Tolerability and Efficacy of L-Serine in Patients With GRIN-related Encephalopathy

NCT04646447 | Unknown

• 1 other identifier: PIC-29-20
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

GRIN-related disorders encompass a new group of Inborn Errors of Metabolism according to the recent nosology published by Ferreira et al (Genet Med, 2019). These rare conditions represent a subtype of paediatric encephalopathies leading to intellectual disability, hypotonia, communication deficits and motor impairment (Orphanet entries: 178469, 289266, 101685, for GRIN1, GRIN2A and GRIN2B, respectively). Mutations leading to glutamatergic hypotransmission can be potentially treated with L-Serine leading to significant clinical benefits in patients according to a pilot study published by our group (Soto et al, 2019). In our study, the investigators will include about 20 spanish patients older than 2 years of age, harbouring GRIN variants functionally anotated as loss-of-function pathogenic variants. The investigators will evaluate dose tolerability, efficacy of the treatment according to neurocognitive and motor scales, as well as the effects of L-serine in microbiome composition.

Conditions

GRIN Related Disorders

Outcome Measures

Primary Outcomes (8)

• Number of participants with any adverse event

  Dose tolerability is based on subject interviews and scheduled assessment evaluating the presence or absence of adverse events. The presence of adverse events will be collected according the doses of L-serine: 250 mg / kg / day and 500 mg / kg / day. Pre-existing conditions (present before intake of study nutreceutical) or pretreatment AEs (onset before intake of study nutraceutical) are considered concomitant diseases and should not be recorded as AEs but should be recorded on the concomitant diseases eCRF page. However, if the subject experiences a worsening, increased frequency, or complication of such a concomitant disease, the worsening, increased frequency, or complication should be recorded as an AE.

  up to 12 months

• Change in mental age with Vineland Adaptive Behavior Scales (VABS) (Vineland-3)

  Exploring the following domains: Communication, Daily Living Skills, Socialization and motor Skills (gross and fine) Once obtained the mental age equivalent, the neuropsychologist test or battery to assess the neurodevelopment will be selected

  Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention

• Change in bayley Scales of Infant and Toddler Development (BSID)

  The Bayley Scales of Infant and Toddler Development (BSID-III) are a set of standardized rating scales, which enable us to assess the cognition, receptive language, expressive language, fine motor and gross motor of children between 1 and 42 months. The Cognitive battery, which consists on the evaluation of the following items: visual perception, attention, memory, objects manipulation and exploration, communication skills and verbal comprehension. Bayley III has a raw score, scale score, composite score, and growth percentile score. All of these scores will be given in the study. A higher score means improvement is better. The high score for cognition is 91, 48 for receptive language, 49 for expressive language, 66 for fine motor and 72 for gross motor evaluation.

  Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention

• Efficiency of the treatment measured by change in the cognitive assessment (Wechsler Intelligence Scale.

  If the mental age is more than 42 months will be considering the followings neuropsychologist test: Specific test will be chosen according the age of the children. 1. The Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV): Age range: 2 years 6 months to 7 years 7 months. An index score can range from 40 to 160. A higher score means improvement is better. 2. The Wechsler Intelligence Scale for Children (WISC V): Age range: Children aged 6:0-16:11. It has 5 composite scores and a Full-Scale Intelligence Quotient (FSIQ) is generated based on seven subtests. The primary index scores range from 45 to 155; the FSIQ ranges from 40 to 160. A higher score means improvement is better. 3. The Wechsler Adult Intelligence Scale (WAIS-IV): Age range: 16 years to 90 years, 11 months. The test has 15 subtests, 10 of which are core subtests that are usually used to measure the four index scores and the FSIQ. A higher score means improvement is better.

  Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention

• Change in the Achenbach System of Empirically Based Assessment (ASEBA) System of Empirically Based Assessment (ASEBA)+

  The Achenbach System of Empirically Based Assessment (ASEBA) for parents and teachers offers a comprehensive approach to assessing adaptive and maladaptive functioning

  Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention

• Change in Gross Motor Function Measure-88

  Items span the spectrum of gross motor activities in five dimensions. A: Lying and Rolling, B: Sitting C: Crawling and Kneeling, D: Standing, and E: Walking, Running and Jumping.

  -3 months, 0 months (start treatment), 3 months, 6 months, 12 months

• Change in Social Communication Questionnaire (SCQ)

  Evaluates communication skills and social functioning in children who may have autism or autism spectrum disorders and The SCQ is a 40-item survey where each question is a 'yes' or 'no' answer. The total possible range of scores is 0-39 (verbal children) or 0-33 (non-verbal children) with higher scores indicative of greater frequency of symptoms. They are completed by parents or other primary caregiver.

  Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention

• Change in the Sleep Disturbance Scale for Children (SDSC)

  The Sleep Disturbance Scale for Children (SDSC) is a 27-item inventory rated on a 5 point Likert-type scale. 0 = least severe and 5 = most severe The instrument's purpose is to categorize sleep disorders in children. As well as giving an overall score the instrument uses five subdomains: disorders of initiating and maintaining sleep, sleep breathing disorders, disorders of arousal, sleep-wake transition disorders, disorders of excessive somnolence, and sleep hyperhidrosis.

  Baseline (approximately 3 months prior to intervention), 0 months (start treatment) and 3, 6 and 12 months post intervention

Secondary Outcomes (1)

• Microbiota composition

  [ Time Frame: 12 months ]

Study Arms (1)

L-serine treatment

EXPERIMENTAL

All patients will receive the same L-serine dose treatment over 12 months. Arm: Experimental: L-Serine 250 mg / kg / day during the first two weeks. From week 3 to 52, 500 mg / kg / day. L-serine orally administered, divided into three doses a day.

Dietary Supplement: L-serine

Interventions

L-serine DIETARY_SUPPLEMENT

L-Serine Arm L-serine is considered as GRAS (generally recognized as safe) by the FDA and has been approved as a normal food additive under CFR172.320. All patients will receive the same L-serine dose treatment over 12 months. Arm: Experimental: L-Serine 250 mg / kg / day during the first two weeks. From week 3 to 52, 500 mg / kg / day. L-serine orally administered, divided into three doses a day. The L-Serine will be manufactured, packaged, labeled and/or distributed by NUTRICIA or delegated contractors. It will be presented in a powdered form of 100 gr of the amino acid L-serine. For oral use. Sufficient L-serine will be dispensed at home considering the dose according the weight of the patient.

L-serine treatment

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis of encephalopathy associated with genetic GRIN variant pathogenic or likely pathogenic, causing a loss-of-function
• Parent(s)/legal representative give written informed consent for participation in the trial; patient assent (if possessing adequate understanding, in the investigator's)
• Patient \& caregiver are willing and able (in the investigator's opinion) to comply with all trial requirements (including the completion of all caregiver assessments by the same caregiver throughout the trial).

You may not qualify if:

• Diagnosis of encephalopathy with absence of genetic GRIN variant pathogenic or likely pathogenic.
• Currently using or has used within the 30 days prior to screening L-Serine supplement
• Patient has been previously randomized into this trial

Sponsors & Collaborators

• Fundació Sant Joan de Déu: lead
• Hospital Sant Joan de Deu: collaborator

Study Sites (1)

Hospital Sant Joan de Deu

Barcelona, Esplugues de Llobregat, Barcelona, 08950, Spain

RECRUITING

MeSH Terms

Interventions

Serine

Intervention Hierarchy (Ancestors)

Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Central Study Contacts

Angels García Cazorla, MD, PHD

CONTACT

0034 93 280 40 00; agarcia@sjdhospitalbarcelona.org

Natalia Juliá Palacios, MD

CONTACT

0034 93 280 40 00; njulia@sjdhospitalbarcelona.org

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2020
• First Posted: November 30, 2020
• Study Start: July 30, 2020
• Primary Completion: August 31, 2021
• Study Completion: May 31, 2022
• Last Updated: November 30, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR

Locations

ES (1)