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

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01972074
• Collaborator: Mclean Hospital (Other)
• Enrollment: 84
• Location: 1
• Arms: 3
• Actual Duration (Months): 38.6
• Patients Per Site Per Month: 2.2

Study Details

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
• 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: Feb 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 Names: 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 [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

Criteria

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

INCLUSION CRITERIA

All Participants:

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

Participants with Autism Spectrum Disorder:

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

2. 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:

1. 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:

4. Lamotrigine

5. Amantadine

6. N-acetylcysteine

7. D-cycloserine

8. 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

9. 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

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

11. Participants who are pregnant and/or nursing

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

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

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

15. 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.

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

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

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

19. Known hypersensitivity to memantine

20. Severe allergies or multiple adverse drug reactions

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Mar 14, 2018

More Information

Publications

None provided.

• 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: Oct 30, 2013
• Last Update Posted: Sep 11, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by 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: 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; Memantine

Study Results

Participant Flow

Recruitment Details	Participants were recruited for 3 years (2015 - 2018). They were recruited from existing and new patients at 3 Massachusetts General Hospital sites: Bressler Program for Autism Spectrum Disorder, Lurie Center for Autism, and Child and Adolescent Outpatient Psychiatry Clinic. Participants were also recruited using flyers and internet advertisements.
Pre-assignment Detail	Per protocol, participants were enrolled when they provided informed consent. They then underwent screening procedures to confirm eligibility. If eligible and willing/able to participate, participants then began study procedures. Some participants dropped out prior to starting study procedures and were, therefore, excluded from this analysis.

Arm/Group Title	Memantine	Placebo	Control Group
Arm/Group Description	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	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	Healthy controls will undergo neuroimaging twice (12 weeks apart) and will receive no intervention during the 12-week window.
Period Title: Overall Study
STARTED	22	21	18
COMPLETED	16	17	15
NOT COMPLETED	6	4	3

Baseline Characteristics

Arm/Group Title	Memantine	Placebo	Control Group	Total
Arm/Group Description	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	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	Healthy controls will undergo neuroimaging twice (12 weeks apart) and will receive no intervention during the 12-week window.	Total of all reporting groups
Overall Participants	22	21	18	61
Age (Count of Participants)
<=18 years	22 100%	21 100%	18 100%	61 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.2 (2.7)	13.3 (2.5)	12.6 (2.7)	13.0 (2.6)
Sex: Female, Male (Count of Participants)
Female	5 22.7%	5 23.8%	6 33.3%	16 26.2%
Male	17 77.3%	16 76.2%	12 66.7%	45 73.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.5%	1 4.8%	1 5.6%	3 4.9%
Not Hispanic or Latino	21 95.5%	20 95.2%	17 94.4%	58 95.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	2 11.1%	2 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	20 90.9%	20 95.2%	15 83.3%	55 90.2%
More than one race	2 9.1%	1 4.8%	1 5.6%	4 6.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	22 100%	21 100%	18 100%	61 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants included in this analysis were exposed to study medication for at least 2 weeks. Participants in the Control Group were excluded from this analysis because they did not receive study medication and, therefore, cannot be categorized into Treatment Responders vs. Treatment Non-Responders.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	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	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
Measure Participants	19	21
Count of Participants [Participants]	9 40.9%	4 19%

Adverse Events

Time Frame	12 Weeks
Adverse Event Reporting Description	Adverse events were collected from participants in the memantine arm and the placebo arm systematically, via regular investigator assessment. At every study visit, study clinicians queried participants and their parent(s)/guardian(s) about any adverse events that may have occurred since the last study visit. Participants in the Control Group were excluded from this analysis because they did not receive study medication and adverse events were not monitored/assessed for the Control Group.
Arm/Group Title	Memantine		Placebo		Control Group
Arm/Group Description	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		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		Healthy controls will undergo neuroimaging twice (12 weeks apart) and will receive no intervention during the 12-week window.
All Cause Mortality
	Memantine		Placebo		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/21 (0%)		0/0 (NaN)
Serious Adverse Events
	Memantine		Placebo		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/21 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Memantine		Placebo		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/22 (63.6%)		9/21 (42.9%)		0/0 (NaN)
Gastrointestinal disorders
Abdominal Discomfort	2/22 (9.1%)	2	1/21 (4.8%)	1	0/0 (NaN)	0
Constipation	0/22 (0%)	0	1/21 (4.8%)	1	0/0 (NaN)	0
Diarrhea	1/22 (4.5%)	1	0/21 (0%)	0	0/0 (NaN)	0
Metabolism and nutrition disorders
Decreased Appetite	2/22 (9.1%)	2	0/21 (0%)	0	0/0 (NaN)	0
Increased Appetite	3/22 (13.6%)	3	0/21 (0%)	0	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	0/22 (0%)	0	1/21 (4.8%)	1	0/0 (NaN)	0
Nervous system disorders
Dizzy/Lightheaded	1/22 (4.5%)	1	1/21 (4.8%)	1	0/0 (NaN)	0
Fatigue	2/22 (9.1%)	2	2/21 (9.5%)	2	0/0 (NaN)	0
Headache	4/22 (18.2%)	5	2/21 (9.5%)	2	0/0 (NaN)	0
Insomnia	3/22 (13.6%)	3	2/21 (9.5%)	2	0/0 (NaN)	0
Sedation	2/22 (9.1%)	2	1/21 (4.8%)	1	0/0 (NaN)	0
Psychiatric disorders
Anxious/Worried	2/22 (9.1%)	2	2/21 (9.5%)	2	0/0 (NaN)	0
Irritability	0/22 (0%)	0	3/21 (14.3%)	3	0/0 (NaN)	0
Irritability & Agitation	1/22 (4.5%)	1	1/21 (4.8%)	1	0/0 (NaN)	0
Self-Harm	1/22 (4.5%)	1	0/21 (0%)	0	0/0 (NaN)	0
Suicidal Ideation	2/22 (9.1%)	2	0/21 (0%)	0	0/0 (NaN)	0
Renal and urinary disorders
Increased Bed Wetting	1/22 (4.5%)	1	0/21 (0%)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Cold/Infection/Allergy	3/22 (13.6%)	3	1/21 (4.8%)	1	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
Rash	0/22 (0%)	0	1/21 (4.8%)	1	0/0 (NaN)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.