Myrosinase Bioactivated Gglucoraphanin for the Treatment of Neurodegenerative Diseases (GRA-MYR-ND)

Официальное название

A Composition Comprising Glucoraphanin, Myrosinase and a Buffered Solution for Use in the Treatment of Neurodegenerative Diseases

Обзор

Glucosinolates (GLs) are phytocompounds mainly found in the Cruciferae (Brassicacea) and Moringa oleifera plants. The hydrolysis of GLs by myrosinase led to the production of isothiocyanate (ITCs). ITCs consumption was associated with different health promoting effects, including to neuroprotective, anti-oxidant and anti-inflammatory capacities. In particular, they showed neuroprotective effects in experimental models of neurodegenerative diseases, including multiple sclerosis (MS) and Parkinson's disease (PD). From different GLs, different ITCs are originated. In particular, from glucoraphanin (GRA) the ITC sulforaphane (SFN) is obtained. The PI of the project is one of the proprietor of a patent (EP2908850B1) for the application of (Rs)-GRA with myrosinase in a buffered solution for the treatment of neurodegenerative diseases. The aim of this project is to evaluate the effects of the administration of bioactivated GRA in different cohorts of adult patients, affected by MS and PD, but also a cohort of pediatric patients affected by neuromuscolar and degenerative diseases. The effects of bioactivated (Rs)-GRA administration will be evaluated with a combination of clinical evaluations and a multiomic (metabolomic, genomic) approach.

Вмешательства

• Препарат bioactivated GRA for adult patients
  adult dose: 50 mg/day of bioactivated GRA for 6 months
• Препарат bioactivated GRA for pediatric patients
  pediatric dose: 10 mg/day of bioactivated GRA for 6 months

Первичные конечные точки

• Unified Parkinson's Disease Rating Scale (UPDRS) Total Score [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Hoehn and Yahr scale [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Expanded Disability Status Scale (EDSS) for Multiple Sclerosis patients [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Cognitive and Neuropsychological Assessments: Montreal Cognitive Assessment (MoCA) and Mini-mental state examination [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Brief Repeatable Battery (BRB) of Neuropsychological Tests for Multiple Sclerosis patients [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Normalized Brain Volume (NBV) [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Normalized Cortical Volume (NCV) [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Change from Baseline in Whole-Brain Fractional Anisotropy (FA) in Multiple Sclerosis Patients [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Change from Baseline in Whole-Brain Mean Diffusivity (MD) in Multiple Sclerosis patients [Срок оценки: Baseline, 6 months (end of treatment), 12 months]
• Non-Motor Symptoms Scale (NMSS) for Parkinson patients [Срок оценки: Baseline, 6 months (end of treatment), 12 months]

Вторичные конечные точки (7)

• Changes in growth parameters, anthropometric measurements and pubertal status. [Срок оценки: Baseline, 3 , 6 (end of the treatment) , and 12 months]
• Changes in Electroencephalogram (EEG) Mean Frequency and Brain Electrical Activity. [Срок оценки: Baseline, 3, 6 ( end of the treatment), 12 months]
• Assessment of Swallowing Function via Dysphagia Outcome and Severity Scale (DOSS) in pediatric patients. [Срок оценки: baseline and 3, 6, 12 months]
• Changes in Psychomotor Development via Griffiths Mental Development Scales 3 (GMDS-3) [Срок оценки: baseline and 3, 6, 12 months.]
• Pediatric Esophageal Motility and Dysphagia Assessment via High-Resolution Manometry (HRM). [Срок оценки: baseline and 3, 6 ( end of the treatment), 12 months]
• Metabolomics and Pharmacokinetic Analysis of Bioactive Compounds and Endogenous Metabolites in pediatric, PD and MS patients [Срок оценки: baseline and 6 months (end of treatment)]
• Transcriptomic Profile and Differential Gene Expression Analysis for PD,MS and pediatric patients. [Срок оценки: baseline and 6 months (end of treatment)]

Критерии участия

Критерии включения

Inclusion Criteria for PD:

• Male or female patients aged between 45-75 years old.
• Clinical diagnosis of PD according to UK Brain Bank Criteria.
• 3 months of clinical stability before study enrolment.
• Anti-parkinsonian medication is fixed for at least 3 months prior to study entry.

Inclusion Criteria for MS:

• Male or female patients 18 years old or older.
• Diagnosis of RR-MS according to McDonald criteria.
• Expanded Disability Status Scale(EDSS) lower or equal to 5.5.
• Stable disease for at least 30 days prior to study entry.
• Stable disease-modifying therapy for at least 3 months prior to study entry.

Common inclusion criteria for MS and PD:

• No changes in drug treatment during 6 months-study treatment.
• Patients understand and comply with the study procedure and are able to complete tests and examinations required by the project.
• Written informed consent.

Inclusion criteria for pediatric patients:

• Eligible patients are those clinically stable;
• Age range from 1 to 10, between 5 and 30 kg.
• Patients not involved in other clinical trials.

Критерии исключения

Exclusion criteria for PD and MS:

• Absolute contraindications to Magnetic Resonance Imaging (MRI).
• Concomitant neurological disease or severe co-morbidities able to influence outcomes such as spinal injury, cancer, dementia, or other central nervous system diseases such as stroke, epilepsy or psychiatric disorders;
• Total score of Mini-Mental State Examination (MMSE)<24.
• Participating in other clinical trials.
• Pregnant/lactating.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Италия · 1 центр

• IRCCS Centro Neurolesi Bonino Pulejo — Messina

Публикации

• Deuschl G, Beghi E, Fazekas F, Varga T, Christoforidi KA, Sipido E, Bassetti CL, Vos T, Feigin VL. The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017. Lancet Public Health. 2020 Oct;5(10):e551-e567. doi: 10.1016/S2468-2667(20)30190-0. PMID 33007212
• Klomparens EA, Ding Y. The neuroprotective mechanisms and effects of sulforaphane. Brain Circ. 2019 Apr-Jun;5(2):74-83. doi: 10.4103/bc.bc_7_19. Epub 2019 Jun 27. PMID 31334360
• Yadav SK, Soin D, Ito K, Dhib-Jalbut S. Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis. J Mol Med (Berl). 2019 Apr;97(4):463-472. doi: 10.1007/s00109-019-01761-5. Epub 2019 Feb 28. PMID 30820593
• Kamal RM, Abdull Razis AF, Mohd Sukri NS, Perimal EK, Ahmad H, Patrick R, Djedaini-Pilard F, Mazzon E, Rigaud S. Beneficial Health Effects of Glucosinolates-Derived Isothiocyanates on Cardiovascular and Neurodegenerative Diseases. Molecules. 2022 Jan 19;27(3):624. doi: 10.3390/molecules27030624. PMID 35163897
• Schepici G, Bramanti P, Mazzon E. Efficacy of Sulforaphane in Neurodegenerative Diseases. Int J Mol Sci. 2020 Nov 16;21(22):8637. doi: 10.3390/ijms21228637. PMID 33207780
• Lotti C, Rubert J, Fava F, Tuohy K, Mattivi F, Vrhovsek U. Development of a fast and cost-effective gas chromatography-mass spectrometry method for the quantification of short-chain and medium-chain fatty acids in human biofluids. Anal Bioanal Chem. 2017 Sep;409(23):5555-5567. doi: 10.1007/s00216-017-0493-5. Epub 2017 Jul 17. PMID 28717897
• Garcia-Aloy M, Ulaszewska M, Franceschi P, Estruel-Amades S, Weinert CH, Tor-Roca A, Urpi-Sarda M, Mattivi F, Andres-Lacueva C. Discovery of Intake Biomarkers of Lentils, Chickpeas, and White Beans by Untargeted LC-MS Metabolomics in Serum and Urine. Mol Nutr Food Res. 2020 Jul;64(13):e1901137. doi: 10.1002/mnfr.201901137. Epub 2020 Jun 22. PMID 32420683
• Ulaszewska, M.M., Trost, K., Stanstrup, J. et al. Urinary metabolomic profiling to identify biomarkers of a flavonoid-rich and flavonoid-poor fruits and vegetables diet in adults: the FLAVURS trial

Идентификаторы

NCT: NCT07360977 · GRA-MYR-ND · PNRR-POC-2022-12376049

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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