Study of Pharmacokinetics, Safety, Efficacy, and Tolerability of Memantine in Children With Autism

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00872898
• Collaborator: Merz Pharmaceuticals GmbH (Industry)
• Enrollment: 124
• Locations: 17
• Arms: 2
• Patients Per Site: 7.3

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the safety and efficacy of memantine extended release, as well as its extent of absorption in pediatric patients with autism.

Condition or Disease	Intervention/Treatment	Phase
Autism	Drug: Memantine - Extended Release (ER); Drug: Placebo	Phase 2

Detailed Description

This is a multicenter, two-part study in pediatric (ages 6 to 18 years) patients diagnosed with autism.

Patients participating in Part One will receive a single open-label dose of memantine. Blood samples for pharmacokinetic analysis will be collected.

Part Two is a randomized, double-blind, placebo-controlled 12-week efficacy and safety study evaluating change in all core domains (social interactions, communication, and restricted interests and repetitive behaviors) of autism.

In the Forest autism trials conducted in children ages 6-12, dosing with an extended release formulation of memantine was weight-based. These weight based dose limits were selected to ensure exposure in terms of area under the curve (AUC) was less than the predefined limit of 2100 ng∙h/mL that represented a 10-fold lower exposure than observed at the NOAEL (No observed adverse effect level) of 15 mg/kg/day in juvenile rats.

The weight-based dose limits in these studies were as follows:

• Group A: ≥ 60 kg; max 15 mg/day

• Group B: 40-59 kg; max 9 mg/day

• Group C: 20-39 kg; max 6 mg/day

• Group D: < 20 kg; max 3 mg/day

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Open-label (Part One) and a Randomized, Double-blind, Placebo-Controlled (Part Two) Study of the Pharmacokinetics, Safety, Efficacy, and Tolerability of Memantine in Pediatric Patients With Autism
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Once daily oral administration of memantine for 12 weeks.	Drug: Memantine - Extended Release (ER); Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.; Other Names: Namenda ER
Placebo Comparator: 2 Once daily oral administration of placebo for 12 weeks.	Drug: Placebo; Placebo capsules, once daily, oral administration.

Outcome Measures

Primary Outcome Measures

1. Extent of Absorption of Memantine (Part One) [Baseline to 144 hours. Measurements were taken 0 (predose), 4, 8, 24, 30, 48, 96 and 144 hours post-dose]

   Area under the plasma concentration vs. time curve (AUC) for memantine, as measured in units of nanogram x hours per milliliter.

2. Change in Total Raw Score of Social Responsiveness Scale [From Baseline to Week 12]

   The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment, ranging from 0 (no impairment) to 195 (severe social impairment). Each item is associated with 1 of 5 subscales (social awareness, social cognition, social communication, social motivation and autistic mannerisms). Each item is rated on a 4-point scale from 1 (not true) to 4 (almost always true). The scores are then transposed to a scale from 0 to 3 and scores are summed within each of the 5 subscales. A higher score indicates greater severity of social impairment.

Secondary Outcome Measures

1. Core Autism Treatment Scale-Improvement: Total Score [At Week 12]

   The Core Autism Treatment Scale-Improvement (CATS-I) is based on rating 14 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 14 (improved) to 98 (worsened). The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).

2. Core Autism Treatment Scale-Improvement: Social Interaction [At Week 12]

   The Core Autism Treatment Scale-Improvement (CATS-I) Social Interaction Subscale is based on rating 9 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 9 (improved) to 63 (worsened). The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).

3. Core Autism Treatment Scale-Improvement: Communication [At Week 12]

   The Core Autism Treatment Scale-Improvement (CATS-I) Communication Subscale is based on rating 5 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 5 (improved) to 35 (worsened). The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).

4. Change in Children's Communication Checklist-2 (CCC-2) - Speech Subscale [From Baseline to Week 12]

   The Children's Communication Checklist-2 (CCC-2) Speech Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

5. Change in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale [From Baseline to Week 12]

   The Children's Communication Checklist-2 (CCC-2) Syntax Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

6. Change in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale [From Baseline to Week 12]

   The Children's Communication Checklist-2 (CCC-2) Semantics Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

7. Change in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale [From Baseline to Week 12]

   The Children's Communication Checklist-2 (CCC-2) Coherence Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

8. Change in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale [From Baseline to Week 12]

   The Children's Communication Checklist-2 (CCC-2) Initiation Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

9. Change in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale [From Baseline to Week 12]

   The Children's Communication Checklist-2 (CCC-2) Scripted Language Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

10. Change in Children's Communication Checklist-2 (CCC-2) - Context Subscale [From Baseline to Week 12]

    The Children's Communication Checklist-2 (CCC-2) Context Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

11. Change in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale [From Baseline to Week 12]

    The Children's Communication Checklist-2 (CCC-2) Nonverbal Communication Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

12. Change in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale [From Baseline to Week 12]

    The Children's Communication Checklist-2 (CCC-2) Social Relations Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

13. Change in Children's Communication Checklist-2 (CCC-2) - Interests Subscale [From Baseline to Week 12]

    The Children's Communication Checklist-2 (CCC-2) Interests Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males or females ages 6 to 12 years

• Diagnosis of autistic disorder, according to DSM-IV-TR using Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule (modules 2 & 3).

• A knowledgeable caregiver capable of providing reliable information about the patient's condition, able to attend all clinic visits with the patient

• Patients over age 12, only if they completed Study MEM-PK-21

Exclusion Criteria:

• Medical history of active epilepsy/seizure disorder except simple febrile seizures

• Participation in any other clinical investigation using an experimental drug within 30 days of the start of this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site	Phoenix	Arizona	United States	85006
2	Forest Investigative Site	Sacramento	California	United States	95817
3	Forest Investigative Site	San Francisco	California	United States	94143
4	Forest Investigative Site	Santa Ana	California	United States	92705
5	Forest Investigative Site	Stanford	California	United States	94305
6	Forest Investigative Site	Jacksonville Beach	Florida	United States	32250
7	Forest Investigative Site	St Petersburg	Florida	United States	33701
8	Forest Investigative Site	Hoffman Estates	Illinois	United States	60169
9	Forest Investigative site	Naperville	Illinois	United States	60563
10	Forest Investigative Site	Indianapolis	Indiana	United States	46202
11	Forest Investigative Site	Cambridge	Massachusetts	United States	02138
12	Forest Investigative Site	Toms River	New Jersey	United States	08755
13	Forest Investigative Site	Voorhees	New Jersey	United States	08043
14	Forest Investigative Site	Manhasset	New York	United States	11030
15	Forest Investigative Site	Cleveland	Ohio	United States	44106
16	Forest Investigative Site	Columbus	Ohio	United States	43210
17	Forest Investigative Site	Oklahoma City	Oklahoma	United States	73116

Sponsors and Collaborators

• Forest Laboratories
• Merz Pharmaceuticals GmbH

Investigators

• Study Director: Ephraim Katz, PhD, Forest Research Institute, a subsidiary of Forest Laboratories, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT00872898
• Other Study ID Numbers: MEM-MD-57A
• First Posted: Mar 31, 2009
• Last Update Posted: Jan 14, 2014
• Last Verified: Nov 1, 2013

• Keywords provided by Forest Laboratories: autism; memantine; pediatric; Forest Laboratories; Autism in pediatric patients
• Additional relevant MeSH terms: Autistic Disorder; Memantine

Study Results

Participant Flow

Recruitment Details	Patients for Part One of the study were recruited during a 15 month period from April of 2009, to June of 2010. Patients for Part Two of the study were recruited for a 37 month period from April of 2009 to April of 2012. All study sites were located in the United States.
Pre-assignment Detail	Part One of the study enrolled 4 patients to determine a safe dosing regimen for Part Two. One patient from Part One of the study also enrolled in Part Two. The 121 patients enrolled in Part Two were randomized after two weeks of single-blind placebo treatment.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily, oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Period Title: Part One - Open Label, Pharmacokinetics
STARTED	0	4
COMPLETED	0	4
NOT COMPLETED	0	0
Period Title: Part One - Open Label, Pharmacokinetics
STARTED	61	60
COMPLETED	50	54
NOT COMPLETED	11	6

Baseline Characteristics

Arm/Group Title	Part One - Memantine	Part Two - Placebo	Part Two - Memantine	Total
Arm/Group Description	Patients received a single dose of 3-mg memantine extended release capsule, oral administration.	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups.	Total of all reporting groups
Overall Participants	3	61	60	124
Age (years) [Mean (Standard Deviation) ]
6 years to 18 years	9.0 (2.6)	8.9 (2.2)	9.0 (2.2)	9.0 (0.1)
Age, Customized (participants) [Number]
6 years to 12 years	3 100%	60 98.4%	59 98.3%	122 98.4%
13 years to 18 years	0 0%	1 1.6%	1 1.7%	2 1.6%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	12 19.7%	8 13.3%	22 17.7%
Male	1 33.3%	49 80.3%	52 86.7%	102 82.3%
Region of Enrollment (participants) [Number]
United States	3 100%	61 100%	60 100%	124 100%

Outcome Measures

1. Primary Outcome

Title	Extent of Absorption of Memantine (Part One)
Description	Area under the plasma concentration vs. time curve (AUC) for memantine, as measured in units of nanogram x hours per milliliter.
Time Frame	Baseline to 144 hours. Measurements were taken 0 (predose), 4, 8, 24, 30, 48, 96 and 144 hours post-dose

Outcome Measure Data

Analysis Population Description

Four patients enrolled in Part One, receiving a single dose of memantine and having evaluable pharmacokinetic parameters (Pharmacokinetic Population)

Arm/Group Title	Memantine
Arm/Group Description	Patients received a single dose of 3-mg memantine extended release capsule, oral administration.
Measure Participants	4
Mean (Standard Deviation) [ng•h/mL]	682.53 (217.77)

2. Secondary Outcome

Title	Core Autism Treatment Scale-Improvement: Total Score
Description	The Core Autism Treatment Scale-Improvement (CATS-I) is based on rating 14 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 14 (improved) to 98 (worsened). The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).
Time Frame	At Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	50.4 (1.0)	48.3 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1197
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -4.9 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change in Total Raw Score of Social Responsiveness Scale
Description	The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment, ranging from 0 (no impairment) to 195 (severe social impairment). Each item is associated with 1 of 5 subscales (social awareness, social cognition, social communication, social motivation and autistic mannerisms). Each item is rated on a 4-point scale from 1 (not true) to 4 (almost always true). The scores are then transposed to a scale from 0 to 3 and scores are summed within each of the 5 subscales. A higher score indicates greater severity of social impairment.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-9.5 (2.6)	-9.6 (2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9781
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -7.2 to 7.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Core Autism Treatment Scale-Improvement: Social Interaction
Description	The Core Autism Treatment Scale-Improvement (CATS-I) Social Interaction Subscale is based on rating 9 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 9 (improved) to 63 (worsened). The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).
Time Frame	At Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily, oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	32.4 (0.7)	31.1 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1459
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -3.2 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Core Autism Treatment Scale-Improvement: Communication
Description	The Core Autism Treatment Scale-Improvement (CATS-I) Communication Subscale is based on rating 5 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 5 (improved) to 35 (worsened). The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).
Time Frame	At Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily, oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	18.0 (0.4)	17.2 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1344
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -1.9 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Speech Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Speech Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-0.4 (0.5)	-0.7 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7000
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -1.5 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Syntax Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-1.1 (0.4)	-1.2 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9069
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Semantics Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-0.2 (0.3)	-0.5 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4679
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.2 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Coherence Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-1.2 (0.5)	-1.2 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9598
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Initiation Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-0.8 (0.5)	-0.9 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9898
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Scripted Language Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-1.0 (0.4)	-0.5 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4228
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -0.7 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Context Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Context Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-1.5 (0.4)	-0.2 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0201
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; 0.2 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Nonverbal Communication Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-0.7 (0.4)	-0.9 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6889
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -1.3 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Social Relations Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-1.0 (0.4)	-0.8 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7481
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.9 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change in Children's Communication Checklist-2 (CCC-2) - Interests Subscale
Description	The Children's Communication Checklist-2 (CCC-2) Interests Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe). The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All of the the 121 randomized patients in Part Two of the study, received at least 1 dose of study drug. The protocol specified Intent-to-Treat (ITT) Population consisted of 107 patients who had at least 1 postbaseline assessment of SRS.

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Once daily oral administration of placebo for 12 weeks.	Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Measure Participants	53	54
Least Squares Mean (Standard Error) [units on a scale]	-0.5 (0.4)	-0.5 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Memantine, Memantine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9500
	Comments
	Method	mixed-model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -1.2 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data for Part One of this study was collected over a 14-month period from May 2009 to July of 2010. Adverse event data for Part Two of this study was collected over a 38-month period from July of 2009 to September of 2012.
Arm/Group Title	Placebo - Part Two, Double-Blind Treatment		Memantine - Part Two, Double-Blind Treatment		Memantine - Part One, Open Label Treatment
Arm/Group Description	Once daily oral administration of placebo for 12 weeks		Once daily oral administration of memantine extended release for 12 weeks. Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups.		Patients received a single dose of 3-mg memantine extended release capsule, oral administration.
All Cause Mortality
	Placebo - Part Two, Double-Blind Treatment		Memantine - Part Two, Double-Blind Treatment		Memantine - Part One, Open Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo - Part Two, Double-Blind Treatment		Memantine - Part Two, Double-Blind Treatment		Memantine - Part One, Open Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		1/60 (1.7%)		0/4 (0%)
Psychiatric disorders
Affective Disorder	0/61 (0%)		1/60 (1.7%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Placebo - Part Two, Double-Blind Treatment		Memantine - Part Two, Double-Blind Treatment		Memantine - Part One, Open Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/61 (50.8%)		37/60 (61.7%)		1/4 (25%)
Gastrointestinal disorders
Vomiting	6/61 (9.8%)		4/60 (6.7%)		0/4 (0%)
General disorders
Irritability	3/61 (4.9%)		5/60 (8.3%)		0/4 (0%)
Pyrexia	4/61 (6.6%)		2/60 (3.3%)		0/4 (0%)
Infections and infestations
Upper respiratory tract infection	7/61 (11.5%)		6/60 (10%)		0/4 (0%)
Influenza	2/61 (3.3%)		4/60 (6.7%)		0/4 (0%)
Nasopharyngitis	6/61 (9.8%)		2/60 (3.3%)		0/4 (0%)
Nervous system disorders
Headache	3/61 (4.9%)		3/60 (5%)		1/4 (25%)
Psychomotor hyperactivity	4/61 (6.6%)		1/60 (1.7%)		0/4 (0%)
Anxiety	4/61 (6.6%)		0/60 (0%)		0/4 (0%)
Psychiatric disorders
Aggression	3/61 (4.9%)		5/60 (8.3%)		0/4 (0%)
Agitation	1/61 (1.6%)		4/60 (6.7%)		0/4 (0%)
Insomnia	3/61 (4.9%)		4/60 (6.7%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/61 (4.9%)		6/60 (10%)		0/4 (0%)
Rhinorrhoea	0/61 (0%)		3/60 (5%)		0/4 (0%)
Nasal congestion	5/61 (8.2%)		1/60 (1.7%)		0/4 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All data generated in this study are the property of Forest Research Institute. An integrated clinical and statistical report will be prepared at the completion of the study. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator and Forest Research Institute.