at 3 months. [ Time Frame: Baseline and 3 months ]
    The level of measurement of N-Acetyl Aspartate (NAA; metabolism) is continuous; greater NAA (ppm) indicates greater metabolism.


Other Outcome Measures:
  1. Changes from Baseline Structural / T1 MRI at 3 months. [ Time Frame: Baseline and 3 months ]
    The level of measurement of grey matter density (structural) is continuous; greater grey matter density indicates greater structural volume.

  2. Changes from Baseline Situational Motivation Scale (SIMS) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    SIMS comprises 16 items on four subscales, Intrinsic motivation (e.g., "I think that this activity is interesting"), Identified regulation (e.g., "I am doing it for my own good"), External regulation (e.g., "I am supposed to do it") and Amotivation (e.g., "I don't see what this activity brings me"). It contains 4 items per subscale scored on a scale from 1 to 7 providing a score between 4 and 28 for each subscale. It has an internal reliability of α = .74 - .83 for the four subscales. Total time taken for test administration is estimated at 5 minutes.

  3. Changes from Baseline EuroQol-5D 3L (EQ-5D-3L) at 3 months and 6 months. [ Time Frame: Baseline, 3 months, and 6 months ]
    EQ-5D-3L consists of 2 parts: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). EQ-5D has 5 dimensions of assessment (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). Each dimension has 3 levels (ordinal): no problem, some problem, and extreme problem. It has an internal reliability of α = .83 and valid among clinically and demographically heterogeneous patients. Total time taken for test administration is estimated at 5 minutes.

  4. Adverse event [ Time Frame: Baseline, 3 motnhs, and 6 months ]
    Adverse event will be recorded in terms of severity, study intervention relationship, action taken regarding study intervention, outcome of adverse event, expected, and serious adverse event.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04399265


Contacts
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Contact: Kah Hui Yap, Master +60165536721 kahhui0411@gmail.com
Contact: Norlinah Mohamed Ibrahim, MRCP +60122145306 norlinah@ppukm.ukm.edu.my

Locations
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Malaysia
UKM Medical Centre Recruiting
Cheras, Kuala Lumpur, Malaysia, 56000
Contact: Kah Hui Yap, Master    0165536721    kahhui0411@gmail.com   
Contact: Norlinah Mohamed Ibrahim, MRCP    +60122145306    norlinah@ppukm.ukm.edu.my   
Sponsors and Collaborators
National University of Malaysia
Radboud University
Investigators
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Principal Investigator: Norlinah Mohamed Ibrahim, MRCP National University of Malaysia
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Responsible Party: Dr Norlinah Mohamed Ibrahim, Professor, National University of Malaysia
ClinicalTrials.gov Identifier: NCT04399265    
Other Study ID Numbers: DIP-2019-007
First Posted: May 22, 2020    Key Record Dates
Last Update Posted: September 11, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr Norlinah Mohamed Ibrahim, National University of Malaysia:
Spinocerebellar ataxia Type 3
Cerebellar Cognitive and Affective Syndrome
Trehalose
Neuropsychology
Magnetic resonance imaging
Additional relevant MeSH terms:
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Ataxia
Cerebellar Ataxia
Spinocerebellar Ataxias
Spinocerebellar Degenerations
Machado-Joseph Disease
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Spinal Cord Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn