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

NCT ID: NCT01972074

Last Updated: 2024-07-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-17
• Study Completion Date: 2018-05-07

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Memantine

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

Group Type: EXPERIMENTAL

Memantine

Intervention Type: DRUG

Capsule

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Capsule

Control Group

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Memantine

Capsule

Intervention Type: DRUG

Placebo

Capsule

Intervention Type: OTHER

Other Intervention Names

Namenda

Eligibility Criteria

Inclusion Criteria

All Participants:

1. Male and female participants, ages 8-17 years (inclusive)

Participants with Autism Spectrum Disorder:

2. Meets Diagnostic and Statistical Manual-5 autism spectrum disorder diagnostic criteria, as established by clinical diagnostic interview

3. 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:

2. 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

Exclusion Criteria

All Participants:

1. IQ ≤70 based, on the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) Vocabulary and Matrix Reasoning subtests

2. Impaired communicative speech

3. Current treatment with the following medications, which are known to impact glutamate levels:

1. Lamotrigine

2. Amantadine

3. N-acetylcysteine

4. D-cycloserine

4. 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

5. 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

6. Initiation of a new psychosocial intervention within 30 days prior to randomization

7. Participants who are pregnant and/or nursing

8. Participants with a history of non-febrile seizures without a clear and resolved etiology

9. Participants with a history of or a current liver or kidney disease

10. Clinically unstable psychiatric conditions or judged to be at serious suicidal risk

11. Participants who meet for alcohol or drug dependence or abuse on the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiological Version. If the participant has a recent history of substance abuse, as an added precaution, there will be a 2-week washout period before initiating the trial. There are no known safety issues relating to memantine and recent history of substance abuse.

12. Serious, stable or unstable, systemic illness, including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease

13. Participants with severe hepatic impairment (Liver Function Tests [LFTs] >3 times the Upper Limit of Normal [ULN])

14. Participants with genitourinary conditions that raise urine Power of Hydrogen (pH) (e.g., renal tubular acidosis, severe infection of the urinary tract)

15. Known hypersensitivity to memantine

16. Severe allergies or multiple adverse drug reactions

17. A non-responder or history of intolerance to memantine after treatment at adequate doses, as determined by the clinician

18. Investigator and his/her immediate family, defined as the Investigator's spouse, parent, child, grandparent, or grandchild.

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Mclean Hospital

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Gagan Joshi

Assistant Professor of Psychiatry, Harvard Medical School; Medical Director, Bressler Program for Autism Spectrum Disorder, Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gagan Joshi, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 41032298 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37811711 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36006807 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2013-P-001826

Identifier Type: -

Identifier Source: org_study_id