Autism Spectrum Disorder
Conditions
Keywords
Autism spectrum disorder, Treatment, Adolescents, Memantine, functional Magnetic Resonance Imaging, MRS, Neuroimaging
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.
Interventions
DRUGMemantine
Capsule
OTHERPlacebo
Capsule
Sponsors
Mclean Hospital
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Memantine 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 | 22 |
| Placebo 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 | 21 |
| Control Group Healthy controls will undergo neuroimaging twice (12 weeks apart) and will receive no intervention during the 12-week window. | 18 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Scanner Unavailable | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Memantine | Placebo | Control Group | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 22 Participants | 21 Participants | 18 Participants | 61 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 13.2 years STANDARD_DEVIATION 2.7 | 13.3 years STANDARD_DEVIATION 2.5 | 12.6 years STANDARD_DEVIATION 2.7 | 13.0 years STANDARD_DEVIATION 2.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 20 Participants | 17 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 20 Participants | 15 Participants | 55 Participants |
| Region of Enrollment United States | 22 participants | 21 participants | 18 participants | 61 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 6 Participants | 16 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 12 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 21 | 0 / 0 |
| other Total, other adverse events | 14 / 22 | 9 / 21 | 0 / 0 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 0 |
Outcome results
Primary
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.
Time frame: 12 Weeks (from Baseline [Week 0] to Endpoint [Week 12])
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Memantine | Treatment Responder | 9 Participants |
| Placebo | Treatment Responder | 4 Participants |