Asperger's, Asperger's Disorder, Autism, Autism Spectrum Disorder (ASD), Autistic Disorder, Pediatric Autism, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS)
Conditions
Keywords
Autism Spectrum Disorder (ASD), Autism, Autistic Disorder, Asperger's Disorder, Asperger's, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Memantine, Pediatric Disorder
Brief summary
The purpose of this study is to evaluate the safety and tolerability of memantine in pediatric (6-12 years old) patients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and to identify responders for participation in a follow-up randomized withdrawal study.
Detailed description
This 50-week multicenter and multinational clinical study is comprised of a 2-week screening period, a 6-week open-label dose-titration period followed by a variable duration maintenance period (up to 42 weeks). Patients with at least 12 weeks of investigational product exposure who meet the protocol specified responder criterion at two consecutive visits separated by at least two weeks are eligible to transition to a randomized withdrawal study. A responder is defined as a patient who demonstrates at least a 10 point improvement (reduction in score) in the Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 total raw score. Weight based dose limits were selected in this study to ensure that exposure in terms of area under the curve (AUC) was less than the predefined limit of 2100 ng·h/mL which represents a 10-fold lower exposure than observed at the No observed adverse effect level (NOAEL) of 15 mg/kg/day in juvenile rats. The weight-based dose limits in this study were as follows: * Group A: ≥ 60 kg; maximum 15 mg/day * Group B: 40-59 kg; maximum 9 mg/day * Group C: 20-39 kg; maximum 6 mg/day * Group D: \< 20 kg; maximum 3 mg/day
Interventions
Memantine extended release 3-mg capsules; the dosages studied ranged from 3 - 15 mg/day; weight based dosing in 4 weight groups; oral administration. Dosing is once daily for up to 48 weeks.
Sponsors
Forest Laboratories
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female outpatients. 2. Age of 6-12. 3. Meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) 4. Have a family that is sufficiently organized and stable to guarantee adequate safety monitoring and continuous attendance to clinic visits for the duration of the study
Exclusion criteria
1. Have enrolled in Study MEM-MD-57A 2. Medical conditions that might interfere with the conduct of the study, confound interpretation of the study results, or endanger the patient's well-being. 3. Participation in any other clinical investigation using an experimental drug within 30 days of screening. 4. Having any primary psychiatric (Axis I) diagnosis other than autism, Asperger's Disorder, and PDD-NOS. 5. Meeting DSM-IV-TR criteria for bipolar I disorder, psychotic disorder not otherwise specified, posttraumatic stress disorder, schizophrenia, or major depressive disorder within the past 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Confirmed Social Responsiveness Scale (SRS) Responders | Visit 1 (Baseline) to Visit 8 (week 48/Final Visit) | A confirmed SRS responder was defined as a patient who had at least 12 weeks of exposure to memantine, and a ≥ 10-point reduction in the SRS total raw score relative to baseline at 2 consecutive visits separated by at least 2 weeks. The SRS is a 65-item, caregiver-rated assessment scale that measures observable items on social behavior and social language use, as well as characteristics of autism in a naturalistic social setting. Each item is rated on a scale from 0 (never true) to 3 (almost always true). The SRS total raw score ranges from 0 to 195; a higher score indicates greater severity of social impairment. |
Countries
Australia, Belgium, Canada, Colombia, Estonia, France, Hungary, Iceland, Italy, New Zealand, Poland, Serbia, Singapore, South Africa, South Korea, Spain, Ukraine, United States
Participant flow
Recruitment details
Patient recruitment occurred over an eleven month period, from June of 2012 to May of 2013, at 118 study sites, located in the United States and 17 other countries.
Pre-assignment details
Enrolled patients went through a 2-week screening period.
Participants by arm
| Arm | Count |
|---|---|
| Memantine Hydrochloride (HCl) Memantine Hydrochloride (HCl) extended-release 3-mg capsules once daily, oral administration. Dosing was 3-mg, 6-mg, 9-mg, 12-mg, or 15-mg per day, based upon patient weight. | 903 |
| Total | 903 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 60 |
| Overall Study | Lack of Efficacy | 19 |
| Overall Study | Lost to Follow-up | 19 |
| Overall Study | Other | 3 |
| Overall Study | Protocol Violation | 14 |
| Overall Study | Withdrawal by Subject | 23 |
Baseline characteristics
| Characteristic | Memantine Hydrochloride (HCl) |
|---|---|
| Age, Continuous | 9.0 Years STANDARD_DEVIATION 1.9 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants |
| Race/Ethnicity, Customized Asian | 54 participants |
| Race/Ethnicity, Customized Black or African American | 54 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 102 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 801 participants |
| Race/Ethnicity, Customized Other | 22 participants |
| Race/Ethnicity, Customized White | 768 participants |
| Region of Enrollment Australia | 0 participants |
| Region of Enrollment Belgium | 11 participants |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment Colombia | 8 participants |
| Region of Enrollment Estonia | 6 participants |
| Region of Enrollment France | 14 participants |
| Region of Enrollment Hungary | 20 participants |
| Region of Enrollment Iceland | 5 participants |
| Region of Enrollment Italy | 6 participants |
| Region of Enrollment Korea, Republic of | 25 participants |
| Region of Enrollment New Zealand | 2 participants |
| Region of Enrollment Poland | 37 participants |
| Region of Enrollment Serbia | 21 participants |
| Region of Enrollment Singapore | 0 participants |
| Region of Enrollment South Africa | 2 participants |
| Region of Enrollment Spain | 17 participants |
| Region of Enrollment Ukraine | 16 participants |
| Region of Enrollment United States | 712 participants |
| Sex/Gender, Customized Female | 144 participants |
| Sex/Gender, Customized Male | 759 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 196 / 903 |
| serious Total, serious adverse events | 6 / 903 |
Outcome results
Primary
Number of Confirmed Social Responsiveness Scale (SRS) Responders
A confirmed SRS responder was defined as a patient who had at least 12 weeks of exposure to memantine, and a ≥ 10-point reduction in the SRS total raw score relative to baseline at 2 consecutive visits separated by at least 2 weeks. The SRS is a 65-item, caregiver-rated assessment scale that measures observable items on social behavior and social language use, as well as characteristics of autism in a naturalistic social setting. Each item is rated on a scale from 0 (never true) to 3 (almost always true). The SRS total raw score ranges from 0 to 195; a higher score indicates greater severity of social impairment.
Time frame: Visit 1 (Baseline) to Visit 8 (week 48/Final Visit)
Population: Of the 906 patients who enrolled in the study 903 received at least 1 dose of open-label treatment to comprise the Safety Population. The Intent to Treat (ITT) population included the 868 patients in the Safety population who also had at least 1 post-Visit 1 assessment of the SRS total raw score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Memantine Hydrochloride (HCl) | Number of Confirmed Social Responsiveness Scale (SRS) Responders | Responders | 517 participants |
| Memantine Hydrochloride (HCl) | Number of Confirmed Social Responsiveness Scale (SRS) Responders | Non responders | 351 participants |