D-aspartate and Therapeutic Exercise (DAsp&TerapEx)

March 13, 2019 updated by: Mario Stampanoni Bassi, Neuromed IRCCS

Promotion of Synaptic Plasticity With D-Aspartate to Favour Recovery Form Cerebral Damage

An important mechanism responsible for clinical recovery after neurological damage of different types is synaptic plasticity. Nervous tissue can enhance or de-energize inter-neuronal transmission at synaptic level in a lasting way. By increasing the efficiency of synaptic transmission, through long-term potentiation (LTP), it is possible to compensate for the loss of synaptic pulses on survived neurons due to brain damage and to restore their function.

At synaptic level, LTP is mainly regulated by NMDA receptors. In animal models induction of plasticity in surviving neurons through the stimulation of NMDA receptors has been shown to limit the clinical manifestations of neuronal damage. Endogenous NMDA is synthesized by methylation of D-aspartate (Asp) by D-aspartatoartate methyltransferase . Moreover, Asp acts as a neurotransmitter capable of activating the NMDA receptor, since its biosynthesis, degradation, absorption and release occurs in the pre-synaptic neuron, and its release determines a response in Post-synaptic neurons. The expression of Asp in the SNC is very abundant during the embryonic period and in early years, whereas it is significantly reduced in adulthood.

Consistent with Asp ability of activating the NMDA receptor, recent studies have shown that oral administration of Asp increases LTP induction in mice. Preliminary studies by our group also showed an increase in LTP amplitude in subjects suffering from progressive forms of Multiple Sclerosis after 2 weeks of daily per os intake of 2660mg Asp.

It is also well known that the therapeutic exercise that characterizes a rehabilitative treatment is able to induce various benefits to the physical-functional and the cognitive-emotional spheres. In this regard, it has been extensively demonstrated how repeatedly performing a motor task can increase cortical excitability through the induction of LTP mechanisms.

Hypothesis Pharmacologically promoting the induction of cortical LTP by the intake of Asp in subjects with various types of brain damage (eg Multiple Sclerosis, Parkinson's Disease, Dementia) may favor the therapeutic effects of rehabilitative treatment.

Specific Objectives Evaluate the effects of Asp in improving the outcome of rehabilitative treatment resulting from brain damage of different origin.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

An important mechanism responsible for clinical recovery after neurological damage of different types is synaptic plasticity. Nervous tissue can enhance or de-energize inter-neuronal transmission at synaptic level in a lasting way. By increasing the efficiency of synaptic transmission, through long-term potentiation (LTP), it is possible to compensate for the loss of synaptic pulses on survived neurons due to brain damage and to restore their function.

At synaptic level, LTP is mainly regulated by NMDA receptors. In animal models induction of plasticity in surviving neurons through the stimulation of NMDA receptors has been shown to limit the clinical manifestations of neuronal damage. Endogenous NMDA is synthesized by methylation of D-aspartate (Asp) by D-aspartatoartate methyltransferase . Moreover, Asp acts as a neurotransmitter capable of activating the NMDA receptor, since its biosynthesis, degradation, absorption and release occurs in the pre-synaptic neuron, and its release determines a response in Post-synaptic neurons. The expression of Asp in the SNC is very abundant during the embryonic period and in early years, whereas it is significantly reduced in adulthood.

Consistent with Asp ability of activating the NMDA receptor, recent studies have shown that oral administration of Asp increases LTP induction in mice. Preliminary studies by our group also showed an increase in LTP amplitude in subjects suffering from progressive forms of Multiple Sclerosis after 2 weeks of daily per os intake of 2660mg Asp.

It is also well known that the therapeutic exercise that characterizes a rehabilitative treatment is able to induce various benefits to the physical-functional and the cognitive-emotional spheres. In this regard, it has been extensively demonstrated how repeatedly performing a motor task can increase cortical excitability through the induction of LTP mechanisms.

Hypothesis Pharmacologically promoting the induction of cortical LTP by the intake of Asp in subjects with various types of brain damage (eg Multiple Sclerosis, Parkinson's Disease, Dementia) may favor the therapeutic effects of rehabilitative treatment.

Specific Objectives A double-blind study to evaluate the effects of D-aspartate in improving the outcome of rehabilitative treatment resulting from brain damage of different origin (eg Multiple Sclerosis, Parkinson's Disease, Dementia). This will be made possible thanks to the specific skills of a multidisciplinary team of neurologists and physiatrists, healthcare professionals such as physiotherapists, occupational therapists, psychologists, speech therapists and the support of a biomedical engineer. These professional figures are already available at the UCK Neurosurgery of the IRCCS Neuromed directed by the proposer and actively collaborate to optimize the therapeutic exercise of patients with neurological damage.

Population of the study This study aims to provide preliminary data on interaction between D-aspartate and therapeutic exercise in inducing LTP cortical phenomena. The sample estimate was made by analogy after a literature analysis. In view of the quite high risk of drop out, our intention is to recruit at least 100 subjects in a population of patients with cerebral injury of various origin, coming to the neurology department of IRRCS Neuromed, Pozzilli.

Inclusion and exclusion criteria are as specified below.

Study design Double-blind prospective study, between randomized, placebo-controlled parallel groups.

Recruited patients will be randomized to receive 2660 mg D-aspartate oral dosing once daily or placebo, in addition to the conventional treatment provided by the relevant staff, for a period of 6 weeks. Patients will also be undergoing a Therapeutic Exercise Program (ET). All conventional therapies taken by patients will be recorded by the operators. Patients will be evaluated at zero time before starting treatment (T-0W) after 6 weeks to evaluate the effects at the end of treatment (T-6W) , and at 12 weeks (T-12W) to evaluate the maintenance of long-term effects. Randomization will be balanced in accordance with age, sex and schooling.

The physiotherapy and/or speech therapy approach will differ among patients considering the different types of brain damage and the different levels of disability, according to the rehabilitation unit team for each case.

Expected results The present study aims to investigate whether the association between pharmacological treatment with D-aspartate and therapeutic exercise may be more effective than just therapeutic exercise in favor of synaptic plasticity and clinical recovery under it, in patients with various forms of brain damage.

The expected result based on previous studies on mice (Errico, 2008, Errico, 2011) is that D-aspartate, promoting neuronal plasticity and acting in synergy with therapeutic exercise, strengthens the recovery of deficits in patients with various types of brain damage.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Isernia
      • Pozzilli, Isernia, Italy, 86077
        • Recruiting
        • IRCCS Neuromed

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

This study aims to provide preliminary data on interaction between D-aspartate and therapeutic exercise in inducing LTP cortical phenomena. The sample estimate was made by analogy after a literature analysis. In view of the risk of abandonment quite high, our intention is to recruit at least 100 subjects in a population of patients with cerebral injury of various origin (such as Multiple Sclerosis, Parkinson Disease, Dementia, Skull Trauma, Stroke, Epilepsy or Other Syndromes Neurological character), related to the neurology department of IRRCS Neuromed by Pozzilli.

Inclusion criteria:

  • Males or females aged between 18 and 80;
  • Presence of brain damage resulting from: Multiple Sclerosis, Parkinson's Disease, Dementia, Cranial Trauma, Neurosurgery, Stroke, Epilepsy, or Other Neurological Syndromes;
  • Patient's ability to adhere to the rehabilitation treatment provided for his / her clinical condition by competent personnel;
  • Female subjects can not be pregnant, can not breastfeed, have been born at least three months before the beginning of the study, undertake not to schedule a pregnancy for the duration of the study;
  • Patients should be able to follow protocol guidelines throughout the study;
  • Patients should be able to understand the aims and risks of the study;
  • Signature of informed consent, approved by our Ethics Committee.

Exclusion criteria:

  • Tumors or systemic infections;
  • Patients with impaired hepatic function (ALT> 3 x ULN, Alcaline Phosphatase> 2 x ULN, bilirubin tot> 2 x ULN if associated with any increase in ALT or alkaline phosphatase); Severe or moderate renal failure;
  • Other contraindications or hypersensitivity to D-aspartate or its excipients;
  • Patients with other pathologies which, according to the scientific officer's opinion, prevent recruitment;
  • Patients unable to even partially understand and want.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: D-aspartato+ET
Patients will be administered oral D-aspartate (2660 mg once daily) for 6 weks. Moreover, patients will receive therapeutic exercise.
Drug: D-Aspartate
Patients will be randomized to receive oral D-aspartatoe (2660 mg, once daily) or placebo,as an addition to conventional therapy as indicated by physicians, for a 6 weeks period.
Other Names:
  • DAA, D-Aspartic acid
Behavioral: Therapeutic exercise
Standard physiotherapy
Other Names:
  • Physiotherapy
PLACEBO_COMPARATOR: Placebo+ET
Patients will be administered oral placebo for 6 weks. Moreover, patients will receive therapeutic exercise.
Drug: Placebo Oral Tablet
Placebo
Behavioral: Therapeutic exercise
Standard physiotherapy
Other Names:
  • Physiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Barthel's Activities of Daily Living (ADL) (O'Sullivan et al 2007)
Time Frame: up to 3 years
quality of life
up to 3 years
FIM
Time Frame: up to 3 years
Functional Independence Measurement (FIM) (Chumney et al., 2010)
up to 3 years
stroke
Time Frame: up to 3 years
NIH Stroke Scale / Score (NIHSS)
up to 3 years
disability
Time Frame: up to 3 years
Expanded Disability Status Scale (EDSS) (Kurtzke, 1983)
up to 3 years
parkinson
Time Frame: up to 3 years
Unified Parkinson's Disease Rating Scale (Rammer et al. )
up to 3 years
depression
Time Frame: up to 3 years
Beck Depression Inventory (BDI) (Beck, 1972)
up to 3 years
neuronal plasticity
Time Frame: up to 3 years
Transcranial Magnetic Stimulation (TMS) will be used to evaluate the change of neuronal plasticity in a subgroup of patients who will not present contraindications to the method. The TMS uses short-lived magnetic fields and high intensity applied at the scalp level to activate the neurons of a small region of the cerebral cortex through an electromagnetic induction. When these impulses are applied repeatedly, it is possible to induce plastic modification of cortical excitability. If these changes are induced at the level of the motor cortex, they can be measured by recording a motor evoked potential (MEP) at the muscle level represented at the stimulated region level. Any increase or decrease in AMP amplitude, which persists after the end of TMS repetitive stimulation, indicates that there have been changes in the cortical, LTP or depression (LTD).
up to 3 years
locomotion and posture
Time Frame: up to 3 years
Stabilometric Platform
up to 3 years
locomotion and posture
Time Frame: up to 3 years
Gait Analysis
up to 3 years
deglutition
Time Frame: up to 3 years
Ectrophysiological and the Fibroendoscopic Deglutition Study
up to 3 years
Cognition
Time Frame: up to 3 years
ad-hoc tasks
up to 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Neuromed IRCCS

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

November 22, 2017

Primary Completion (ANTICIPATED)

July 1, 2020

Study Completion (ANTICIPATED)

December 1, 2022

Study Registration Dates

First Submitted

July 12, 2017

First Submitted That Met QC Criteria

July 20, 2017

First Posted (ACTUAL)

July 25, 2017

Study Record Updates

Last Update Posted (ACTUAL)

March 15, 2019

Last Update Submitted That Met QC Criteria

March 13, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Neuromed

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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