TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders

NCT07377032 | Recruiting Phase 3 DMC

• 1 other identifier: TAP-GRIN
• Study Type: interventional
• Target: 40
• Locations: 3 countries
• Sites: 3

Brief Summary

The goal of this clinical study is to find out whether L-serine dietary supplementation helps improve overall clinical functioning in children and young adults (2-30 years) with GRIN-related neurodevelopmental disorders (GRIN-NDD) caused by loss-of-function (LoF) variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D. It will also assess the safety and tolerability of L-serine. The main questions it aims to answer are: Does L-serine improve overall clinical status, measured mainly by the Clinical Global Impression-Severity (CGI-S) score? Does L-serine improve behaviour, cognition, adaptive functioning, motor skills, sleep, and (in those with epilepsy) seizure frequency and EEG findings? What side effects or medical problems occur during L-serine compared with placebo? Do neurophysiological measures (including TMS-EMG/TMS-EEG) change with treatment and potentially act as biomarkers of response? Researchers will compare L-serine to a placebo (maltodextrin powder with similar appearance/texture) using a randomised, double-blind, placebo-controlled "n-of-1" approach, where each participant receives both treatments in alternating periods. Results from multiple single-patient trials will then be combined (aggregated) to estimate the overall treatment effect across the study population. Participants will: Complete a 4-week baseline period with assessments (and seizure diary use where applicable) Receive L-serine and placebo in alternating 3-month periods within each cycle (minimum 2 cycles, up to 4 cycles; each cycle lasts 6 months) Take the assigned study product by mouth 3 times per day at 500 mg/kg/day (maximum 30 g/day for participants ≥60 kg) Have the first 7 days of each 3-month period treated as washout, with data from that week not analysed Attend regular clinic visits for clinical exams, safety labs, and standardized assessments of global status, behaviour/cognition, motor function, and sleep If they have epilepsy: keep a seizure diary and undergo EEG assessments after each treatment period In some sites (Italy and France): undergo TMS-based neurophysiology testing Optionally, a subset may join a cellular biomarker substudy (blood collection to generate iPSC-derived neuronal models and organoids) to explore treatment effects in variant-specific lab models.

Conditions

Epilepsy; Neurodevelopmental Disorder (Diagnosis); GRIN-related Disorders; GRIN1; GRIN2A; GRIN2B; GRIN2D

Outcome Measures

Primary Outcomes (1)

• Change in Clinical Global Impression - Severity (CGI-S) score

  The Clinical Global Impression - Severity (CGI-S) scale is a clinician-rated measure of overall illness severity. The primary outcome is the within-subject difference in CGI-S score comparing L-serine supplementation with placebo, assessed at the end of each treatment period relative to baseline. Lower CGI-S scores indicate less severe overall clinical status.

  From baseline to the end of each 3-month treatment period, assessed repeatedly across all completed treatment cycles (minimum 2 cycles, up to 4 cycles; total study duration up to approximately 104 weeks).

Secondary Outcomes (10)

• Number of adverse events

  From baseline through the end of the last treatment period and the 2-week post-treatment safety follow-up (up to approximately 110 weeks).

• Change in Clinical Global Impression - Improvement (CGI-I) score

  Assessed at the end of each 3-month treatment period across all completed treatment cycles (minimum 2 cycles, up to 4 cycles; up to approximately 104 weeks)

• Change in behavioural functioning

  From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).

• Change in adaptive functioning

  From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).

• Change in cognitive performance

  From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).

Study Arms (2)

Experimental group

ACTIVE COMPARATOR

L-serine supplementation is administered as an oral powder for solution and used as an add-on intervention to participants' existing standard of care. L-serine is a naturally occurring amino acid and is classified as a food for special medical purposes. In this study, L-serine is used to increase the availability of its enantiomer D-serine, an endogenous co-agonist of the N-methyl-D-aspartate receptor (NMDAR), with the aim of enhancing NMDAR-mediated neurotransmission in individuals with GRIN-related neurodevelopmental disorders caused by loss-of-function variants. The intervention is delivered using a randomised, double-blind, placebo-controlled n-of-1 design, in which each participant receives both L-serine and placebo in alternating treatment periods. L-serine and placebo are identical in appearance, packaging, and method of administration to maintain blinding. Treatment allocation within each cycle is determined by a computer-generated randomisation schedule managed by unblinded

Dietary Supplement: L-serine

Placebo

PLACEBO COMPARATOR

Placebo is administered as an oral powder for solution and serves as the comparator to L-serine supplementation. The placebo consists primarily of maltodextrin, a readily digestible carbohydrate that is commonly used as an inert control substance in clinical studies. It is classified as a food-grade product and contains no active amino acids or pharmacologically active ingredients. The placebo is formulated to be indistinguishable from L-serine with respect to appearance, texture, solubility, and method of administration, in order to maintain blinding of participants, caregivers, investigators, and study staff. Packaging, labelling, and dosing instructions are identical to those used for the active intervention. The placebo is administered orally in three divided daily doses, following the same dosing schedule and duration as the active intervention within the randomised, double-blind, n-of-1 trial design. Each placebo treatment period lasts three months, with the first seven days d

Other: Maltodextrin (Placebo)

Interventions

L-serine DIETARY_SUPPLEMENT

L-serine supplementation is administered as an oral powder for solution and used as an add-on intervention to participants' existing standard of care. L-serine is a naturally occurring amino acid and is classified as a food for special medical purposes. In this study, L-serine is used to increase the availability of its enantiomer D-serine, an endogenous co-agonist of the N-methyl-D-aspartate receptor (NMDAR), with the aim of enhancing NMDAR-mediated neurotransmission in individuals with GRIN-related neurodevelopmental disorders caused by loss-of-function variants. The intervention is delivered using a randomised, double-blind, placebo-controlled n-of-1 design, in which each participant receives both L-serine and placebo in alternating treatment periods. L-serine and placebo are identical in appearance, packaging, and method of administration to maintain blinding. Treatment allocation within each cycle is determined by a computer-generated randomisation schedule managed by unblinded s

Experimental group

Maltodextrin (Placebo) OTHER

Placebo is administered as an oral powder for solution and serves as the comparator to L-serine supplementation. The placebo consists primarily of maltodextrin, a readily digestible carbohydrate that is commonly used as an inert control substance in clinical studies. It is classified as a food-grade product and contains no active amino acids or pharmacologically active ingredients. The placebo is formulated to be indistinguishable from L-serine with respect to appearance, texture, solubility, and method of administration, in order to maintain blinding of participants, caregivers, investigators, and study staff. Packaging, labelling, and dosing instructions are identical to those used for the active intervention. The placebo is administered orally in three divided daily doses, following the same dosing schedule and duration as the active intervention within the randomised, double-blind, n-of-1 trial design. Each placebo treatment period lasts three months, with the first seven days de

Placebo

Eligibility Criteria

• Age: 2 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Clinical diagnosis of a GRIN-related neurodevelopmental disorder (GRIN-NDD)
• Presence of a pathogenic or likely pathogenic loss-of-function (LoF) variant in GRIN1, GRIN2A, GRIN2B, or GRIN2D
• Parent(s), caregiver(s), or legally authorised representative(s) have been informed of the nature of the study and have provided written informed consent.
• Participants who are able to do so have provided written informed consent or assent, according to local regulations and cognitive capacity.
• Parent(s)/caregiver(s) are willing and able to comply with study procedures and visits, in the opinion of the investigator.
• Participants who have previously received L-serine supplementation are willing to discontinue L-serine for at least one week prior to the baseline observation period.

You may not qualify if:

• Age younger than 2 years at screening.
• Known hypersensitivity or intolerance to L-serine, placebo, or any excipients used in the study formulations.
• Presence of a clinically significant unstable medical condition (other than epilepsy) that, in the investigator's judgement, may place the participant at increased risk or interfere with study participation.
• Any other significant disease or disorder that may compromise participant safety, affect study outcomes, or impair the participant's ability to complete the study procedures.
• Inadequate supervision by parent(s) or caregiver(s), as judged by the investigator.
• Participation in another clinical trial involving an investigational medicinal product within the previous 6 months.
• Female participants who are pregnant or breastfeeding.
• Presence of a GRIN1, GRIN2A, GRIN2B, or GRIN2D variant for which a clear loss-of-function effect cannot be demonstrated.

Sponsors & Collaborators

• Meyer Children's Hospital IRCCS: lead

Study Sites (3)

Hospices Civils de Lyon

Lyon, 69002, France

NOT YET RECRUITING

Meyer Children's Hospital

Florence, 50139, Italy

RECRUITING

Children's Memorial Health Institute

Warsaw, Poland

RECRUITING

MeSH Terms

Conditions

Epilepsy; Neurodevelopmental Disorders; Disease

Interventions

Serine; maltodextrin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Central Study Contacts

Simona Balestrini, Md, PhD

CONTACT

00390555662719; simona.balestrini@meyer.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Model Details: Aggregated series of n-of-1 trials

Study Record Dates

• First Submitted: January 19, 2026
• First Posted: January 29, 2026
• Study Start: August 29, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: January 29, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1); FR (1); IT (1)