Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder

NCT01972074 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 2013-P-001826
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a 12-week, randomized-controlled trial of memantine hydrochloride (Namenda) for the treatment of social impairment in adolescents with autism spectrum disorder (ASD). The investigators will also conduct pre- and post-treatment neuroimaging (functional magnetic resonance imaging \[fMRI\] and hydrogen magnetic resonance spectroscopy \[HMRS\]) to assess neural functional deficits in adolescents with autism spectrum disorder compared to healthy volunteer adolescents. This pre- and post-neuroimaging will also be used to assess any effects of memantine therapy on neural function in adolescents with autism spectrum disorder. The investigators hypothesize that short-term memantine monotherapy will be safe, well-tolerated, and effective in improving the core symptoms of autism spectrum disorder in adolescents with autism spectrum disorder. Additionally, the investigators hypothesize that following memantine therapy, adolescents with autism spectrum disorder will exhibit a decrease in glutamate (Glu) concentration in the anterior cingulate cortex (ACC) and a change towards normalization in altered functional connectivity of the anterior cingulate cortex and medial temporal lobes, consistent with improvement in social impairments in autism spectrum disorder. The investigators hypothesize that compared to healthy volunteer participants, participants with autism spectrum disorder will significantly differ on neuroimaging measures at baseline but that following memantine therapy, the difference between autism spectrum disorder and healthy volunteer neuroimaging data will decrease.

Conditions

Autism Spectrum Disorder

Keywords

Autism spectrum disorder; Treatment; Adolescents; Memantine; functional Magnetic Resonance Imaging; MRS; Neuroimaging

Outcome Measures

Primary Outcomes (1)

• Treatment Responder

  Treatment responders are defined as having a 25% reduction, from baseline to endpoint, in Social Responsiveness Scale, Second Edition: School-Age, Parent Report (SRS-2) total raw score and an Autism Spectrum Disorder Clinical Global Impression-Improvement (ASD CGI-I) score ≤2. The Social Responsiveness Scale, Second Edition (SRS-2) is a 65-item rating scale completed by the parents/guardians of children ages 4-18. It is used to measure the severity of autism spectrum disorder symptoms. Each item is rated on a 4-point Likert scale, ranging from 1=Not True to 4=Almost Always True. Higher scores indicate a higher severity of autism spectrum disorder symptoms. The Autism Spectrum Disorder Clinical Global Impression-Improvement subscale (ASD CGI-I) is a clinician-rated measure of the improvement of autism spectrum disorder symptoms. The subscale is rated on a 7-point Likert scale, ranging from 1=Very Much Improved to 7=Very Much Worse. Higher scores indicate less symptom improvement.

  12 Weeks (from Baseline [Week 0] to Endpoint [Week 12])

Study Arms (3)

Memantine

EXPERIMENTAL

Participants in the placebo arm will receive placebo (no active ingredients) in capsule form twice daily. It will be administered twice daily for 12 weeks. Participants will undergo neuroimaging before and after the 12-week treatment phase. Placebo: Capsule

Drug: Memantine

Placebo

PLACEBO COMPARATOR

Participants in the memantine arm will receive memantine in capsule form twice daily. It will be administered twice daily for 12 weeks (including a 4-week titration phase to a maximum dose of 20 mg per day). Participants will undergo neuroimaging before and after the 12-week treatment phase. Memantine: Capsule

Other: Placebo

Control Group

NO INTERVENTION

Healthy controls will undergo neuroimaging twice (12 weeks apart) and will receive no intervention during the 12-week window.

Interventions

Memantine DRUG

Capsule

Also known as: Namenda

Memantine

Placebo OTHER

Capsule

Placebo

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• All Participants:
• Male and female participants, ages 8-17 years (inclusive)
• Participants with Autism Spectrum Disorder:
• Meets Diagnostic and Statistical Manual-5 autism spectrum disorder diagnostic criteria, as established by clinical diagnostic interview
• At least moderate severity of social impairment, as measured by a total raw score of ≥85 on the parent/guardian-completed Social Responsiveness Scale, Second Edition (SRS-2) and a score of ≥4 on the clinician-administered Autism Spectrum Disorder Clinical Global Impression-Severity scale (ASD CGI-S)
• Healthy Control Participants:
• \. Age-, sex-, and IQ-matched with participants with autism spectrum disorder 3. No Axis I diagnoses, as established by the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiological Version (K-SADS-E) and confirmed by clinical diagnostic interview 4. No significant traits of autism spectrum disorder, as measured by a total raw score of \<60 on the parent/guardian-completed Social Responsiveness Scale, Second Edition

You may not qualify if:

• All Participants:
• IQ ≤70 based, on the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) Vocabulary and Matrix Reasoning subtests
• Impaired communicative speech
• Current treatment with the following medications, which are known to impact glutamate levels:
• Lamotrigine
• Amantadine
• N-acetylcysteine
• D-cycloserine
• Current treatment with a psychotropic medication, not listed above, on a dose that has not been stable for at least 4 weeks prior to study baseline
• Co-administration of drugs that compete with memantine for renal elimination using the same renal cationic system, including hydrochlorothiazide, triamterene, metformin, cimetidine, ranitidine, quinidine, and nicotine
• Initiation of a new psychosocial intervention within 30 days prior to randomization
• Participants who are pregnant and/or nursing
• Participants with a history of non-febrile seizures without a clear and resolved etiology
• Participants with a history of or a current liver or kidney disease
• Clinically unstable psychiatric conditions or judged to be at serious suicidal risk

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Mclean Hospital: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (3)

• Joshi G, Gonenc A, DiSalvo M, Faraone SV, Ceranoglu TA, Yule AM, Uchida M, McDougle CJ, Wozniak J. Memantine to Treat Social Impairment in Youths With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2025 Oct 1;8(10):e2534927. doi: 10.1001/jamanetworkopen.2025.34927.

  PMID: 41032298 DERIVED

• Iffland M, Livingstone N, Jorgensen M, Hazell P, Gillies D. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2023 Oct 9;10(10):CD011769. doi: 10.1002/14651858.CD011769.pub2.

  PMID: 37811711 DERIVED

• Brignell A, Marraffa C, Williams K, May T. Memantine for autism spectrum disorder. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013845. doi: 10.1002/14651858.CD013845.pub2.

  PMID: 36006807 DERIVED

MeSH Terms

Conditions

Autism Spectrum Disorder

Interventions

Memantine

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Amantadine; Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Gagan Joshi, MD
• Organization: Massachusetts General Hospital

joshi.gagan@mgh.harvard.edu

(617) 724-1541

Study Officials

• Gagan Joshi, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Psychiatry, Harvard Medical School; Medical Director, Bressler Program for Autism Spectrum Disorder, Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital

Study Record Dates

• First Submitted: October 24, 2013
• First Posted: October 30, 2013
• Study Start: February 17, 2015
• Primary Completion: May 7, 2018
• Study Completion: May 7, 2018
• Last Updated: July 1, 2024
• Results First Posted: September 11, 2019

Record last verified: 2024-06

Locations

US (1)