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

• ClinicalTrials.gov Identifier: NCT01972074
• Recruitment Status: Completed
• First Posted: October 30, 2013
• Results First Posted: September 11, 2019
• Last Update Posted: September 11, 2019
• Sponsor: Massachusetts General Hospital
• Collaborator: Mclean Hospital
• Information provided by (Responsible Party): Gagan Joshi, Massachusetts General Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Autism Spectrum Disorder	Drug: Memantine; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
• Actual Study Start Date: February 17, 2015
• Actual Primary Completion Date: May 7, 2018
• Actual Study Completion Date: May 7, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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	Drug: Memantine; Capsule; Other Name: Namenda
Placebo Comparator: 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	Other: Placebo; Capsule
No Intervention: Control Group; Healthy controls will undergo neuroimaging twice (12 weeks apart) and will receive no intervention during the 12-week window.

Outcome Measures

Primary Outcome Measures :

1. Treatment Responder [ Time Frame: 12 Weeks (from Baseline [Week 0] to Endpoint [Week 12]) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 8 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

Mclean Hospital

Investigators

• Principal Investigator: Gagan Joshi, MD; Massachusetts General Hospital

  Study Documents (Full-Text)

Documents provided by Gagan Joshi, Massachusetts General Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] March 14, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• 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, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01972074
• Other Study ID Numbers: 2013-P-001826
• First Posted: October 30, 2013
• Results First Posted: September 11, 2019
• Last Update Posted: September 11, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gagan Joshi, Massachusetts General Hospital:

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

Additional relevant MeSH terms:

Disease; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Pathologic Processes; Neurodevelopmental Disorders; Mental Disorders; Memantine; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents